Betibeglogene Autotemcel Gene Therapy for Non-ß0/ß0 Genotype ß-Thalassemia.

BACKGROUND: Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent ß-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the ß-globin (ßA-T87Q) gene. METHODS: In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent ß-thalassemia and a non-ß0/ß0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months). RESULTS: A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. CONCLUSIONS: Treatment with beti-cel resulted in a sustained HbAT87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-ß0/ß0 genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.).

Ten facts about land systems for sustainability.

Land use is central to addressing sustainability issues, including biodiversity conservation, climate change, food security, poverty alleviation, and sustainable energy. In this paper, we synthesize knowledge accumulated in land system science, the integrated study of terrestrial social-ecological systems, into 10 hard truths that have strong, general, empirical support. These facts help to explain the challenges of achieving sustainability in land use and thus also point toward solutions. The 10 facts are as follows: 1) Meanings and values of land are socially constructed and contested; 2) land systems exhibit complex behaviors with abrupt, hard-to-predict changes; 3) irreversible changes and path dependence are common features of land systems; 4) some land uses have a small footprint but very large impacts; 5) drivers and impacts of land-use change are globally interconnected and spill over to distant locations; 6) humanity lives on a used planet where all land provides benefits to societies; 7) land-use change usually entails trade-offs between different benefits-"win-wins" are thus rare; 8) land tenure and land-use claims are often unclear, overlapping, and contested; 9) the benefits and burdens from land are unequally distributed; and 10) land users have multiple, sometimes conflicting, ideas of what social and environmental justice entails. The facts have implications for governance, but do not provide fixed answers. Instead they constitute a set of core principles which can guide scientists, policy makers, and practitioners toward meeting sustainability challenges in land use.

Luspatercept stimulates erythropoiesis, increases iron utilization, and redistributes body iron in transfusion-dependent thalassemia.

Luspatercept, a ligand-trapping fusion protein, binds select TGF-ß superfamily ligands implicated in thalassemic erythropoiesis, promoting late-stage erythroid maturation. Luspatercept reduced transfusion burden in the BELIEVE trial (NCT02604433) of 336 adults with transfusion-dependent thalassemia (TDT). Analysis of biomarkers in BELIEVE offers novel physiological and clinical insights into benefits offered by luspatercept. Transfusion iron loading rates decreased 20% by 1.4 g (~7 blood units; median iron loading rate difference: -0.05 ± 0.07 mg Fe/kg/day, p< .0001) and serum ferritin (s-ferritin) decreased 19.2% by 269.3 ± 963.7 µg/L (p < .0001), indicating reduced macrophage iron. However, liver iron content (LIC) did not decrease but showed statistically nonsignificant increases from 5.3 to 6.7 mg/g dw. Erythropoietin, growth differentiation factor 15, soluble transferrin receptor 1 (sTfR1), and reticulocytes rose by 93%, 59%, 66%, and 112%, respectively; accordingly, erythroferrone increased by 51% and hepcidin decreased by 53% (all p < .0001). Decreased transfusion with luspatercept in patients with TDT was associated with increased erythropoietic markers and decreasing hepcidin. Furthermore, s-ferritin reduction associated with increased erythroid iron incorporation (marked by sTfR1) allowed increased erythrocyte marrow output, consequently reducing transfusion needs and enhancing rerouting of hemolysis (heme) iron and non-transferrin-bound iron to the liver. LIC increased in patients with intact spleens, consistent with iron redistribution given the hepcidin reduction. Thus, erythropoietic and hepcidin changes with luspatercept in TDT lower transfusion dependency and may redistribute iron from macrophages to hepatocytes, necessitating the use of concomitant chelator cover for effective iron management.

Disadvantaged Neighborhoods Continue to Bear the Burden of Gun Violence.

INTRODUCTION: Gun violence is a pervasive and dynamic public health crisis causing substantial burden on communities and healthcare systems in the United States. Risk factor and outcome analyses are crucial to develop effective interventions. The aim of this study was to assess firearm injury in a diverse community setting as it relates to neighborhood socioeconomic disadvantage and changes over time following large-scale local interventions. METHODS: All county residents with firearm injury presenting to a Level 1 Trauma Center from January 2012 to December 2021 were retrospectively reviewed. Area Deprivation Index (ADI) was used to measure neighborhood socioeconomic disadvantage based on a nine-digit zip code at patients' home address. Injuries were also stratified by 5-year time periods, 2012-2016 and 2017-2021. Demographics and clinical data were analyzed including injury severity, hospital course, and discharge location. Data were compared by ADI quintile and between time periods using chi-squared, one-way analysis of variance, and Cochran-Armitage test. RESULTS: A total of 1044 injuries were evaluated. Patients were 93% male with mean age of 29 y (standard deviation 10.2) and were concentrated in the most disadvantaged neighborhoods (74% ADI Q5). Black or African American race was greater in the most disadvantaged ADI groups (76% versus 47%-66%; P <0.001). Percentage of total injuries in the most disadvantaged ADI group rose from 71% to 78% over time (P = 0.006). Mortality occurred in 154 (15%) patients overall, while most (71%) were discharged to home. Mortality declined from 18% to 11% over time (P <0.001). Medicaid utilization rose from 42% to 77% alongside a decrease in self-pay status from 44% to 4% (P <0.001). There were no clinically significant group differences in injury severity or clinical characteristics. CONCLUSIONS: Firearm injury remains concentrated in the most socioeconomically disadvantaged neighborhoods, and this disparity is increasing over time. Medicaid utilization rose and mortality decreased in this population over time. This research presents a method to inform and monitor local gun violence interventions using ADI to address public health equity.

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).

Health-related quality of life in patients with ß-thalassemia: Data from the phase 3 BELIEVE trial of luspatercept.

BACKGROUND: Patients with transfusion-dependent (TD) ß-thalassemia require long-term red blood cell transfusions (RBCTs) that lead to iron overload, impacting health-related quality of life (HRQoL). METHODS: The impact of luspatercept, a first-in-class erythroid maturation agent, versus placebo on HRQoL of patients with TD ß-thalassemia was evaluated in the phase 3 BELIEVE trial. HRQoL was assessed at baseline and every 12 weeks using the 36-item Short Form Health Survey (SF-36) and Transfusion-dependent Quality of Life questionnaire (TranQol). Mean change in HRQoL was evaluated from baseline to week 48 for patients receiving luspatercept + best supportive care (BSC) and placebo + BSC and between luspatercept responders and non-responders. RESULTS: Through week 48, for both groups, mean scores on SF-36 and TranQol domains were stable over time and did not have a clinically meaningful change. At week 48, more patients who achieved clinical response (≥50% reduction in RBCT burden over 24 weeks) in the luspatercept + BSC group had improvement in SF-36 Physical Function compared with placebo + BSC (27.1% vs. 11.5%; p = .019). CONCLUSIONS: Luspatercept + BSC reduced transfusion burden while maintaining patients' HRQoL. HRQoL domain improvements from baseline through 48 weeks were also enhanced for luspatercept responders.

The clinical relevance of detectable plasma iron species in iron overload states and subsequent to intravenous iron-carbohydrate administration.

Many disorders of iron homeostasis (e.g., iron overload) are associated with the dynamic kinetic profiles of multiple non-transferrin bound iron (NTBI) species, chronic exposure to which is associated with deleterious end-organ effects. Here we discuss the chemical nature of NTBI species, challenges with measuring NTBI in plasma, and the clinical relevance of NTBI exposure based on source (iron overload disorder vs. intravenous iron-carbohydrate complex administration). NTBI is not a single entity but consists of multiple, often poorly characterized species, some of which are kinetically non-exchangeable while others are relatively exchangeable. Prolonged presence of plasma NTBI is associated with excessive tissue iron accumulation in susceptible tissues, with consequences, such as endocrinopathy and heart failure. In contrast, intravenous iron-carbohydrate nanomedicines administration leads only to transient NTBI appearance and lacks evidence for association with adverse clinical outcomes. Assays to measure plasma NTBI are typically technically complex and remain chiefly a research tool. There have been two general approaches to estimating NTBI: capture assays and redox-activity assays. Early assays could not avoid capturing some iron from transferrin, thus overestimating NTBI. By contrast, some later assays may have promoted the donation of NTBI species to transferrin during the assay procedure, potentially underestimating NTBI levels. The levels of transferrin saturation at which NTBI species have been detectable have varied between different methodologies and between patient populations studied.

SLN124, a GalNAc conjugated 19-mer siRNA targeting tmprss6, reduces plasma iron and increases hepcidin levels of healthy volunteers.

SLN124, an N-acetylgalactosamine conjugated 19-mer short interfering RNA, is being developed to treat iron-loading anemias (including beta-thalassemia and myelodysplastic syndromes) and myeloproliferative neoplasms (polycythemia vera). Through hepatic targeting and silencing of the TMPRSS6 gene, SLN124 increases endogenous hepcidin synthesis. This is the first clinical report of an siRNA targeting a component of iron homeostasis. This first-in-human, phase 1 study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of SLN124 (1.0, 3.0, and 4.5 mg/kg) in healthy volunteers. Twenty-four participants were randomized in three sequential cohorts of eight subjects, each to receive a single dose of either SLN124 or placebo (6:2 randomization), administered subcutaneously. There were no serious or severe adverse events, or discontinuations due to adverse events, and most treatment-emergent adverse events were mild, including transient mild injection site reactions, resolving without intervention. SLN124 was rapidly absorbed, with a median tmax of 4-5 h across all treatment groups, and largely eliminated from plasma by 48 h. Plasma concentrations increased in a greater than dose proportional fashion between treatment groups. In all SLN124 groups, a dose-related effect was observed across iron metabolism markers, and across erythroid markers, SLN124 resulted in increased plasma hepcidin levels, peaking around Day 29, and consequent dose-related sustained reductions in plasma iron and transferrin saturation with decreased reticulocyte production, MCHC, and MCV. Results suggest duration of action lasting up to 56 days after a single SLN124 dose, on hepcidin and hematological parameters of iron metabolism (serum iron and TSAT).

The Bottom Line: Trauma Center Viability During COVID-19.

INTRODUCTION: The COVID-19 pandemic was a potential threat to the viability of trauma centers and health systems in general. We sought to answer the question of how COVID-19 was associated with patient characteristics as well as trauma center volume, finances, and viability. METHODS: We reviewed 6375 patients admitted to our verified Level 1 trauma center during two time periods: pre-COVID (February 2019-February 2020) and COVID (March 2020-March 2021). Three thousand ninety-nine patients were admitted pre-COVID and 3276 were admitted during COVID. Data including case-mix index (CMI), total contribution margin, insurance status, age, race, gender, ethnicity, and injury mechanism were collected from the trauma registry and finance databases and analyzed. A P < 0.05 was considered significant. RESULTS: Trauma admissions decreased initially during COVID but returned to and ultimately surpassed admission trends pre-COVID. Trauma revenue and patient acuity increased significantly along with a decrease in the number of underinsured patients during COVID. When evaluating all service lines, the trauma center was the highest contributor to overall hospital revenue. CONCLUSIONS: Despite a decrease in admissions for other service lines and a pause in elective surgeries during the pandemic, the trauma center remained unaffected. In addition, trauma was the most significant contributor to the bottom line of the health system. These findings underscore the need to maintain and even increase trauma center resources and staffing to ensure that optimal care is provided to critically ill and injured patients.

Trauma Incidence During the New Jersey COVID-19 Stay-At-Home Order: A Multicenter Study.

INTRODUCTION: Given the early surge of COVID-19 in New Jersey (NJ), a statewide executive order (EO) to stay-at-home was instituted on March 22, 2020. We hypothesized that the EO would result in a decreased number of trauma admissions, length of stay, and resources utilized in trauma patients at NJ trauma centers. METHODS: In an institutional review board-approved, retrospective, multicenter study, trauma registries at three level one trauma centers in NJ were queried from March 22 to June 14 in 2020 and compared to the same timeframe the year prior. Epidemiological and clinical data were obtained including demographics, select preexisting conditions, mechanism of injury, injury severity score, resources utilized, and outcomes. RESULTS: 1859 trauma patients were evaluated during the EO versus 2201 the year prior. During the EO, trauma patients were less likely to be transferred from another hospital (21% versus 29% P < 0.05), more likely to have a penetrating mechanism (16% versus 12% P < 0.05), were equally likely to require a procedure (P = 0.44) and had similar injury severity score (5 [interquartile range [IQR] 1-9] versus 5 [IQR 1-9], P = 0.73). There was no significant difference in ventilator days (0 [IQR 0-1] versus 0 [IQR 0-2] P = 0.08), intensive care unit days (2 [IQR 0-4] versus 2 [IQR 0-3] P = 0.99), or length of stay (2 [IQR 1-5] versus 2 [IQR 1-6] P = 0.73). Patients were more likely to be sent home than to rehabilitation or long-term acute care hospital during the EO (81% versus 78%, P = 0.02). CONCLUSIONS: The 2020 COVID-19 EO was associated with a significantly different epidemiology with a higher rate of penetrating injury during the EO, and similar volume of injured patients evaluated.

OUTCOMES OF MISSED DIAGNOSIS OF PEDIATRIC APPENDICITIS, NEW-ONSET DIABETIC KETOACIDOSIS, AND SEPSIS IN FIVE PEDIATRIC HOSPITALS.

BACKGROUND: Missed diagnosis can predispose to worse condition-specific outcomes. OBJECTIVE: To determine 90-day complication rates and hospital utilization after a missed diagnosis of pediatric appendicitis, new-onset diabetic ketoacidosis (DKA), and sepsis. METHODS: We evaluated patients under 21 years of age visiting five pediatric emergency departments (EDs) with a study condition. Case patients had a preceding ED visit within 7 days of diagnosis and underwent case review to confirm a missed diagnosis. Control patients had no preceding ED visit. We compared complication rates and utilization between case and control patients after adjusting for age, sex, and insurance. RESULTS: We analyzed 29,398 children with appendicitis, 5366 with DKA, and 3622 with sepsis, of whom 429, 33, and 46, respectively, had a missed diagnosis. Patients with missed diagnosis of appendicitis or DKA had more hospital days and readmissions; there were no significant differences for those with sepsis. Those with missed appendicitis were more likely to have abdominal abscess drainage (adjusted odds ratio [aOR] 3.0, 95% confidence interval [CI] 2.4-3.6) or perforated appendicitis (aOR 3.1, 95% CI 2.5-3.8). Those with missed DKA were more likely to have cerebral edema (aOR 4.6, 95% CI 1.5-11.3), mechanical ventilation (aOR 13.4, 95% CI 3.8-37.1), or death (aOR 28.4, 95% CI 1.4-207.5). Those with missed sepsis were less likely to have mechanical ventilation (aOR 0.5, 95% CI 0.2-0.9). Other illness complications were not significantly different by missed diagnosis. CONCLUSIONS: Children with delayed diagnosis of appendicitis or new-onset DKA had a higher risk of 90-day complications and hospital utilization than those with a timely diagnosis.

Use of Cold-Stored Whole Blood is Associated With Improved Mortality in Hemostatic Resuscitation of Major Bleeding: A Multicenter Study.

OBJECTIVE: The aim of this study was to identify a mortality benefit with the use of whole blood (WB) as part of the resuscitation of bleeding trauma patients. BACKGROUND: Blood component therapy (BCT) is the current standard for resuscitating trauma patients, with WB emerging as the blood product of choice. We hypothesized that the use of WB versus BCT alone would result in decreased mortality. METHODS: We performed a 14-center, prospective observational study of trauma patients who received WB versus BCT during their resuscitation. We applied a generalized linear mixed-effects model with a random effect and controlled for age, sex, mechanism of injury (MOI), and injury severity score. All patients who received blood as part of their initial resuscitation were included. Primary outcome was mortality and secondary outcomes included acute kidney injury, deep vein thrombosis/pulmonary embolism, pulmonary complications, and bleeding complications. RESULTS: A total of 1623 [WB: 1180 (74%), BCT: 443(27%)] patients who sustained penetrating (53%) or blunt (47%) injury were included. Patients who received WB had a higher shock index (0.98 vs 0.83), more comorbidities, and more blunt MOI (all P <0.05). After controlling for center, age, sex, MOI, and injury severity score, we found no differences in the rates of acute kidney injury, deep vein thrombosis/pulmonary embolism or pulmonary complications. WB patients were 9% less likely to experience bleeding complications and were 48% less likely to die than BCT patients ( P <0.0001). CONCLUSIONS: Compared with BCT, the use of WB was associated with a 48% reduction in mortality in trauma patients. Our study supports the use of WB use in the resuscitation of trauma patients.

Whole Blood in Trauma Resuscitation: What Is the Real Cost?

INTRODUCTION: Whole blood (WB) has gained popularity in trauma resuscitation within the past 5 y. Previously, its civilian use was limited due to advances in blood component fractionation and fears of hemolysis and infectious disease transmission. Although there are studies and review articles on the efficacy of WB, the analysis of cost pertaining to the use of WB is limited. MATERIALS AND METHODS: We performed a retrospective 1:1 propensity-matched analysis of 280 subjects comparing trauma patients receiving resuscitation with blood component therapy (BCT) to those receiving WB plus BCT between January 2014 and July 2019. WB was used for patients who arrived in hemorrhagic shock with systolic blood pressure <90 mmHg due to either penetrating or blunt trauma. Endpoints included the number of units of WB, packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, and cryoprecipitate each patient received. Institution costs for each component were compared in the form of price ratios. Comparisons were made using Wilcoxon rank-sum tests with a P value of ≤0.05 considered statistically significant. RESULTS: The use of WB was associated with a statistically significant decrease in the number of PRBCs used when compared to BCT. This holds true with the cost of PRBCs being lower among the WB group when the price is controlled. Similarly, a trend was found where FFP, platelets, and cryoprecipitate use and cost showed an absolute decrease between WB and BCT groups. The use of WB is associated with decreased total cost as well (P = 0.1660), although not statistically significant. CONCLUSIONS: Adding WB to BCT for trauma resuscitation was associated with lower red blood cell use and cost. A similar trend was found that absolute total cost and absolute cost of FFP, platelets, and cryoprecipitate use was lower when WB was added. WB wastage was minimized due to repurposing WB into PRBCs when WB lifespan ended.

Pediatric Traumatic Injury Emergency Department Visits and Management in US Children's Hospitals From 2010 to 2019.

STUDY OBJECTIVE: To examine trends in trauma-related pediatric emergency department (ED) visits and management in US children's hospitals over 10 years. METHODS: This is a retrospective, descriptive study of the Pediatric Health Information Systems database, including encounters from 33 US children's hospitals. We included patients aged 0 to 19 years with traumatic injuries from 2010 to 2019 identified using International Classification of Diseases-9 and -10 codes. The primary outcome was prevalence of trauma-related ED visits. The secondary outcomes included ED disposition, advanced imaging use, and trauma care costs. We examined trends over time with Poisson regression models, reporting incidence rate ratios (IRRs) with 95% confidence intervals (CIs). We compared demographic groups with rate differences with 95% CIs. RESULTS: Trauma-related visits accounted for 367,072 ED visits (16.3%) in 2010 and 479,458 ED visits (18.1%) in 2019 (IRR 1.022, 95% CI 1.018 to 1.026). From 2010 to 2019, 54.6% of children with traumatic injuries belonged to White race and 23.9% had Hispanic ethnicity. Institutional hospitalization rates (range 3.8% to 14.9%) decreased over time (IRR 0.986, 95% CI 0.977 to 0.994). Hospitalizations from 2010 to 2019 were higher in White children (8.9%) than in children of other races (6.4%) (rate difference 2.56, 95% CI 2.51 to 2.61). Magnetic resonance imaging for brain (IRR 1.05, 95% CI 1.04 to 1.07) and cervical spine (IRR 1.03, 95% CI 1.02 to 1.05) evaluation increased. The total trauma care costs were $6.7 billion, with median costs decreasing over time. CONCLUSION: During the study period, pediatric ED visits for traumatic injuries increased, whereas hospitalizations decreased. Some advanced imaging use increased; however, median trauma costs decreased over time.

The Effect of COVID-19 Stay-At-Home Orders on the Rate of Pediatric Foreign Body Ingestions.

BACKGROUND: Foreign body ingestions are a common presentation in the emergency department (ED), particularly in young children. OBJECTIVE: We sought to determine whether the COVID-19 pandemic lockdowns had an effect on the proportion of foreign body ingestions. METHODS: We performed a retrospective review of the Pediatric Health Information System for patients younger than 19 years who were identified by International Classification of Diseases, Tenth Revision codes for foreign body ingestion. We analyzed patients in the following three groups: young children (younger than 5 years), school-aged children (5-12 years), and adolescents (13 years and older), using an interrupted time series analysis. Our primary outcome was the difference in proportion of foreign body ingestions. We compared 1 year after the declaration of the COVID-19 pandemic (March 13, 2020 to March 31, 2021) with the previous 3 years (March 1, 2017 to March 12, 2020). RESULTS: Total pediatric ED encounters decreased in the post period (p < 0.01); 4902 patients per year presented for foreign body ingestion pre-COVID-19 shutdown vs. 5235 patients per year post-COVID-19 shutdown. In all three age groups (young children, school-age children, and adolescents), there was a higher proportion of foreign body ingestions post-COVID-19 shutdown (p < 0.01, p < 0.01, and p = 0.028, respectively), driven primarily by the decrease in total ED encounters. In the youngest age group (younger than 5 years), there was also a significant increase in slope for foreign body ingestions post-COVID-19 (p = 0.010). CONCLUSIONS: The proportion of foreign body ingestions increased after the declaration of the COVID-19 pandemic, primarily driven by an overall decrease in total ED volume.

Pharmacologic Restraint Use During Mental Health Visits in Pediatric Emergency Departments.

OBJECTIVES: To evaluate the trends and hospital variation in the use of pharmacologic restraint among pediatric mental health visits in the emergency department (ED). STUDY DESIGN: We examined ED visits with a mental health diagnosis in patients aged 3-21 years at children's hospital EDs from 2009 to 2019. We calculated the frequency of pharmacologic restraint use and determined visit characteristics associated with restraint use. We calculated cumulative percent change for visits with restraints and for all mental health visits. We used logistic regression to test trends over time and evaluate hospital variation in the frequency of restraint use. RESULTS: We identified 389 885 mental health ED visits (54.9% female, median age 14.3 years) and 13 643 (3.5%) visits with pharmacologic restraint use. Characteristics associated with pharmacologic restraint use were late adolescent age (18-21 years), male sex, Black race, non-Latino ethnicity, public insurance, and admission to the hospital (P < .001). During the study period, both mental health ED visits increased by 268% and mental health ED visits with pharmacologic restraint use increased by 370%. The rate of pharmacologic restraint in this patient population remained constant. Hospital use of pharmacologic restraint for mental health visits varied significantly across hospitals (1.6%-11.8%, P < .001). CONCLUSIONS: Pediatric mental health ED visits with and without pharmacologic restraint are increasing over time. In addition, the overall number of pharmacologic restraint use has increased threefold. Significant hospital variation in pharmacologic restraint use signifies an opportunity for standardization of care and restraint reduction.

Declines in the Number of Lumbar Punctures Performed at United States Children's Hospitals, 2009-2019.

OBJECTIVE: To evaluate trends in lumbar puncture (LP) performance among US children's hospitals to assess how these trends may impact pediatric resident trainee exposure to LP. STUDY DESIGN: We quantified LPs for emergency department (ED) and inpatient encounters at 29 US children's hospitals from 2009 to 2019. LP was defined by either a LP procedure code or cerebrospinal fluid culture billing code. Temporal trends and hospital variation in LP were assessed using logistic regression analysis. RESULTS: A total of 215 030 LPs were performed during the study period (0.8% of all encounters). Twenty six thousand and five hundred twenty three and 16 696 LPs were performed in the 2009 and 2018 academic years, respectively (overall 37.1% reduction, per-year OR, 0.935; 95% CI, 0.922-0.948; P < .001), and the rate of LP decreased from 10.9 per 1000 hospital encounters to 6.0 per 1000 hospital encounters over the same period. CONCLUSIONS: LP rates have declined across US children's hospitals over the past decade, potentially resulting in reduced clinical exposure for pediatric resident trainees. Improved procedural simulation during residency may augment the clinical experience.

A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease.

New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin (Hb) for oxygen, thus inhibiting HbS polymerization and downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD, followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg per day) in patients with sickle cell anemia. The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof of concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg per day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased Hb and reduction in hemolysis and percentage of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. These trials were registered at www.clinicaltrials.gov as #NCT02285088 and #NCT03041909.

Intravenous iron preparations transiently generate non-transferrin-bound iron from two proposed pathways.

Intravenous iron-carbohydrate complex preparations (IVIPs) are non-interchangeable pro-drugs: their pharmacokinetics (PK) varies determined by semi-crystalline iron core and carbohydrate shell structures, influences pharmacodynamics (PD) and thus efficacy and safety. Examining PK/PD relationships of 3 IVIPs we identify a two-pathway model of transient NTBI generation following single dose administration. 28 hypoferremic non-anemic patients randomized to 200mg iron as ferric carboxymaltose (Fe-carboxymaltose), iron sucrose (Fe-sucrose), iron isomaltoside 1000 (Fe-isomaltoside-1000), n=8/arm, or placebo, n=4, on a 2-week PK/PD study, had samples analysed for total serum iron, IVIP-iron, transferrin-bound iron (TBI) by HPLC-ICP-MS, transferrin saturation (TSAT), serum ferritin (s-Ferritin) by standard methods, non-TBI (NTBI) and hepcidin as published before. IVIP-dependent increases in these parameters returned to baseline in 48-150h, except for s-Ferritin and TSAT. NTBI was low with Fe-isomaltoside-1000 (0.13µM at 8h), rapidly increased with Fe-sucrose (0.8µM at 2h, 1.25µM at 4h), and delayed for Fe-carboxymaltose (0.57µM at 24h). NTBI AUCs were 7-fold greater for Fe-carboxymaltose and Fe-sucrose than for Fe-isomaltoside-1000. Hepcidin peak time varied, but not AUC or mean levels. s-Ferritin levels and AUC were highest for Fe-carboxymaltose and greater than placebo for all IVIPs. We propose 2 mechanisms for the observed NTBI kinetics: rapid and delayed NTBI appearance consistent with direct (circulating IVIP-to-plasma) and indirect (IVIP-to-macrophage-to-plasma) iron release based on IVIP plasma half-life and s-Ferritin dynamics. IVIPs generate different, broadly stability- and PK-dependent, NTBI and s-Ferritin signatures, which may influence iron bioavailability, efficacy and safety. Longer-term studies should link NTBI exposure to subsequent safety and efficacy parameters and potential clinical consequences.

Insight into small molecule binding to the neonatal Fc receptor by X-ray crystallography and 100 kHz magic-angle-spinning NMR.

Aiming at the design of an allosteric modulator of the neonatal Fc receptor (FcRn)-Immunoglobulin G (IgG) interaction, we developed a new methodology including NMR fragment screening, X-ray crystallography, and magic-angle-spinning (MAS) NMR at 100 kHz after sedimentation, exploiting very fast spinning of the nondeuterated soluble 42 kDa receptor construct to obtain resolved proton-detected 2D and 3D NMR spectra. FcRn plays a crucial role in regulation of IgG and serum albumin catabolism. It is a clinically validated drug target for the treatment of autoimmune diseases caused by pathogenic antibodies via the inhibition of its interaction with IgG. We herein present the discovery of a small molecule that binds into a conserved cavity of the heterodimeric, extracellular domain composed of an α-chain and ß2-microglobulin (ß2m) (FcRnECD, 373 residues). X-ray crystallography was used alongside NMR at 100 kHz MAS with sedimented soluble protein to explore possibilities for refining the compound as an allosteric modulator. Proton-detected MAS NMR experiments on fully protonated [13C,15N]-labeled FcRnECD yielded ligand-induced chemical-shift perturbations (CSPs) for residues in the binding pocket and allosteric changes close to the interface of the two receptor heterodimers present in the asymmetric unit as well as potentially in the albumin interaction site. X-ray structures with and without ligand suggest the need for an optimized ligand to displace the α-chain with respect to ß2m, both of which participate in the FcRnECD-IgG interaction site. Our investigation establishes a method to characterize structurally small molecule binding to nondeuterated large proteins by NMR, even in their glycosylated form, which may prove highly valuable for structure-based drug discovery campaigns.