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Intrauterine Growth Retardation Leads to the Development of Type 2 Diabetes in the Rat Rebecca A. Simmons , Lori J. Templeton and Shira J. Gertz Division of Neonatology, Department of Pediatrics, University of Pennsylvania and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Abstract Intrauterine growth retardation has been linked to the development of type 2 diabetes in later life. The mechanisms underlying this phenomenon are unknown. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Bilateral uterine artery ligation was performed on day 19 of gestation (term is 22 days) in the pregnant rat; sham-operated pregnant rats served as controls. Birth weights of intrauterine growth–retarded (IUGR) animals were significantly lower than those of controls until ∼7 weeks of age, when IUGR rats caught up to controls. Between 7 and 10 weeks of age, the growth of IUGR rats accelerated and surpassed that of controls, and by 26 weeks of age, IUGR rats were obese ( P < 0.05 vs. controls). No significant differences were observed in blood glucose and plasma insulin levels at 1 week of age. However, between 7 and 10 weeks of age, IUGR rats developed mild fasting hyperglycemia and hyperinsulinemia ( P < 0.05 vs. controls). At age 26 weeks, IUGR animals had markedly elevated levels of glucose ( P < 0.05 vs. controls). IUGR animals were glucose-intolerant and insulin-resistant at an early age. First-phase insulin secretion in response to glucose was also impaired early in life in IUGR rats, before the onset of hyperglycemia. There were no significant differences in β-cell mass, islet size, or pancreatic weight between IUGR and control animals at 1 and 7 weeks of age. However, in 15-week-old IUGR rats, the relative β-cell mass was 50% that of controls, and by 26 weeks of age, β-cell mass was less than one-third that of controls ( P < 0.05). The data presented here support the hypothesis that an abnormal intrauterine milieu can induce permanent changes in glucose homeostasis after birth and lead to type 2 diabetes in adulthood. Footnotes Address correspondence and reprint requests to Rebecca Simmons, MD, University of Pennsylvania, BRB II/III 13th floor, 421 Curie Blvd., Philadelphia, PA 19104. E-mail: rsimmons{at}mail.med.upenn.edu . Received for publication 24 May 2000 and accepted in revised form 20 June 2001. IUGR, intrauterine growth–retarded.

In this study, maternal vaccination with an mRNA vaccine during pregnancy was less common among infants hospitalized for Covid-19 than among controls. The effectiveness of maternal vaccination against Covid-19 hospitalization of infants was 52% overall and was greater when delta, rather than omicron, was predominant.

Gestational Diabetes Leads to the Development of Diabetes in Adulthood in the Rat Judd Boloker , Shira J. Gertz and Rebecca A. Simmons From the Division of Neonatology, Department of Pediatrics, University of Pennsylvania and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Abstract We have developed a model of gestational diabetes in the rat to determine whether an altered metabolic intrauterine milieu is directly linked to the development of diabetes later in life. Uteroplacental insufficiency is induced in the pregnant rat on day 19 of gestation. Sham-operated animals serve as controls. Offspring are growth retarded at birth; however, they catch up by 5–7 weeks of age. At ∼8 weeks of age, they are bred to normal males. During pregnancy, these animals develop progressive hyperglycemia and hyperinsulinemia accompanied by impaired glucose tolerance and insulin resistance. Offspring, designated as infants of a diabetic mother (IDMs), are heavier at birth and remain heavy throughout life. IDMs are insulin resistant very early in life, and glucose homeostasis is progressively impaired. Defects in insulin secretion are detectable as early as 5 weeks of age. By 26 weeks of age, IDMs are overtly diabetic. These data demonstrate that the altered metabolic milieu of the diabetic pregnancy causes permanent defects in glucose homeostasis in the offspring that lead to the development of diabetes later in life. Footnotes Address correspondence and reprint requests to Rebecca Simmons, MD, University Pennsylvania, BRB II/III 13th Floor, 421 Curie Blvd., Philadelphia, PA 19104. E-mail: rsimmons{at}mail.med.upenn.edu . Received for publication 15 May 2001 and accepted in revised form 7 February 2002. BrdU, 5-bromo-2′deoxyuridine; 2-DG, 2-deoxyglucose; IDM, infant of a diabetic mother; IUGR, intrauterine growth-retarded; STZ, streptozotocin. DIABETES

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection 1 , 2 , yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases. A cross-reactive antibody and T cell response is identified in a large portion of patients with multisystem inflammatory syndrome in children.

Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (<5, 5–11, 12–21 years) in 177 pediatric patients hospitalized with severe acute COVID-19, acute MIS-C, and in convalescent samples of outpatients with mild COVID-19 during 2020 and early 2021. Across all patients, less than 10% show neutralizing antibody titers against Omicron. Children <5 years of age hospitalized with severe acute COVID-19 have lower neutralizing antibodies to SARS-CoV-2 variants compared with patients >5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children. The antibody response to the SARS-CoV-2 Omicron variant is not well studied in children. Here, the authors provide an age-stratified analysis of SARS-CoV-2 neutralizing capacity of sera from children with acute or convalescent COVID-19 as well as children with multisystem inflammatory syndrome.

Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 children’s hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality ( P  = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands ( P  = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung–immune system–microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes. By leveraging paired microbiome and human gene expression data from pediatric patients who underwent hematopoietic cell transplantation, distinct lung–immune system–microorganism interactions were identified as important drivers of fatal lung injury.

The Glasgow Coma Scale (GCS) score has not been validated in children younger than 5 years and the clinical circumstances at the time of assignment can limit its applicability. This study describes the distribution of GCS scores in the population, the relationship between injury characteristics with the GCS score, and the association between the tripartite stratification of the GCS on mortality in children with severe traumatic brain injury (TBI). The first 200 children from a multi-center comparative effectiveness study in severe TBI (inclusion criteria: age 0–18 years, GCS ≤8 at the time of intracranial pressure [ICP] monitoring) were analyzed. After tripartite stratification of GCS scores (Group A, GCS 3; Group B, GCS 4 - 5; and Group C, GCS 6 - 8), analyses of variance and chi-square testing were performed. Mean age was 7.61 years ±5.33 and mortality was 19.1%. There was no difference in etiology or type/mechanism of injury between groups. However, groups demonstrated differences in neuromuscular blockade, endotracheal intubation, pre-hospital events (cardiac arrest and apnea), coagulopathy, and pupil response. Mortality between groups was different (42.2% Group A, 22.6% Group B, and 3.8% Group C; p < 0.001), and adding pupil response improved mortality associations. In children younger than 5 years of age, a similar relationship between GCS and mortality was observed. Overall, GCS score at the time of ICP monitor placement is strongly associated with mortality across the pediatric age range. Development of models with GCS and other factors may allow identification of subtypes of children after severe TBI for future studies.

Acute neurological involvement occurs in some patients with multisystem inflammatory syndrome in children (MIS-C), but few data report neurological and psychological sequelae, and no investigations include direct assessments of cognitive function 6 to 12 months after discharge. To characterize neurological, psychological, and quality of life sequelae after MIS-C. This cross-sectional cohort study was conducted in the US and Canada. Participants included children with MIS-C diagnosed from November 2020 through November 2021, 6 to 12 months after hospital discharge, and their sibling or community controls, when available. Data analysis was performed from August 2022 to May 2023. Diagnosis of MIS-C. A central study site remotely administered a onetime neurological examination and in-depth neuropsychological assessment including measures of cognition, behavior, quality of life, and daily function. Generalized estimating equations, accounting for matching, assessed for group differences. Sixty-four patients with MIS-C (mean [SD] age, 11.5 [3.9] years; 20 girls [31%]) and 44 control participants (mean [SD] age, 12.6 [3.7] years; 20 girls [45%]) were enrolled. The MIS-C group exhibited abnormalities on neurological examination more frequently than controls (15 of 61 children [25%] vs 3 of 43 children [7%]; odds ratio, 4.7; 95% CI, 1.3-16.7). Although the 2 groups performed similarly on most cognitive measures, the MIS-C group scored lower on the National Institutes of Health Cognition Toolbox List Sort Working Memory Test, a measure of executive functioning (mean [SD] scores, 96.1 [14.3] vs 103.1 [10.5]). Parents reported worse psychological outcomes in cases compared with controls, particularly higher scores for depression symptoms (mean [SD] scores, 52.6 [13.1] vs 47.8 [9.4]) and somatization (mean [SD] scores, 55.5 [15.5] vs 47.0 [7.6]). Self-reported (mean [SD] scores, 79.6 [13.1] vs 85.5 [12.3]) and parent-reported (mean [SD] scores, 80.3 [15.5] vs 88.6 [13.0]) quality of life scores were also lower in cases than controls. In this cohort study, compared with contemporaneous sibling or community controls, patients with MIS-C had more abnormal neurologic examinations, worse working memory scores, more somatization and depression symptoms, and lower quality of life 6 to 12 months after hospital discharge. Although these findings need to be confirmed in larger studies, enhanced monitoring may be warranted for early identification and treatment of neurological and psychological symptoms.

This report describes the epidemiology and clinical course of patients younger than 21 years of age from 26 states who had multisystem inflammatory syndrome. Many were infected with SARS-CoV-2 at least 1 to 2 weeks before syndrome onset. The median age of the patients was 8.3 years, and 73% were previously healthy.