Social Determinants of Health and Health-Related Quality of Life following Pediatric Septic Shock: Secondary Analysis of the Life After Pediatric Sepsis Evaluation Dataset, 2014-2017.

OBJECTIVES: Social determinants of health (SDOH) are associated with disparities in disease severity and in-hospital outcomes among critically ill children. It is unknown whether SDOH are associated with later outcomes. We evaluated associations between SDOH measures and mortality, new functional morbidity, and health-related quality of life (HRQL) decline among children surviving septic shock. DESIGN: Secondary analysis of the Life After Pediatric Sepsis Evaluation (LAPSE) prospective cohort study was conducted between 2014 and 2017. SETTING: Twelve academic U.S. PICUs were involved in the study. PATIENTS: Children younger than 18 years with community-acquired septic shock were involved in the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed associations between race, ethnicity, income, education, marital status, insurance, language, and home U.S. postal code with day 28 mortality, new functional morbidity at discharge per day 28, and HRQL decline using logistic regression. Of 389 patients, 32% (n = 98) of families had household income less than $50,000 per year. Median Pediatric Risk of Mortality (PRISM) score was 11 (interquartile range 6, 17). We found that English language and Area Deprivation Index less than 50th percentile were associated with higher PRISM scores. Mortality was 6.7% (n = 26), new functional morbidity occurred in 21.8% (n = 78) of patients, and HRQL decline by greater than 10% occurred in 31.0% of patients (n = 63). We failed to identify any association between SDOH measures and mortality, new functional morbidity, or HRQL decline. We are unable to exclude the possibility that annual household income greater than or equal to $50,000 was associated with up to 81% lesser odds of mortality and, in survivors, more than three-fold greater odds of HRQL decline by greater than 10%. CONCLUSIONS: In this secondary analysis of the 2014-2017 LAPSE dataset, we failed to identify any association between SDOH measures and in-hospital or postdischarge outcomes following pediatric septic shock. This finding may be reflective of the high illness severity and single disease (sepsis) of the cohort, with contribution of clinical factors to functional and HRQL outcomes predominating over prehospital and posthospital SDOH factors.

Gamification of a Low-Fidelity Paper Doll to Teach Primary Survey to Pediatric Residents.

When critically ill pediatric patients arrive in the emergency department (ED), a rapid physical evaluation is performed in order to systematically evaluate and address life-threatening conditions. This is commonly referred to as the primary survey. At our institution, pediatric residents are frequently tasked with this role, but they have limited training for or experience with this task. Quality improvement review of real resuscitation recordings at our institution revealed delays in initiation and incomplete primary surveys. We sought to utilize gamification to standardize and optimize reproducible training for the primary survey task for pediatric residents using a low-fidelity paper doll model simulation to improve primary survey performance in actual resuscitations.

Association Between Language Use and ICU Transfer and Serious Adverse Events in Hospitalized Pediatric Patients Who Experience Rapid Response Activation.

Background: Hospitalized patients and caregivers who use a language other than English have worse health outcomes, including longer length of stay, more frequent readmissions, and increased rates of in-hospital adverse events. Children who experience clinical deterioration (as measured by a Rapid Response Team event) during a hospitalization are at increased risk for adverse events and mortality. Methods: We describe the results of a retrospective cohort study using hospital records at a free-standing, quaternary children's hospital, to examine the association of language of care with outcomes (transfer to intensive care, adverse event, mortality prior to discharge) following Rapid Response Team event, and whether increased interpreter use among patients who use a language other than English is associated with improved outcomes following Rapid Response Team event. Results: In adjusted models, Rapid Response Team events for patients who use a language other than English were associated with higher transfer rates to intensive care (RR 1.1, 95% CI 1.01, 1.21), but not with adverse event or mortality. Among patients who use a language other than English, use of 1-2 interpreted sessions per day was associated with lower transfer rates to intensive care compared to use of less than one interpreted session per day (RR 0.79, 95% 0.66, 0.95). Conclusion: Rapid Response Team events for hospitalized children of families who use a language other than English are more often followed by transfer to intensive care, compared with Rapid Response Team events for children of families who use English. Improved communication with increased interpreter use for hospitalized children who use a language other than English may lead to improvements in Rapid Response Team outcomes.

Stop the Bleed Training for High School Students: Guardian Attitudes and Their Association with Prior Trauma.

BACKGROUND: Uncontrolled bleeding is the leading preventable cause of death after injury. Stop the Bleed (STB) is a bleeding control training with proposed expansion into schools. However, the attitudes of guardians, specifically those with past trauma/injury, towards expanding STB into schools are unknown. METHODS: A cross-sectional survey evaluated guardian attitudes towards STB training in high schools, and compared responses between guardians based on the experience of prior trauma. Logistic regression models evaluated the association between prior trauma and guardian-reported acceptability of STB training. RESULTS: Of 750 guardians who received the survey, 484 (64.5%) responded. Most guardians (95.3%) wanted their child trained. Few (4.2%) felt this training would be harmful; 44.9% felt their child might be held responsible if something went wrong, and 28.4% reported it might be too scary for their child. In adjusted models, guardians with prior trauma were more likely to want their child trained (odds ratio [OR] = 3.50, 95% confidence interval [CI] 1.11-15.50), and identify STB as important to them (OR = 4.07, 95% CI 1.66-12.26). CONCLUSION: Our results support STB training in high schools, and guardians with a trauma history may be more likely to want their child trained. Further work to understand the perceived potential harm, and work to design trauma-informed first-response trainings is warranted.

Grounded in Justice: An Equity Framework for Chief Residents.

The 2019-2020 academic year was unprecedented, with navigating the COVID-19 pandemic and meaningfully engaging with the causes and consequences of long-standing racism and social injustice in the United States. In this article, the authors, all former chief residents, reflect on how they carried out their role during this last year using an approach that was grounded in equity and justice. They describe a framework based on their experiences, including setting the tone and culture of the residency program; providing medical education, teaching, and feedback; advocating for resident well-being and inclusion; participating in quality improvement and hospital policymaking; and partnering for institutional change. They end with a call to action to reconceptualize the role of the chief resident to include the genuine work of diversity, equity, and inclusion to ensure a more equitable future.

Pediatric Cancer in Northern Tanzania: Evaluation of Diagnosis, Treatment, and Outcomes.

PURPOSE: The majority of new diagnoses of pediatric cancer are made in resource-poor countries, where survival rates range from 5% to 25% compared with 80% in high-resource countries. Multiple factors, including diagnostic and treatment capacities and complex socioeconomic factors, contribute to this variation. This study evaluated the available resources and outcomes for pediatric patients with cancer at the first oncology treatment center in northern Tanzania. METHODS: Qualitative interviews were completed from July to August 2015 to determine available staff, hospital, diagnostic, treatment, and supportive care resources. A retrospective review of hospital admissions and clinic visits from January 2010 to August 2014 was completed. A total of 298 patients were identified, and data from 182 patient files were included in this review. RESULTS: Diagnostic, treatment, and supportive capacities are limited for pediatric cancer care. The most common diagnoses were Burkitt lymphoma (n = 32), other non-Hodgkin lymphoma (n = 26), and Wilms tumor (n = 25). A total of 40% of patients (n = 72) abandoned care. There was a 20% 2-year event-free survival rate, which was significantly affected by patient age, method of diagnosis, and year of diagnosis. CONCLUSION: To our knowledge, this is the first review of pediatric cancer outcomes in northern Tanzania. The study identified areas for future development to improve pediatric cancer outcomes, which included strengthening of training and diagnostic capacities, development of registries and research databases, and the need for additional research to reduce treatment abandonment.

A toolbox of immunoprecipitation-grade monoclonal antibodies to human transcription factors.

A key component of efforts to address the reproducibility crisis in biomedical research is the development of rigorously validated and renewable protein-affinity reagents. As part of the US National Institutes of Health (NIH) Protein Capture Reagents Program (PCRP), we have generated a collection of 1,406 highly validated immunoprecipitation- and/or immunoblotting-grade mouse monoclonal antibodies (mAbs) to 737 human transcription factors, using an integrated production and validation pipeline. We used HuProt human protein microarrays as a primary validation tool to identify mAbs with high specificity for their cognate targets. We further validated PCRP mAbs by means of multiple experimental applications, including immunoprecipitation, immunoblotting, chromatin immunoprecipitation followed by sequencing (ChIP-seq), and immunohistochemistry. We also conducted a meta-analysis that identified critical variables that contribute to the generation of high-quality mAbs. All validation data, protocols, and links to PCRP mAb suppliers are available at http://proteincapture.org.

Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis.

Nucleic acid binding polymers (NABPs) have been extensively used as vehicles for DNA and RNA delivery. More recently, we discovered that a subset of these NABPs can also serve as anti-inflammatory agents by capturing pro-inflammatory extracellular nucleic acids and associated protein complexes that promote activation of toll-like receptors (TLRs) in diseases such as lupus erythematosus. Nucleic-acid-mediated TLR signaling also facilitates tumor progression and metastasis in several cancers, including pancreatic cancer (PC). In addition, extracellular DNA and RNA circulate on or within lipid microvesicles, such as microparticles or exosomes, which also promote metastasis by inducing pro-tumorigenic signaling in cancer cells and pre-conditioning secondary sites for metastatic establishment. Here, we explore the use of an NABP, the 3rd generation polyamidoamine dendrimer (PAMAM-G3), as an anti-metastatic agent. We show that PAMAM-G3 not only inhibits nucleic-acid-mediated activation of TLRs and invasion of PC tumor cells in vitro, but can also directly bind extracellular microvesicles to neutralize their pro-invasive effects as well. Moreover, we demonstrate that PAMAM-G3 dramatically reduces liver metastases in a syngeneic murine model of PC. Our findings identify a promising therapeutic application of NABPs for combating metastatic disease in PC and potentially other malignancies.

Optimization of PEGylated nanoemulsions for improved pharmacokinetics of BCS class II compounds.

The objective of the study was the optimization of nanoemulsion formulations to prevent their rapid systemic clearance after intravenous administration. An amphiphilic PEG derivative DSPE-PEG (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(polyethylene glycol) with different chain lengths and concentration was used as a nanoemulsion droplet surface modifier. The danazol loading in all nanoemulsions was kept on the same level of ∼2 mg/mL. In the present investigation, PEGylated and non-PEGylated nanoemulsions were compared in vitro phagocytosis by incubating with lung macrophages and in vivo after intravenous administration in rats. Danazol-containing nanoemulsions (NE) modified with various PEG chain lengths (2000-10 000) and concentrations (3-12 mg/mL) were prepared and characterized. Nanoemulsion droplets were reproducibly obtained in the size range of 213-340 nm. The non-PEGylated NE had the surface charge of -25.4 mV. This absolute charge value decreased with increasing chain length and concentration. With increase in chain length and density the macrophage uptake decreased which could be due to decrease in surface charge and hydrophilicity of droplets. The greatest shielding of the NE droplets was reached with DSPE-PEG5000 at the concentration of 6 mg/mL where the surface charge changed to -1.27 mV. Following intravenous administration a maximum danazol exposure (401 ± 68.2 h ng/mL) was observed with the lowest clearance rate (5.06 ± 0.95 L/h/kg) from 6 mg/mL DSPE-PEG5000 nanoemulsion. PEG5000 and PEG10000 altered the pharmacokinetic of danazol by decreasing clearance and volume of distribution which is likely explained by the presence of hydrophilic shields around the droplets that prevent their rapid systemic clearance and tissue partitioning.

Evaluation of a nanoemulsion formulation strategy for oral bioavailability enhancement of danazol in rats and dogs.

The objective of this study was to determine whether nanoemulsion formulations constitute a viable strategy to improve the oral bioavailability of danazol, a compound whose poor aqueous solubility limits its oral bioavailability. Danazol-containing oil-in-water nanoemulsions (NE) with and without cosurfactants stearylamine (SA) and deoxycholic acid (DCA) were prepared and characterized. Nanoemulsion droplets size ranging from 238 to 344 nm and with surface charges of -24.8 mV (NE), -26.5 mV (NE-DCA), and +27.8 mV (NE-SA) were reproducibly obtained. Oral bioavailability of danazol in nanoemulsions was compared with other vehicles such as PEG400, 1% methylcellulose (MC) in water (1% MC), Labrafil, and a Labrafil/Tween 80 (9:1) mixture, after intragastric administration to rats and after oral administration of NE-SA, a Labrafil solution, or a Danocrine® tablet to dogs. The absolute bioavailability of danazol was 0.6% (PEG400), 1.2% (1% MC), 6.0% (Labrafil), 7.5% (Labrafil/Tween80), 8.1% (NE-DCA), 14.8% (NE), and 17.4% (NE-SA) in rats, and 0.24% (Danocrine), 6.2% (Labrafil), and 58.7% (NE-SA) in dogs. Overall, danazol bioavailability in any nanoemulsion was higher than any other formulation. Danazol bioavailability from NE and NE-SA was 1.8- to 2.2-fold higher than NE-DCA nanoemulsion and could be due to significant difference in droplet size.