Impact of patient race/ethnicity on emergency department management of pediatric gastroenteritis in the setting of a clinical pathway.

BACKGROUND: Acute gastroenteritis (AGE) is a common pediatric diagnosis in emergency medicine, accounting for 1.7 million visits annually. Little is known about racial/ethnic differences in care in the setting of standardized care models. METHODS: We used quality improvement data for children 6 months to 18 years presenting to a large, urban pediatric emergency department (ED) treated via a clinical pathway for AGE/dehydration between 2011 and 2018. Race/ethnicity was evaluated as a single variable (non-Hispanic [NH]-White, NH-Black, Hispanic, and NH-other) related to ondansetron and intravenous fluid (IVF) administration, ED length of stay (LOS), hospital admission, and ED revisits using multivariable regression. RESULTS: Of 30,849 ED visits for AGE/dehydration, 18.0% were NH-White, 57.2% NH-Black, 12.5% Hispanic, and 12.3% NH-other. Multivariable mixed-effects generalized linear regression controlling for age, sex, triage acuity, payer, and language revealed that, compared to NH-White patients, NH-other patients were more likely to receive ondansetron (adjusted odds ratio [95% CI] = 1.30 [1.17 to 1.43]). NH-Black, Hispanic, and NH-other patients were significantly less likely to receive IVF (0.59 [0.53 to 0.65]; 0.74 [0.64 to 0.84]; 0.74 [0.65 to 0.85]) or be admitted to the hospital (0.54 [0.45 to 0.64]; 0.62 [0.49 to 0.78]; 0.76 [0.61 to 0.94]), respectively. NH-Black and Hispanic patients had shorter LOS (median = 245 minutes for NH-White, 176 NH-Black, 199 Hispanic, and 203 NH-other patients) without significant differences in ED revisits. CONCLUSIONS: Despite the presence of a clinical pathway to guide care, NH-Black, Hispanic, and NH-other children presenting to the ED with AGE/dehydration were less likely to receive IVF or hospital admission and had shorter LOS compared to NH-White counterparts. There was no difference in patient revisits, which suggests discretionary overtreatment of NH-White patients, even with clinical guidelines in place. Further research is needed to understand the drivers of differences in care to develop interventions promoting equity in pediatric emergency care.

Scalp Lesions in a Pediatric Patient with Hyper IgM Syndrome: Clinical and Histologic Mimicry of Cryptococcus neoformans Infection.

We report a case of cutaneous cryptococcosis due to Cryptococcus neoformans in a pediatric patient with hyper IgM syndrome with scalp lesions that resembled tinea capitis on gross examination and mimicked juvenile xanthogranuloma on histologic examination. This case highlights the importance of considering cutaneous cryptococcosis in patients with hyper IgM syndrome.

Therapeutic targeting of HES1 transcriptional programs in T-ALL.

Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1-induced leukemogenesis strictly required for tumor cell survival. Mechanistically, we demonstrate that HES1 directly downregulates the expression of BBC3, the gene encoding the PUMA BH3-only proapoptotic factor in T-cell acute lymphoblastic leukemia. Finally, we identify perhexiline, a small-molecule inhibitor of mitochondrial carnitine palmitoyltransferase-1, as a HES1-signature antagonist drug with robust antileukemic activity against NOTCH1-induced leukemias in vitro and in vivo.

A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia.

Efforts to identify and annotate cancer driver genetic lesions have been focused primarily on the analysis of protein-coding genes; however, most genetic abnormalities found in human cancer are located in intergenic regions. Here we identify a new long range-acting MYC enhancer controlled by NOTCH1 that is targeted by recurrent chromosomal duplications in human T cell acute lymphoblastic leukemia (T-ALL). This highly conserved regulatory element, hereby named N-Me for NOTCH MYC enhancer, is located within a broad super-enhancer region +1.47 Mb from the MYC transcription initiating site, interacts with the MYC proximal promoter and induces orientation-independent MYC expression in reporter assays. Moreover, analysis of N-Me knockout mice demonstrates a selective and essential role of this regulatory element during thymocyte development and in NOTCH1-induced T-ALL. Together these results identify N-Me as a long-range oncogenic enhancer implicated directly in the pathogenesis of human leukemia and highlight the importance of the NOTCH1-MYC regulatory axis in T cell transformation and as a therapeutic target in T-ALL.

Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin.

Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs), NAD(+)-dependent enzymes, link cellular energy status with responses to environmental stresses. Skin is frequently exposed to the DNA damaging effects of UV irradiation, a known etiology in skin cancer. Thus, understanding the defense mechanisms in response to UV, including the role of SIRTs and PARPs, may be important in developing skin cancer prevention strategies. Here, we report expression of the seven SIRT family members in human skin. SIRTs gene expressions are progressively upregulated in A431 epidermoid carcinoma cells (SIRTs1 and 3), actinic keratoses (SIRTs 2, 3, 5, 6, and 7) and squamous cell carcinoma (SIRTs 1-7). Photodamage induces dynamic changes in SIRT expression with upregulation of both SIRT1 and SIRT4 mRNAs. Specific losses of SIRT proteins occur early after photodamage followed by accumulation later, especially for SIRT4. Niacin restriction, which decreases NAD(+), the sirtuin substrate, results in an increase in acetylated proteins, upregulation of SIRTs 2 and 4, increased inherent DNA damage, alterations in SIRT responses to photodamage, abrogation of PARP activation following photodamage, and increased sensitivity to photodamage that is completely reversed by repleting niacin. These data support the hypothesis that SIRTs and PARPs play important roles in resistance to photodamage and identify specific SIRTs that respond to photodamage and may be targets for skin cancer prevention.