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What's new in pediatrics

What's new in pediatrics
Carrie Armsby, MD, MPH
Alison G Hoppin, MD
Elizabeth TePas, MD, MS
Mary M Torchia, MD
Laurie Wilkie, MD, MS
Literature review current through: Nov 2022. | This topic last updated: Dec 30, 2022.

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.


Risk of drug overdose in young people prescribed benzodiazepines for sleep disorders (December 2022)

Prescription database studies indicate that benzodiazepines are commonly prescribed for insomnia, despite risks and the availability of safer options. In a recent cohort study in the United States that included over 90,000 children and young adults (age 10 to 29 years) with a sleep disorder who were prescribed a new insomnia medication, benzodiazepines were associated with increased risk of drug overdose in the next six months compared with alternative insomnia medications (trazodone, hydroxyzine, zolpidem, zaleplon, eszopiclone) [1]. Risk was highest among individuals who had also received an opioid prescription in the preceding three months. We do not prescribe benzodiazepines for insomnia in patients taking opioids or in those with a substance use disorder. (See "Pharmacotherapy for insomnia in adults", section on 'Shared warnings and precautions'.)

Screening for anxiety in children and adolescents (December 2022)

Anxiety in children and adolescents interferes with social, emotional, and academic development. The United States Preventive Services Task Force (USPSTF) now recommends screening for anxiety in all individuals aged 8 to 18 years old [2]. This updated recommendation is supported by a meta-analysis that included 39 studies with 6065 subjects in that age range and showed moderate accuracy of screening tools and moderate benefit of treatment on symptom response and disease remission [3]. The harms associated with screening and subsequent treatment were minimal. Our approach is consistent with these recommendations. We use the Screen for Child Anxiety-Related Emotional Disorders (SCARED) tool, which is available in the public domain. (See "Anxiety disorders in children and adolescents: Assessment and diagnosis", section on 'Screening'.)

Semaglutide for treatment of obesity in adolescents (November 2022)

Glucagon-like peptide (GLP-1) analogs are important options for treatment of type 2 diabetes and/or obesity in adults. In a 68-week randomized trial in 201 adolescents with obesity, patients assigned to weekly subcutaneous semaglutide, a GLP-1 analog, had substantial weight loss compared to lifestyle intervention alone (placebo-adjusted change in body mass index -6 kg/m2 [95% CI -7.3 to -4.6]; change in weight -17.7 kg [95% CI -21.8 to -13.7]) [4]. This treatment effect is much greater than in a trial of liraglutide in adolescents. Gastrointestinal adverse events were common in both semaglutide and placebo-treated groups but were generally mild and rarely led to treatment discontinuation. These findings suggest that subcutaneous semaglutide may become an important option for treatment of obesity and/or type 2 diabetes in adolescents, pending regulatory approvals. (See "Prevention and management of childhood obesity in the primary care setting", section on 'Pharmacotherapy'.)

Synthetic ("tobacco-free") oral nicotine product use in teenagers (October 2022)

New synthetic nicotine products are available as gum, lozenges, gummies, and pouches. Features that may promote increased use among youth include availability in appealing flavors, readily concealed forms, and marketing messages such as "tobacco-free" that imply minimal harm. In a survey of 9th and 10th grade students in Southern California in late 2021, these products were the second-most common nicotine source (after e-cigarettes) and more common than combustible tobacco [5]. The US Food and Drug Administration has issued warning letters to manufacturers and retailers regarding illegal marketing of many of these products [6,7]. (See "Prevention of smoking and vaping initiation in children and adolescents", section on 'Oral nicotine products'.)

Sexual abuse of children in health care settings (September 2022)

The American Academy of Pediatrics has released a new policy to assist health care professionals and organizations in efforts to prevent sexual abuse of children in health care settings and to ensure an appropriate institutional response to allegations of sexual abuse perpetrated by a health care provider [8]. Key actions that health care organizations should take to protect children include pre-employment screening of all personnel who have access to children in a health care setting; education of all employees regarding staff-patient boundary setting, chaperone use during examination of sensitive body regions (ie, perineum and, in adolescent females, breast examination), and the individual responsibility to report concern for sexual abuse by other health care providers to the proper authorities; and policies that ensure all patient, parent/caregiver, or staff allegations of sexual abuse perpetrated by a health care receive prompt documentation, timely investigation, and, when there is sufficient suspicion for sexual abuse, adherence to mandated reporting, if not already performed. (See "Management and sequelae of sexual abuse in children and adolescents", section on 'Sexual abuse in health care settings'.)

Low-intensity guided self-help intervention for childhood obesity (July 2022)

Initial treatment of childhood obesity is ideally performed in the primary care setting to provide maximal access, but most effective interventions are high intensity, requiring >26 hours of provider contact. In a new trial of 164 school-aged children with obesity that compared a lower-intensity program (five hours of provider contact and home use of a self-help manual) with a high-intensity program (family-based behavioral treatment in an academic center), reduction of obesity at six months was similar with both approaches [9]. However, attrition was lower in the lower-intensity program. These findings support the role of a well-designed, low-intensity intervention in the primary care setting as an effective and practical approach to management of childhood obesity. (See "Prevention and management of childhood obesity in the primary care setting", section on 'Intensity of intervention'.)

Ultrasound guidance for peripheral intravenous line placement in children (June 2022)

In children, ultrasound guidance is well established for central venous access, but its role for placement of peripheral intravenous (PIV) lines is less clear. A new meta-analysis including five randomized trials performed in children with difficult intravenous access (DIVA) found improved rates of first attempt success (odds ratio 4.6) and overall success (odds ratio 3.3) for ultrasound-guided compared with standard (landmark) techniques during PIV line placement [10]. Based on these data, we suggest using ultrasound-guidance as the initial approach for placing PIV lines in children (but not neonates) with high DIVA scores. (See "Principles of ultrasound-guided venous access", section on 'Children with difficult access'.)

Firearms are the leading cause of death in children in the United States (June 2022)

Firearm injury (homicide, suicide, or unintentional) is a major cause of morbidity and mortality in the United States. In 2019, firearms surpassed motor vehicle crashes (MVC) as the leading cause of death in children and adolescents (age 1 to 19 years) [11-13]. This finding highlights the increasing numbers of firearm deaths, driven largely by homicides in adolescents, as well as the success of interventions to prevent MVC deaths such as car seats, booster seats, side airbags, rear facing cameras, and lane departure warnings. (See "Firearm injuries in children: Prevention", section on 'Firearm injuries'.)


New NF-kB-mediated autoinflammatory disease (ROSAH syndrome) (November 2022)

Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) syndrome is an autosomal dominant disorder caused by gain-of-function heterozygous missense variants in the alpha kinase 1 gene (ALPK1). A recent study confirmed that ROSAH is an autoinflammatory disorder mediated by enhanced nuclear factor kappa B (NF-kB) signaling [14]. In this small case series, immunomodulation with anticytokine therapy was associated with improved autoinflammatory disease manifestations including fatigue, headache, and arthralgia, and also intraocular inflammation in those who did not have advanced retinal disease. Additional studies are needed to determine the best choice of therapy and whether earlier treatment can prevent development of disease manifestations. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'ALPK1 gain-of-function defects (ROSAH syndrome)'.)

Timing of cow's milk protein introduction in infants and risk of allergy (November 2022)

Current guidelines recommend introducing highly allergenic foods, including cow's milk (CM) protein, in infants who are exclusively breast fed, beginning around four to six months of age. A prospective cohort study in 1298 children that examined the timing of receipt of CM-based formula supplementation after delivery and first reported introduction of CM-based formula or other CM products found that introduction at <2 weeks of age followed by continued exposure was associated with the lowest subsequent risk of development of parent-reported adverse reactions to CM (IgE- or non-IgE mediated) between 2 to 13 years of age [15]. This and other accumulating data suggest that very early introduction and continued ingestion of CM protein in some form (other than liquid, whole CM) may reduce the risk of developing CM allergy, although further studies are needed. (See "Introducing highly allergenic foods to infants and children", section on 'Introduction in the general population'.)

COVID-19 and asthma control in children (November 2022)

Initial data suggested that COVID-19 did not increase asthma morbidity in children, contrary to that expected for a viral respiratory infection. However, asthma control may have improved during the early waves of the pandemic due to an overall decrease in viral respiratory infections. A comparison of nearly 62,000 children with asthma from 108 health care systems in the United States from March 2020 through February 2021 found that a SARS CoV-2 polymerase chain reaction-positive test was associated with increased rates of emergency department visits, hospitalizations, and use of short-acting beta agonist and oral glucocorticoids in the six months following the positive test compared with those who tested negative [16]. This reinforces the importance of patients continuing medications necessary to maintain optimal asthma control so as to better weather COVID-19 and other viral respiratory infections. (See "Asthma in children younger than 12 years: Management of persistent asthma with controller therapies", section on 'Advice related to Covid-19'.)

Allergen immunotherapy for atopic dermatitis (October 2022)

Allergen immunotherapy (AIT) is a well-established treatment for allergic rhinoconjunctivitis and asthma, but studies of its utility for atopic dermatitis (AD) are mixed. In a new meta-analysis, the addition of AIT (either subcutaneous or sublingual, mostly using house dust mites as the allergen) or placebo was evaluated in 23 randomized trials that enrolled nearly 2000 children and adults with AD who were not controlled with standard therapy (either topical corticosteroids or calcineurin inhibitors) [17]. Patients receiving add-on AIT more often experienced a clinically important decrease in AD severity and improvement in quality of life. Thus, add-on AIT may be beneficial for patients who have eczema that is not controlled with conventional therapies and proven sensitization to house dust mites. AIT may be especially helpful for patients with concomitant allergic rhinoconjunctivitis or asthma. (See "Treatment of atopic dermatitis (eczema)", section on 'Allergen immunotherapy'.)

Group A Streptococcus prophylaxis in patients with acute rheumatic heart disease (June 2022)

Patients with acute rheumatic fever (ARF) require antibiotic prophylaxis to prevent recurrent group A Streptococcus pharyngitis and progression of their cardiac disease. Benzathine penicillin G (BPG) given intramuscularly (IM) every 28 days is the preferred regimen for most patients (table 1). However, prior case series and case reports have described sudden death within minutes of IM BPG administration in patients with severe acute rheumatic heart disease; these events are now attributed to vasovagal syncope with coronary hypoperfusion rather than anaphylaxis. For patients with a history of ARF who have developed severe, symptomatic valvular disease, New York Heart Association class III or IV heart failure, or ventricular dysfunction (ejection fraction <50 percent), a new American Heart Association recommends prophylaxis with an oral antibiotic (eg, oral penicillin V) rather than IM BPG [18]. We agree with this recommendation. (See "Acute rheumatic fever: Treatment and prevention", section on 'Severe valvular disease'.)


Laboratory monitoring for isotretinoin therapy (September 2022)

Reduced monitoring of liver function and lipid tests in healthy patients receiving isotretinoin has been proposed based upon data that suggest low utility of monthly testing. A Delphi consensus study in which acne experts responded to a series of surveys found at least 70 percent consensus for checking alanine aminotransferase (ALT) and triglyceride levels within one month prior to isotretinoin therapy and after reaching the peak isotretinoin dose [19]. There was also consensus that several other laboratory tests were not necessary, such as complete blood count panels, basal metabolic panels, and select liver function and lipid tests. Although these findings align with the trend towards reduced laboratory monitoring for healthy patients taking isotretinoin, no consensus was achieved for some commonly obtained tests, and additional study is necessary to confirm the best approach to monitoring. Additionally, individual patient characteristics may warrant a different approach to laboratory testing. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Evidence'.)


Xylazine adulteration of illicit drugs (December 2022)

Xylazine is an alpha-2 agonist and a chemical analogue of clonidine that is used in veterinary medicine for sedation and analgesia. In humans, xylazine overdose has caused major toxicity consisting of coma, apnea, bradycardia, and hypotension as well as severe, necrotic skin ulcerations after repeated parenteral use. Xylazine is increasingly found as an adulterant in illicit drugs, especially heroin and fentanyl, with rising reports of serious side effects. As a result, the US Food and Drug Administration has issued an alert to health care professionals and a letter to stakeholders [20]. Xylazine poisoning is on the differential diagnosis for patients with suspected opioid overdose that does not respond to naloxone administration. Treatment consists of supportive care. There is no rapid diagnostic testing for xylazine poisoning or safe antidote. (See "Clonidine and related imidazoline poisoning", section on 'Imidazoline agents'.)

Administration of vasoactive therapy by peripheral IV in children with shock (October 2022)

For children with shock who require vasoactive therapy, central venous access is preferred. However, delivery of vasoactive therapy by peripheral intravenous (PIV) access may be used during initial resuscitation while central venous access is obtained. In a recent retrospective cohort study of over 750 critically ill children receiving vasoactive infusions for shock, of 231 children who initially received vasoactive therapy by PIV (93 patients with septic shock), extravasation occurred in 4 patients (1.7 percent, all hand vein sites) with no long-term complications; 46 percent of these patients ultimately did not require central venous access and had full recovery [21]. These findings confirm prior data that the delivery of dilute vasoactive medications by the most proximal peripheral vein in selected children with shock is safe. The decision and timing of central venous catheter placement depends on the expected severity and trajectory of shock, as well as other clinical needs that may require central venous access. (See "Septic shock in children: Rapid recognition and initial resuscitation (first hour)", section on 'Indications for vasoactive agents'.)

Risk of meningitis in febrile young infants with a positive urinalysis (October 2022)

Existing American Academy of Pediatrics guidelines suggest that cerebrospinal fluid (CSF) studies be obtained in otherwise low-risk febrile young infants (29 to 60 days old) with elevated blood inflammatory markers (IMs) (table 2), independent of urinalysis (UA) results. However, prior studies have found that for these infants, the risk of meningitis is low. In a secondary analysis of a prospective cohort study of nearly 700 well-appearing, previously healthy, febrile young infants (29 to 60 days old) with a positive UA, none had bacterial meningitis, including the 204 individuals with elevated procalcitonin or absolute neutrophil count [22]. Based on these findings, for otherwise low-risk febrile young infants 29 to 60 days old with elevated IMs and a positive UA, we no longer suggest obtaining CSF studies. Our practice is unchanged with regard to febrile infants in this age group who have elevated IMs and a negative UA (CSF recommended) or normal IMs and a positive UA (CSF not recommended). (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on '29 to 60 days old'.)

Severe complications of button battery ingestion in children (October 2022)

Button battery (BB) ingestion with esophageal impaction in children is a true emergency that can cause life-threatening complications. In a systematic review of 361 pediatric cases of BB ingestion resulting in severe complications (95 percent with esophageal impaction), death occurred in 19 percent of patients [23]. Hemorrhage from vascular injuries, primarily aortoesophageal fistulae, was the most common cause of death. Among patients with vascular injuries, those who died had a longer duration of impaction than those who survived (median 144 versus 11 hours, respectively). These findings highlight the importance of timely recognition of BB ingestion with esophageal impaction and emergency BB removal. (See "Button and cylindrical battery ingestion: Clinical features, diagnosis, and initial management", section on 'Complications'.)

New guidance for pediatric advanced life support in patients with confirmed or suspected COVID-19 (August 2022)

The American Academy of Pediatrics (AAP) has released specific guidance for advanced life support of children with suspected or confirmed COVID-19 that supplements the previously released 2022 guidance provided by the American Heart Association [24]. Among the key changes from prior guidance, modifications to in-hospital pediatric resuscitation no longer emphasize endotracheal intubation as a priority procedure to reduce aerosol exposure during pediatric cardiopulmonary resuscitation (CPR). Other changes focus on ventilated children who arrest: They should have the advanced airway checked to ensure that it is connected, patent, and in proper position and then remain connected to a closed ventilator system with an inline high efficiency particulate air filter. If they are prone at the time of arrest, they should initially receive compressions with the hand centered over the T7 to T10 vertebral bodies and then be safely turned to the supine position to continue CPR. The AAP guidance also provides initial ventilator settings to use during pediatric CPR. (See "Pediatric advanced life support (PALS)", section on 'COVID-19 patients (suspected or confirmed)'.)

Laryngospasm during pediatric sedation outside of the operating room (August 2022)

Laryngospasm during pediatric procedural sedation is rare but serious, and a better understanding of risk factors may help guide care. In the largest study to date, which included over 275,000 sedations in children performed outside of the operating room, the unadjusted prevalence of laryngospasm was 3.3 per 1,000 cases [25]. On adjusted analysis, risk factors for laryngospasm included concurrent upper respiratory infection (odds ratio [OR] 3.9), airway procedures (OR 3.7), and, compared with propofol alone, use of propofol with ketamine (OR 2.5) or with dexmedetomidine (OR 2.1). Risks associated with ketamine and propofol as single agents were similar. These findings provide a strong rationale for appropriate airway expertise for all providers of pediatric sedation and identify important factors to consider when determining sedation regimens for children. (See "Procedural sedation in children outside of the operating room", section on 'Adverse outcomes'.)

Noninvasive respiratory support for acutely ill infants and young children (June 2022)

The best approach to noninvasive respiratory support (high-flow nasal cannula oxygen therapy [HFNC] or continuous positive airway pressure [CPAP]) in critically ill infants and children is unclear. A recent unblinded, randomized, multicenter trial compared HFNC with CPAP in more than 570 critically ill infants and children (approximately 50 percent with bronchiolitis; 20 to 25 percent with asthma or other respiratory illness; and others with illnesses such as sepsis) [26]. The duration of noninvasive respiratory support and the proportion requiring endotracheal intubation were similar in both groups. Patients assigned to HFNC required less sedation and had a shorter duration of critical care and hospitalization. These findings suggest that HFNC is at least as good as CPAP for noninvasive support of critically ill children and may provide better patient comfort. (See "High-flow nasal cannula oxygen therapy in children", section on 'Comparison with other modes of oxygen delivery' and "Bronchiolitis in infants and children: Treatment, outcome, and prevention", section on 'HFNC and CPAP'.)


Completely automated insulin delivery systems for type 1 diabetes (October 2022)

For patients with type 1 diabetes (T1D), completely automated insulin delivery systems promise enhanced glycemic management without the substantial time and training required for use of partially automated systems. In a 13-week unblinded trial in which 219 patients with T1D (ages 6 to 79 years, A1C 5.5 to 13.1 percent) were randomly assigned to a fully automated insulin delivery system or standard care (any mode of insulin delivery coupled with continuous glucose monitoring), the fully automated system led to a greater reduction in A1C (mean adjusted difference in A1C -0.5 percent) [27]. Participants assigned to fully automated insulin delivery also had a higher percentage of time spent in the target glucose range without increased frequency of hypoglycemia. Completely automated insulin delivery systems may enable expanded use of continuous insulin therapy among patients with T1D. (See "Insulin therapy for children and adolescents with type 1 diabetes mellitus", section on 'Closed-loop insulin pumps' and "Continuous subcutaneous insulin infusion (insulin pump)", section on 'Insulin-only, completely automated system (bionic pancreas)'.)

Open-source automated insulin delivery systems in type 1 diabetes (September 2022)

The use of do-it-yourself automated insulin delivery (AID) systems is increasingly common among individuals with type 1 diabetes, but evidence regarding the effectiveness and safety of these systems has been limited. In a 24-week trial in 97 patients (48 children and 49 adults) on insulin pump therapy for type 1 diabetes, an open-source AID system conferred greater improvement in percentage of time spent in target glucose range than sensor-augmented insulin pump therapy (adjusted difference 14 percentage points) [28]. These findings support the potential utility of open-source AID algorithms for selected individuals with type 1 diabetes who are willing to invest in learning these systems. (See "Continuous subcutaneous insulin infusion (insulin pump)", section on 'Do-it-yourself automated insulin delivery systems'.)

Dulaglutide for type 2 diabetes in adolescents (September 2022)

Adolescents with type 2 diabetes (T2D) who do not achieve glycemic control with lifestyle intervention and metformin monotherapy may require combination pharmacotherapy with insulin; disadvantages of insulin therapy include weight gain, need for frequent monitoring/dose adjustment, and risk of hypoglycemia. In a recent randomized trial of 154 adolescents with T2D that evaluated dulaglutide, an extended-release glucose-like peptide agonist (GLP-1), as an adjunct to lifestyle measures with or without standard pharmacologic intervention, patients assigned to dulaglutide had significantly better glycemic control compared with placebo at 26 weeks (estimated treatment difference for change in A1C from baseline -1.4 percentage points, 95% CI -1.9 to -0.8) with no significant effect on body mass index [29]. More patients receiving dulaglutide had gastrointestinal side effects. These findings are similar to results from previous small trials in adolescents using other GLP-1 agonists, and, along with indirect evidence in adults, support our suggestion for GLP-1 agonists in adolescents who do not achieve glycemic targets with metformin alone or combined with basal insulin. (See "Management of type 2 diabetes mellitus in children and adolescents", section on 'Trials of GLP-1 agonists'.)


COVID-19 vaccination in patients with inflammatory bowel disease (July 2022)

Data on the immunogenicity of COVID-19 vaccines in patients with inflammatory bowel disease (IBD) are accumulating. In a meta-analysis of 31 studies including nearly 9500 patients with IBD who completed a COVID-19 vaccination series, the pooled seroconversion rate was 96 percent [30]. Seroconversion rates were not significantly different by drug therapy (ie, biologics, small molecules, immunomodulators, and/or glucocorticoids). In most studies that reported durability of serologic response, antibody titers began declining four weeks after vaccination. These data provide some reassurance for patients on immunosuppressive medications and lend support for additional vaccine doses in patients with IBD. (See "COVID-19: Issues related to gastrointestinal disease in adults", section on 'COVID-19 vaccination'.)

Mild direct hyperbilirubinemia in newborns and later development of biliary atresia (June 2022)

Biliary atresia (BA) usually comes to medical attention after the first few weeks of life, when a young infant presents with jaundice and conjugated hyperbilirubinemia, defined as conjugated or direct bilirubin ≥1 mg/dL (17.1 micromol/L). In a new study of 346 infants who had direct bilirubin measured within the first three days of life, direct bilirubin >0.45 mg/dL (7.7 micromol/L) was a predictor of later diagnosis of BA (sensitivity 100 percent, specificity 15.4 percent), although confidence intervals were wide [31]. These findings suggest that mild elevations of serum conjugated or direct bilirubin in neonates may be predictors of later development of BA; such infants should be monitored and evaluated further to permit early diagnosis of BA. (See "Biliary atresia", section on 'Laboratory studies'.)

Outbreak of acute hepatitis in young children (June 2022)

In early 2022, an outbreak of acute hepatitis was identified among young children in several countries, including the United States. Preliminary analysis suggested a possible link with adenovirus type 41. However, analysis of data from four large administrative databases in the United States through March 2022 showed no overall increase in hospitalizations for hepatitis of unknown cause compared to before the COVID-19 pandemic and no increase in adenovirus types 40/41 positivity [32]. Thus, it is unclear whether the reported cases in the United States represent a novel cause of acute hepatitis or a previously existing phenomenon, and whether there is a relationship with adenovirus infection. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on 'Diarrheal illness'.)


Risk of progression to dementia in Down syndrome (October 2022)

Down syndrome (DS) is now considered a genetically determined form of Alzheimer disease (AD), with an estimated age of onset (53.8 years) and age of death (58.4 years) similar to that seen in autosomal dominant AD [33]. In one series of 632 adults with DS and varying levels of cognitive disability (436 asymptomatic, 69 with prodromal AD, and 127 with AD dementia) followed for five years, progression to AD dementia was seen in 17.1 percent of asymptomatic patients and was age dependent (0.6 percent for age <40 years, 21.1 percent for 40 to 44 years, 41.4 for 45 to 49 years, and 57.5 for ≥50 years) [34]. Patients with DS should be monitored closely for cognitive decline, particularly after age 40 years. (See "Down syndrome: Management", section on 'Alzheimer disease'.)

Gene therapy for mucopolysaccharidosis type VI (September 2022)

Current management of the various forms of mucopolysaccharidosis (MPS) involves enzyme replacement therapy (ERT), but this approach is costly, requires lifelong infusions, and has limited efficacy on skeletal, cardiac, pulmonary, and ophthalmologic complications. In a phase-I/II open-label study of ex vivo gene therapy for MPS VI, nine patients >4 years of age were sequentially enrolled to receive autologous hematopoietic cell transplantation with cells transduced with one of three doses (low, intermediate, and high) of an adenovirus vector expressing arylsulfatase B (ARSB) [35]. Over the two-year study period, patients in the high-dose group had sustained serum levels of ARSB that were sufficient to blunt accumulation of glycosaminoglycans such that resumption of ERT was not required, and no clinical deterioration was noted. Low- and intermediate-dose gene therapy was less efficacious. No serious adverse events attributable to therapy were reported. Additional studies are needed before this becomes a standard therapeutic option for MPS. (See "Mucopolysaccharidoses: Treatment", section on 'Stem cell gene therapy using viral vectors'.)

Racial disparities in genetic testing (July 2022)

Racial disparities exist across the spectrum of medical care. A new series of vignettes illustrates how racial disparities can interfere with timely diagnosis of genetic conditions [36]. Reasons for a delay in diagnoses may be due to provider factors (lack of familiarity with presentations in individuals with non-European backgrounds, implicit or explicit racial bias), health care system issues (lack of health care access, bias in genetic testing panel components), and patient factors (lack of trust). Suggestions for improvement are provided. (See "Genetic testing", section on 'Racial disparities'.)


Preoperative chemotherapy in bilateral Wilms tumor (November 2022)

Studies are investigating the strategy of preoperative chemotherapy followed by kidney parenchymal-sparing resection for patients with bilateral Wilms tumor. In long-term follow-up of a single arm, prospective study in almost 200 patients with bilateral Wilms tumor, this strategy was associated with a four-year overall survival rate of 95 percent [37]. It was greater for those with low-risk disease, intermediate-risk disease, and blastemal-type tumors than for those with high-risk diffuse anaplasia (>90 versus 72 percent). Fewer than 3 percent of patients required bilateral nephrectomy. For patients with bilateral Wilms tumor, we continue to suggest preoperative chemotherapy followed by kidney parenchymal-sparing resection rather than more extensive bilateral kidney resection. (See "Treatment and prognosis of Wilms tumor", section on 'Bilateral kidney involvement'.)

Frequency of transfusion reactions in children and adults (August 2022)

Transfusion reactions range from bothersome to life threatening. A new meta-analysis of >1.3 million transfusion reactions has documented a nearly twofold higher frequency of acute transfusion reactions in children than in adults [38]. Children were more likely than adults to have reactions to red blood cells and platelets, but not to plasma. Allergic and febrile nonhemolytic transfusion reactions were most common. The only type of reactions seen more frequently in adults were delayed hemolytic and delayed serologic reactions. Early signs and symptoms may not distinguish between benign and more serious events, and all acute transfusion reactions must be considered potentially serious until fully evaluated. (See "Approach to the patient with a suspected acute transfusion reaction", section on 'Frequency of reactions'.)


Increasing invasive group A streptococcal infections among children in Europe (December 2022)

Several European countries, including England, France, Ireland, the Netherlands, and Sweden, have reported an increased rate of invasive group A streptococcal (GAS) infections among children <10 years old during the fall and winter of 2022 compared with prior years [39,40]. This increase parallels a >3-fold rise in reported cases of scarlet fever and may reflect an early GAS season coinciding with an increase in circulating respiratory viruses. No increase in antibiotic resistance has been observed among isolated GAS strains. Enhanced surveillance activities have been implemented in the affected areas and public health organizations are emphasizing the importance of early recognition of GAS infections, particularly scarlet fever, and prompt treatment. (See "Invasive group A streptococcal infections in children", section on 'Incidence'.)

Palivizumab for prevention of hospitalization during the 2022-2023 RSV season (November 2022)

During the COVID-19 pandemic, interseasonal respiratory syncytial virus (RSV) activity increased in some regions, resulting in increased pediatric hospitalizations. In regions with interseasonal activity similar to that in a typical fall-winter season, expert groups supported administration of palivizumab to eligible children outside of the typically recommended schedule. If regional RSV activity persists at high levels through the fall and winter of the 2022-2023 RSV season, the American Academy of Pediatrics supports administration of more than five consecutive doses of palivizumab to eligible children who initiated palivizumab earlier than typically recommended [41]. Information about state-level RSV activity in the United States is available from the Centers for Disease Control and Prevention. We agree with this endorsement. (See "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Increased interseasonal activity during COVID-19 pandemic'.)

Expanded ACIP recommendations for oral cholera vaccine (October 2022)

CVD 103-HgR (Vaxchora) is a single-dose, live attenuated oral cholera vaccine derived from Vibrio cholerae serotype O1; it was licensed by the US Food and Drug Administration and recommended by the Advisory Committee on Immunization Practices (ACIP) in 2016 for adults age 18 to 64 years traveling to areas of active cholera transmission. In 2022, the ACIP expanded the age group to include individuals age 2 to 17 years who meet these criteria [42]. Thus far, assessment of CVD 103-HgR vaccine benefit in children has been based on safety and immunogenicity data rather than direct assessment of vaccine efficacy. We are in agreement with this guidance. (See "Cholera: Clinical features, diagnosis, treatment, and prevention", section on 'For travelers to high-risk areas'.)

Updated recommendations for pneumococcal vaccination in children and adolescents (September 2022)

Updated guidance from the Advisory Committee on Immunization Practices (ACIP) permits interchangeable use of the recently licensed 15-valent pneumococcal conjugate vaccine (PCV15) and 13-valent PCV (PCV13) for routine infant immunization and immunization of high-risk children and adolescents (table 3) [43]. PCV15 contains the 13 serotypes included in PCV13 plus serotypes 22F and 33F (table 4), which accounted for 15 to 23 percent of invasive pneumococcal disease cases in children <18 years in the United States during 2018 to 2019. In prelicensure randomized trials, PCV15 demonstrated immunogenicity and safety similar to those of PCV13. We agree with the ACIP recommendations for PCV15. Clinical trials of the 20-valent PCV in children are ongoing. (See "Pneumococcal vaccination in children", section on 'Conjugate vaccines'.)

New ACIP recommendations for seasonal influenza vaccination (September 2022)

In August 2022, the Advisory Committee on Immunization Practices (ACIP) issued new recommendations for seasonal influenza vaccination in the United States [44]. The ACIP now recommends that adults aged ≥65 years preferentially receive any one of the following higher dose or adjuvanted influenza vaccines: quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), quadrivalent recombinant influenza vaccine (RIV4), or quadrivalent adjuvanted inactivated influenza vaccine (aIIV4) (table 5). In addition, the approved age indication for the cell culture–based inactivated influenza vaccine has been changed from ≥2 years to ≥6 months. We are in agreement with this guidance. (See "Seasonal influenza vaccination in adults", section on 'Choice of vaccine formulation' and "Seasonal influenza in children: Prevention with vaccines", section on 'Influenza vaccines'.)


Initial target for parenteral protein intake in extremely low birthweight infants (December 2022)

Recommended targets for parenteral amino acid (AA) intake in premature infants are between 2.5 and 3.5 g/kg/day, but the optimal target for extremely low birthweight infants (ELBW, birthweight <1000 g) is unknown. A new randomized trial in nearly 500 ELBW infants compared outcomes for infants with high (AA 3.4 g/kg/day) versus low intake (AA 2.6 g/kg/day) for the first five days of life [45]. At two years of age, the infants who received the higher AA dose were more likely to have moderate to severe neurodisability compared with those who received lower doses (16.5 versus 8.6 percent; adjusted relative risk [aRR] 1.95, 95% CI 1.09-3.48). There were no differences in mild neurodevelopmental impairment or in most other components of the Bayley III. These results are the basis for our suggested target of 2.5 g/kg/day of AA in parenteral nutrition for ELBW infants during the first week of life. (See "Parenteral nutrition in premature infants", section on 'Amino acids'.)

DHA supplementation for very low birth weight infants (November 2022)

The long-term effect of enteral supplementation with docosahexaenoic acid (DHA) on cognitive outcomes in low birth weight premature infants has been inconsistent. In a continuation of an earlier trial in 480 premature infants <29 weeks gestation assigned to DHA (60 mg/kg per day) or placebo at the initiation of enteral feeding, scores for full-scale intelligence quotient (IQ) at five years of corrected age were higher for the DHA-supplemented group (mean difference 3.5 points [95% CI 0.4-6.5], a 4-point difference is clinically relevant) [46]. Based on these findings and benefits identified for other comorbidities of prematurity in other studies, we suggest that premature infants receiving human milk also receive supplementation with DHA. Our approach is to add a human milk fortifier that contains these nutrients to breast milk. (See "Long-chain polyunsaturated fatty acids (LCPUFA) for preterm and term infants", section on 'Very low birth weight infants'.)

Updated guidance on neonatal hyperbilirubinemia (October 2022)

The American Academy of Pediatrics (AAP) has updated its clinical practice guidance on management of hyperbilirubinemia in term and late preterm newborns ≥35 weeks of gestation [47]. Key changes from earlier guidelines include:

Initial newborn screening can be performed either with a laboratory test (ie, total serum bilirubin [TSB]) or transcutaneous bilirubin (TcB) device; abnormal TcB results require confirmation with TSB

Guidance for follow-up after newborn bilirubin screening has been updated (table 6)

Higher treatment TSB thresholds are used for initiating phototherapy (figure 1A-B) and exchange transfusion (figure 2A-B)

New guidance is provided for "escalation of care" to rapidly address dangerously high bilirubin concentrations (algorithm 1)

We generally agree with the updated AAP guidance. Importantly, since the new treatment thresholds are higher than in previous guidelines, delays in starting phototherapy are more likely to result in dangerously high TSB levels. Thus, when treatment is indicated, it should begin promptly. (See "Screening for hyperbilirubinemia in term and late preterm newborn infants" and "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns" and "Escalation of care for term and late preterm newborns with unconjugated hyperbilirubinemia".)

Antenatal corticosteroids for anticipated preterm birth before 23 weeks (October 2022)

The value of antenatal corticosteroids (ACS) in pregnancies between 21 and 23 weeks of gestation is controversial. In an observational cohort study including over 400 infants born at 220/7 to 236/7 weeks of gestation, administration of a complete course of ACS was associated with higher survival to discharge compared with no ACS (54 versus 36 percent); however, most survivors had major morbidity when evaluated at 36 weeks postmenstrual age (survival without major morbidity: 27 percent with ACS, 10 percent without ACS) [48]. Shared decision-making (parents, obstetrical and neonatal staff) is particularly important at this gestational age when parents are faced with a decision affecting their child's survival and quality of life. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on '22+0 to 22+6 weeks'.)


Gene therapy for early childhood cerebral adrenoleukodystrophy (November 2022)

Standard treatment for the early childhood cerebral form of adrenoleukodystrophy (ALD), caused by pathogenic variants in the ABCD1 gene, is allogenic hematopoietic cell transplantation (HCT), if the child has a human leukocyte antigen (HLA)-matched donor. Recently, the US Food and Drug Administration (FDA) approved elivaldogene autotemcel, a novel ex vivo lentiviral gene therapy consisting of autologous HCT using stem cells transfected with manufactured ABCD1 complementary DNA [49]. The approval was based upon published and unpublished data showing that survival at nine months following treatment appeared to be better in patients treated with either HLA-matched allogenic HCT or elivaldogene autotemcel compared with HLA-mismatched allogenic HCT [50]. No patient treated with elivaldogene autotemcel developed graft-versus-host disease, which can complicate allogenic HCT. These results suggest that elivaldogene autotemcel may have comparable efficacy for early cerebral ALD compared with allogeneic HCT and may be safer, particularly when compared with HLA-mismatched allogenic HCT. However, given the relatively short follow-up, the results should be regarded as preliminary. The FDA label carries a boxed warning about the risk of hematologic malignancy and life-threatening myelodysplastic syndrome. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy", section on 'Autologous HCT with ex vivo gene therapy'.)

Mechanisms causing disability accrual in multiple sclerosis (October 2022)

An analysis of the large Novartis-Oxford multiple sclerosis data set evaluated the two main mechanisms leading to accrual of disability in multiple sclerosis (MS), which are relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) [51]. The study found that RAW contributed to disability progression primarily in the early stages of MS. PIRA was also present early in the course of all MS phenotypes (relapsing and progressive) and became the main driver of disability in the later stages. Early use of disease-modifying therapy (DMT) delayed disability progression by several years. These findings help to clarify the relative contributions of RAW and PIRA to disability accrual in MS and support the importance of starting DMT early in the course of MS. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Relapsing versus progressive disease'.)

Visual and vestibular assessments in children with concussion (August 2022)

The American Academy of Pediatrics has released a new policy that highlights vision symptoms in children and adolescents with concussion [52]. The policy provides guidance on the components of a complete evaluation of the visual system after concussion (movie 1 and table 7). It also reviews the importance of identifying visual and vestibular deficits during assessment of concussion to confirm the diagnosis and to identify patients at risk for prolonged symptoms who may benefit from specific academic adjustments or specialist referral. (See "Concussion in children and adolescents: Clinical manifestations and diagnosis", section on 'Physical examination'.)


Management of pediatric torus (buckle) fractures of the wrist (July 2022)

Torus fractures of the wrist are stable compression fractures that are located at the distal metaphysis or the radius or ulna, where the bone is most porous (image 1); treatment is aimed at pain relief and comfort. Immobilization with a splint is the typical approach. In a large multicenter randomized trial (nearly 1000 children 4 to 15 years old), pain at three days was similar for patients assigned to a soft elastic bandage versus splint immobilization and remained equivalent through 42 days of follow-up [53]. Functional recovery was also similar in the two groups. However, 11 percent of children assigned to a soft bandage returned to receive splint immobilization because of pain. Based upon these findings, either a soft elastic bandage or a short-arm splint provides adequate treatment for torus fractures, and the choice of treatment should be in accordance with patient/caregiver preference. Regardless of chosen treatment, clear instructions on pain management are required. (See "Distal forearm fractures in children: Initial management", section on 'Torus (buckle) fracture'.)

  1. Bushnell GA, Gerhard T, Keyes K, et al. Association of Benzodiazepine Treatment for Sleep Disorders With Drug Overdose Risk Among Young People. JAMA Netw Open 2022; 5:e2243215.
  2. US Preventive Services Task Force, Mangione CM, Barry MJ, et al. Screening for Anxiety in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. JAMA 2022; 328:1438.
  3. Viswanathan M, Wallace IF, Cook Middleton J, et al. Screening for Anxiety in Children and Adolescents: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2022; 328:1445.
  4. Weghuber D, Barrett T, Barrientos-Pérez M, et al. Once-Weekly Semaglutide in Adolescents with Obesity. N Engl J Med 2022; 387:2245.
  5. Harlow AF, Vogel EA, Tackett AP, et al. Adolescent Use of Flavored Non-Tobacco Oral Nicotine Products. Pediatrics 2022; 150.
  6. US Food and Drug Administration news release: FDA Warns Manufacturer for Marketing Illegal Flavored Nicotine Gummies (8/18/22). Available at: (Accessed on September 30, 2022).
  7. US Food and Drug Administration: Regulation and enforcement of non-tobacco nicotine (NTN) products. Available at: (Accessed on September 30, 2022).
  8. Laskey A, Haney S, Northrop S, COUNCIL ON CHILD ABUSE AND NEGLECT. Protecting Children From Sexual Abuse by Health Care Professionals and in the Health Care Setting. Pediatrics 2022; 150.
  9. Rhee KE, Herrera L, Strong D, et al. Guided Self-Help for Pediatric Obesity in Primary Care: A Randomized Clinical Trial. Pediatrics 2022; 150.
  10. Mitchell EO, Jones P, Snelling PJ. Ultrasound for Pediatric Peripheral Intravenous Catheter Insertion: A Systematic Review. Pediatrics 2022; 149.
  11. Andrews AL, Killings X, Oddo ER, et al. Pediatric Firearm Injury Mortality Epidemiology. Pediatrics 2022; 149.
  12. Lee LK, Douglas K, Hemenway D. Crossing Lines - A Change in the Leading Cause of Death among U.S. Children. N Engl J Med 2022; 386:1485.
  13. Goldstick JE, Cunningham RM, Carter PM. Current Causes of Death in Children and Adolescents in the United States. N Engl J Med 2022; 386:1955.
  14. Kozycki CT, Kodati S, Huryn L, et al. Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome. Ann Rheum Dis 2022; 81:1453.
  15. Switkowski KM, Oken E, Rifas-Shiman SL, et al. Timing of Cow's Milk Protein Introduction and Childhood Adverse Reactions to Cow's Milk. J Allergy Clin Immunol Pract 2022; 10:2713.
  16. Chou CC, Morphew T, Ehwerhemuepha L, Galant SP. COVID-19 infection may trigger poor asthma control in children. J Allergy Clin Immunol Pract 2022; 10:1913.
  17. Yepes-Nuñez JJ, Guyatt GH, Gómez-Escobar LG, et al. Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms. J Allergy Clin Immunol 2022.
  18. Sanyahumbi A, Ali S, Benjamin IJ, et al. Penicillin Reactions in Patients With Severe Rheumatic Heart Disease: A Presidential Advisory From the American Heart Association. J Am Heart Assoc 2022; 11:e024517.
  19. Xia E, Han J, Faletsky A, et al. Isotretinoin Laboratory Monitoring in Acne Treatment: A Delphi Consensus Study. JAMA Dermatol 2022; 158:942.
  20. FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs. US Food & Drug Administration. (Accessed on November 10, 2022).
  21. Levy RA, Reiter PD, Spear M, et al. Peripheral Vasoactive Administration in Critically Ill Children With Shock: A Single-Center Retrospective Cohort Study. Pediatr Crit Care Med 2022; 23:618.
  22. Mahajan P, VanBuren JM, Tzimenatos L, et al. Serious Bacterial Infections in Young Febrile Infants With Positive Urinalysis Results. Pediatrics 2022; 150.
  23. Akinkugbe O, James AL, Ostrow O, et al. Vascular Complications in Children Following Button Battery Ingestions: A Systematic Review. Pediatrics 2022; 150.
  24. Morgan RW, Atkins DL, Hsu A, et al. Guidance for Cardiopulmonary Resuscitation of Children With Suspected or Confirmed COVID-19. Pediatrics 2022; 150.
  25. Cosgrove P, Krauss BS, Cravero JP, Fleegler EW. Predictors of Laryngospasm During 276,832 Episodes of Pediatric Procedural Sedation. Ann Emerg Med 2022; 80:485.
  26. Ramnarayan P, Richards-Belle A, Drikite L, et al. Effect of High-Flow Nasal Cannula Therapy vs Continuous Positive Airway Pressure Therapy on Liberation From Respiratory Support in Acutely Ill Children Admitted to Pediatric Critical Care Units: A Randomized Clinical Trial. JAMA 2022; 328:162.
  27. Bionic Pancreas Research Group, Russell SJ, Beck RW, et al. Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes. N Engl J Med 2022; 387:1161.
  28. Burnside MJ, Lewis DM, Crocket HR, et al. Open-Source Automated Insulin Delivery in Type 1 Diabetes. N Engl J Med 2022; 387:869.
  29. Arslanian SA, Hannon T, Zeitler P, et al. Once-Weekly Dulaglutide for the Treatment of Youths with Type 2 Diabetes. N Engl J Med 2022; 387:433.
  30. Jena A, James D, Singh AK, et al. Effectiveness and Durability of COVID-19 Vaccination in 9447 Patients With IBD: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2022; 20:1456.
  31. Liao FM, Chang KC, Wu JF, et al. Direct Bilirubin and Risk of Biliary Atresia. Pediatrics 2022; 149.
  32. Kambhampati AK, Burke RM, Dietz S, et al. Trends in Acute Hepatitis of Unspecified Etiology and Adenovirus Stool Testing Results in Children - United States, 2017-2022. MMWR Morb Mortal Wkly Rep 2022; 71:797.
  33. Iulita MF, Garzón Chavez D, Klitgaard Christensen M, et al. Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome. JAMA Netw Open 2022; 5:e2212910.
  34. Videla L, Benejam B, Pegueroles J, et al. Longitudinal Clinical and Cognitive Changes Along the Alzheimer Disease Continuum in Down Syndrome. JAMA Netw Open 2022; 5:e2225573.
  35. Brunetti-Pierri N, Ferla R, Ginocchio VM, et al. Liver-directed adeno-associated virus–mediated gene therapy for mucopolysaccharidosis type VI. NEJM Evid 2022; 1.
  36. Omorodion J, Dowsett L, Clark RD, et al. Delayed diagnosis and racial bias in children with genetic conditions. Am J Med Genet A 2022; 188:1118.
  37. Chintagumpala MM, Perlman EJ, Tornwall B, et al. Outcomes based on histopathologic response to preoperative chemotherapy in children with bilateral Wilms tumor: A prospective study (COG AREN0534). Cancer 2022; 128:2493.
  38. Wang Y, Sun W, Wang X, et al. Comparison of transfusion reactions in children and adults: A systematic review and meta-analysis. Pediatr Blood Cancer 2022; 69:e29842.
  39. World Health Organization disease outbreak news: Increased incidence of scarlet fever and invasive Group A Streptococcus infection - multi-country, available at: (Accessed on December 19, 2022).
  40. United Kingdom Health Security Agency: Group A streptococcal infections: report on seasonal activity in England, 2022 to 2023, available at: (Accessed on December 19, 2022).
  41. American Academy of Pediatrics. Updated guidance: Use of palivizumab prophylaxis to prevent hospitalization from severe respiratory syncytial virus infection during the 2022-2023 RSV season. (Accessed on November 18, 2022).
  42. Collins JP, Ryan ET, Wong KK, et al. Cholera Vaccine: Recommendations of the Advisory Committee on Immunization Practices, 2022. MMWR Recomm Rep 2022; 71:1.
  43. Kobayashi M, Farrar JL, Gierke R, et al. Use of 15-Valent Pneumococcal Conjugate Vaccine Among U.S. Children: Updated Recommendations of the Advisory Committee on Immunization Practices - United States, 2022. MMWR Morb Mortal Wkly Rep 2022; 71:1174.
  44. Grohskopf LA, Blanton LH, Ferdinands JM, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022-23 Influenza Season. MMWR Recomm Rep 2022; 71:1.
  45. Bloomfield FH, Jiang Y, Harding JE, et al. Early Amino Acids in Extremely Preterm Infants and Neurodisability at 2 Years. N Engl J Med 2022; 387:1661.
  46. Gould JF, Makrides M, Gibson RA, et al. Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years. N Engl J Med 2022; 387:1579.
  47. Kemper AR, Newman TB, Slaughter JL, et al. Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics 2022; 150.
  48. Chawla S, Wyckoff MH, Rysavy MA, et al. Association of Antenatal Steroid Exposure at 21 to 22 Weeks of Gestation With Neonatal Survival and Survival Without Morbidities. JAMA Netw Open 2022; 5:e2233331.
  49. FDA Roundup: September 20, 2022. Available at: (Accessed on September 22, 2022).
  50. Skysona (elivaldogene autotemcel) prescribing information. Available at: (Accessed on September 22, 2022).
  51. Lublin FD, Häring DA, Ganjgahi H, et al. How patients with multiple sclerosis acquire disability. Brain 2022; 145:3147.
  52. Master CL, Bacal D, Grady MF, et al. Vision and Concussion: Symptoms, Signs, Evaluation, and Treatment. Pediatrics 2022; 150.
  53. Perry DC, Achten J, Knight R, et al. Immobilisation of torus fractures of the wrist in children (FORCE): a randomised controlled equivalence trial in the UK. Lancet 2022; 400:39.
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