Children's Hospital Oakland Research Institute
  • Oakland, California, United States
Recent publications
Self-determination refers to an individual's capacity and opportunities to act as a causal agent in their own lives to make choices, decisions, and set goals. The current study examined self- and parent-reports of the AIR Self-Determination Scale in transition-aged autistic youth (Based on stakeholder preferences, we use identity-first(autistic) or neutral language (on the autism spectrum) (Bottema-Beutel in JAMA 3:18–29, 2020)). Autistic youth completed depression and executive function measures, and parents rated their child's social-communication and executive function difficulties. Despite differences between youth and parent reports, both youth and their parents reported lower self-determination skills (capacity) than opportunities to practice self-determined behaviors. Both depression and executive function skills were related to self-determination capacity, highlighting potential intervention targets for transition-aged youth to facilitate increased self-determination and potentially improved adult outcomes.
Introduction Research has identified positive associations between green space and physical and mental health outcomes. Substance use outcomes, however, have received considerably less attention. This study investigates the association between residential greenness and substance use through an analysis of alcohol, tobacco, and marijuana use among youth and young adults. Methods This study utilized three waves (2016–2018) of the Canadian Community Health Survey (CCHS), as well as residential greenness data from the Canadian Urban Environmental Health Consortium (CANUE). Multinomial logistic regression was used to explore variation in the pattern of substance use between greenness quartiles. The sample included 14,070 youth and young adults (15–25 years). Results Residential greenness was not associated with alcohol use in general but was associated with lower odds of frequent binge drinking. Residential greenness was also associated with lower odds of tobacco use and greater odds of marijuana use. Conclusion This study provides evidence that residential greenness is associated with patterns of substance use. The strength and direction of association, however, is highly contingent upon the substance under investigation. Living in greener neighborhoods may confer certain benefits to substance use and abuse among youth and young adults.
Genetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations.
Background Head and neck cancer (HNC) surgery remains an important component of management but is associated with a high rate of surgical site infection (SSI). We aimed to assess the safety and efficacy of a topical mucosal antiseptic bundle in preventing SSI and evaluate microbial predictors of infection through a genomic sequencing approach. Methods This study was an open-label, single-arm, single-center, phase 2 trial of a topical mucosal antiseptic bundle in patients with HNC undergoing aerodigestive tract resection and reconstruction. Patients underwent topical preparation of the oral mucosa with povidone-iodine (PI) and chlorhexidine gluconate (CHG) pre- and intra-operatively followed by oral tetracycline ointment every 6 hours for 2 days post-operatively. The primary outcome was change in bacterial bioburden at the oral surgical site. Secondary outcomes included safety, SSI, and microbial predictors of infection. Findings Of 27 patients screened between January 8, 2021, and May 14, 2021, 26 were enrolled and 25 completed the study. There were no antiseptic-related adverse events. The topical mucosal antiseptic bundle significantly decreased oral bacterial colony-forming units from pre-operative levels (log10 mean difference 4·03, 95%CI 3·13–4·;92). There were three SSI (12%) within 30 days. In correlative genomic studies, a distinct set of amplicon sequence variants in the post-operative microbiome was associated with SSI. Further, despite no instance of post-operative orocervical fistula, metagenomic sequence mapping revealed the oral cavity as the origin of the infectious organism in two of the three SSI. Interpretation The bacterial strains which subsequently caused SSI were frequently identified in the pre-operative oral cavity. Accordingly, a topical antiseptic bundle decreased oral bacterial bioburden throughout the peri-operative period and was associated with a low rate of SSI, supporting further study of topical antisepsis in HNC surgery. Funding Alliance Oncology.
Manifestations of sickle cell disease (SCD) begin early in childhood and cause morbidity and decreased life expectancy. Hematopoietic stem cell transplantation (HSCT) is curative but associated with risk of mortality attributable to the transplant. This risk should be counterbalanced with SCD morbidity and mortality. A severity score using a Bayesian network model was previously validated to predict the risk of death in adult individuals with SCD. The objective of this study is to calculate the severity scores of participants in a multicenter cohort of Brazilians with SCD, using a previously published Bayesian network–derived score, associated with risk of death and then compare the severity scores between participants with and without an indication for HSCT as defined by the Brazilian Ministry of Health (MoH) criteria. This is an observational, retrospective study. We analyzed 2063 individuals with sickle cell anemia from the Recipient Epidemiology and Donor Evaluation Study-III Brazil SCD cohort and applied a Bayesian network–derived score to compare candidates and non-candidates for HSCT according to the Brazilian MoH transplant criteria. Classical statistical methods were used to analyze data and make comparisons. We compared severity scores between cohort members with (n = 431) and without (n = 1632) HSCT indications according to Brazilian MoH. Scores were not different in adult participants with ≥1 HSCT indication when compared to those with no indication (mean 0.342 versus 0.292; median 0.194 versus 0.183, P = .354) and receiver operating characteristic curves did not demonstrate an obvious threshold to differentiate participants with or without HSCT indications. Severity score may predict risk of death but does not differentiate HSCT candidates. Current indications should be evaluated to ensure that patients with more severe disease who might benefit from HSCT are appropriately identified.
Progress improving zinc nutrition globally is slowed by limited understanding of population zinc status. This challenge is compounded when small differences in measurement can bias the determination of zinc deficiency rates. Our objective was to evaluate zinc analytical accuracy and precision among different instrument types and sample matrices using a standardized method. Participating laboratories analyzed zinc content of plasma, serum, liver samples, and controls, using a standardized method based on current practice. Instrument calibration and drift were evaluated using a zinc standard. Accuracy was evaluated by percent error vs. reference, and precision by coefficient of variation (CV). Seven laboratories in 4 countries running 9 instruments completed the exercise: 4 atomic absorbance spectrometers (AAS), 1 inductively coupled plasma optical emission spectrometer (ICP-OES), and 4 ICP mass spectrometers (ICP-MS). Calibration differed between individual instruments up to 18.9% ( p < 0.001). Geometric mean (95% CI) percent error was 3.5% (2.3%, 5.2%) and CV was 2.1% (1.7%, 2.5%) overall. There were no significant differences in percent error or CV among instrument types ( p = 0.91, p = 0.15, respectively). Among sample matrices, serum and plasma zinc measures had the highest CV: 4.8% (3.0%, 7.7%) and 3.9% (2.9%, 5.4%), respectively ( p < 0.05). When using standardized materials and methods, similar zinc concentration values, accuracy, and precision were achieved using AAS, ICP-OES, or ICP-MS. However, method development is needed for improvement in serum and plasma zinc measurement precision. Differences in calibration among instruments demonstrate a need for harmonization among laboratories.
Objective: Fetuses with severe congenital heart disease (CHD) have altered blood flow patterns. Prior work to assess fetal combined cardiac output (CCO) is limited by sample size and lack of longitudinal gestational data. Our aim was to evaluate CCO in CHD fetuses to determine whether the presence of single ventricle (SV) physiology or aortic obstruction impacts fetal blood flow and cardiovascular hemodynamics. Method: Prospective study including singleton fetuses with CHD (n=141) and controls (n=118) who underwent a mid and late gestation fetal echocardiogram. Ventricular cardiac output was calculated using the standard computation. CCO was derived as the sum of the right and left cardiac outputs and indexed to estimated fetal weight. Results: Fetuses with two ventricle (2V) CHD had significantly higher CCO compared to controls and SV-CHD fetuses. Fetuses with SV-CHD had similar CCO compared to controls. Fetuses with 2V-CHD and aortic obstruction had significantly higher CCO than fetuses with SV-CHD and aortic obstruction. Conclusion: Our findings suggest that the SV can compensate and increase CCO despite the lack of a second functioning ventricle however, the degree of compensation may be insufficient to support the increased blood flow needed to overcome the hemodynamic and physiologic alternations seen with severe CHD. This article is protected by copyright. All rights reserved.
Purpose: Patients with MYC-amplified medulloblastoma (MB) have poor prognosis and frequently develop recurrence, thus new therapeutics to prevent recurrence are needed. Experimental design: We evaluated OLIG2 expression in a panel of mouse Myc-driven MB tumors, patient MB samples, and patient-derived xenograft (PDX) tumors and analyzed radiation sensitivity in OLIG2-high and OLIG2-low tumors in PDX lines. We assessed the effect of inhibition of OLIG2 by OLIG2-CRISPR or the small molecule inhibitor CT-179 combined with radiotherapy on tumor progression in PDX models. Results: We found that MYC-associated MB can be stratified into OLIG2-high and OLIG2-low tumors based on OLIG2 protein expression. In MYC-amplified MB PDX models, OLIG2-low tumors were sensitive to radiation and rarely relapsed, whereas OLIG2-high tumors were resistant to radiation and consistently developed recurrence. In OLIG2-high tumors, irradiation eliminated the bulk of tumor cells; however, a small number of tumor cells comprising OLIG2- tumor cells and rare OLIG2+ tumor cells remained in the cerebellar tumor bed when examined immediately post-irradiation. All animals harboring residual resistant tumor cells developed relapse. The relapsed tumors mirrored the cellular composition of the primary tumors with enriched OLIG2 expression. Further studies demonstrated that OLIG2 was essential for recurrence, as OLIG2 disruption with CRISPR-mediated deletion or with the small-molecule inhibitor CT-179 prevented recurrence from the residual radioresistant tumor cells. Conclusions: Our studies reveal that OLIG2 is a biomarker and an effective therapeutic target in a high-risk subset of MYC-amplified MB, and OLIG2 inhibitor combined with radiotherapy represents a novel effective approach for treating this devastating disease.
The sheep is a valuable model to test whether hormone mechanisms that sexually differentiate the brain underlie the expression of sexual partner preferences because as many as 8% of rams prefer same-sex partners. Epigenetic factors such as DNA methylation act as mediators in the interaction between steroid hormones and the genome. Variations in the epigenome could be important in determining morphological or behavior differences among individuals of the same species. In this study, we explored DNA methylation differences in the hypothalamus of male oriented rams (MORs) and female oriented rams (FORs). We employed reduced representation bisulfite sequencing (RRBS) to generate a genome-wide map of DNA methylation and RNA-Seq to profile the transcriptome. We found substantial DNA methylation and gene expression differences between FORs and MORs. Although none of the differentially methylated genes yielded significant functional terms directly associated with sex development, three differentially expressed genes were identified that have been associated previously with sexual behaviors. We hypothesize that these differences are involved in the phenotypic variation in ram sexual partner preferences, whereas future studies will have to find the specific mechanisms. Our results add an intriguing new dimension to sheep behavior that should be useful for further understanding epigenetic and transcriptomic involvement.
Acute lymphoblastic leukemia (ALL) in children is associated with a distinct neonatal cytokine profile. The basis of this neonatal immune phenotype is unknown, but potentially related to maternal-fetal immune receptor interactions. We conducted a case-control study of 226 case child-mother pairs and 404 control child-mother pairs to evaluate the role of interaction between human leukocyte antigen (HLA) genotypes in the offspring and maternal killer immunoglobulin-like receptor (KIR) genotypes in the etiology of childhood ALL, while considering potential mediation by neonatal cytokines and the immune-modulating enzyme arginase-II (ARG-II). We observed different associations between offspring HLA-maternal KIR activating profiles and the risk of ALL in different predicted genetic ancestry groups. For instance, in Latino subjects who experience the highest risk of childhood leukemia, activating profiles were significantly associated with a lower risk of childhood ALL (odds ratio, OR=0.59; 95% confidence interval, CI:0.49, 0.71) and a higher level of ARG-II at birth (coefficient=0.13; 95%CI:0.04, 0.22). HLA-KIR activating profiles were also associated with a lower risk of ALL in non-Latino Asians (OR=0.63; 95%CI:0.38, 1.01), however with lower TNF- level (coefficient=-0.27; 95%CI:-0.49, -0.06). Among non-Latino White subjects, no significant association was observed between offspring HLA-maternal KIR interaction and ALL risk, or cytokine levels. The current study reports the association between offspring HLA-maternal KIR interaction and the development of childhood ALL with variation by predicted genetic ancestry. We also observed some associations between activating profiles and immune factors related to cytokine control; however, cytokines did not demonstrate causal mediation of the activating profiles on ALL risk.
Background A point mutation in sickle cell disease (SCD) alters one amino acid in the ß-globin subunit of hemoglobin, with resultant anemia and multiorgan damage that typically shortens lifespan by decades. Because SCD is caused by a single mutation, and hematopoietic stem cells (HSCs) can be harvested, manipulated, and returned to an individual, it is an attractive target for gene correction. Results An optimized Cas9 ribonucleoprotein (RNP) with an ssDNA oligonucleotide donor together generated correction of at least one ß-globin allele in more than 30% of long-term engrafting human HSCs. After adopting a high-fidelity Cas9 variant, efficient correction with minimal off-target events also was observed. In vivo erythroid differentiation markedly enriches for corrected ß-globin alleles, indicating that erythroblasts carrying one or more corrected alleles have a survival advantage. Significance These findings indicate that the sickle mutation can be corrected in autologous HSCs with an optimized protocol suitable for clinical translation.
Sugar intake, particularly fructose, is implicated as a factor contributing to insulin resistance via hepatic de novo lipogenesis (DNL). A nine-day fructose reduction trial, controlling for other dietary factors and weight, in children with obesity and metabolic syndrome, decreased DNL and mitigated cardiometabolic risk (CMR) biomarkers. Ceramides are bioactive sphingolipids whose dysregulated metabolism contribute to lipotoxicity, insulin resistance, and CMR. We evaluated the effect of fructose reduction on ceramides and correlations between changes observed and changes in traditional CMR biomarkers in this cohort. Analyses were completed on data from 43 participants. Mean weight decreased (−0.9 ± 1.1 kg). The majority of total and subspecies ceramide levels also decreased significantly, including dihydroceramides, deoxyceramides and ceramide-1-phoshates. Change in each primary ceramide species correlated negatively with composite insulin sensitivity index (CISI). Change in deoxyceramides positively correlated with change in DNL. These results suggest that ceramides decrease in response to dietary fructose restriction, negatively correlate with insulin sensitivity, and may represent an intermediary link between hepatic DNL, insulin resistance, and CMR.
Few studies have described the goals and wishes of parents caring for their children with rare diseases, specifically when children are unable to communicate their preferences directly. The purpose of this study was to describe the parent’s understanding of their child’s illness, goals of care, and what mattered most to their child from the parent’s perspective. Six families completed a feasibility study of the FAmily CEntered (FACE)-Rare pACP intervention. Qualitative content analysis was performed on transcripts of videotaped responses to the Respecting Choices Next Steps pACP Conversation facilitated conversation guide about the goals of care. Codes were grouped into themes, with direct participant quotations representing the themes. Five themes emerged: getting out and moving freely; feeling included and engaged; managing symptoms and disease burden; coordinating care among many care team members; and managing today and planning for the future. In the context of pACP, families reported that what mattered most to their children included the freedom of movement and human connection and engagement, while parents strived to be effective caregivers and advocates for their child with a rare and severely disabling disease.
The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8676 children, 3–4 months of age, born with HLA-susceptibility genotypes for islet autoimmunity (IA) and type 1 diabetes (T1D). Whole-genome sequencing (WGS) was performed in 1119 children in a nested case–control study design. Telomere length was estimated from WGS data using five tools: Computel, Telseq, Telomerecat, qMotif and Motif_counter. The estimated median telomere length was 5.10 kb (IQR 4.52–5.68 kb) using Computel. The age when the blood sample was drawn had a significant negative correlation with telomere length (P = 0.003). European children, particularly those from Finland (P = 0.041) and from Sweden (P = 0.001), had shorter telomeres than children from the U.S.A. Paternal age (P = 0.019) was positively associated with telomere length. First-degree relative status, presence of gestational diabetes in the mother, and maternal age did not have a significant impact on estimated telomere length. HLA-DR4/4 or HLA-DR4/X children had significantly longer telomeres compared to children with HLA-DR3/3 or HLA-DR3/9 haplogenotypes (P = 0.008). Estimated telomere length was not significantly different with respect to any IA (P = 0.377), IAA-first (P = 0.248), GADA-first (P = 0.248) or T1D (P = 0.861). These results suggest that telomere length has no major impact on the risk for IA, the first step to develop T1D. Nevertheless, telomere length was shorter in the T1D high prevalence populations, Finland and Sweden.
GPIHBP1, an endothelial cell (EC) protein, captures lipoprotein lipase (LPL) within the interstitial spaces (where it is secreted by myocytes and adipocytes) and transports it across ECs to its site of action in the capillary lumen. GPIHBP1's 3-fingered LU domain is required for LPL binding, but the function of its acidic domain (AD) has remained unclear. We created mutant mice lacking the AD and found severe hypertriglyceridemia. As expected, the mutant GPIHBP1 retained the capacity to bind LPL. Unexpectedly, however, most of the GPIHBP1 and LPL in the mutant mice was located on the abluminal surface of ECs (explaining the hypertriglyceridemia). The GPIHBP1-bound LPL was trapped on the abluminal surface of ECs by electrostatic interactions between the large basic patch on the surface of LPL and negatively charged heparan sulfate proteoglycans (HSPGs) on the surface of ECs. GPIHBP1 trafficking across ECs in the mutant mice was normalized by disrupting LPL-HSPG electrostatic interactions with either heparin or an AD peptide. Thus, GPIHBP1's AD plays a crucial function in plasma triglyceride metabolism; it sheathes LPL's basic patch on the abluminal surface of ECs, thereby preventing LPL-HSPG interactions and freeing GPIHBP1-LPL complexes to move across ECs to the capillary lumen.
Objectives: This study aimed to determine if the use of intranasal (IN) fentanyl in the pediatric emergency department of 2 to 5 μg/kg at doses greater than 100 μg is associated with adverse events in pediatric patients. Methods: We performed a retrospective chart review of patients receiving IN fentanyl at an urban, tertiary care emergency department in Memphis, TN, from January 1, 2011, to December 31, 2017. All adverse events documented through the hospital's voluntary safety reporting system involving IN fentanyl were reviewed to determine patient outcomes. Results: A total of 3205 patients received greater than 100 μg of IN fentanyl during the study period from 2011 to 2017. The average (SD) patient age was 13.7 (2.65) years, ranging from 5 to 18 years. The mean (SD) initial dose was 162 (30) μg ranging from 102 to 265 μg (2 doses were given greater than 200 μg in the study period). Initial average (SD) dose for weight was 2.62 (0.5) μg/kg. A total of 13 adverse events were documented, with only 3 occurring at doses greater than 100 μg. No patients required the reversal agent naloxone or invasive respiratory support. Conclusions: To our knowledge, this is the first study using doses greater than 100 μg of IN fentanyl in a pediatric population. Our results indicate that fentanyl can be safely administered at doses of greater than 100 μg without any clinically significant adverse outcomes observed for 7 years of use. It is our hope that this information will increase utilization of IN fentanyl for treatment of acute pain in emergency departments and in the prehospital setting.
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98 members
Jung Suh
  • Nutrition and Metabolism Center
Beate Illek
  • Cystic Fibrosis Research Laboratory
Ronald M Krauss
  • Atherosclerosis Research
Elizabeth A Trachtenberg
  • Center for Genetics, and Center for Immunobiology & Vaccine Development
Vasanthy Narayanaswami
  • Department of Chemistry and Biochemistry
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