Changes in Size and Demographic Composition of Transgender and Gender Non-Binary Population Receiving Care at Integrated Health Systems.

OBJECTIVE: To examine temporal changes in the number and demographic composition of transgender/gender non-binary (TGNB) population using data from integrated health care systems. METHODS: Electronic health records from Kaiser Permanente health plans in Georgia and Northern and Southern California were used to identify TGNB individuals, who sought care from January 2006 to December 2014, and the data were analyzed by year, site, age, and sex assigned at birth. RESULTS: In 2006, the number of TGNB people (and corresponding 95% CI) per 100 000 population were 3.5 (1.9, 6.3) in Georgia, 5.5 (4.8, 6.4) in Southern California, and 17 (16, 19) in Northern California. In 2014, these frequencies increased to 38 (32, 45), 44 (42, 46), and 75 (72, 78) per 100 000 population, respectively. When analyzed by age, the most rapid increase was observed among persons 18 to 25 years old, and this increase accelerated after 2010. The ratio of transmasculine to transfeminine persons also changed from 1:1.7 in 2006 to 1:1 in 2014 overall and from 1:1 in 2006 to 1.8:1 in 2014 among persons <18 years of age. CONCLUSION: This analysis confirms previous observations that the proportion of TGNB people is growing, especially among young adults. The composition of the TGNB population is also changing from predominantly transfeminine to roughly 1:1 overall and to predominantly transmasculine in children and adolescents.

The ubiquitin-associated (UBA) domain of SCCRO/DCUN1D1 protein serves as a feedback regulator of biochemical and oncogenic activity.

Amplification of squamous cell carcinoma-related oncogene (SCCRO) activates its function as an oncogene in a wide range of human cancers. The oncogenic activity of SCCRO requires its potentiating neddylation domain, which regulates its E3 activity for neddylation. The contribution of the N-terminal ubiquitin-associated (UBA) domain to SCCRO function remains to be defined. We found that the UBA domain of SCCRO preferentially binds to polyubiquitin chains in a linkage-independent manner. Binding of polyubiquitin chains to the UBA domain inhibits the neddylation activity of SCCRO in vivo by inhibiting SCCRO-promoted nuclear translocation of neddylation components and results in a corresponding decrease in cullin-RING-ligase-promoted ubiquitination. The results of colony formation and xenograft assays showed a mutation in the UBA domain of SCCRO that reduces binding to polyubiquitin chains, significantly enhancing its oncogenic activity. Analysis of 47 lung and head and neck squamous cell carcinomas identified a case with a frameshift mutation in SCCRO that putatively codes for a protein that lacks a UBA domain. Analysis of data from The Cancer Genome Atlas showed that recurrent mutations cluster in the UBA domains of SCCRO, lose the ability to bind to polyubiquitinated proteins, and have increased neddylation and transformation activities. Combined, these data suggest that the UBA domain functions as a negative regulator of SCCRO function. Mutations in the UBA domain lead to loss of inhibitory control, which results in increased biochemical and oncogenic activity. The clustering of mutations in the UBA domain of SCCRO suggests that mutations may be a mechanism of oncogene activation in human cancers.

SCCRO3 (DCUN1D3) antagonizes the neddylation and oncogenic activity of SCCRO (DCUN1D1).

The activity of cullin-RING type ubiquitination E3 ligases is regulated by neddylation, a process analogous to ubiquitination that culminates in covalent attachment of the ubiquitin-like protein Nedd8 to cullins. As a component of the E3 for neddylation, SCCRO/DCUN1D1 plays a key regulatory role in neddylation and, consequently, cullin-RING ligase activity. The essential contribution of SCCRO to neddylation is to promote nuclear translocation of the cullin-ROC1 complex. The presence of a myristoyl sequence in SCCRO3, one of four SCCRO paralogues present in humans that localizes to the membrane, raises questions about its function in neddylation. We found that although SCCRO3 binds to CAND1, cullins, and ROC1, it does not efficiently bind to Ubc12, promote cullin neddylation, or conform to the reaction processivity paradigms, suggesting that SCCRO3 does not have E3 activity. Expression of SCCRO3 inhibits SCCRO-promoted neddylation by sequestering cullins to the membrane, thereby blocking its nuclear translocation. Moreover, SCCRO3 inhibits SCCRO transforming activity. The inhibitory effects of SCCRO3 on SCCRO-promoted neddylation and transformation require both an intact myristoyl sequence and PONY domain, confirming that membrane localization and binding to cullins are required for in vivo functions. Taken together, our findings suggest that SCCRO3 functions as a tumor suppressor by antagonizing the neddylation activity of SCCRO.

Determining Normative Values for Cerebrospinal Fluid Profiles in Infants.

BACKGROUND: Previous studies of reference values for cerebrospinal fluid (CSF) profiles have been limited by small sample size and few exclusion criteria. OBJECTIVE: To determine age-specific normative CSF white blood cell count (WBC), glucose, and protein values in infants ≤90 days old. METHODS: Performed a retrospective cross-sectional study of infants ≤90 days old who had a diagnostic lumbar puncture between 2008 and 2016. Infants with bacterial meningitis, bacteremia, UTI, positive CSF herpes simplex virus polymerase chain reaction (PCR) result, traumatic lumbar puncture, ventriculoperitoneal shunt, prematurity, recent seizure, previous antibiotic use, and history of a complex chronic condition were excluded for calculations to determine normative values. Data on demographics and CSF values (WBC with differential, protein, glucose, enterovirus PCR) were collected. CSF values were compared by age and by enterovirus PCR results using Kruskal-Wallis and Wilcoxon rank tests. RESULTS: A total of 1029 out of 2000 patients were included and divided into 3 age groups: 0 to 28 days, 29 to 60 days, 61 to 90 days. CSF WBC values were significantly greater for 0- to 28-day old infants (median: 3, 95th percentile: 14) than for 29- to 60-day and 61- to 90-day old infants (median: 2 and 2; 95th percentile: 7 and 11, respectively) (P < .001). With each month of life, the median CSF protein significantly decreased and glucose significantly increased. In the CSF WBC differential, monocytes were found to be prevalent. CONCLUSION: We determined age-specific normative components for CSF profile values for infants 0 to 90 days.

Dexamethasone Versus Prednisone in Children Hospitalized for Acute Asthma Exacerbations.

BACKGROUND AND OBJECTIVES: Extensive literature supports using dexamethasone (DEX) in children presenting to the emergency department (ED) with mild-to-moderate asthma exacerbations; however, only limited studies have assessed this in hospitalized children. In this study, we evaluate the outcomes of DEX versus prednisone/prednisolone (PRED) use in children hospitalized for mild-to-moderate asthma exacerbations. METHODS: This multisite retrospective cohort study included children between 3 and 21 years of age hospitalized to a tertiary care children's hospital system between January 1, 2013, and December 31, 2017, with a primary discharge diagnosis of acute asthma exacerbation or status asthmaticus. Primary study outcome was mean hospital length of stay (LOS). Secondary outcomes included PICU transfers during initial hospitalization and ED revisits and hospital readmissions within 10 days after discharge. Generalized linear models were used to model logged LOS as a function of steroid and demographic and clinical covariates. The analysis was stratified by initial steroid timing. RESULTS: Of the 1410 children included, 981 received only DEX and 429 received only PRED. For children who started oral steroids after hospital arrival, DEX cohort had a significantly shorter adjusted mean hospital LOS (DEX 24.43 hours versus PRED 29.38 hours; P = .03). For children who started oral steroids before hospital arrival, LOS did not significantly differ (DEX 26.72 hours versus PRED 25.20 hours; P = .45). Rates of PICU transfers, ED revisits, and hospital readmissions were uncommon events. CONCLUSION: Children hospitalized with mild-to-moderate asthma exacerbations have significantly shorter hospital LOS when starting DEX rather than PRED on admission.