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Delving Deeper Into Maternal COVID-19 Vaccination and Neonatal Outcomes

• 1 Department of Bioinformatics, Harvard Medical School, Boston, Massachusetts
• 2 Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan
• Original Investigation Newborn and Early Infant Outcomes Following Maternal COVID-19 Vaccination During Pregnancy Sarah C. J. Jorgensen, PharmD, MPH; Samantha S. M. Drover, PhD; Deshayne B. Fell, PhD; Peter C. Austin, PhD; Rohan D’Souza, MD, PhD; Astrid Guttmann, MDCM, MSc; Sarah A. Buchan, PhD; Sarah E. Wilson, MD; Sharifa Nasreen, PhD; Kevin L. Schwartz, MD, MSc; Mina Tadrous, PharmD, PhD; Kumanan Wilson, MD, MSc; Jeffrey C. Kwong, MD, MSc JAMA Pediatrics
• Comment & Response Delving Deeper Into Maternal COVID-19 Vaccination and Neonatal Outcomes—Reply Sarah C. J. Jorgensen, PharmD, PhD; Deshayne B. Fell, PhD; Jeffrey C. Kwong, MD, MSc JAMA Pediatrics

To the Editor We appreciate reading the work by Jorgensen et al 1 examining associations between maternal COVID-19 vaccination during pregnancy and neonatal outcomes. The authors conducted rigorous analyses of this critical public health issue with a robust sample size. However, there are some limitations to consider.

First, it is important to acknowledge in study limitations that the analyses lacked adjustments for race and ethnicity despite the availability of visual racial and ethnic quintiles data. Given well-documented racial and ethnic disparities in both adverse maternal and neonatal outcomes risk during the pandemic (eg, maternal morbidity for Black women has been found to be disproportionally higher than that of Hispanic and White women in the US 2 ), understanding the role of vaccination in these disparities is crucial. Furthermore, previous research has indicated that structural racism and the stressors brought about by the COVID-19 pandemic can exacerbate the risk of adverse neonatal outcomes, such as preterm birth. 3 We believe the study could be strengthened by incorporating race and ethnicity data.

Hsieh TYJ , Wei JC. Delving Deeper Into Maternal COVID-19 Vaccination and Neonatal Outcomes. JAMA Pediatr. 2024;178(4):419. doi:10.1001/jamapediatrics.2023.6680

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• Volume 81, Issue 1
• Recent advances in neonatology
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• Department of Paediatrics
• King’s Healthcare NHS Trust
• King’s College Hospital
• London SE5 9RS
• Queen Mary’s Hospital
• Kent DA14 6LT
• S A BOKHARI

https://doi.org/10.1136/fn.81.1.F1

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Although this article is published in the Fetal and Neonatal Edition, it was originally commissioned to be of interest to general paediatricians who are not specialists in neonatology, but who are responsible for the provision of much of the UK’s neonatal care.

This review aims to provide a brief update of the most important recent changes in neonatal medicine.

Surfactant treatment

Exogenous surfactant has now been in use for nearly a decade. Surfactant reduces neonatal mortality from respiratory distress syndrome (RDS) by about 40% and reduces complications like air leaks by up to 60%. 1-3 The combination of postnatal surfactant with antenatal steroids is more effective than either treatment alone. 4 Surfactant treatment has no effect against chronic lung disease (CLD), gross maternal haemorrhage–intraventricular haemorrhage (GMH–IVH), and patent ductus arteriosus (PDA). 5 The controversies that remain are not to do with surfactant use in typical RDS, but are about which product is superior; whether there is a lower gestation or weight limit at which surfactant should be withheld; and the choice between rescue and prophylactic treatment. Indications for surfactant use in conditions other than RDS, such as meconium aspiration syndrome, are beginning to emerge. 6

PROPHYLAXIS VS RESCUE TREATMENT

Now that it is accepted surfactant improves the outlook for neonatal RDS, the critical issue is timing. The simple answer seems to be that treatment should be given as early as possible, once a preterm baby is intubated, and ideally within the first few breaths of life. Seven randomised controlled trials have compared surfactant treatment at birth (prophylaxis) with treatment a few hours later (rescue). Prophylaxis was more effective than rescue treatment. 7 The odds ratios (95% confidence intervals) in favour of prophylaxis were 0.59 (0.46 to 0.76) for neonatal mortality, 0.62 (0.42 to 0.89) for pneumothoraces, and 0.54 (0.36 to 0.82) for pulmonary interstitial emphysema. Current recommendations are to give prophylactic surfactant to all babies who are intubated for resuscitation at less than 32 weeks of gestation.

Later administration of surfactant will be beneficial in larger infants who develop RDS, and in some trials the first treatment has been as late as 72 hours after birth. There is little evidence to support surfactant administration beyond this time. Multiple doses are better than a single dose for infants who remain ventilated. 8

Where infants are to be transferred, surfactant should still be administered as early as possible and before transfer. However, it is important that those using this treatment are familiar with the rapid changes in ventilator requirements which often follow the administration of natural surfactants. There is no evidence that harm has been done by giving either natural or synthetic prophylactic surfactant. There is a practical problem with one or two of the surfactants as they involve delivering large volumes into the trachea, and a divided dose may be necessary. The answer would be to use a method or a product where this is not an issue, but the ideal solution to this problem has yet to be found.

NATURAL vs SYNTHETIC SURFACTANT

Four surfactants are licensed in the UK for treating babies. They are animal derived and synthetic surfactants. The animal derived surfactants comprise Curosurf, which is an extract of pig lung mince and given in a volume of 1.25 to 2.5 ml/kg, and Survanta, an extract of cow lung mince with three added lipids, given as a dose of 4 ml/kg. These surfactants contain the apoproteins SP-B and SP-C, and these are thought to enhance their properties. The synthetic surfactants comprise Exosurf, a mixture of the key phospholipid DPPC, hexadecanol, and tyloxapol, given in a volume of 5 ml/kg, and ALEC, a mixture of DPPC and phosphatidylglycerol, given as a dose of 1.2 ml, regardless of size.

Fifteen studies have compared different surfactants, seven of which were of suitable quality for meta-analysis. 9 Six of these trials compared Survanta and Exosurf; the other trial compared Infasurf and Exosurf. The meta-analyses support a significant reduction in the risk of pneumothorax (0.69 CI 0.57 to 0.85), and showed a non-significant trend towards reduced mortality. Soll’s conclusion was that: “on clinical grounds, natural surfactant extracts were the more desirable choice.” The onset of action is more rapid with animal derived surfactants than with artificial surfactants. This means that the babies treated with these surfactants need to be carefully monitored and their ventilator settings adjusted appropriately. Concern has been expressed because rapid effects lead to temporary changes in cerebral blood flow velocity and EEG recordings. There is currently no evidence to suggest that this more rapid onset of action has any deleterious effects.

UPPER AND LOWER GESTATIONAL AGE LIMITS FOR SURFACTANT TREATMENT

Although the data are limited due to small numbers in trials, the data that can be extracted show benefit for the smallest of babies. 10 11 Gestational or weight limits for either giving or withholding surfactant are not helpful, and may deprive babies who could benefit from surfactant use.

INDICATIONS FOR SURFACTANT USE IN OTHER CONDITIONS

There have been several small trials on the use of surfactant outside the classic indication of RDS, such as sepsis, pulmonary haemorrhage, or meconium aspiration syndrome. 12 All of these show some benefits. Most convincing to date is the trial using beractant (Survanta) in ventilated cases of meconium aspiration syndrome. Using a higher than normal dose of this surfactant (150 mg or 6 ml/kg), the trial showed improving oxygenation, and reduced air leaks, severity of pulmonary morbidity, and shorter inpatient stay among term infants. 6

Inhaled nitric oxide

The discovery that endothelium derived relaxing factor (EDRF) was in fact a gas, NO, has revolutionised thinking about several diseases. The NO pathway seems to have a crucial role in the vasoactivity of the pulmonary vascular bed. 13 PPHN may be in part due to a deficiency of or resistance to NO, 14 and the endothelial cellular defects may represent a final common pathway for the diverse causes for PPHN.

Once suitable delivery systems were developed, inhaled NO was first tested in neonatal pilot studies and then full scale randomised controlled trials. The results of a large trial on the use of inhaled NO in full term infants with hypoxic respiratory failure were published in 1997. 15 The results showed that babies who received NO were less likely to require extra corporeal membrane oxygen (ECMO). Most of these babies were pre-treated with surfactant. The dose of NO used was 20 to 80 ppm; infants who responded usually did so at the lower dose, although a few responded only to the higher dose. The results have been confirmed in further trials, which again showed no difference between doses of 5, 20, or 80 ppm. 16 17 Methaemoglobinaemia of greater than 7% (normally less than 1%) was more common in the group who received 80 ppm. Theoretical concerns about an increase in bleeding time have not so far translated into clinical complications.

NO needs to be used with caution in clinical treatment. The gas must be carefully diluted down to a concentration of 10–80 ppm in oxygen/air, and the concentration monitored before it can be safely administered to babies. Nitric oxide is oxidised to higher oxides of nitrogen (NO 2 to NO x ) in the presence of oxygen. Nitrogen dioxide (NO 2 ) is a toxic gas that has already been comprehensively studied as a component of car exhaust fumes. Current occupational health guidelines limit exposure of NO 2 to 5 ppm, and histological changes have been seen in lungs exposed to 25 ppm of NO 2 . NO must be added to the baby’s inspired gases right at the patient manifold of the circuit, to limit contact time between NO and oxygen, and the concentrations of NO 2 to NO x must be monitored in the expiratory limb. Waste gas must be scavenged to avoid contaminating the working environment, and ventilators purged after use. Nitrogen dioxide does not accumulate beyond safe levels if equipment is used carefully. Once started, inhaled NO should be cautiously weaned as there may be down regulation, often transient, of endogenous NO synthetase activity. 18 Nitric oxide is now well established as a treatment for PPHN, a condition for which a multitude of injectable vasodilators had previously been tried without any randomised controlled trial evidence to support improved outcome from any of them.

Treatment with high frequency oscillatory ventilation plus inhaled NO may be more successful than with inhaled NO or HFOV alone in severe PPHN. 19 This study also suggested that the differences in responses may partly be related to the specific diseases associated with PPHN. These workers concluded that for patients with PPHN, which was complicated by severe lung disease, response rates for HFOV plus inhaled NO were better than HFOV or inhaled NO alone with conventional ventilation. For patients without clinically significant parenchymal disease, both inhaled NO and HFOV plus inhaled NO were more effective than HFOV alone.

Inhaled NO has been used in situations other than classic PPHN. The NINOS group reviewed inhaled NO in congenital diaphragmatic hernias and concluded that it did not reduce the need for ECMO or the incidence of death. 20 Fifty three infants were enrolled into this trial; in spite of aggressive management, including ventilation, alkalosis, surfactant, inhaled NO and ECMO, the mortality was almost 50% in both arms of the trial. The place of inhaled NO in treating premature babies who have pulmonary hypertension as a component of their RDS, also remains uncertain. One four way prospective trial comparing dexamethasone and inhaled NO, concluded that both or neither failed to show any benefit for any group. 21

Prophylaxis against group B streptococcal infection

Group B streptococcus is the leading cause of serious neonatal infection. Infants who are infected with it can require prolonged hospital stay, and a third of the survivors sustain permanent sequelae. There is no doubt that selective intrapartum prophylaxis is effective, and this has been confirmed by a meta-analysis which showed a 30-fold reduction in group B streptococcal disease. 22 23 More than a decade has passed since the first clinical trial showed the effectiveness of intrapartum antibiotic prophylaxis, 24 but still prevention strategies have not been implemented widely or consistently, and the incidence of neonatal group B streptococcal infection has not declined.

The alternative strategies currently available and the difficult choices they present were recently thoroughly reviewed by Isaacs. 25 The choice between inactivity (treating only symptomatic babies), universal screening, and treating on the basis of risk factors alone remains. Isaacs concluded that preventive measures may not be justified in terms of cost effectiveness when the incidence was below 0.6 per 1000, but there are no accurate incidence figures for most of the UK. In the Northern Region the incidence was recently estimated as at least 1 case per 1000 deliveries whereas in Oxford it was 0.5 per 1000. 26 Confirmed cases of early onset group B streptococcal infection reported to the Public Health Laboratory Service this year suggest an incidence of exactly 0.6 per 1000, uncomfortably near a level at which screening ought to be considered for the UK population.

Extra corporeal membrane oxygenation

ECMO involves oxygenating blood outside the body and providing cardiovascular support, using complex machinery resembling that used for cardiopulmonary bypass. ECMO can be used only in babies weighing more than 2 kg, and candidates for this treatment usually have PPHN or meconium aspiration syndrome. ECMO has now been used on over 11000 infants worldwide, with 80% survival reported. Traditional ECMO uses two large gauge catheters, usually one in the jugular vein and one in the carotid artery. 27 This form of veno-arterial ECMO involves permanent sacrifice of one carotid artery, and more recently veno-venous ECMO has become more popular. While babies are on ECMO the ventilator is reduced to “rest”settings, allowing the lungs to recover without barotrauma. In general, about two weeks is the maximum time for which babies can safely be sustained on ECMO.

The UK collaborative ECMO trial enrolled 185 infants in two years; 30 of 93 infants allocated ECMO died compared with 54 of 92 allocated conventional care. 28 Two thirds of the cases were enrolled in the first 12 months of the trial, in 1993–94. Infants with congenital diaphragmatic hernia are an important subgroup for whom no benefit from ECMO has yet been shown, but small numbers of cases preclude a meta-analysis and some centres claim good results. Only four of the 35 infants with CDH in the UK trial survived, and all were in the ECMO arm of the trial. Concern about quality of survival remains. Forty five of 62 (73%) babies treated with ECMO in the UK trial seemed to be normal at one year of follow up. The international registry records that 17% of infants treated this way sustain an intracranial haemorrhage or infarction. 29 A five year follow up of 103 children treated with ECMO revealed a 17% prevalence of major disability, with concern about difficult behaviour and academic failure in a higher percentage. 30 Deafness seems to be a particular risk.

The ECMO trial began just about the time that the first babies were being treated with NO, and the numbers of neonates being offered ECMO each year in the UK is currently declining. There seems little doubt that the facility needs to be available in the UK, at a few specifically designated centres that can maintain levels of expertise because they are caring for enough cases each year. Because of the small number of ECMO centres, the difficulty for the future will be in identifying and referring appropriate cases in time. An oxygenation index of 40 or above predicted 60% mortality in the ECMO trial, and if this index does not rapidly fall with NO and/or HFOV, too much time should not be wasted in considering ECMO. Ten of the 30 deaths in the ECMO arm of the UK trial occurred among the 15 infants who were allocated to ECMO, but did not actually receive it.

High frequency oscillation ventilation

High frequency oscillatory ventilation alternately subjects the lungs to positive and negative pressure at very fast rates, usually about 10 Hz (10 cycles per second). Special equipment is required to achieve effective ventilation at such high frequencies, and of the three oscillators available in the UK, only the Sensormedics 3100/3100A has been used in randomised controlled trials. The Sensormedics is a dedicated oscillator. The other available oscillators are the Draeger Babylog 8000 and the SLE HV2000 ventilator. Oscillators are powerful tools, and there is no doubt that in “rescue” mode HFOV can save infants with severe RDS who have failed to respond to conventional ventilation and surfactant. 31 HFOV is particularly effective in hypercarbia. What is less certain is the role of HFOV as the primary mode of ventilation in RDS in very small babies who have received antenatal steroids and postnatal surfactant. 32 The Provo trial 33 randomly allocated 125 babies with RDS at less than 35 weeks of gestation who had received surfactant. Those who were ventilated with HFOV fared better than those ventilated conventionally in the short term, with more survivors without chronic lung disease at 30 days. Although there has been some concern about the high number of babies still ventilated at a month (half the HFOV group and all the conventionally ventilated group), the incidence of ultrasound abnormalities and retinopathy of prematurity was the same. Even this large study only enrolled 21 babies with a birthweight of less than 1 kg. HFOV is not the same as high frequency jet ventilation (HFJV). This involves the delivery of a jet of gas directly into the trachea, and lacks an active expiratory phase. Recent evaluations from the USA suggest an excess of cystic periventricular leucomalacia (PVL) in survivors ventilated this way. The increased risk of PVL is perhaps due to hypocarbia. 34 35 A meta-analysis of trials of high frequency ventilation revealed a higher incidence of intraventricular haemorrhage and PVL which disappeared if the results of the large HiFi trial were excluded. 36 37 HFOV is currently reserved for rescue treatment in most UK neonatal units, although a large MRC sponsored trial of the use of HFOV from birth in infants 26–29 weeks of gestation (the UKOS trial) is actively recruiting.

• ↵ Soll RF. Update Software. Prophylactic administration of natural surfactant (Cochrane review) . 4 edn. Oxford: 1998. .
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For children with mild sleep-disordered breathing (SDB) and relevant symptoms, little evidence has been available to guide a choice between adenotonsillectomy and watchful waiting. In a randomized trial in 459 children 3 to <13 years with tonsillar hypertrophy and mild SDB (defined by habitual snoring with occasional episodes of obstruction with apnea per hour of sleep), executive function and attention were similar for individuals assigned to adenotonsillectomy compared with watchful waiting at 12 months follow-up [ 10 ]. However, children treated with adenotonsillectomy had greater decrease in snoring, obstruction with apnea or hypopnea, blood pressure, and caregiver-reported symptoms (sleep symptoms, behavioral problems, sleepiness) as well as increased quality of life. These findings support our suggestion to offer adenotonsillectomy to children with mild obstructive sleep apnea and relevant symptoms although watchful waiting is a reasonable alternative. (See "Management of obstructive sleep apnea in children", section on 'Adenotonsillectomy' .)

Cannabinoids and mental health in adolescents (December 2023)

Cannabis use is associated with an increased risk of mental health disorders. However, little is known about the effects of cannabidiol (CBD), a nonpsychoactive component of cannabis used for anorexia and childhood epilepsy, or of recreational synthetic cannabinoids. In a school-based survey from the United Kingdom that included over 6500 adolescents ages 13 to 14 years, reported use of cannabis, CBD, or synthetic cannabinoids were each associated with probable depression, anxiety disorder, or conduct disorder, as well as with auditory hallucinations [ 11 ]. For each disorder, the risk appeared greatest with synthetic cannabinoids. This study highlights the need for further investigation into the association between mental health effects in youth and the different types of cannabinoids. We advise adolescents (and younger children) to avoid cannabis consumption, including CBD. (See "Substance use disorder in adolescents: Epidemiology, clinical features, assessment, and diagnosis", section on 'Cannabis, cannabidiol, and synthetic cannabinoids' .)

High blood lead levels in US children after eating cinnamon applesauce pouches (November 2023)

The Centers for Disease Control and Prevention have issued a health alert following reports of high blood lead levels from several states for a total of 22 children who were fed cinnamon-containing applesauce pouches that were subsequently found to contain extremely high concentrations of lead [ 12 ]. Children who have eaten a recalled product should undergo blood lead testing. Clinicians should advise parents, primary caregivers, and guardians to not buy specific cinnamon-containing apple puree or applesauce products named in the US Food and Drug Administration announcement and to discard any recalled products that they have purchased. (See "Childhood lead poisoning: Exposure and prevention", section on 'Food' and "Childhood lead poisoning: Clinical manifestations and diagnosis", section on 'Laboratory evaluation' and "Childhood lead poisoning: Management" .)

ALLERGY, IMMUNOLOGY, AND RHEUMATOLOGY

Association between gut bacteriophage abundance and asthma risk (April 2024)

The abundance and diversity of gut flora and their interaction with the immune system have been associated with a predisposition to childhood asthma. A recent study examined the role of the fecal virome, predominantly comprising temperate bacteriophages, in a Danish birth cohort of 647 one-year-old children who were subsequently longitudinally assessed for asthma [ 13 ]. The relative abundance of certain viral families was associated with subsequent asthma development, and the viromes in turn were associated with early life exposures (eg, siblings and season of birth). The association between virome and asthma was not mediated by the impact on gut bacteria, suggesting independent effects on the developing immune system. (See "Risk factors for asthma", section on 'Influence of microbiome' .)

Multisystem inflammatory syndrome in children incidence and severity (March 2024)

Although multisystem inflammatory syndrome in children (MIS-C) is increasingly rare as the overall COVID-19 burden declines, it continues to be associated with substantial morbidity. In 2023, 117 patients with MIS-C were reported to the Centers for Disease Control and Prevention, resulting in an estimated incidence of 0.11 cases per million person-months [ 14 ]. Of these patients, 50 percent required care in an intensive care unit, 34 percent experienced shock, and 27 percent experienced cardiac dysfunction; mortality was 2.6 percent (3 patients). More than 80 percent of patients were SARS-CoV2 vaccine eligible but had not been vaccinated; among 20 patients who had been vaccinated, 60 percent likely had waning immunity at the time of diagnosis. This study suggests that MIS-C severity remains high, but that SARS-CoV2 vaccination may provide some degree of protection. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis", section on 'Epidemiology' .)

Baricitinib for refractory juvenile idiopathic arthritis (November 2023)

Janus kinase (JAK) inhibitors are one of several options for children with polyarticular juvenile idiopathic arthritis (pJIA) that is refractory to conventional therapy (eg, methotrexate with or without a biologic tumor necrosis factor inhibitor). In a phase 3, randomized trial of 220 children aged 2 to 17 years with JIA (66 percent with pJIA) who had inadequate response or intolerance to standard therapy, patients assigned to the investigational JAK inhibitor baricitinib had a longer time to disease flare compared with placebo [ 15 ]. During the study period, fewer patients receiving baricitinib had a flare compared with placebo (17 versus 51 percent, respectively), but more infections occurred in the baricitinib group than the placebo group. However, rates of serious adverse events were similar in both groups. Baricitinib compares favorably with tofacitinib , another JAK inhibitor used in refractory pJIA, but is not yet approved for this indication. (See "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Baricitinib' .)

DEVELOPMENTAL AND BEHAVIORAL PROBLEMS

Pharmacotherapy for ADHD and mortality risk (April 2024)

Attention deficit hyperactivity disorder (ADHD) is associated with higher mortality than in the general population; whether treatment modifies that risk is unclear. In an observational study of nearly 149,000 individuals with ADHD in Sweden (mean age 17 years), initiation of medication within three months of diagnosis was associated with lower all-cause mortality (hazard ratio [HR] 0.79) as well as lower mortality from unnatural causes (eg, suicide, unintentional injury, and accidental poisoning; HR 0.75) over the ensuing two years [ 16 ]. While the study could not control for unmeasured confounders that may have impacted mortality risk (eg, lifestyle factors, social support), these data generally lend further support for pharmacotherapy of ADHD. (See "Attention deficit hyperactivity disorder in adults: Treatment overview", section on 'Benefits of stimulant treatment' .)

Infertility and autism spectrum disorder (December 2023)

Patients with infertility often ask about the impact of the disorder and its treatment on risk of autism spectrum disorder (ASD) in offspring. In a large population-based cohort study comparing ASD risk among children whose parents had subfertility (an infertility consultation without treatment), infertility treatment, or neither (unassisted conception), children in the subfertility and infertility treatment groups had a small increased risk of ASD compared with unassisted conception but the absolute risk was low (2.5 to 2.7 per 1000 person-years versus 1.9 per 1000 person-years with unassisted conception) [ 17 ]. The increased risk was similar in the subfertile and infertility treatment groups, suggesting that infertility treatment was not a major risk factor. Obstetrical and neonatal factors (eg, preterm birth) appeared to mediate a sizeable proportion of the increased risk for ASD. (See "Assisted reproductive technology: Infant and child outcomes", section on 'Confounders' .)

EMERGENCY MEDICINE

ENDOCRINOLOGY

Proposed formal diagnostic criteria for hypophosphatasia in children and adults (March 2024)

Hypophosphatasia is a rare form of osteomalacia caused by pathogenic variants in the tissue nonspecific alkaline phosphatase gene ( ALPL ). Missed or delayed diagnosis is common, in part due to lack of formal diagnostic criteria. An international working group has proposed diagnostic criteria for hypophosphatasia in both children and adults [ 18 ]. Two major criteria or one major and two minor criteria are considered sufficient for diagnosis. For both children and adults, major criteria include a pathogenic (or likely pathogenic) variant in ALPL and elevated natural substrate concentrations (eg, pyridoxal 5'-phosphate). Additional major criteria for adults are atypical femoral fracture and recurrent metatarsal fractures and, for children, early loss of primary teeth and radiographic evidence of rickets. These criteria highlight the variable phenotypic expression of hypophosphatasia and the importance of considering this diagnosis in individuals with metabolic bone disease. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia in adults", section on 'Low alkaline phosphatase (hypophosphatasia)' and "Skeletal dysplasias: Specific disorders", section on 'Hypophosphatasia' .)

Janus kinase inhibition to preserve insulin secretion in early onset type 1 diabetes (January 2024)

In type 1 diabetes, the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been implicated in immune-mediated beta cell destruction. In a trial in 91 individuals (aged 10 to 30 years) with new-onset type 1 diabetes (diagnosed within 100 days), participants were randomly assigned to daily treatment with the oral JAK1/2 inhibitor baricitinib (n = 60) or placebo (n = 31) [ 19 ]. After 48 weeks of therapy, insulin secretion was greater with baricitinib compared with placebo (median stimulated mean C-peptide level 0.65 versus 0.43 nmol/L per minute, respectively). A1C, frequency of hypoglycemia, and the percentage of time spent in the target glucose range (70 to 180 mg/dL [3.9 to 10 mmol/L]) were not significantly different between groups. JAK/STAT pathway inhibition is a promising strategy for preserving insulin secretion in new-onset type 1 diabetes. (See "Type 1 diabetes mellitus: Prevention and disease-modifying therapy", section on 'Cytokine-directed therapies' .)

Investigational once-weekly basal insulin therapy (insulin icodec) for the treatment of adults with type 1 diabetes (November 2023)

Ultra-long-acting insulin icodec is an investigational basal insulin therapy that requires only once-weekly dosing. In a trial in 655 adults with type 1 diabetes (mean A1C approximately 7.6 percent), participants were randomly assigned to basal insulin therapy with once-weekly insulin icodec or once-daily insulin degludec [ 20 ]. After 26 weeks, the mean reduction in A1C was similar in the icodec and degludec groups (-0.47 and -0.51 percentage points, respectively). However, insulin icodec led to a nearly twofold higher combined rate of clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycemia (2836 versus 1495 events with insulin degludec). Additional studies are needed to determine whether risk of hypoglycemia will limit the use of ultra-long-acting insulin in individuals with type 1 diabetes. (See "General principles of insulin therapy in diabetes mellitus", section on 'Basal insulin analogs' .)

GASTROENTEROLOGY, HEPATOLOGY, AND NUTRITION

Budesonide oral suspension for eosinophilic esophagitis (March 2024)

In patients with eosinophilic esophagitis (EoE), use of topical glucocorticoids has been limited by lack of regulatory approval and potentially inconsistent drug delivery. Budesonide oral suspension is a formulation that was recently approved by the US Food and Drug Administration for treating EoE in adults and pediatric patients ages 11 years and older [ 21,22 ]. Approval was informed by clinical trials showing that topical budesonide resulted in higher rates of histologic remission and symptomatic improvement compared with placebo. We anticipate using budesonide oral suspension as the preferred topical glucocorticoid for treating EoE. (See "Treatment of eosinophilic esophagitis (EoE)", section on 'Topical glucocorticoids' .)

Dupilumab for refractory eosinophilic esophagitis (February 2024)

Few data are available on the use of dupilumab (a monoclonal antibody) for treating refractory eosinophilic esophagitis. In a cohort study of 46 patients with refractory eosinophilic esophagitis, dupilumab therapy was associated with histologic remission (defined as <15 eosinophils/high-power field) in 37 patients (80 percent) and with symptomatic improvement in 42 patients (91 percent) after a median of six months [ 23 ]. These data support our approach of using dupilumab for patients with eosinophilic esophagitis who have not responded to other therapies (eg, topical glucocorticoids). (See "Treatment of eosinophilic esophagitis (EoE)", section on 'Dupilumab' .)

Testing for hepatitis C virus infection in infants with perinatal exposure (November 2023)

Perinatally acquired hepatitis C virus (HCV) infection in the United States has increased sharply since 2010. New guidance from the Centers for Disease Control and Prevention recommends early testing for infants with perinatal exposure to HCV ( algorithm 1 ) [ 24 ]:

● Test for HCV RNA during early infancy after two months of age, and ideally before six months of age.

● After 18 months of age, test any infant who has not previously been tested by measuring anti-HCV antibodies, with reflexive testing for HCV RNA.

A negative HCV RNA result at any time point after two months of age virtually excludes HCV infection and further testing is not required. Children with a positive HCV RNA test before three years of age should have repeat testing for HCV RNA before initiating antiviral therapy to determine whether they have spontaneously cleared the infection. This new guidance is consistent with our previous recommendations for early testing for infants with perinatal exposure to HCV. (See "Hepatitis C virus infection in children", section on 'How to test' .)

GENETIC AND METABOLIC DISORDERS

Investigational gene therapy for autosomal recessive deafness (March 2024)

Gene therapies for single gene disorders are an area of active study. In two recent studies, children with autosomal recessive deafness 9, a type of congenital deafness, were treated with gene therapy to supply functional otoferlin, encoded by the OTOF gene, using an adeno-associated virus vector injected into cochlear cells [ 25,26 ]. Of eight treated children, seven had significant improvements in hearing. This therapy has not been approved by the US Food and Drug Administration. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Inherited single gene disorders' .)

N-acetyl-l-leucine (NALL) for Niemann-Pick disease type C (February 2024)

Niemann-Pick disease type C (NPD-C) is a rare lysosomal disease with a wide phenotypic spectrum; most patients have onset in childhood with cerebellar ataxia and slowly progressive neurologic deterioration. Investigational therapies include N-acetyl-l-leucine (NALL), a putative neuroprotective agent that improves cellular energy production and reduces neuroinflammation. In a recent placebo-controlled, 12-week crossover trial of 60 patients (age ≥4 years) with NPD-C, treatment with NALL was well tolerated and led to improved neurologic status on a scale that measures ataxia and other neurologic signs and symptoms [ 27 ]. While these results are promising, longer-term trials are needed to determine if NALL is beneficial for patients with NPD-C. (See "Overview of Niemann-Pick disease", section on 'Experimental therapies' .)

HEMATOLOGY AND ONCOLOGY

Emicizumab in infants with hemophilia A (April 2024)

Emicizumab is a monoclonal antibody that substitutes for the function of factor VIII; initial use has focused on older patients with factor VIII inhibitors. Now, two new studies report safety and efficacy in infants, most of whom did not have inhibitors. In HAVEN 7, there were no spontaneous bleeds or intracerebral bleeds [ 28 ]. In the second study, annualized bleeding rate decreased from 2 to 1 [ 29 ]. Neither study observed serious adverse events. Emicizumab is an attractive option due to its efficacy, lower rate of factor VIII exposure, and maintenance dosing schedule (subcutaneously once every other week), but use requires specialized knowledge of monitoring, risks, and treatment of breakthrough bleeding. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab efficacy and adverse events' .)

Updates on congenital fibrinogen disorders (April 2024)

Congenital fibrinogen disorders are rare and remain underdiagnosed. New publications address the clinical manifestations of these disorders and provide obstetric guidance:

● A new report from the Rare Bleeding Disorders database described 123 patients with afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia and characterized bleeding and thrombotic manifestations [ 30 ]. (See "Disorders of fibrinogen", section on 'Clinical manifestations' .)

● New guidelines from the International Society on Thrombosis and Hemostasis (ISTH) provide target fibrinogen levels and advice for managing postpartum bleeding and thromboprophylaxis in individuals with congenital fibrin disorders [ 31 ]. (See "Disorders of fibrinogen", section on 'Conception and pregnancy' .)

A high index of suspicion for these disorders and multidisciplinary management are required.

New international guideline for PK deficiency (March 2024)

A new international expert guideline for diagnosis and treatment of pyruvate kinase (PK) deficiency has been published [ 32 ]. Key recommendations include testing in any individual with nonimmune hemolytic anemia after exclusion of hemoglobin and red blood cell (RBC) membrane disorders, acceptance of genetic testing alone for diagnosis, regular RBC transfusions for children <5 years with symptomatic anemia, monitoring for iron overload and its complications, use of mitapivat for symptomatic anemia in adults who are not receiving transfusions and do not have two nonmissense mutations, and discontinuing mitapivat for lack of efficacy. These guidelines are consistent with the advice in UpToDate. (See "Pyruvate kinase deficiency", section on 'Treatment' .)

Hemoglobin nadir in transfusion-dependent thalassemia (March 2024)

Thalassemia experts generally target a nadir hemoglobin of 9.5 to 10.5 in patients with transfusion-dependent thalassemia (TDT), but supporting evidence for this has been very limited. A new retrospective study evaluated outcomes in 779 patients with TDT and reported that higher pretransfusion hemoglobin (the nadir between regular transfusions) correlated with improved 10-year survival [ 33 ]. The survival benefit was not seen with ferritin >1000 ng/mL, emphasizing the importance of addressing iron overload. While several caveats apply to interpretation, this study supports our practice of targeting a nadir of 9.5 to 10.5 g/dL in TDT. (See "Management of thalassemia", section on 'Supporting evidence' .)

No benefit of routine thromboprophylaxis for children with ALL (January 2024)

Whether routine thromboprophylaxis reduces the risk of thrombotic complications in patients with acute lymphoblastic leukemia (ALL) has been debated. In a multicenter randomized trial of over 500 children and adolescents with newly diagnosed pre-B or T cell ALL, patients assigned to prophylactic anticoagulation with apixaban compared with standard care alone had similar rates of symptomatic venous thrombosis (1.6 versus 2.3 percent, respectively) and asymptomatic venous thrombosis (11 versus 15 percent) [ 34 ]. Nonmajor bleeding episodes (mostly epistaxis) occurred more frequently in the apixaban group (4 versus 1 percent). These data do not support the routine use of thromboprophylaxis in children with ALL, although it may be warranted in selected patients with additional risk factors for thrombosis. (See "Thromboembolism in children with cancer", section on 'Primary prevention' .)

Maintenance eflornithine in high-risk neuroblastoma (January 2024)

For patients with high-risk neuroblastoma (HRNBL), there is interest in investigating novel maintenance therapies such as eflornithine, an ornithine decarboxylase inhibitor. In an externally controlled analysis of almost 100 patients with HRNBL who completed multimodality treatment and maintenance immunotherapy, extended maintenance therapy with eflornithine was associated with improved overall survival (hazard ratio 0.38) [ 35 ]. Based on these data, the US Food and Drug Administration approved eflornithine as maintenance therapy in patients with HRNBL who achieve at least a partial response to prior systemic agents and complete maintenance immunotherapy. Since maintenance eflornithine is not standard across all institutions, this agent may be offered on a case-by-case basis. (See "Treatment and prognosis of neuroblastoma" .)

Methemoglobinemia in infants due to contaminated hospital water supply (January 2024)

Methemoglobinemia is a potentially life-threatening condition in which heme iron becomes oxidized, preventing oxygen delivery. A report from a hospital in Japan described methemoglobinemia in 10 neonates who were fed infant formula prepared with tap water from the general hospital water supply [ 36 ]. The cause was identified as high levels of nitrites, and the source was traced to contamination by an anticorrosion agent from the heating system that entered the water supply due to a malfunctioning valve. All 10 survived, although 3 required methylene blue therapy. Infants are especially susceptible to methemoglobinemia because they have lower baseline levels of the enzyme that converts heme iron back to its normal state. (See "Methemoglobinemia", section on 'Nitrates and nitrites (from foods, drugs, preservatives, and chemicals)' .)

INFECTIOUS DISEASES AND IMMUNIZATIONS

Pemivibart for prevention of COVID-19 in selected immunocompromised patients (April 2024)

Monoclonal antibodies have been used as adjunctive pre-exposure prophylaxis to reduce the risk of COVID-19 in individuals expected to have suboptimal response to vaccination, although emergence of variants that escape neutralization limit their utility. In March 2024 in the United States, the novel monoclonal antibody pemivibart received emergency use authorization (EUA) to prevent COVID-19 in individuals age 12 years or older (weighing at least 40 kg) who have moderate-to-severe immunocompromising conditions ( table 1 ) [ 37 ]. Pemivibart is active against JN.1, the dominant SARS-CoV-2 variant. We suggest pemivibart in individuals at the highest risk for vaccine nonresponse (eg, those with hematologic malignancy or recent history of transplantation) as long as it remains active against the main circulating variants. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Limited role for monoclonal antibodies in selected patients' .)

Precautions for individuals with COVID-19 in the community (April 2024)

In March 2024, the United States Centers for Disease Control and Prevention updated guidance for precautions for people with COVID-19 in the community [ 38 ]. Such individuals should stay at home until their symptoms are improving and they have been afebrile for 24 hours without the use of antipyretics. They can subsequently resume normal activities but are encouraged to use other precautions (eg, masking, social distancing, good ventilation) for an additional five days to further reduce the risk of transmission to others. These measures are particularly important when around persons who are at increased risk for severe disease (eg, advanced age, immunocompromise, cardiopulmonary disease). (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection" .)

Nirsevimab effectiveness in infants (March 2024)

During the 2023-24 respiratory syncytial virus (RSV) season, infants could receive the monoclonal antibody nirsevimab for the first time to protect against RSV-related hospitalization. In a case-control study of almost 700 infants <8 months old who were hospitalized in the United States for an acute respiratory illness during this RSV season, almost 60 percent tested positive for RSV; almost all of these patients had not received nirsevimab [ 39 ]. Among infants who tested negative for RSV, 18 percent had received nirsevimab. Estimated effectiveness against RSV-associated hospitalization among nirsevimab recipients was 90 percent. These data provide additional support for recommendations to administer nirsevimab to all infants <8 months old upon entering their first RSV season and to all newborns during the RSV season unless the birthing parent received RSV vaccination during pregnancy. (See "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Immunoprophylaxis' .)

Short-course antibiotic therapy in children with febrile UTI (February 2024)

In children with urinary tract infection (UTI) without suspected kidney involvement, there is controversy about the duration of empiric antibiotic therapy. In an unblinded trial from Italy of amoxicillin-clavulanate to treat UTI, 142 children three months to five years of age were randomly assigned to a 10-day course (standard) or a 5-day course (short) of antibiotics [ 40 ]. Fewer children assigned to the short course had recurrent UTI within 30 days of antibiotic completion (2.8 versus 14.3 percent [difference -11.5 percent, 95% CI -20.5 to -2.5]). Rates of resistance to amoxicillin-clavulanate within 5 days following completion of antibiotics (1.4 versus 4.3 percent) and within 30 days (1.4 versus 0 percent) were similar. This trial lends further support for a 5-day course of antibiotics to treat UTI when kidney involvement is not suspected. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Preferred empiric oral regimens' .)

R21/Matrix-M vaccine to prevent malaria in children (November 2023, Modified February 2024)

In October 2023, the World Health Organization (WHO) approved the R21/Matrix-M vaccine for prevention of malaria in children [ 41 ]. In a placebo-controlled randomized trial of 4800 children (age 5 to 36 months) in four African countries, 12-month efficacy of a three-dose vaccine series against clinical malaria was 75 percent at sites with seasonal transmission and 68 percent at sites with year-round transmission [ 42,43 ]. The vaccine was well tolerated. Injection site pain and fever were the most frequent adverse events. Together with the RTS,S/AS01 vaccine (recommended by the WHO in 2021), this approval is expected to facilitate sufficient vaccine supply to benefit all children living in areas where malaria is a public health risk. (See "Malaria: Epidemiology, prevention, and control", section on 'R21/Matrix-M vaccine' .)

Nirsevimab to prevent severe respiratory syncytial virus in infants (January 2024)

Nirsevimab is a new antibody that prevents severe respiratory syncytial virus (RSV) infection in infants. In a trial conducted in France, Germany, and the United Kingdom, more than 8000 otherwise healthy infants ≤12 months, born at ≥29 weeks' gestation, and entering their first RSV season were assigned to receive one dose of nirsevimab or no intervention [ 44 ]. The group who received nirsevimab had fewer hospitalizations for RSV-associated lower respiratory tract infection (0.3 versus 1.5 percent, efficacy 83.2 percent, 95% CI 67.8-92.0) and fewer infants with an oxygen saturation <90 percent (0.1 versus 0.5 percent, efficacy 75.7 percent, 95% CI 32.8-92.9). These findings further support the use of nirsevimab for RSV immunoprophylaxis in infants. (See "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Immunoprophylaxis' .)

NEONATOLOGY

Neurodevelopmental effects of donor versus birth parent milk (March 2024)

For very low birth weight infants, feeding fortified human milk from the birth parent rather than preterm formula appears to have beneficial effects on cognitive development and significantly reduces the risk of necrotizing enterocolitis (NEC); whether cognitive benefits are seen with donor milk is unclear. In a randomized trial of 483 extremely preterm infants without access to birth parent milk that compared fortified donor milk with preterm formula during the birth hospitalization, individuals assigned to donor milk had similar cognitive development outcomes at approximately two years of age but had a lower risk of NEC during hospitalization (adjusted risk difference -5 percent) [ 45 ]. Despite the lack of benefit on cognitive outcomes, these findings support our suggestion to use fortified donor milk rather than preterm formula for very low birth weight infants without access to birth parent milk. (See "Human milk feeding and fortification of human milk for premature infants", section on 'Use of donor milk' .)

No benefit of early treatment of PDA in extremely preterm neonates (January 2024)

The optimal timing for intervention in extremely preterm (EPT) neonates with patent ductus arteriosus (PDA) is debated; some centers favor early pharmacologic treatment while others favor expectant supportive care initially. In a multicenter, placebo-controlled trial involving >650 EPT neonates with large PDA, early treatment with ibuprofen resulted in higher rates of PDA closure by three weeks of age, but it did not reduce mortality, moderate or severe bronchopulmonary dysplasia, or other neonatal morbidities [ 46 ]. Based on these findings and results from prior clinical trials, we suggest expectant supportive care for PDA rather than early pharmacologic therapy.(See "Patent ductus arteriosus (PDA) in preterm infants: Management and outcome", section on 'Comparison of approaches' .)

Delayed cord clamping in preterm births (December 2023)

Increasing evidence supports delaying cord clamping in preterm births. In an individual participant data meta-analysis of randomized trials of delayed versus immediate cord clamping at births <37 weeks (over 3200 infants), delaying cord clamping for >30 seconds reduced infant death before discharge (6 versus 8 percent) [ 47 ]. In a companion network meta-analysis evaluating the optimal duration of delay, a long delay (≥120 seconds) significantly reduced death before discharge compared with immediate clamping; reductions also occurred with delays of 15 to <120 seconds but were not statistically significant [ 48 ]. For preterm births that do not require resuscitation, we recommend delayed rather than immediate cord clamping. We delay cord clamping for at least 30 to 60 seconds as approximately 75 percent of blood available for placenta-to-fetus transfusion is transfused in the first minute after birth. (See "Labor and delivery: Management of the normal third stage after vaginal birth", section on 'Preterm infants' .)

Long-term neurodevelopmental outcomes for preterm infants receiving minimally invasive surfactant (November 2023)

The technique of administering surfactant via thin intratracheal catheter (called minimally invasive surfactant therapy [MIST]) to preterm neonates with respiratory distress syndrome reduces the risk of bronchopulmonary dysplasia (BPD), but the long-term impact is uncertain. In a recent follow-up report of a multicenter international trial, infants who received MIST had lower rates of hospitalization for respiratory illness at two years but similar neurodevelopmental outcomes compared with those in the control group [ 49 ]. These findings and results from prior trials suggest that MIST improves short- and long-term pulmonary outcomes (ie, reduced need for intubation, reduced incidence of BPD, and reduced respiratory illnesses during the first two years). However, these benefits may not translate into meaningful improvements in long-term neurodevelopmental outcomes. Nevertheless, we continue to use MIST in appropriate candidates given the demonstrated pulmonary benefits. (See "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Minimally invasive surfactant therapy (MIST)' .)

NEPHROLOGY AND UROLOGY

Single versus divided doses of oral corticosteroids for nephrotic syndrome (March 2024)

Prednisone or prednisolone is the initial treatment of choice for children with idiopathic nephrotic syndrome (NS). In a randomized trial in 60 children with a first episode of NS, a single daily dose and divided-dose therapy both induced remission within six weeks in all participants [ 50 ]. Suppression of the hypothalamic-pituitary-adrenal axis after six weeks of therapy was more common in children treated with divided-dose therapy (100 percent) compared with those treated with single-dose therapy (83 percent). These findings support our practice of using single daily doses of prednisone for this condition. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial steroid course' .)

Serial amnioinfusions for bilateral renal agenesis (January 2024)

Bilateral renal agenesis (BRA) is incompatible with extrauterine life because prolonged oligohydramnios results in pulmonary hypoplasia, leading to postnatal respiratory failure. A prospective study (RAFT) assessed use of serial amnioinfusions to treat 18 cases of BRA diagnosed at <26 weeks of gestation [ 51 ]. Of the 17 live births, 14 survived ≥14 days and had placement of dialysis access, but only 6 survived to hospital discharge. Of the 4 children alive at 9 to 24 months of age, 3 had experienced a stroke and none had undergone transplant. These findings show that serial amnioinfusions for BRA mitigates pulmonary hypoplasia and increases short-term survival and access to dialysis; however, long-term outcome remains poor with no survival to transplantation. Serial amnioinfusions remain investigational and should be offered only as institutional review board-approved research. (See "Renal agenesis: Prenatal diagnosis", section on 'Investigative role of therapeutic amnioinfusion' .)

Givinostat for Duchenne muscular dystrophy (April 2024)

The histone deacetylase inhibitor givinostat was recently approved by the US Food and Drug Administration for the treatment of Duchenne muscular dystrophy (DMD) in patients six years of age and older. Approval was based on results from a small randomized trial, which suggest that givinostat may slow DMD progression [ 52 ]. Benefit was found on only one outcome (the four-stair climb test), as shown by a smaller performance decline from baseline to 72 weeks for the givinostat group compared with placebo (1.25 versus 3.03 seconds); statistical significance was marginal. Adverse effects of givinostat include gastrointestinal disturbances, thrombocytopenia, elevated triglycerides, fever, and potential QTc interval prolongation. While givinostat may be used in combination with glucocorticoid therapy and genetic therapies, its role in the treatment of DMD remains to be defined, and further data are needed to confirm benefit. (See "Duchenne and Becker muscular dystrophy: Glucocorticoid and disease-modifying treatment", section on 'Givinostat' .)

Intrathecal gene therapy for giant axonal neuropathy (April 2024)

Giant axonal neuropathy (GAN) is a severe, hereditary neurodegenerative disorder of childhood characterized by a motor and sensory polyneuropathy with ataxia. In a small dose-escalation study in 14 children with GAN, intrathecal administration of an adeno-associated virus-based gigaxonin-containing transgene was associated with slowing of functional decline at 6 to 24 months compared with the pretreatment baseline, and electrodiagnostic studies improved in some patients [ 53 ]. Cerebrospinal fluid pleocytosis was observed in nearly all patients within six months after gene transfer but was asymptomatic and self-limited with immunosuppression; two deaths at 8 and 60 months after treatment were deemed possibly related to disease progression and unlikely related to the transgene. These promising results support the possibility of future disease-modifying therapy for GAN, pending further safety and efficacy assessments. (See "Overview of hereditary neuropathies", section on 'Giant axonal neuropathy' .)

Benign acute childhood myositis (January 2024)

Benign acute childhood myositis (BACM) is a self-limited syndrome associated with calf pain and creatinine kinase elevation, often following infection with influenza. In a retrospective study of 65 patients with BACM, the median age was 6.6 years and 66 percent of patients were male [ 54 ]. The most common symptoms were bilateral calf pain, refusal to walk, and diffuse weakness. The median creatinine kinase was 1827 U/L, which normalized after an average of seven days. Early recognition of this syndrome allows the clinician to avoid an unnecessary evaluation for other muscle diseases. (See "Overview of viral myositis", section on 'Benign acute childhood myositis' .)

Vamorolone for Duchenne muscular dystrophy (December 2023)

Glucocorticoid treatment with prednisone or deflazacort for Duchenne muscular dystrophy (DMD) is associated with improved motor function, but adverse effects include weight gain, slowing of growth, and bone loss. Vamorolone , a novel steroid, was designed to reduce adverse effects of glucocorticoid therapy for DMD. In the VISION-DMD trial, vamorolone treatment led to improvement on several motor outcomes compared with placebo, while efficacy was similar compared with prednisone [ 55 ]. Prednisone treatment (but not vamorolone) led to growth deceleration and bone biomarker abnormalities. Based on these findings, the US Food and Drug Administration approved vamorolone for children age ≥2 years with DMD [ 56 ]. We suggest glucocorticoid treatment for children with DMD and anticipate using vamorolone as an alternative to prednisone and deflazacort. (See "Duchenne and Becker muscular dystrophy: Glucocorticoid and disease-modifying treatment", section on 'Benefits of glucocorticoid therapy' .)

Acute encephalopathy with biphasic seizures and late reduced diffusion (November 2023)

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a parainfectious syndrome characterized by presentation with febrile status epilepticus (FSE) followed by a brief seizure-free period before recurrence of seizures in clusters. In a retrospective study from Japan of 55 patients presenting with FSE, the development of AESD in 11 patients was associated with longer time from seizure onset to hospital arrival, presence of hypoxia, and later treatment with antiseizure medications [ 57 ]. These findings suggest that shortening the seizure duration by early effective treatment and preventing hypoxia during ambulance transportation might reduce the risk of AESD. (See "Clinical features and evaluation of febrile seizures", section on 'Acute encephalopathy with biphasic seizures and late reduced diffusion' .)

Expert panel on epilepsy with eyelid myoclonia (November 2023)

Epilepsy with eyelid myoclonia (EEM; Jeavons syndrome) is a female-predominant generalized epilepsy syndrome with onset from 3 to 12 years of age characterized by eyelid myoclonia, photosensitivity, and eye closure-induced seizures or paroxysms on electroencephalography (EEG). Recently, an international expert panel found a strong consensus that EEM is often underdiagnosed, that a correct diagnosis can only be made with EEG including photic stimulation, and that an earlier age at onset is associated with an increased risk of intellectual disability and drug-resistant epilepsy [ 58 ]. Management generally involves reducing exposure to provoking factors (eg, visual stimuli, various sources of natural and artificial light) and use of antiseizure medication such as levetiracetam or valproate [ 59 ]. (See "Photosensitive epilepsies", section on 'Epilepsy with eyelid myoclonia (Jeavons syndrome)' .)

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Stanford Medicine delivers first FDA-approved cell-based therapy for solid tumors

The FDA recently approved the first cell-based therapy — widely used in treating blood cancers — for solid tumors. Stanford Medicine treated the first patient with advanced melanoma.

May 6, 2024 - By Krista Conger

Allison Betof Warner speaks with a patient who received CAR-T therapy for melanoma. Stanford Medicine

In March, Stanford Medicine became the first center in the nation to treat a patient with metastatic melanoma using a new cell-based therapy approved by the Food and Drug Administration. The therapy, which offers hope for people with advanced melanoma whose cancers have resisted immunotherapies, is the first cell-based therapy approved by the FDA to treat solid tumors.

Cell-based therapies — in which immune cells are collected from a patient and treated or genetically modified to enhance their cancer-fighting ability — are not new. Chimeric antigen receptor T-cell therapies, or CAR-T therapies, have been used for several years to fight blood cancers such as leukemias.

The new treatment, which uses immune cells harvested from a patient’s tumor called tumor-infiltrating lymphocytes, exploits the body’s own natural cancer-fighting ability. Once the tumor-infiltrating lymphocytes, or T cells, are harvested, they are encouraged in the laboratory to multiply into billions of cancer-fighting cells, then returned to the patient about a month later.

“These cells are naturally existing T cells that target multiple aspects of the existing tumor,” said assistant professor of medicine Allison Betof Warner , MD, PhD. “Before now, there was no approved therapy for people with melanoma whose cancers had progressed after immunotherapy and/or targeted therapy. Now we can bring the promise of cell therapy to these patients.”

In contrast to tumor-infiltrating lymphocytes, which are not genetically modified, CAR-T therapies use genetic engineering to modify a patient’s T cells to recognize and respond to a specific molecule or molecules on the surfaces of cancer cells. Doing so requires researchers to predict which molecules will serve as the best targets — easier for blood cancers than for solid tumors.

“We are very excited to move cell-based therapies beyond blood cancers,” said David Miklos ,  MD, PhD, professor of medicine and chief of bone marrow transplantation and cellular therapy. “This has been a long time coming, but now we have a new standard of care for these patients.”

Stanford Medicine is one of fewer than 30 centers around the country offering the treatment.

The therapy, called lifileucel and commercially known as Amtagvi, is marketed by San Carlos-based Iovance Biotherapeutics.

Clinical trials of lifileucel for metastatic melanoma that worsened while on standard treatment found that about 30% of 153 patients who received the therapy had their tumors shrink or disappear. Of those, 40% experienced no progression of their cancers for at least 18 months after the one-time infusion.

A quarter-century of research

Tumor-infiltrating lymphocyte therapy was first conceived of in the late 1980s by Steven Rosenberg, MD, PhD, at the National Cancer Institute. In the intervening decades, he and others optimized the treatment and conducted clinical trials exploring its promise. In October, Rosenberg was awarded the National Medal of Technology and Innovation, in part for his role in bringing tumor-infiltrating lymphocyte therapies to the clinic.

For the treatment, surgeons first remove a sample of the tumor and collect any T cells it contains. These cells have already infiltrated and started to fight the tumor, presumably by recognizing a variety of molecules on the surfaces of the cancer cells. These T cells are grown in the laboratory for about one month in the presence of a growth-promoting immune molecule called IL-2.

IL-2 stimulates the cells to divide repeatedly, generating an army of billions. While the cells are growing in the laboratory, the patient undergoes chemotherapy to deplete existing lymphocytes — creating a biological niche for the newly energized cells to further expand when they are returned to the patient.

“Normally, when you remove a tumor from a patient with cancer, you throw it away,” Miklos said. “But these trials have shown that the lymphocytes that tumor contains are gold. Your body is already trying to fight these cancers. We’re just helping it out.”

After the cells are returned, the patient is given several doses of IL-2 to further encourage the expansion of the cancer-fighting cells.

The technique works particularly well with melanomas, which are flush with lymphocytes. But Betof Warner and Miklos feel that improvements in the cell-expansion technique may make it useful even for tumors such as lung and colorectal cancers that tend to have fewer infiltrating immune cells — a class of tumor known as “immune cold.”

Researchers worldwide are now conducting clinical trials of tumor-infiltrating lymphocytes in other solid cancers including non-small cell lung cancer, advanced colorectalm and breast cancer, while other trials are investigating the effect of combining lifileucel with immunotherapy as a first-line treatment for advanced melanoma.

Not every person with metastatic melanoma will qualify for the therapy under the terms of the FDA approval. People need to be relatively healthy with good heart, kidney, and lung function and able to withstand the preparative immune-depleting chemotherapy given before the infusion. They also must have seen their cancers worsen while on immunotherapies or targeted treatment that are currently the standard of care for these cancers. Betof Warner estimates that, of the 8,000 to 10,000 or so people diagnosed with advanced melanomas each year in the United States, about 2,000 people will qualify if patients are identified appropriately and referred to authorized treatment centers.

The researchers are also investigating which molecules the tumor-infiltrating lymphocytes are targeting, with the hopes of making even more targeted treatments.

“We study the tumor that we remove from the patient, as well as the cells we return to the patient and compare that with the patient’s clinical response,” Betof Warner said. “Eventually we hope to predict and improve the responses based on the lymphocytes found in the tumor. Are they healthy? What molecules on the cancer cells are they targeting? Although there is more to learn, we are excited to have another option, another line of treatment for these advanced cancers.”

See also: The promise of TIL Therapy

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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Research shows altered regulation of genes linked to prostate cancer among firefighters

by Shipherd Reed, University of Arizona

Firefighters may have an increased risk of prostate cancer due to on-the-job chemical exposures, according to new research from the University of Arizona Mel and Enid Zuckerman College of Public Health and University of Michigan in collaboration with fire service partners and researchers around the country through the Fire Fighter Cancer Cohort Study.

Prostate cancer is the leading incident cancer among U.S. males. Firefighters are diagnosed with prostate cancer at a rate 1.21 times higher than the general population, possibly because of chemical exposures including smoke and firefighting foam during firefighting.

Some of those chemicals can affect how genes are expressed through a process called epigenetic modification , and certain epigenetic modifications, including DNA methylation, contribute to cancer development. Researchers found evidence that experienced firefighters had different epigenetic modifications than new firefighters in regions linked to prostate cancer.

"With these published findings, we have clear evidence of the health risks that firefighters face due to cumulative exposure on the job," said Jeff Burgess, MD, MPH, director of the Center for Firefighter Health Collaborative Research and professor at the Zuckerman College of Public Health.

The paper, "Firefighting, per- and polyfluoroalkyl substances, and DNA methylation of genes associated with prostate cancer risk," is published in the journal Environmental and Molecular Mutagenesis .

Burgess, also a member of the BIO5 Institute, has been investigating firefighter health for decades. He collaborated with lead author Margaret Quaid, MS, and researcher Jackie Goodrich, Ph.D., from the University of Michigan, who led the analysis on the methylation of genes.

They found that experienced firefighters had different epigenetic modifications at chromosome 8q24—a particular area of the genome where epigenetic modifications have been linked to prostate cancer risk—compared with new firefighters.

One class of chemicals that is linked with epigenetic modifications is per- and polyfluoroalkyl substances, or PFAS, which are used in firefighting foam as well as in many household items , including nonstick pans and water-resistant clothing. The research team also investigated whether there was a link between exposure to PFAS and epigenetic modification.

The results showed that, in many fire departments, new and experienced firefighters had similar exposure to PFAS. However, exposure to a specific PFAS chemical—branched perfluorooctanoic acid, or PFOA—was linked to epigenetic modifications.

"This study demonstrates the power of the Fire Fighter Cancer Cohort Study to combine data across grants—in this case awards from the Federal Emergency Management Agency in 2014, 2015 and 2018—to more powerfully evaluate questions from the fire service, this time around exposures and increased prostate cancer risk," Burgess said.

Other co-authors from the Zuckerman College of Public Health include toxicologist Shawn Beitel, MSc, research program administrative officer of the Firefighter Health Collaborative Research Program, and Sally Littau, health research coordinator. John Gulotta and Darin Wallentine of the Tucson Fire Department also contributed.

The research team included members from the University of Miami, Rutgers University, the National Institute for Occupational Safety and Health at the Centers for Disease Control and Prevention, the Los Angeles County Fire Department, the Orange County Fire Authority, and the Fire Protection Research Foundation.

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• Review Article
• Published: 10 June 2019

Recent progress in global newborn health: thinking beyond acute to strategic care?

• Anna Hedstrom 1 , 2 ,
• Krystle Perez 1 , 2 ,
• Rachel Umoren   ORCID: orcid.org/0000-0003-2356-9278 1 ,
• Maneesh Batra 1 , 2 &
• Cyril Engmann 1 , 2 , 3  

Journal of Perinatology volume  39 ,  pages 1031–1041 ( 2019 ) Cite this article

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Advancements in neonatal care globally highlight ongoing disparities in neonatal outcomes between low-income countries (LICs) and high-income countries (HICs). Drivers of this gap are primarily prematurity, infection, and intrapartum-related events. Significant success is being achieved; however, for neonatal outcomes in LIC to approximate those of HICs within a generation, acceleration of the current trajectory of progress is needed. This requires a renewed focus on newborn-specific and newborn-sensitive strategies. Newborn-specific strategies are those directly affecting the well-being of the neonate. Newborn-sensitive strategies address the broader macro-environmental drivers that affect underlying neonatal outcomes such as decreased poverty, improved sanitation, and increased maternal empowerment and health. To create such an enabling macro-environment requires significant political will, financing, advocacy, and policy generation. This manuscript highlights recent advances in newborn research, programming, policy, and funding, and highlights key opportunities to bend the curve on advancing neonatal health globally.

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Acknowledgements

We thank Peder Digre and Sharanya Rajagopal for their contributions to Figures 1 and 3 in this manuscript.

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Hedstrom, A., Perez, K., Umoren, R. et al. Recent progress in global newborn health: thinking beyond acute to strategic care?. J Perinatol 39 , 1031–1041 (2019). https://doi.org/10.1038/s41372-019-0384-z

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New super-pure silicon chip opens path to powerful quantum computers

Researchers at the Universities of Melbourne and Manchester have invented a breakthrough technique for manufacturing highly purified silicon that brings powerful quantum computers a big step closer.

The new technique to engineer ultra-pure silicon makes it the perfect material to make quantum computers at scale and with high accuracy, the researchers say.

Project co-supervisor Professor David Jamieson, from the University of Melbourne, said the innovation – published today in Communication Mater ials , a Nature journal – uses qubits of phosphorous atoms implanted into crystals of pure stable silicon and could overcome a critical barrier to quantum computing by extending the duration of notoriously fragile quantum coherence .

“Fragile quantum coherence means computing errors build up rapidly. With robust coherence provided by our new technique, quantum computers could solve in hours or minutes some problems that would take conventional or ‘classical’ computers – even supercomputers – centuries,” Professor Jamieson said.

Quantum bits or qubits* – the building blocks of quantum computers – are susceptible to tiny changes in their environment, including temperature fluctuations. Even when operated in tranquil refrigerators near absolute zero (minus 273 degrees Celsius), current quantum computers can maintain error-free coherence for only a tiny fraction of a second.  

University of Manchester co-supervisor Professor Richard Curry said ultra-pure silicon allowed construction of high-performance qubit devices – a critical component required to pave the way towards scalable quantum computers.  

“What we’ve been able to do is effectively create a critical ‘brick’ needed to construct a silicon-based quantum computer. It’s a crucial step to making a technology that has the potential to be transformative for humankind,” Professor Curry said. 

Lead author Ravi Acharya, a joint University of Manchester/University of Melbourne Cookson Scholar, said the great advantage of silicon chip quantum computing was it used the same essential techniques that make the chips used in today’s computers.

“Electronic chips currently within an everyday computer consist of billions of transistors — these can also be used to create qubits for silicon-based quantum devices. The ability to create high quality silicon qubits has in part been limited to date by the purity of the silicon starting material used. The breakthrough purity we show here solves this problem." 

Professor Jamieson said the new highly purified silicon computer chips house and protect the qubits so they can sustain quantum coherence much longer, enabling complex calculations with greatly reduced need for error correction.

“Our technique opens the path to reliable quantum computers that promise step changes across society, including in artificial intelligence, secure data and communications, vaccine and drug design, and energy use, logistics and manufacturing,” he said.

Silicon – made from beach sand – is the key material for today’s information technology industry because it is an abundant and versatile semiconductor : it can act as a conductor or an insulator of electrical current, depending on which other chemical elements are added to it.

“Others are experimenting with alternatives, but we believe silicon is the leading candidate for quantum computer chips that will enable the enduring coherence required for reliable quantum calculations,” Professor Jamieson said.

“The problem is that while naturally occurring silicon is mostly the desirable isotope silicon-28, there’s also about 4.5 percent silicon-29. Silicon-29 has an extra neutron in each atom’s nucleus that acts like a tiny rogue magnet, destroying quantum coherence and creating computing errors,” he said.

The researchers directed a focused, high-speed beam of pure silicon-28 at a silicon chip so the silicon-28 gradually replaced the silicon-29 atoms in the chip, reducing silicon-29 from 4.5 per cent to two parts per million (0.0002 per cent). 

“The great news is to purify silicon to this level, we can now use a standard machine – an ion implanter – that you would find in any semiconductor fabrication lab, tuned to a specific configuration that we designed,” Professor Jamieson said.

In previously published research with the ARC Centre of Excellence for Quantum Computation and Communication Technology , the University of  Melbourne set – and still holds – the world record for single-qubit coherence of 30 seconds using silicon that was less purified. 30 seconds is plenty of time to complete error-free, complex quantum calculations.

Professor Jamieson said the  largest existing quantum computers had more than 1000 qubits, but errors occurred within milliseconds due to lost coherence.

“Now that we can produce extremely pure silicon-28, our next step will be to demonstrate that we can sustain quantum coherence for many qubits simultaneously. A reliable quantum computer with just 30 qubits would exceed the power of today's supercomputers for some applications,” he said.

This latest work was supported by research grants from the Australian and UK governments.  Professor Jamieson’s collaboration with the University of Manchester is supported by a Royal Society Wolfson Visiting Fellowship.

A 2020 report from Australia’s CSIRO  estimated that quantum computing in Australia has potential to create 10,000 jobs and $2.5 billion in annual revenue by 2040.

“Our research takes us significantly closer to realising this potential,” Professor Jamieson said.

*A qubit – such as an atomic nucleus, electron, or photon – is a quantum object when it is in a quantum superposition of multiple states. Coherence is lost when the qubit reverts to a single state and becomes a classical object like a conventional computer bit, which is only ever one or zero and never in superposition.

• Quantum Computers
• Spintronics Research
• Computers and Internet
• Computer Science
• Distributed Computing
• Information Technology
• Quantum computer
• Quantum entanglement
• Introduction to quantum mechanics
• Quantum tunnelling
• Quantum dot
• Quantum mechanics
• John von Neumann

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Materials provided by University of Melbourne . Note: Content may be edited for style and length.

Journal Reference :

• Ravi Acharya, Maddison Coke, Mason Adshead, Kexue Li, Barat Achinuq, Rongsheng Cai, A. Baset Gholizadeh, Janet Jacobs, Jessica L. Boland, Sarah J. Haigh, Katie L. Moore, David N. Jamieson, Richard J. Curry. Highly 28Si enriched silicon by localised focused ion beam implantation . Communications Materials , 2024; 5 (1) DOI: 10.1038/s43246-024-00498-0

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