Engineered Mycobacterium tuberculosis triple-kill-switch strain provides controlled tuberculosis infection in animal models.

Human challenge experiments could accelerate tuberculosis vaccine development. This requires a safe Mycobacterium tuberculosis (Mtb) strain that can both replicate in the host and be reliably cleared. Here we genetically engineered Mtb strains encoding up to three kill switches: two mycobacteriophage lysin operons negatively regulated by tetracycline and a degron domain-NadE fusion, which induces ClpC1-dependent degradation of the essential enzyme NadE, negatively regulated by trimethoprim.

Immunomodulatory metabolites in IgE-mediated food allergy and oral immunotherapy outcomes based on metabolomic profiling.

Background: The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown.

Objective: To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multiethnic cohorts and responses to OIT.

Methods: Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N = 384), a Costa Rican cohort of children with asthma (N = 1040), and a peanut OIT trial (N = 20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterward).

Intravenous Bacillus Calmette-Guérin (BCG) Induces a More Potent Airway and Lung Immune Response than Intradermal BCG in Simian Immunodeficiency Virus-infected Macaques.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading causes of death due to an infectious agent. Coinfection with HIV exacerbates M. tuberculosis infection outcomes in people living with HIV.

Intravenous BCG induces a more potent airway and lung immune response than intradermal BCG in SIV-infected macaques.

Tuberculosis (TB), caused by (Mtb), is one of the leading causes of death due to an infectious agent. Coinfection with HIV exacerbates Mtb infection outcomes in people living with HIV (PLWH). Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, is effective in infants, but its efficacy in adolescents and adults is limited.

CD8+ lymphocytes are critical for early control of tuberculosis in macaques.

The functional role of CD8+ lymphocytes in tuberculosis remains poorly understood. We depleted innate and/or adaptive CD8+ lymphocytes in macaques and showed that loss of all CD8α+ cells (using anti-CD8α antibody) significantly impaired early control of Mycobacterium tuberculosis (Mtb) infection, leading to increased granulomas, lung inflammation, and bacterial burden. Analysis of barcoded Mtb from infected macaques demonstrated that depletion of all CD8+ lymphocytes allowed increased establishment of Mtb in lungs and dissemination within lungs and to lymph nodes, while depletion of only adaptive CD8+ T cells (with anti-CD8β antibody) worsened bacterial control in lymph nodes.

Haptoglobin Gene Expression and Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A COG-ALTE03N1 Report.

Background: Anthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The high interindividual variability in risk suggests the need to understand the underlying pathogenesis.

Objectives: The authors interrogated differentially expressed genes (DEGs) to identify genetic variants serving regulatory functions or genetic variants not easily identified when using genomewide array platforms.

Frontofacial Features of Unilateral Lambdoid Craniosynostosis: A Multicenter Assessment.

Unlabelled: Unilateral lambdoid craniosynostosis is differentiated from deformational plagiocephaly primarily by assessing the cranium from posterior and bird's-eye views. Findings include posterior displacement of the ipsilateral ear, ipsilateral occipitomastoid bossing, ipsilateral occipitoparietal flattening, contralateral parietal bossing, and contralateral frontal bossing. Diagnosis based off facial morphology may be an easier approach because the face is less obstructed by hair and head-coverings, and can easily be assessed when supine.

Vaccination with intravenous BCG protects macaques with pre-existing SIV infection from tuberculosis.

Tuberculosis (TB) is the most common cause of death in people living with HIV. BCG delivered intradermally (ID) is the only licensed vaccine to prevent TB. However, it offers little protection from pulmonary TB in adults.

Mycobacterium tuberculosis-Specific CD4 T Cells Expressing Transcription Factors T-Bet or RORγT Associate with Bacterial Control in Granulomas.

Despite the extensive research on CD4 T cells within the context of Mycobacterium tuberculosis (Mtb) infections, few studies have focused on identifying and investigating the profile of Mtb-specific T cells within lung granulomas. To facilitate the identification of Mtb-specific CD4 T cells, we identified immunodominant epitopes for two Mtb proteins, namely, Rv1196 and Rv0125, using a Mauritian cynomolgus macaque model of Mtb infection, thereby providing data for the synthesis of MHC class II tetramers. Using tetramers, we identified Mtb-specific cells within different immune compartments, postinfection.

Early Postoperative Congenital Cardiac Catheterization Outcomes: A Multicenter Study.

Background: Early postoperative catheterizations (EPOCs) within 6 weeks after a congenital heart surgical procedure can treat residual lesions and provide important clinical information. However, EPOCs are often assumed to impose additional risk on a vulnerable patient population. This study aimed to describe the EPOC population, evaluate procedural safety, compare EPOC patients with procedure-matched non-EPOC patients, and determine risk factors for poor outcomes using data from the Congenital Cardiac Catheterization Project on Outcomes registry.

Characterization of natural killer cells in the blood and airways of cynomolgus macaques during Mycobacterium tuberculosis infection.

Background: Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and kills more than 1.5 million people each year.

Methods: We examine the frequency and function of NK cells in the blood and airways over the course of Mtb infection in a TB macaque model and demonstrate differences in NK marker expression between the two compartments.

Machine Learning in Metopic Craniosynostosis: Does Phenotypic Severity Predict Long-Term Esthetic Outcome?

Background: There have been few longitudinal studies assessing the effect of preoperative phenotypic severity on long-term esthetic outcomes in metopic craniosynostosis. This study evaluates the relationship between metopic severity and long-term esthetic outcomes using interfrontal angle (IFA) and CranioRate, a novel metopic synostosis severity measure.

Methods: Patients with metopic craniosynostosis who underwent bifrontal orbital advancement and remodeling between 2012 and 2017 were reviewed.

Decrease in Pediatric Invasive Pneumococcal Disease During the COVID-19 Pandemic.

Measures to limit SARS-CoV-2 transmission in 2020 reduced other viral infections. Among 7 US children's hospitals, invasive pneumococcal disease cumulative incidence decreased by 46% in 2020 vs 2017-2019. Limited droplet transmission of pneumococci and preceding viral pathogens may be responsible.

T cell transcription factor expression evolves over time in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a global health concern, yearly resulting in 10 million new cases of active TB. Immunologic investigation of lung granulomas is essential for understanding host control of bacterial replication. Here, we identify and compare the pathological, cellular, and functional differences in granulomas at 4, 12, and 20 weeks post-infection in Chinese cynomolgus macaques.

The Clinical Significance of Clinocephaly in Late-Presentation Sagittal Craniosynostosis.

The diagnosis of late-presentation sagittal suture craniosynostosis (SCS) can be challenging, especially in the setting of subtle physical exam findings. The clinical significance of clinocephaly-a retro-coronal concavity along the midvault-in this context remains unknown. The aim of this study is to evaluate the predictive value of clinocephaly in identifying late-presentation SCS.

The Crooked Nose: A Practical Guide to Successful Management.

Learning Objectives: After studying this article, the participant should be able to: (1) Preoperatively evaluate the patient with a crooked nose. (2) Develop a comprehensive preoperative plan specific to the patient. (3) Effectively "deconstruct" and rebuild the crooked nose to address both aesthetic and functional concerns.

Cost analysis of sialendoscopy for the treatment of salivary gland disorders in children.

Introduction: Recent advances in Otolaryngology have changed the diagnosis and therapy for salivary gland disorders. Sialendoscopy-assisted surgery is a minimally invasive, conservative procedure for functional preservation of the affected gland. The goals of this study are to assess the indications, use, and outcomes of pediatric sialendoscopy at a tertiary pediatric institution as well as to analyze the direct cost related to the diagnosis and treatment of patients with sialolithiasis and Juvenile Recurrent Parotitis managed with sialendoscopy.

A Three-Dimensional-Based Morphometric Analysis of a Standardized Overcorrection Technique for Fronto-Orbital Advancement in Metopic Craniosynostosis.

Introduction: The concept of "overcorrection" for trigonocephaly has been reported to achieve both anterior cranial fossa expansion and normalization of craniofacial form. The purpose of this study is to describe in detail a standardized technique to fronto-orbital advancement utilizing the concept of "overcorrection" and objectively evaluate intermediate results.

Methods: This retrospective study included patients with isolated metopic synostosis who underwent surgery via the proposed surgical technique and age and sex-matched unaffected controls.

Effects of Age on Delayed Facial Palsy After Otologic Surgery: A Systematic Review and Meta-Analysis.

Objectives: To report 4 cases of delayed facial palsy (DFP) after pediatric middle ear (ME) surgery and systematically review and analyze the associated literature to evaluate the effects of age on DFP etiology, management, and prognosis.

Methods: Systematic review of PubMed, Cochrane Library, and Embase for articles related to DFP after cochlear implantation (CI) was performed. These articles were assessed for level of evidence, methodological limitations, and number of cases.

Predicting Severe Asthma Exacerbations in Children: Blueprint for Today and Tomorrow.

Severe asthma exacerbations are the primary cause of morbidity and mortality in children with asthma. Accurate prediction of children at risk for severe exacerbations, defined as those requiring systemic corticosteroids, emergency department visit, and/or hospitalization, would considerably reduce health care utilization and improve symptoms and quality of life. Substantial progress has been made in identifying high-risk exacerbation-prone children.

Octanoate is differentially metabolized in liver and muscle and fails to rescue cardiomyopathy in CPT2 deficiency.

Long-chain fatty acid oxidation is frequently impaired in primary and systemic metabolic diseases affecting the heart; thus, therapeutically increasing reliance on normally minor energetic substrates, such as ketones and medium-chain fatty acids, could benefit cardiac health. However, the molecular fundamentals of this therapy are not fully known. Here, we explored the ability of octanoate, an eight-carbon medium-chain fatty acid known as an unregulated mitochondrial energetic substrate, to ameliorate cardiac hypertrophy in long-chain fatty acid oxidation-deficient hearts because of carnitine palmitoyltransferase 2 deletion (Cpt2).

A government mandated consent safely reduces opioid utilization for major pediatric genitourinary surgeries.

Introduction: We describe the effect of a state mandated opioid consent on opioid utilization and multimodal pain use for major pediatric genitourinary surgeries.

Methods: All patients who underwent an inpatient pediatric genitourinary surgery at the Children's Hospital of Pittsburgh between August 2015 and February 2020 were identified. Inpatient and outpatient multimodal pain control utilization were assessed.