Injury and Forensic Examination of the Victim

2025-05-19

Survivors of sexual assault require comprehensive, efficient, and sensitive care as soon as possible after the assault. Survivors have physical and emotional sequelae after sexual violence (SV) that must be addressed. This chapter reviews the literature on genital and body injury, common locations of genital injury, genital injury in consensual intercourse, skin color’s role, and best practices. In addition, this chapter outlines the forensic examination, and treatment as well as collection of evidence from a victim of sexual assault. Examination as soon as possible after sexual assault is needed for early intervention and treatment of physical injuries and collection of transferred forensic evidence from the victim’s body. Specialized training in the forensic examination is advised for physicians and sexual assault nurse examiners.

Impact of chronic pain on acute pain trajectories in sickle cell disease: Insights from the sickle cell disease treatment with arginine therapy (STArT) randomized controlled trial

Blood · 2025-11-03

Abstract Background/Methods: STArT (NCT04839354) was a phase-3 double-blind, randomized placebo-controlled trial of intravenous (IV) arginine therapy in participants aged 3-21 years with sickle cell disease (SCD) and vasoocclusive episode (VOE) pain requiring IV opioids. STaRT was conducted at 10 US sites utilizing the Pediatric Emergency Care Applied Research Network (PECARN). Enrolled participants were randomized 1:1 to receive either study drug or placebo within 12 hours of receiving their first dose of IV opioid. The primary outcome was time-to-crisis- resolution defined as the time in hours from study drug delivery to the last dose of IV opioid. Secondary outcomes included total parenteral opioid & patient reported outcomes (PROMIS) at admission, discharge, and 7-12 days post-discharge. Participants were classified at enrollment as having chronic pain (CP) if they experienced pain on ‘15 or more days of the month’ or ‘atleast half the days of the month’ for the last 6 months. Methods: We compared demographic and clinical characteristics and change in pain score (enrollment-discharge) by CP group. We then examined pain intensity trajectories of the highest daily pain score (0-10) during hospitalization in study participants by CP status at enrollment; to do so, we included CP status as a main effect and CP status X follow-up day as an interaction term in linear mixed models. Similar models were also examined with sex as a main effect. Finally, a four-level sex-CP variable as a main effect and sex-CP X follow-up day as an interaction were assessed. Unadjusted models were examined, as were models adjusted for total opioid received in IV morphine milligram equivalent/kilogram body weight. Results: Two hundred and seventy-one participants were randomized and received study drug (129-arginine, 142-placebo), and data on presence of CP was available for 268 participants. The median age of participants was 15.1 years (IQR 11.2-17.7), 71.3% (n=191) of participants were age 12 and older, and 51.9 %, (n=139) were male. Most had Hemoglobin SS genotype (70.1%, n=188). Most participants were prescribed HU (75.7%, n= 203) and 21.1% (n=54) received chronic transfusion therapy. About half (51%) reported that they experienced CP, and 77.2% (n=207) experienced 3 or more healthcare visits for pain in the 12 months prior to enrollment. Almost all reported a pain score of 6 or higher at arrival to the Emergency Department. Clinical characteristics at enrollment were similar across CP groups, except that the CP group was more likely to have a history of acute chest syndrome (p=0.013) and asthma (p=0.026). Participants in the CP group were also more likely to report 3 or more healthcare visits for pain in the 12 months prior to enrollment (p<0.001). We found a significantly lower change in pain score (enrollment-discharge) in the CP group (mean 3.9, SD 3.2) compared to the non-CP group (mean 4.8, SD 3.4, p=0.018). Participants with CP were more likely to return to the ED within 28-days. The mean number of follow-up number of days with pain score assessments was 3.82 days (SD 1.99 days). Examining trends in highest pain intensity score during hospitalization, we found a significant decrease in pain score for the entire cohort (p<0.001), with an average 0.18-point decrease (slope estimate -0.18, 95% CI: -0.28, -0.08) in highest pain score for every day of measurement. There was no difference in decrease in pain score by sex. The interaction between CP X follow-up day was significant (p<0.001), indicating a difference in trends by CP status; the CP group had a slower decrease in pain (slope estimate -0.05, 95% CI -0.19, 0.08) as compared to non-CP group (slope estimate -0.42, 95% CI -0.58, -0.26). The interaction between follow-up day and sex-CP was significant (p=0.007), indicating that pain trajectories over time differ by sex-CP level. Both male and female participants with CP experienced a significantly smaller decline in daily high pain scores over time compared to those without CP. Conclusion: About half of children and young adults hospitalized with SCD VOE have CP. Children and young adults with CP, compared to those without CP, experience a smaller magnitude of change in pain score and a slower decline in pain during hospitalization. These findings should be considered in the study design and selection of study outcomes for future SCD acute pain clinical trials.

The psychometric properties of the stoplight pain scale in children with sickle cell disease

Blood · 2025-11-03

Abstract Background: Effective pain management begins with accurate pain assessment for children with sickle cell disease (SCD) experiencing a vaso-occlusive episodes (VOE). While most scales measure pain, these traditional tools do not guide therapeutic intervention directly and rely on a healthcare provider to decide what to do instead of allowing the child to direct it. The Stoplight Pain Scale (SPS) is a novel, child friendly, 3-face scale that integrates pain assessment with guidance for its management. Combining a red-yellow-green color scheme with cartoon faces and directive action phrases, SPS categorizes pain as “green” (I'm ok; I feel fine right now), “yellow” (I'm not sure; Ask me again later), and “red” (I hurt; I need something to feel better). SPS has shown early promise in assessing acute pain in children, but its validity for use in SCD-VOE, particularly for repeated measures over time, has not been previously investigated. Objective: To evaluate the validity of the SPS in children with SCD-VOE presenting to the emergency department. Methods: This prospective observational cohort study was a planned sub-study of a multicenter phase-3 randomized controlled trial evaluating the efficacy of intravenous arginine for SCD-VOE. Endorsed by the Pediatric Emergency Care Applied Research Network (PECARN) and conducted at 10 US sites from 2022-2024, the study enrolled children aged 3 to 21 years. Participants rated their pain using the SPS and verbal Numeric Rating Scale (NRS) at enrollment and daily through hospital discharge. Descriptive statistics and correlations were calculated overall and then stratified by age using cluster bootstrapped 95% confidence intervals to account for repeated measures. Pearson correlation coefficients between the two scales at the first, last, lowest, and highest recorded measures were also computed and assessed. Results: Ninety-eight participants contributed 394 assessments for up to 8 hospital days. The mean (SD) child age was 13.0 (4.6) years; 46% were male, 74% had HB-SS genotype, and 44% reported >3 hospitalizations in the prior year. At enrollment, pain severity using SPS was “green” in 17.2%, “yellow” in 37.9%, and “red” in 44.8%. Median (IQR) NRS pain score was 7 (5, 9). SPS and NRS scores were strongly correlated (r=0.77; 95% CI 0.72, 0.82), supporting convergent validity which demonstrated the degree to which these two tools that are intended to measure pain produced similar results. Correlation was strong for lowest reported values (r =0.73; p<0.001) and moderate for highest reported values (r=0.64; p=0.001). Correlation was better for children aged 6-12 years (r=0.83; 95% CI 0.77, 0.89) compared to 13–17-year-olds (r=0.70; 95% CI 0.59, 0.80) and those greater than 17 years (r=0.65; 95% CI 0.45, 0.78). Discriminant validity was supported by changes in pain scores from the first to the last recorded measure: “green” increased from 19.6% at enrollment to 62.9% at discharge, while “red” decreased from 43.3% to 13.4%. SPS demonstrated responsiveness to change by detecting meaningful changes over time, particularly in response to hospital interventions resulting in decreasing “red” and increasing “green” responses over hospitalization days; for example, “red” decreased from 50% on day 1 to 18% on day 8; and “green” increased from 17% on day 1 to 55% on day 3. Conclusion: The SPS demonstrated good convergent validity, discriminant validity and responsiveness to change in children with SCD-VOE. Overall, there is evidence that this simple, easy-to-implement SPS is a valid assessment tool for children with SCD-VOE. This holds value in the pediatric emergency department setting to rapidly indicate need for analgesia, and its applications extend into reassessments in the inpatient setting. Notably, SPS may be particularly suitable for younger children, a vulnerable group for whom reliable pain assessment is challenging. Further research is warranted to investigate the role of this tool in improving the quality and timeliness of VOE pain management for children with SCD.

A Quality Improvement Project to Increase Nurse-initiated Care from Triage and Improve Timeliness to Care in the Pediatric Emergency Department

Pediatric Quality and Safety · 2025-11-01

Introduction: Initiating care during emergency department (ED) triage is an effective way to decrease time to treatment. Triage nurse-initiated standing orders (SOs) are safe, evidence-based, and allow care to begin for patients before provider evaluation. We describe a multidisciplinary approach to increase the use of SOs across 2 pediatric EDs. Methods: Interventions for this quality improvement initiative were driven by frontline staff input and included education, fostering competition among nurses, individual feedback, and editing of SOs. The primary outcome measure was the use of SO per patient encounter, monitored using a U-chart. The secondary outcome measures were time to dexamethasone in patients with asthma and provider time to disposition for discharged patients with gastroenteritis or streptococcal pharyngitis, monitored by X-bar and S-charts. The process measure was the percentage of orders placed outside of SOs, monitored by a P-chart. The balancing measure was the length of stay for patients with gastroenteritis and streptococcal pharyngitis. Results: The rate of SOs improved from 165 to 234 per 1,500 patient encounters at the main campus and from 53 to 82 per 500 patient encounters at the satellite campus, each resulting in statistical process control chart centerline shifts. There was an improvement in the process measure at both pediatric EDs. Conclusions: SO use increased across the 2 campuses. SO use is associated with shorter length of stay, decreased time to medication, and decreased provider time to disposition for 3 specific patient populations. SOs improve throughput and can be used in the care of pediatric patients.

Sickle cell disease treatment with arginine therapy (STArT) – results of a phase-3 randomized controlled trial

Blood · 2025-11-03 · 2 citations

Abstract Background: Vaso-occlusive pain episodes (VOE) are the leading cause of emergency department (ED) visits and hospitalizations for patients with sickle cell disease (SCD). Yet, FDA-approved drugs for SCD-VOE are lacking. During SCD-VOE, patients develop an acute arginine (Arg) deficiency that is associated with adverse clinical outcomes including longer time-to-crisis-resolution (TCR), and greater total parenteral opioid use (TPO) during hospitalization. Multiple RCTs in the US, Brazil, Nigeria, and Egypt have established that supplementation with Arg is safe, has opioid-sparing effects, improves pain scores, blood pressure, and cardiopulmonary function and decreases length of hospital stay. We and others have shown that Arg increases nitric oxide production, improves mitochondrial function, and decreases both oxidative stress and biomarkers of hemolysis and inflammation. A phase-3 RCT was needed. Objective: To determine the efficacy and safety of intravenous (IV) Arg for SCD-VOE. Methods: We conducted a multicenter, double-blind, phase-3 RCT of IV Arg therapy in subjects aged 3-21 years with SCD-VOE receiving IV opioids at 10 US sites utilizing the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 with a sample size goal of 360 patients. Within 12 hours of receiving their first dose of IV opioids, enrolled participants were randomized 1:1 to receive either 1) a one-time loading dose of IV Arg (200 mg/kg with a max of 20g) followed by a standard dose of 100 mg/kg (max 10g three times/day) or 2) placebo (normal saline) at equivalent volumes/duration as the study drug. Participants, research staff, and investigators were blinded to the patient's randomization. The primary outcome was TCR defined as the time in hours from study drug delivery to the last dose of IV opioid delivery. Secondary outcomes included TPO, defined as total IV morphine equivalents in mg/kg from study drug delivery to last parenteral opioid) and patient reported outcomes (PROMIS) at admission, discharge, and 7-12 days post-discharge. This protocol utilized FDA-IND#66943, registered with ClinicalTrials.gov (NCT04839354).Results: The STArT trial was halted early for futility to achieve the primary outcome of TCR. A total of 2,629 patients were screened, 1034 were eligible, 741 were approached, 293 consented, and 271 randomized who received study drug (129-Arg, 142-placebo) with enrollment milestones nearly a year ahead of schedule. Mean age ±standard deviation (SD) was 14±4 years, 51% were male, 71% had Hb-SS, 76% on hydroxyurea, and 41% had chronic pain (SCD-pain ≥15 days/month for the last 6 months). Demographics were similar across study arms. TCR was similar in the Arg arm vs placebo (82±80 vs. 89±152 hours, p=0.98). TPO was also similar across both arms (2.6±4.5 vs 1.9±2.8mg/kg, p=0.33). No differences in safety outcomes, adverse events, pain scores, PROMIS Pain Interference, Behavior or Fatigue were noted. 54 subjects had or developed acute chest syndrome (ACS). Among participants with ACS, there was a mean 76-hour difference in TCR in those treated with Arg vs placebo (108±98, n=29 vs. 184±327, n=25; p=0.16; median difference of 34 hours) that was not statistically significant. Larger than expected site variation, outliers and SD occurred; sample size recalculation based on STArT data would require randomization of over 900 subjects. Conclusion: All phase-3 RCTs for SCD-VOE to date have failed to meet their primary outcomes after promising phase-2 RCTs. The PECARN STArT trial is the latest addition to this list, stopped early for futility to achieve the primary outcome of TCR. There were no safety concerns. Ultimately, RCTs evaluating orphan drugs for SCD-VOE face significant challenges due to shorter hospital lengths of stay over the last 20 years, and extensive interpatient variability in TCR that could confound RCT outcome measures. Larger than expected SD and outliers occurred. Clinically relevant differences in TCR among patients with VOE-ACS treated with Arg similar to a prior RCT (Morris et al, Am J Hematol 2025) requires further study with a larger sample size. Dialogue between the FDA, ASH, SCD researchers and patients is needed to identify more ideal outcome measures beyond TCR, currently FDA-preferred for orphan drug approval.

Hospital Variations in Time‐To‐Crisis‐Resolution Among Children and Adolescents With Sickle Cell Disease

American Journal of Hematology · 2025-11-05

Analysis of the placebo cohort in the STArT trial shows that patient characteristics and hospital site strongly influence time-to-crisis-resolution and total opioid use in children and young adults with sickle cell disease, highlighting the need to account for these factors in the design of future clinical trials. To date, all phase-3 randomized controlled trials (RCTs) for vaso-occlusive pain episodes (VOE) among patients with sickle cell disease (SCD) have failed to meet their primary outcome of shortening time-to-crisis resolution after promising phase-2 RCTs. The Sickle Cell Disease Treatment with Arginine Therapy (STArT) trial was recently added to the list of RCTs closed early [1-3]. STArT was a multi-center, double-blind, phase-3 RCT to assess the efficacy of intravenous arginine therapy on time-to-crisis resolution, defined as the time in hours from study drug delivery to the last dose of parenteral opioids in children and young adults with SCD failing outpatient management for VOE [2]. Leveraging the high-quality research infrastructure in the Pediatric Emergency Care Applied Research Network (PECARN) [4], STArT aimed to enroll 360 subjects. Unlike prior RCTs for SCD-VOE that have been closed early due to insufficient patient accrual [1-3], STArT was closed early after the enrollment of 274 participants, surpassing enrollment milestones nearly a year ahead of schedule, following an interim analysis that identified futility to demonstrate reduced time to crisis resolution in the intervention arm. Despite its premature closure, STArT is one of the largest RCTs for pediatric SCD-VOE to date and provides the ideal platform to answer crucial questions regarding clinical trial design to further discourse on appropriate outcomes for SCD-VOE. Thus, our objective was to determine the association between patient and hospital characteristics and time-to-crisis resolution, hospital length of stay (LOS), and total opioid use (TPO) for SCD-VOE. We conducted a cross-sectional analysis of data collected on patients age 3–21 years with SCD-VOE requiring parenteral opioid analgesic therapy who were randomized to placebo in the STArT trial at 10 participating sites (Supplemental Table 1). Univariable analysis and a multivariable linear regression model were constructed to identify patient and enrollment site variables at ED presentation that were associated with time-to-crisis-resolution. Detailed methodology and exclusion criteria of STArT have been previously described [2]. For the purposes of this analysis, we limited our population to participants randomized to placebo to avoid any potential impact that intravenous arginine would have on key outcomes evaluated in this secondary analysis. The STArT trial primary outcome was time-to-crisis-resolution. Hospital LOS stay was also analyzed, measured as time between ED presentation and the time of order placement for hospital discharge. We also included TPO usage in intravenous morphine equivalents (mg/kg) from the time of study drug delivery until hospital discharge. Chronic pain was defined as patient-reported SCD-related pain on ≥ 15 days per month for the prior 6 months [5]. Prior surgeries were collected per patient/family report and chart review. Statistical analyses are summarized in the Supplemental Methods. Of 274 subjects enrolled, 142 were randomized to placebo (mean age 14.2 ± 4.6 years; 56% male; 67.4% with hemoglobin-SS genotype; Supplemental Figure 1; Supplemental Table 2) and 141 were included in this analysis. One participant had a time-to-crisis-resolution of 1724 h and was excluded as an outlier. Mean time-to-crisis-resolution was 77.0 ± 64.0 h, with a median (IQR) of 65.6 (31.1, 110.1) hours. Time-to-crisis-resolution strongly correlated with hospital LOS and TPO (Supplemental Figure 2). Younger children had longer time-to-crisis-resolution than older children (Figure 1A). In contrast, data from a prior single-center phase-2 trial suggested that older children had longer time-to-crisis-resolution (Figure 1B) [6]. The established association between age and LOS [6-8] was diluted when analyzing single-institution vs. multicenter data. Time-to-crisis-resolution varied substantially by site of enrollment (Figure 2A). The median and mean time-to-crisis-resolution varied by site as much as 114 h and 80 h, respectively. Inpatient clinical care was provided by inpatient hematology subspeciality services in all but one participating hospital (n = 9/10, 90%). No sites used a day hospital. All patients presented to the emergency department. In unadjusted comparisons, participants who had zero ED visits within the prior 12 months not resulting in hospitalization had over 29 h longer time-to-crisis-resolution compared to participants with > 1 prior ED visit not resulting in hospitalization (Table 1). A total of 82% (n = 37/45) of participants in the zero ED visits category required hospitalization every time they visited the ED. Participants with a history of bacteremia had time-to-crisis-resolution that was, on average, 34 h longer than those who did not have prior positive blood culture results. Additionally, participants who experienced chronic pain, depression, or prior surgeries experienced longer time-to-crisis-resolution compared to those without these. While only 19.0% of patients with chronic pain reported depression, 57.9% of patients with depression reported chronic pain. Subjects with current VOE lasting ≥ 24 h prior to ED presentation also experienced significantly longer time-to-crisis-resolution compared to those with pain < 24 h. However, in adjusted comparisons, the only factors that remained independently associated with longer time-to-crisis-resolution were the number of prior ED visits not resulting in hospitalization and a history of prior surgeries (Table 1). The most common surgeries included cholecystectomy (38%) and splenectomy (27%), with 10 patients (13%) having had both (Supplemental Table 3). Factors associated with TPO are summarized in Supplemental Results, (Supplemental Table 4) and discussed in Supplemental Discussion. In adjusted comparisons, the presence of fever, acute chest syndrome at presentation and site remained significantly associated with TPO use. Complications that were not present at the time of ED arrival but developed during hospital admission and their association with time-to-crisis-resolution and TPO are summarized in (Supplemental Tables 5–6). This study identified key patient and site-level factors present at the time of trial enrollment that were independently associated with longer time-to-crisis-resolution and greater total parenteral opioid use. We also found that patients with ED encounters that nearly always resulted in hospitalization versus those with ED encounters discharged home, and those with prior surgeries, experienced significantly longer time-to-crisis-resolution. Patients with pain typically requiring admission from the ED may represent a group at risk for longer hospitalizations. Additionally, since cholecystectomy represented the majority of surgeries encountered, this variable may be reflective of a more severe clinical phenotype experiencing a higher hemolytic rate. We also observed substantial variation in time-to-crisis-resolution by site of enrollment. Prior studies have described large variations in LOS by age reproduced across different institutions and patient cohorts, where the youngest patients have had the shortest LOS while the oldest experience the longest LOS [6, 7, 9]. However, in the STArT trial, we observed the opposite, with the youngest experiencing the longest LOS, and site rather than age demonstrating a stronger association. While variations in SCD-VOE treatment practices by hospital are recognized [10], our study extends these findings by elucidating site-specific variation in time-to-crisis-resolution. Although not measured in our study, this may be due, in part, to hospital-level practices. This is critically important to note when designing multicenter clinical trials as variations in hospital LOS may depend on the site and not just patient-level factors, which may potentially obscure the impact of treatments on outcomes like time-to-crisis-resolution. Chronic pain, depression, and duration of pain before ED presentation > 24 h were all significantly associated with a longer time-to-crisis-resolution in univariable comparisons and are likely measuring overlapping patient characteristics. To our knowledge, this is the first SCD-VOE study to assess for chronic pain based on patient-reported SCD-related pain on ≥ 15 days per month for the prior six months [5]. This feature may identify patients likely to remain in the hospital for an extended duration. Chronic pain is discussed further in the Supplement. Potential confounders in clinical outcomes based on age, sex, genotype, and hydroxyurea use were a priori assumptions considered in our statistical analysis plan; however, it was surprising that none of these variables achieved statistical significance. This study highlights additional previously unrecognized confounders to be considered for successful SCD-VOE study design. Furthermore, hospital LOS for SCD-VOE has decreased significantly over the last 20 years, from over a week to < 72 h [6]. Median time-to-crisis-resolution among our placebo cohort was only 65.6 h, with notable interpatient variability. As sites implement SCD-VOE guidelines [11, 12], treatment becomes more standardized and interventions are unlikely to significantly influence these outcomes within such a short time period [6]. It may be more feasible to impact time-to-crisis-resolution in patients with longer hospital stays, like those with acute chest syndrome or patients outside the US where hospitalizations remain longer than a week [13, 14]. These findings are crucial to consider in the design of future RCTs. If there are certain populations with inherently longer time-to-crisis-resolution, then adjustments for these populations must be made in both the study design and the sample size determination. In fact, in a post hoc sample size calculation noting these differences in time-to-crisis-resolution, it was estimated that > 900 participants would need to be enrolled to detect a 17-h difference in time-to-crisis-resolution. The results of our analyses should be interpreted in the context of their limitations (Supplemental Discussion). Ultimately, larger-than-expected outliers and standard deviations, numerous confounders and site-based practice variations have been identified in this placebo cohort that are difficult to control for. Given the inherent differences in time-to-crisis-resolution and TPO among some patient populations, these outcomes may not be ideal for SCD-VOE trials. Failure to recognize site and patient level factors that contribute to differences in these outcomes may be contributing to suboptimal phase-3 clinical trial results. At a minimum, these differences should be accounted for in the design of future therapeutic trials. Dialog between stakeholders including the FDA, American Society of Hematology, and investigators is urgently needed to identify more ideal outcome measures beyond time-to-crisis-resolution, which is currently the FDA-preferred outcome for orphan drug regulatory approval for acute SCD-VOE. Chris A. Rees designed the research question, oversaw site enrollment, analyzed and interpreted the data, and wrote the manuscript; Claudia R. Morris designed the research question and the protocol, oversaw study implementation across sites, coordinated data collection, contributed to data interpretation, and co-wrote the manuscript. Rawan Korman and Dunia Hatabah contributed to patient enrollment and consent, analyzed and interpreted the data and critically reviewed the manuscript; T. Charles Casper contributed to the study and protocol design, led the protocol statistical analysis plan and critically reviewed this manuscript, Monica Harding contributed to statistical analysis and data interpretation alongside T. Charles Casper, Noor Alzraikat critically reviewed and finalized the manuscript. All other authors contributed to patient enrollment and consent, oversaw study implementation at their sites, and critically reviewed the manuscript. All authors approved the final manuscript. We would like to thank the site investigators and research coordinators who conducted this study. We are also grateful the patients with SCD and their parents and guardians for their participation, without whom none of this work would be possible. The STArT study was conducted under an active Investigational New Drug application (IND# 66943) with the U.S. Food and Drug Administration (FDA) and was approved by the University of Utah Institutional Review Board (IRB) on May 3, 2021 (IRB# 00136000), which served as the single IRB of record for all participating sites, which relied on the single IRB. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Oversight was provided by an independent Data and Safety Monitoring Board (DSMB) by NIH/NHLBI. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit the manuscript for publication. Patients were enrolled in the STArT study if they met eligibility criteria while receiving clinical care for sickle cell disease–related vaso-occlusive episodes (SCD-VOE) in participating emergency departments. After receiving information about the study verbally and/or electronically, patients were invited to participate. Written or electronic informed consent was obtained from all participants aged 18 years or older. For participants under 18 years of age, written or electronic permission was obtained from a parent or legal guardian, and verbal or written assent was obtained from participants aged 6–17 when appropriate. The authors of this manuscript have no competing interests and nothing to declare related to this manuscript. Orphan designation was awarded by the FDA to Claudia R. Morris in May 2024. CRM is the inventor or co-inventor of several UCSF-Benioff Children's Hospital Oakland patents that include nutritional supplements and is an inventor/co-inventor of several Emory University School of Medicine patents/patent-pending applications for nutritional supplements for autism, coronaviruses, and pain, is a consultant for CSL Behring, F. Hoffmann-La Roche LTD, and Pfizer, is on the Scientific Advisory Board of TRILITY, is an editor of the Sickle Cell Disease-Fever and Sickle Cell Disease-Pain reference for UpToDate, is the Founder and Executive Director for Food as Medicine Therapeutics LLC and Sigma Spero LLC, is a member of American Society of Hematology (ASH) Sickle Cell Disease Research Priorities working group since February 2024 till present, and has received research support from the United States Food and Drug Administration, Health Resources & Services Administration (HRSA, agency of the US Department of Health and Human Services) and the National Institutes of Health. Carlton Dampier, MD has received research support from Pfizer. Elliott P. Vichinsky is a committee member of Highlights of ASH Presentation, section editor for UpToDate, and a consultant for Global Blood Therapeutics Inc., Genesis Therapeutics and Vindico Medical Education—GBT CME event. Melanie E. Fields has received research grants from NIH (R01HL157188, R01HL169591); consulting fees from Dedham Group, Guidepoint, Pfizer; participation on an Advisory Board for Pfizer; equity ownership of Proclara Biosciences. Individual participant data that underlies the results reported in this article, after de-identification can be made available upon reasonable request after June 2027. Proposals and requests should be directed to [email protected]. Data requestors will need to sign a data access and confidentiality agreement. Data S1: ajh70129-sup-0001-Supinfo.docx. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Secretory phospholipase A2 (sPLA2) during vaso-occlusive pain episodes (VOE) and acute chest syndrome (ACS) in sickle cell disease (SCD): Results from a prospective multi-center randomized controlled trial (RCT)

Blood · 2025-11-03

Abstract Background: Acute chest syndrome (ACS) is the leading cause of morbidity and mortality in children with SCD, often developing during vaso-occlusive episodes (VOE) with minimal or no early clinical signs. Most children present with a normal lung exam, making prompt detection challenging. Secretory phospholipase A2 (sPLA2), a potent inflammatory mediator, has been shown to rise prior to ACS onset and may aid in predicting its development and severity in the acute setting. Objective: Assess sPLA2 as a marker for ACS risk and severity in patients with SCD hospitalized for VOE Methods: Cross-sectional analysis of data from a multicenter, double-blind, placebo-controlled, phase-3 RCT (NCT04839354) evaluating intravenous arginine therapy in patients aged 3–21 years with SCD-VOE conducted at 10 pediatric emergency departments (ED) in the US, endorsed by the Pediatric Emergency Care Applied Research Network (PECARN). Plasma sPLA2 levels at ED presentation, hospital day 2, and on the day of hospital discharge (DC) were analyzed via enzyme-linked immunosorbent assay (ELISA). sPLA2 level ≥48 ng/mL is considered elevated based on an established SCD-specific cutoff. ACS severity was classified as mild (no oxygen/transfusion), moderate (required oxygen/transfusion), or severe (required BIPAP, intubation, or PICU admission). Vital signs and clinical labs were analyzed. Results: Overall 271 patients were randomized, and 251 had sufficient blood samples for sPLA2 assessment at presentation and were included in the analysis (mean age 14±4 years; 53% male, 73% HbSS/Sβ°, and 75% on hydroxyurea). Mean plasma sPLA₂ level at ED presentation was 116±131 ng/mL, with elevated levels ≥48 ng/mL in 60% of patients with VOE. ACS was diagnosed in 21% of patients enrolled (n=52), with 18 diagnosed in the ED and 34 were later diagnosed with ACS during admission. Although the majority of ACS patients (85%) had a normal respiratory exam at ED presentation, 71% had elevated sPLA2 levels ≥48 ng/mL. Patients diagnosed with ACS at any point during enrollment (n=52) had significantly higher mean plasma sPLA2levels (n=52) at ED presentation compared to patients with no ACS (n=199) (152±147 vs 107±126 ng/mL, p=0.01). Moreover, patients with ACS exhibited significantly higher mean peak plasma sPLA2compared to subjects who never developed ACS (263±169 vs164±164 ng/mL respectively, p&amp;lt;0.001). The SCD-specific cutoff of sPLA2≥48 ng/mL yielded a sensitivity=85%, specificity=33%, NPV=89% and PPV=25% in predicting ACS. When comparing serial plasma sPLA2levels, mean sPLA2 at ED presentation was highest among patients presenting with ACS (198±182 ng/mL, n=18) with a positive chest x-ray (CXR) in the ED, followed by those with a negative CXR in ED who developed ACS during hospitalization (128±120 ng/mL, n=34). Notably, both groups demonstrated significantly higher sPLA2 levels at presentation compared to patients with No-ACS (106±125 ng/mL; p=0.02). This trend persisted throughout the hospital course, with mean sPLA2 levels continuing to rise by Day 2 and remaining significantly elevated at DC in both ACS groups compared to No-ACS (p&amp;lt;0.001). In the ACS cohort, 19 (36%) cases were classified as mild, 24 (46%) as moderate, and 9 (17%) were severe. Plasma sPLA2 levels at ED presentation increased with ACS severity, showing a stepwise rise from mild to moderate to severe cases. Subjects with severe ACS had a mean sPLA2 level that is 1.5-fold higher than those with mild disease (192±200 vs 122±140 ng/mL respectively) though not significant with the small sample size. A total of 16 patients presented to the ED with fever and 60 patients developed fever during their hospital stay (total n=76). Peak plasma sPLA2levels were significantly higher in febrile (n=76) versus afebrile (n=175) patients (254±19 vs 120±10 ng/mL, p&amp;lt;0.0001). ED plasma sPLA2levels correlated positively with several vital signs and clinical laboratory parameters including heart rate (r=0.42, p&amp;lt;0.001), respiratory rate (r=0.14, p=0.02), white blood cells (r= 0.48, p&amp;lt;0.001) and neutrophils (r=0.40, p&amp;lt;0.001). Moreover, sPLA2correlated negatively with lymphocytes (r=-0.42, p&amp;lt;0.001) and hemoglobin/hematocrit (r=-0.26, p&amp;lt;0.001). Conclusions: sPLA2 remains promising as a biomarker for ACS risk. We show it is also associated with ACS severity in children with SCD, supporting its potential role in acute clinical decision-making. Combined with other predictors, it may enhance early diagnosis and guide management.

Revisiting acute chest syndrome (ACS) associated with sickle cell disease (SCD) vaso-occlusive pain episodes (VOE): Insight from a prospective, multicenter Phase-3 randomized controlled trial

Blood · 2025-11-03

Abstract Background: ACS occurs in up to 20% of hospitalized patients with SCD-VOE, often prolonging and complicating hospital stay. Despite its clinical significance, variations exist in the management and outcomes of ACS across institutions. Objective: Determine prevalence of ACS in children and young adults hospitalized for SCD-VOE and describe emergency department (ED) presentation, clinical course and practice variation across institutions. Methods: Cross-sectional analysis of data collected from a PECARN-endorsed multicenter, double-blinded, randomized, placebo-controlled phase-3 trial of intravenous arginine therapy in hospitalized patients with SCD-VOE aged 3-21 (NCT04839354) at 10 pediatric EDs across the US. ACS defined by radiology-interpreted chest radiograph (CXR) positive for new infiltrate and clinical team diagnosis. ACS severity was defined a priori as mild (no oxygen (O2) use or RBC transfusion), moderate (O2 use or transfusion), or severe (bilevel positive airway pressure (BiPAP) use, intubation, or pediatric intensive care unit (PICU) transfer). Results: 271 patients enrolled (median age 15[11,18] years, 51% male; 74% HbSS/Sb°; 76% on Hydroxyurea (HU). ACS occurred in 20% (n=54; median age 13[9,16] years; 76% male; 89% HbSS/Sb°; 80% on HU); 18 diagnosed in the ED, and 36 diagnosed during their hospitalization. 72% of patients with inpatient-diagnosed ACS had a negative CXR in the ED with a mean time to diagnosis of 2.4±1.6 days. Patients with ACS at any time were significantly younger (13[9,16] vs 15[12,18] years, p=0.004), predominantly male (76% vs 45%, p&amp;lt;0.001), and had HbSS/Sb° (89% vs 70%, p=0.0005) vs no ACS. In the ED, ACS patients had more O2 desaturations at &amp;lt;94% (37% vs 12%, p&amp;lt;0.001), higher frequency of cough (32%vs18%, p=0.04), wheeze (15%vs6%, p=0.04), and chest pain (59%vs39%, p=0.009) vs no ACS. No significant difference in fever across groups. 83% of patients with ACS presented with a normal respiratory exam in the ED. ACS patients had lower hemoglobin (g/dL;p&amp;lt;0.001) and lymphocyte counts (cells/µL;p=0.02), but higher %reticulocyte (p&amp;lt;0.001), white blood cell counts (x109/L;p=0.001), and absolute neutrophil counts (cells/µL;p=0.02) vs no ACS. Clinical outcomes were worse in patients with ACS vs no ACS, with longer length of stay (LOS; 139[93,189] vs 71[46,113] hours, p&amp;lt;0.001), higher opioid utilization (2.3[0.8,3.9] vs 1.1[0.4,2.1] mg/kg, p=0.001), more transfusions (61%vs14%, p&amp;lt;0.001), O2 use (76%vs20%, p&amp;lt;0.001), BiPAP use (20%vs2%, p&amp;lt;0.001) and PICU transfers (15%vs1%, p&amp;lt;0.001). Patients with inpatient-diagnosed ACS had longer LOS vs patients with ED-diagnosed ACS (142[113,213] vs 105[52,161] hours, p=0.03). 56% of ED-diagnosed ACS was mild, with no significant difference in LOS based on severity. However, only 25% of inpatient-diagnosed ACS were mild; LOS was significantly longer in moderate/severe vs mild ACS. Viral testing was performed in 67% of ACS patients, with 36% positivity for various viral pathogens without a predominant viral isolate. Across all sites, 96% of patients received antibiotics (50% ceftriaxone, 28% ampicillin-sulbactam, 7% vancomycin, 11% other) and 82% received azithromycin. Site-level use ranged from 0-100% for ceftriaxone and 50-100% for azithromycin. 80% received albuterol, 40% received inhaled steroids, and 11% received anticoagulation. No pulmonary emboli were reported. Of the 61% of patients transfused across sites, inter-site transfusion rate varied between 0-100%. Sex, age, ED O2 saturation &amp;lt;94%, hemoglobin, &amp; chest pain were independently associated with ACS in the multivariate model with an AUC=0.80. Conclusion: ACS remains common in patients with SCD-VOE (20%), with 14% of ACS diagnosed during their hospital stay. Two-thirds of subjects who developed ACS had a CXR done in the ED that was negative. ACS may have been missed in patients who did not get a CXR, and radiographic changes often lag behind symptoms. Lack of ACS-specific clinical signs and symptoms, including a normal ED respiratory exam in most patients, may delay diagnosis. Patients with inpatient-diagnosed ACS had a more severe hospital course vs those with ED-diagnosed ACS. Considerable practice variation exists in ACS management across institutions, with variable use of antibiotics and transfusion protocols. Further research on standardizing ACS treatment may be warranted. Oxygen desaturation in the ED was associated with a &amp;gt;3.6-fold greater risk of ACS, not included in prior ACS risk models.

Optimizing Advanced Imaging of the Pediatric Patient in the Emergency Department: Technical Report

PEDIATRICS · 2024-06-27 · 18 citations

Advanced diagnostic imaging modalities, including ultrasonography, computed tomography, and magnetic resonance imaging, are key components in the evaluation and management of pediatric patients presenting to the emergency department. Advances in imaging technology have led to the availability of faster and more accurate tools to improve patient care. Notwithstanding these advances, it is important for physicians, physician assistants, and nurse practitioners to understand the risks and limitations associated with advanced imaging in children and to limit imaging studies that are considered low value, when possible. This technical report provides a summary of imaging strategies for specific conditions where advanced imaging is commonly considered in the emergency department. As an accompaniment to the policy statement, this document provides resources and strategies to optimize advanced imaging, including clinical decision support mechanisms, teleradiology, shared decision-making, and rationale for deferred imaging for patients who will be transferred for definitive care.

Integrating GWAS with a gene co‐expression network better prioritizes candidate genes associated with root metaxylem phenes in maize

The Plant Genome · 2024-07-22 · 1 citations

Root metaxylems are phenotypically diverse structures whose function is particularly important under drought stress. Significant research has dissected the genetic machinery underlying metaxylem phenotypes in dicots, but that of monocots are relatively underexplored. In maize (Zea mays), a robust pipeline integrated a genome-wide association study (GWAS) of root metaxylem phenes under well-watered and water-stress conditions with a gene co-expression network to prioritize the strongest gene candidates. We identified 244 candidate genes by GWAS, of which 103 reside in gene co-expression modules most relevant to xylem development. Several candidate genes may be involved in biosynthetic processes related to the cell wall, hormone signaling, oxidative stress responses, and drought responses. Of those, six gene candidates were detected in multiple root metaxylem phenes in both well-watered and water-stress conditions. We posit that candidate genes that are more essential to network function based on gene co-expression (i.e., hubs or bottlenecks) should be prioritized and classify 33 essential genes for further investigation. Our study demonstrates a new strategy for identifying promising gene candidates and presents several gene candidates that may enhance our understanding of vascular development and responses to drought in cereals.