Sickle Cell Disease Treatment with Arginine Therapy (STArT): study protocol for a phase 3 randomized controlled trial.

BACKGROUND: Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults. METHODS: STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant\u27s randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE. DISCUSSION: Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children. TRIAL REGISTRATION: The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354)

A Quality Improvement Initiative to Improve Emergency Department Care for Pediatric Patients with Sickle Cell Disease.

ObjectiveTo determine whether a quality improvement (QI) initiative would result in more timely assessment and treatment of acute sickle cell-related pain for pediatric patients with sickle cell disease (SCD) treated in the emergency department (ED).MethodsWe created and implemented a protocol for SCD pain management in the ED with the goals of improving (1) mean time from triage to first analgesic dose; (2) percentage of patients that received their first analgesic dose within 30 minutes of triage, and (3) percentage of patients who had pain assessment performed within 30 minutes of triage and who were re-assessed within 30 minutes after the first analgesic dose.ResultsSignificant improvements were achieved between baseline (55 patient visits) and post order set implementation (165 visits) in time from triage to administration of first analgesic (decreased from 89.9 ± 50.5 to 35.2 ± 22.8 minutes, P < 0.001); percentage of patient visits receiving pain medications within 30 minutes of triage (from 7% to 53%, P < 0.001); percentage of patient visits assessed within 30 minutes of triage (from 64% to 99.4%, P < 0.001); and percentage of patient visits re-assessed within 30 minutes of initial analgesic (from 54% to 86%, P < 0.001).ConclusionsImplementation of a QI initiative in the ED led to expeditious care for pediatric patients with SCD presenting with pain. A QI framework provided us with unique challenges but also invaluable lessons as we address our objective of decreasing the quality gap in SCD medical care

Physical restraint use in children with mental and behavioral health emergencies in the prehospital setting.

OBJECTIVE: Emergency medical services (EMS) transport for mental and behavioral health (MBH) emergencies occurs frequently in children, yet little is understood regarding prehospital physical restraint use despite the potential for serious adverse events. We aim to describe restraint use prevalence and primary impressions among children with MBH emergencies. METHODS: This is a retrospective cross-sectional study of children with MBH emergencies evaluated by Alameda County (ALCO), California EMS from January 1, 2012 to December 31, 2018. Patient demographics and clinical variables were collected from the EMS records including sex, age at time of encounter, year of encounter, transport destination, medication use, and primary impression(s). The primary outcome was the use of physical restraints. Descriptive statistics were used to characterize the primary outcome and associated demographic and diagnostic features, as well as temporal use patterns. Sex and age were compared between restrained and non-restrained youth using chi-square analysis. RESULTS: Over the 7-year study period, ALCO EMS transported 9775 children with MBH emergencies. Of these transports, 1205 (12.3%) were physically restrained. Most children restrained had the primary impression of behavioral/psychiatric crisis (51.1%), psychiatric crisis (27.4%), and behavioral-other (12.4%) and the remaining children (9.1%) had a non-psychiatric/behavioral health primary impression. Over time, there was no statistically significant change in either number of children with MBH emergencies transported or physical restraint rate. CONCLUSIONS: More than 1 in 8 children with MBH emergencies are being physically restrained during EMS transport. Restraint rate did not substantially change over time. Further studies to understand existing restraint rates and EMS resources available to address acute agitation in children are needed to inform quality and care enhancing initiatives

Physical restraint use in children with mental and behavioral health emergencies in the prehospital setting

Abstract Objective Emergency medical services (EMS) transport for mental and behavioral health (MBH) emergencies occurs frequently in children, yet little is understood regarding prehospital physical restraint use despite the potential for serious adverse events. We aim to describe restraint use prevalence and primary impressions among children with MBH emergencies. Methods This is a retrospective cross‐sectional study of children with MBH emergencies evaluated by Alameda County (ALCO), California EMS from January 1, 2012 to December 31, 2018. Patient demographics and clinical variables were collected from the EMS records including sex, age at time of encounter, year of encounter, transport destination, medication use, and primary impression(s). The primary outcome was the use of physical restraints. Descriptive statistics were used to characterize the primary outcome and associated demographic and diagnostic features, as well as temporal use patterns. Sex and age were compared between restrained and non‐restrained youth using chi‐square analysis. Results Over the 7‐year study period, ALCO EMS transported 9775 children with MBH emergencies. Of these transports, 1205 (12.3%) were physically restrained. Most children restrained had the primary impression of “behavioral/psychiatric crisis” (51.1%), “psychiatric crisis” (27.4%), and “behavioral–other” (12.4%) and the remaining children (9.1%) had a non‐psychiatric/behavioral health primary impression. Over time, there was no statistically significant change in either number of children with MBH emergencies transported or physical restraint rate. Conclusions More than 1 in 8 children with MBH emergencies are being physically restrained during EMS transport. Restraint rate did not substantially change over time. Further studies to understand existing restraint rates and EMS resources available to address acute agitation in children are needed to inform quality and care enhancing initiatives

LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer

Abstract Long noncoding RNAs (lncRNAs) are emerging as regulators of gene expression in pathogenesis, including cancer. Recently, lncRNAs have been implicated in progression of specific subtypes of breast cancer. One aggressive, basal‐like subtype associates with increased EGFR signaling, while another, the HER2‐enriched subtype, engages a kin of EGFR. Based on the premise that EGFR‐regulated lncRNAs might control the aggressiveness of basal‐like tumors, we identified multiple EGFR‐inducible lncRNAs in basal‐like normal cells and overlaid them with the transcriptomes of over 3,000 breast cancer patients. This led to the identification of 11 prognostic lncRNAs. Functional analyses of this group uncovered LINC01089 (here renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal‐like and in HER2‐positive tumors, and the low expression of which predicts poor patient prognosis. Interestingly, EGF rapidly downregulates LIMT expression by enhancing histone deacetylation at the respective promoter. We also find that LIMT inhibits extracellular matrix invasion of mammary cells in vitro and tumor metastasis in vivo. In conclusion, lncRNAs dynamically regulated by growth factors might act as novel drivers of cancer progression and serve as prognostic biomarkers

Sickle Cell Disease Treatment with Arginine Therapy (STArT): study protocol for a phase 3 randomized controlled trial

Abstract Background Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults. Methods STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant’s randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE. Discussion Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children. Trial registration The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354)