Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age.

BACKGROUND: Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 µg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported. RESULTS: In part 1 of the trial, 751 children received 50-µg or 100-µg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-µg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 µg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-µg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-µg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant. CONCLUSIONS: Two 50-µg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Evaluation of mRNA-1273 Vaccine in Children 6 Months to 5 Years of Age.

BACKGROUND: The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-µg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these children was noninferior to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives were to determine the incidences of Covid-19 and severe acute respiratory syndrome coronavirus 2 infection after administration of mRNA-1273 or placebo. RESULTS: On the basis of safety and immunogenicity results in part 1 of the trial, the 25-µg dose was evaluated in part 2. In part 2, 3040 children 2 to 5 years of age and 1762 children 6 to 23 months of age were randomly assigned to receive two 25-µg injections of mRNA-1273; 1008 children 2 to 5 years of age and 593 children 6 to 23 months of age were randomly assigned to receive placebo. The median duration of follow-up after the second injection was 71 days in the 2-to-5-year-old cohort and 68 days in the 6-to-23-month-old cohort. Adverse events were mainly low-grade and transient, and no new safety concerns were identified. At day 57, neutralizing antibody geometric mean concentrations were 1410 (95% confidence interval [CI], 1272 to 1563) among 2-to-5-year-olds and 1781 (95% CI, 1616 to 1962) among 6-to-23-month-olds, as compared with 1391 (95% CI, 1263 to 1531) among young adults, who had received 100-µg injections of mRNA-1273, findings that met the noninferiority criteria for immune responses for both age cohorts. The estimated vaccine efficacy against Covid-19 was 36.8% (95% CI, 12.5 to 54.0) among 2-to-5-year-olds and 50.6% (95% CI, 21.4 to 68.6) among 6-to-23-month-olds, at a time when B.1.1.529 (omicron) was the predominant circulating variant. CONCLUSIONS: Two 25-µg doses of the mRNA-1273 vaccine were found to be safe in children 6 months to 5 years of age and elicited immune responses that were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study.

INTRODUCTION: The EMBRACE study (Clinical Trials No. NCT02462759) evaluated nusinersen in infants/children with infantile- or later-onset spinal muscular atrophy (SMA) who were ineligible for the ENDEAR and CHERISH studies. METHODS: Participants were randomized to intrathecal nusinersen (12-mg scaled equivalent dose; n = 14) or sham procedure (n = 7) in part 1 (~14 months) and subsequently received open-label nusinersen for ~24 months in part 2 of the study. RESULTS: Part 1 was stopped early after the demonstration of motor function benefit with nusinersen in ENDEAR. There were no nusinersen-related adverse events (AEs) and no study discontinuations due to nusinersen-related AEs. The most common AEs included pyrexia, cough, pneumonia, and upper respiratory tract infections. Motor milestone responder rates were higher in those receiving nusinersen at last available assessment (93%) than in those receiving sham procedure in part 1 (29%) or transitioned from sham to nusinersen in part 2 (83%). This functional improvement was observed despite the small sample size and shortened part 1 trial duration that undermined the power of the study to demonstrate such treatment effects at a significant level. DISCUSSION: Nusinersen demonstrated a favorable long-term benefit-risk profile in this broad population of individuals with infantile- or later-onset SMA.

Bedside ultrasound in the diagnosis of skull fractures in the pediatric emergency department.

Bedside ultrasound has become a diagnostic tool that is commonly used in the emergency department. In trained hands, it can be used to diagnose multiple pathologies. In this case series, we describe the utility of ultrasound in diagnosing skull fractures in pediatric patients with scalp hematomas.

Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study.

BACKGROUND: Nusinersen showed a favourable benefit-risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of nusinersen over 3 years. METHODS: This phase 2, open-label, multicentre, dose-escalation study was done in three university hospital sites in the USA and one in Canada. Infants aged between 3 weeks and 6 months with two or three SMN2 gene copies and infantile-onset spinal muscular atrophy were eligible for inclusion. Eligible participants received multiple intrathecal loading doses of 6 mg equivalent nusinersen (cohort 1) or 12 mg dose equivalent (cohort 2), followed by maintenance doses of 12 mg equivalent nusinersen. The protocol amendment on Jan 25, 2016, changed the primary efficacy endpoint from safety and tolerability to reaching motor milestones, assessed using the Hammersmith Infant Neurological Examination section 2 (HINE-2) at the last study visit, in all participants who successfully completed the loading dose period and day 92 assessment. The statistical analysis plan was amended on Feb 10, 2016, to include additional analyses of the subgroup of participants with two SMN2 copies. Adverse events were assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov (NCT01839656). FINDINGS: Between May 3, 2013, and July 9, 2014, 20 symptomatic participants with infantile-onset spinal muscular atrophy (12 boys and 8 girls; median age at diagnosis 78 days [range 0-154]) were enrolled. Median time on study was 36·2 months (IQR 20·6-41·3). The primary endpoint of an incremental improvement in HINE-2 developmental motor milestones was reached by 12 (63%) of 19 evaluable participants. In the 13 participants with two SMN2 copies treated with 12 mg nusinersen, the HINE-2 motor milestone total score increased steadily from a baseline mean of 1·46 (SD 0·52) to 11·86 (6·18) at day 1135, representing a clinically significant change of 10·43 (6·05). At study closure (Aug 21, 2017), 15 (75%) of 20 participants were alive. 101 serious adverse events were reported in 16 (80%) of 20 participants; all five deaths (one in cohort 1 and four in cohort 2) were likely to be related to spinal muscular atrophy disease progression. INTERPRETATION: Our findings are consistent with other trials of nusinersen and show improved survival and attainment of motor milestones over 3 years in patients with infantile-onset spinal muscular atrophy, with a favourable safety profile. FUNDING: Biogen and Ionis Pharmaceuticals.

Point-of-care ultrasound diagnosis of pediatric cholecystitis in the ED.

OBJECTIVE: The diagnosis of cholecystitis or biliary tract disease in children and adolescents is an uncommon occurrence in the emergency department and other acute care settings. Misdiagnosis and delays in diagnosing children with cholecystitis or biliary tract disease of up to months and years have been reported in the literature. We discuss the technique and potential utility of point-of-care ultrasound evaluation in a series of pediatric patients with suspected cholecystitis or biliary tract disease. METHODS: We present a nonconsecutive case series of pediatric and adolescent patients with abdominal pain diagnosed with cholecystitis or biliary tract disease using point-of-care ultrasound. The published sonographic criteria is 3 mm or less for the upper limits of normal gallbladder wall thickness and is 3 mm or less for normal common bile duct diameter (measured from inner wall to inner wall) in children. Measurements above these limits were considered abnormal, in addition to the sonographic presence of gallstones, pericholecystic fluid, and a sonographic Murphy's sign. RESULTS: Point-of care ultrasound screening detected 13 female pediatric patients with cholecystitis or biliary tract disease when the authors were on duty over a 5-year period. Diagnoses were confirmed by radiology imaging or at surgery and surgical pathology. CONCLUSIONS: Point-of-care ultrasound to detect pediatric cholecystitis or biliary tract disease may help avoid misdiagnosis or delays in diagnosis in children with abdominal pain.

Effect of bedside ultrasound on management of pediatric soft-tissue infection.

BACKGROUND: Superficial soft-tissue infections (SSTI) are frequently managed in the emergency department (ED). Soft-tissue bedside ultrasound (BUS) for SSTI has not been specifically studied in the pediatric ED setting. OBJECTIVE: To evaluate the effect of a soft-tissue BUS evaluation on the clinical diagnosis and management of pediatric superficial soft-tissue infection. METHODS: We conducted a prospective observational study in two urban academic pediatric EDs. Eligible patients were aged < 18 years presenting with suspected SSTI. Before BUS, treating physicians were asked to assess the likelihood of subcutaneous fluid collection and whether further treatment would require medical management or invasive management. A trained emergency physician then performed a BUS of the lesion(s). A post-test questionnaire assessed whether the physician changed the initial management plan based on the results of the BUS. RESULTS: BUS changed management in 11/50 cases. After initial clinical assessment, 20 patients were designated to receive invasive management, whereas the remaining 30 patients were designated to receive medical management. Management changed in 6/20 in the invasive group. In the medical group, 5/30 patients changed management. BUS had a sensitivity of 90% (95% confidence interval [CI] 77-100%) and specificity of 83% (05% CI 70-97%), whereas clinical suspicion had a sensitivity of 75% (95% CI 56-94%) and specificity of 80% (95% CI 66-94%) in detecting fluid collections requiring drainage. CONCLUSIONS: BUS evaluation of pediatric SSTI may be a useful clinical adjunct for the emergency physician. It changed management in 22% of cases by detecting subclinical abscesses or avoiding unnecessary invasive procedures.

Ultrasound soft-tissue applications in the pediatric emergency department: to drain or not to drain?

Soft tissue infections frequently prompt visits to the pediatric emergency department. The incidence of these infections has increased markedly in recent years. The emergence of community-acquired methicillin-resistant Staphylococcus aureus is associated with an increasing morbidity, mortality, and frequency of abscess formation. Bedside ultrasound may have a significant impact in the management of patients that present to the pediatric emergency department with soft tissue infections, including cellulitis, cutaneous abscess, peritonsillar abscess, and necrotizing fasciitis. Ultrasound is an efficient, noninvasive diagnostic tool which can augment the physician's clinical examination. Ultrasound has been shown to be superior to clinical judgment alone in determining the presence or the absence of occult abscess formation, ensuring appropriate management and limiting unnecessary invasive procedures.

Bedside ultrasound in pediatric emergency medicine fellowship programs in the United States: little formal training.

BACKGROUND: Bedside ultrasound (BUS) can provide critical information in a rapid and noninvasive manner to the emergency physician. It is widely used in emergency departments (ED) throughout the nation. Literature shows that BUS shortens patient stay and increases patient satisfaction. General emergency medicine (EM) residencies incorporate BUS training in their curricula. However, there are limited data about the training that pediatric emergency medicine (PEM) fellows receive. OBJECTIVE: To determine the extent of training and use of BUS in PEM fellowship programs. METHODS: A 29-question survey was mailed to all (57) PEM fellowship program directors in the spring of 2006. RESULTS: The response rate was 81% (46/57). Fifty-seven percent (26/46) of the responding PEM fellowship program directors reported that their faculty used BUS in their departments. At 50% (23/46) of programs, fellows perform BUS studies. Sixty-five percent (30/46) of PEM fellowships reported that their fellows receive some BUS training, but only 15 of these programs included BUS training in the curriculum as a 2- to 4-week ultrasound rotation.Sixty-five percent (30/46) of PEM fellowship programs had access to an ultrasound machine, but only 28% (13/46) of programs had their own machine. The main reason not to own an ultrasound machine was a lack of ultrasound expertise in their department (67%, 22/33). Bedside ultrasound training was provided by general EM physicians in 57% (17/30) of programs. Eighty-seven percent of the directors agree that BUS training would benefit their practice.The 2 factors significantly associated with the likelihood of having formal BUS training were access to an ultrasound machine (87% vs 55% P=0.04) and presence of an adult ED with an EM residency at the program (80% vs 42% P=0.03). Pediatric emergency medicine fellowship programs at children's hospitals were significantly less likely to have formal training (33.3% vs 74.2%; P=0.01). CONCLUSIONS: Despite literature supporting the benefits of BUS in the ED, many PEM fellowship programs do not incorporate BUS training for their PEM fellows. Most PEM fellows who receive training in BUS are instructed by physicians trained in EM, not PEM.

Pediatric emergency medicine point-of-care ultrasound: summary of the evidence.

The utility of point-of-care ultrasound is well supported by the medical literature. Consequently, pediatric emergency medicine providers have embraced this technology in everyday practice. Recently, the American Academy of Pediatrics published a policy statement endorsing the use of point-of-care ultrasound by pediatric emergency medicine providers.  To date, there is no standard guideline for the practice of point-of-care ultrasound for this specialty. This document serves as an initial step in the detailed "how to" and description of individual point-of-care ultrasound examinations.  Pediatric emergency medicine providers should refer to this paper as reference for published research, objectives for learners, and standardized reporting guidelines.