Publications by authors named "T Charles Casper"

121 Publications

Increased Prevalence of Familial Autoimmune Disease in Children With Opsoclonus-Myoclonus Syndrome.

Neurol Neuroimmunol Neuroinflamm 2021 Nov 2;8(6). Epub 2021 Sep 2.

From the Department of Neurology (J.D.S.), Massachusetts General Hospital, Boston; Department of Neurology (J.D.S., J.M.K., M.P.G.), Boston Children's Hospital, MA; Harvard Medical School (J.D.S., K.D.M.), Boston, MA; Division of Neurology (J.D.S.), Department of Pediatrics, Children's Hospital of Los Angeles, CA; Department of Neurology (J.D.S.), Keck School of Medicine at the University of Southern California, Los Angeles; Department of Pediatrics (R.C., T.C.C.), University of Utah School of Medicine, Salt Lake City; Department of Neurology and Neurotherapeutics (B.M.G.), The University of Texas Southwestern Medical Center at Dallas, TX; UCSF Weill Institute for Neurosciences (E.W.), Department of Neurology, University of California San Francisco, CA; Computational Health Informatics Program (S.W.K., K.D.M.), Boston Children's Hospital, MA; and Department of Pediatrics (S.W.K., K.D.M.), Boston Children's Hospital, MA.

Background And Objectives: Opsoclonus-myoclonus syndrome (OMS) is a rare autoimmune disorder associated with neuroblastoma in children, although idiopathic and postinfectious etiologies are present in children and adults. Small cohort studies in homogenous populations have revealed elevated rates of autoimmunity in family members of patients with OMS, although no differentiation between paraneoplastic and nonparaneoplastic forms has been performed. The objective of this study was to investigate the prevalence of autoimmune disease in first-degree relatives of pediatric patients with paraneoplastic and nonparaneoplastic OMS.

Methods: A single-center cohort study of consecutively evaluated children with OMS was performed. Parents of patients were prospectively administered surveys on familial autoimmune disease. Rates of autoimmune disease in first-degree relatives of pediatric patients with OMS were compared using Fisher exact test and χ analysis: (1) between those with and without a paraneoplastic cause and (2) between healthy and disease (pediatric multiple sclerosis [MS]) controls from the United States Pediatric MS Network.

Results: Thirty-five patients (18 paraneoplastic, median age at onset 19.0 months; 17 idiopathic, median age at onset 25.0 months) and 68 first-degree relatives (median age 41.9 years) were enrolled. One patient developed systemic lupus erythematosus 7 years after OMS onset. Paraneoplastic OMS was associated with a 50% rate of autoimmune disease in a first-degree relative compared with 29% in idiopathic OMS ( = 0.31). The rate of first-degree relative autoimmune disease per OMS case (14/35, 40%) was higher than healthy controls (86/709, 12%; < 0.001) and children with pediatric MS (101/495, 20%; = 0.007).

Discussion: In a cohort of pediatric patients with OMS, there were elevated rates of first-degree relative autoimmune disease, with no difference in rates observed between paraneoplastic and idiopathic etiologies, suggesting an autoimmune genetic contribution to the development of OMS in children.
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http://dx.doi.org/10.1212/NXI.0000000000001079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422990PMC
November 2021

Single-cell and single-nucleus RNA-seq uncovers shared and distinct axes of variation in dorsal LGN neurons in mice, non-human primates, and humans.

Elife 2021 09 2;10. Epub 2021 Sep 2.

Allen Institute for Brain Science, Seattle, United States.

Abundant evidence supports the presence of at least three distinct types of thalamocortical (TC) neurons in the primate dorsal lateral geniculate nucleus (dLGN) of the thalamus, the brain region that conveys visual information from the retina to the primary visual cortex (V1). Different types of TC neurons in mice, humans, and macaques have distinct morphologies, distinct connectivity patterns, and convey different aspects of visual information to the cortex. To investigate the molecular underpinnings of these cell types, and how these relate to differences in dLGN between human, macaque, and mice, we profiled gene expression in single nuclei and cells using RNA-sequencing. These efforts identified four distinct types of TC neurons in the primate dLGN: magnocellular (M) neurons, parvocellular (P) neurons, and two types of koniocellular (K) neurons. Despite extensively documented morphological and physiological differences between M and P neurons, we identified few genes with significant differential expression between transcriptomic cell types corresponding to these two neuronal populations. Likewise, the dominant feature of TC neurons of the adult mouse dLGN is high transcriptomic similarity, with an axis of heterogeneity that aligns with core vs. shell portions of mouse dLGN. Together, these data show that transcriptomic differences between principal cell types in the mature mammalian dLGN are subtle relative to the observed differences in morphology and cortical projection targets. Finally, alignment of transcriptome profiles across species highlights expanded diversity of GABAergic neurons in primate versus mouse dLGN and homologous types of TC neurons in primates that are distinct from TC neurons in mouse.
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http://dx.doi.org/10.7554/eLife.64875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412930PMC
September 2021

Gut microbiome is associated with multiple sclerosis activity in children.

Ann Clin Transl Neurol 2021 Sep 19;8(9):1867-1883. Epub 2021 Aug 19.

Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

Objective: To identify features of the gut microbiome associated with multiple sclerosis activity over time.

Methods: We used 16S ribosomal RNA sequencing from stool of 55 recently diagnosed pediatric-onset multiple sclerosis patients. Microbiome features included the abundance of individual microbes and networks identified from weighted genetic correlation network analyses. Prentice-Williams-Peterson Cox proportional hazards models estimated the associations between features and three disease activity outcomes: clinical relapses and both new/enlarging T2 lesions and new gadolinium-enhancing lesions on brain MRI. Analyses were adjusted for age, sex, and disease-modifying therapies.

Results: Participants were followed, on average, 2.1 years. Five microbes were nominally associated with all three disease activity outcomes after multiple testing correction. These included butyrate producers Odoribacter (relapse hazard ratio = 0.46, 95% confidence interval: 0.24, 0.88) and Butyricicoccus (relapse hazard ratio = 0.49, 95% confidence interval: 0.28, 0.88). Two networks of co-occurring gut microbes were significantly associated with a higher hazard of both MRI outcomes (gadolinium-enhancing lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.29 (1.08, 1.54) and 1.42 (1.18, 1.71), respectively; T2 lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.34 (1.15, 1.56) and 1.41 (1.21, 1.64), respectively). Metagenomic predictions of these networks demonstrated enrichment for amino acid biosynthesis pathways.

Interpretation: Both individual and networks of gut microbes were associated with longitudinal multiple sclerosis activity. Known functions and metagenomic predictions of these microbes suggest the important role of butyrate and amino acid biosynthesis pathways. This provides strong support for future development of personalized microbiome interventions to modify multiple sclerosis disease activity.
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http://dx.doi.org/10.1002/acn3.51441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419410PMC
September 2021

Oral Ondansetron Administration in Children Seeking Emergency Department Care for Acute Gastroenteritis: A Patient-Level Propensity-Matched Analysis.

Ann Emerg Med 2021 Aug 11. Epub 2021 Aug 11.

Sections of Pediatric Emergency Medicine and Gastroenterology, Departments of Pediatrics and Emergency Medicine, Alberta Children's Hospital, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Study Objective: This study aimed to explore oral ondansetron usage and impact on outcomes in clinical practice.

Methods: This observational study was a planned secondary analysis of 2 trials conducted in 10 US and 6 Canadian institutions between 2014 and 2017. Children 3 to 48 months old with gastroenteritis and ≥3 episodes of vomiting in the 24 hours preceding emergency department (ED) presentation were included. Oral ondansetron was administered at the discretion of the provider. The principal outcomes were intravenous fluid administration and hospitalization at the index visit and during the subsequent 72 hours and diarrhea and vomiting frequency during the 24 hours following the ED visit.

Results: In total, 794 children were included. The median age was 16.0 months (interquartile range 10.0 to 26.0), and 50.1% (398/794) received oral ondansetron. In propensity-adjusted analysis (n=528), children administered oral ondansetron were less likely to receive intravenous fluids at the index visit (adjusted odds ratio [aOR] 0.50; 95% confidence interval [CI] 0.29 to 0.88). There were no differences in the frequencies of intravenous fluid administration within the first 72 hours (aOR 0.65; 95% CI 0.39 to 1.10) or hospitalization at the index visit (aOR 0.31; 95% CI 0.09 to 1.10) or the subsequent 72 hours (aOR 0.52; 95% CI 0.21 to 1.28). Episodes of vomiting (aRR 0.86; 95% CI 0.63 to 1.19) and diarrhea (aRR 1.11; 95% CI 0.93 to 1.32) during the 24 hours following ED discharge also did not differ.

Conclusion: Among preschool-aged children with gastroenteritis seeking ED care, oral ondansetron administration was associated with a reduction in index ED visit intravenous fluid administration; it was not associated with intravenous fluids administered within 72 hours, hospitalization, or vomiting and diarrhea in the 24 hours following discharge.
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http://dx.doi.org/10.1016/j.annemergmed.2021.06.003DOI Listing
August 2021

Serum Sodium Concentration and Mental Status in Children With Diabetic Ketoacidosis.

Pediatrics 2021 Sep 9;148(3). Epub 2021 Aug 9.

Department of Psychology, University of California, Davis, Davis, California.

Objectives: Diabetic ketoacidosis (DKA) is typically characterized by low or low-normal serum sodium concentrations, which rise as hyperglycemia resolves. In retrospective studies, researchers found associations between declines in sodium concentrations during DKA and cerebral injury. We prospectively investigated determinants of sodium concentration changes and associations with mental status alterations during DKA.

Methods: Using data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in Diabetic Ketoacidosis Trial, we compared children who had declines in glucose-corrected sodium concentrations with those who had rising or stable concentrations. Children were randomly assigned to 1 of 4 intravenous fluid protocols that differed in infusion rate and sodium content. Data from the first 4, 8, and 12 hours of treatment were analyzed for 1251, 1086, and 877 episodes, respectively.

Results: In multivariable analyses, declines in glucose-corrected sodium concentrations were associated with higher sodium and chloride concentrations at presentation and with previously diagnosed diabetes. Treatment with 0.45% (vs 0.9%) sodium chloride fluids was also associated with declines in sodium concentration; however, higher rates of fluid infusion were associated with declines in sodium concentration only at 12 hours. Frequencies of abnormal Glasgow Coma Scale scores and clinical diagnoses of cerebral injury were similar in patients with and without declines in glucose-corrected sodium concentrations.

Conclusions: Changes in glucose-corrected sodium concentrations during DKA treatment are influenced by the balance of free-water loss versus sodium loss at presentation and the sodium content of intravenous fluids. Declines in glucose-corrected sodium concentrations are not associated with mental status changes during treatment.
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http://dx.doi.org/10.1542/peds.2021-050243DOI Listing
September 2021
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