The Maresin 1-LGR6 axis decreases respiratory syncytial virus-induced lung inflammation.

The resolution of infection is an active process with specific molecular and cellular mechanisms that temper inflammation and enhance pathogen clearance. Here, the specialized pro-resolving mediator (SPM) Maresin 1 (MaR1) inhibited respiratory syncytial virus (RSV)-induced inflammation. inlerleukin-13 production from type 2 innate lymphoid cells (ILC) and CD4 T helper type 2 cells was decreased by exogenous MaR1. In addition, MaR1 increased amphiregulin production and decreased RSV viral transcripts to promote resolution. MaR1 also promoted interferon-ß production in mouse lung tissues and also in pediatric lung slices. MaR1 significantly inhibited the RSV-triggered aberrant inflammatory phenotype in FoxP3-expressing Tregs. The receptor for MaR1, leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6), was constitutively expressed on Tregs. Following RSV infection, mice lacking Lgr6 had exacerbated type 2 immune responses with an increased viral burden and blunted responses to MaR1. Together, these findings have uncovered a multi-pronged protective signaling axis for MaR1-Lgr6, improving Tregs's suppressive function and upregulating host antiviral genes resulting in decreased viral burden and pathogen-mediated inflammation, ultimately promoting restoration of airway mucosal homeostasis.

Long-read assembly and comparative evidence-based reanalysis of Cryptosporidium genome sequences reveal expanded transporter repertoire and duplication of entire chromosome ends including subtelomeric regions.

Cryptosporidiosis is a leading cause of waterborne diarrheal disease globally and an important contributor to mortality in infants and the immunosuppressed. Despite its importance, the Cryptosporidium community has only had access to a good, but incomplete, Cryptosporidium parvum IOWA reference genome sequence. Incomplete reference sequences hamper annotation, experimental design, and interpretation. We have generated a new C. parvum IOWA genome assembly supported by Pacific Biosciences (PacBio) and Oxford Nanopore long-read technologies and a new comparative and consistent genome annotation for three closely related species: C. parvum, Cryptosporidium hominis, and Cryptosporidium tyzzeri We made 1926 C. parvum annotation updates based on experimental evidence. They include new transporters, ncRNAs, introns, and altered gene structures. The new assembly and annotation revealed a complete Dnmt2 methylase ortholog. Comparative annotation between C. parvum, C. hominis, and C. tyzzeri revealed that most "missing" orthologs are found, suggesting that the biological differences between the species must result from gene copy number variation, differences in gene regulation, and single-nucleotide variants (SNVs). Using the new assembly and annotation as reference, 190 genes are identified as evolving under positive selection, including many not detected previously. The new C. parvum IOWA reference genome assembly is larger, gap free, and lacks ambiguous bases. This chromosomal assembly recovers all 16 chromosome ends, 13 of which are contiguously assembled. The three remaining chromosome ends are provisionally placed. These ends represent duplication of entire chromosome ends including subtelomeric regions revealing a new level of genome plasticity that will both inform and impact future research.

Long-term outcomes and patterns of relapse in patients with bilateral Wilms tumor or bilaterally predisposed unilateral Wilms tumor, a report from the COG AREN0534 study.

The objective of this study is to report the long-term timing and patterns of relapse for children enrolled in Children's Oncology Group AREN0534, a multicenter phase III clinical trial conducted from 2009 to 2015. Participants included children with bilateral Wilms tumor (BWT) or unilateral WT with genetic predisposition to develop BWT followed for up to 10 years. Smoothed hazard (risk) functions for event-free survival (EFS) were plotted so that the timing of events could be visualized, both overall and within pre-specified groups. Two hundred and twenty-two children (190 BWT and 32 unilateral WT with BWT predisposition) were followed for a median of 8.6 years. Fifty events were reported, of which 48 were relapse/progression. The overall 8-year EFS was 75% (95% confidence interval: 69%-83%). The highest risk for an EFS event was immediately after diagnosis with a declining rate over 2 years. A second peak of events was observed around 4 years after diagnosis, and a small number of events were reported until the end of the follow-up period. In subset analyses, later increases in risk were more commonly observed in patients with female sex, anaplastic histology, negative lymph nodes or margins, and favorable histology Wilms tumor patients with post-chemotherapy intermediate risk. Among relapses that occurred after 2 years, most were to the kidney. These patterns suggest that late events may be second primary tumors occurring more commonly in females, although more investigation is required. Clinicians may consider observation of patients with BWT beyond 4 years from diagnosis.

Bilateral Wilms tumor with anaplasia: A report from the Children's Oncology Group Study AREN0534.

INTRODUCTION: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. METHODS: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. RESULTS: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months. CONCLUSION: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.

Visibility and Size of the Pancreatic Duct and Common Bile Duct on Routine 2D MRI Sequences in Children Without Pancreaticobiliary Disease.

Background: Pancreatic duct (PD) or common bile duct (CBD) dilatation can indicate ductal pathology, but limited data describe normal pediatric duct measurements on routine 2D MR sequences. Objective: To characterize the visibility and diameter of the PD and CBD on 2D MR images in children without pancreaticobiliary disease. Methods: This retrospective study included patients who underwent abdominal MRI using a rapid protocol (comprised of noncontrast axial and coronal 2D SSFSE sequences) to assess for suspected appendicitis or ovarian torsion in the emergency department setting between January 23, 2023, and September 13, 2023, excluding patients with a pancreatic or hepatobiliary abnormality on MRI or laboratory assessment. Four radiologists independently reviewed examinations. Reviewers recorded PD visibility in each of four segments (head, neck, body, and tail) and CBD visibility, and measured PD diameter in each segment and maximal CBD diameter. Duct measurements by age were characterized by linear regression analyses. Results: The study included 177 patients [112 female, 65 female; mean age, 12.3±3.4 years (range, 5.1-17.7 years)]. The observers reported PD visibility in the head in 32.5-93.5%, neck in 18.4-71.5%, body in 22.3-69.8%, and tail in 7.3-25.7%, and in all four segments in 6.2-22.4%, of patients. Maximum PD diameter in any segment, as a mean across observers, was 1.8 mm (range across observers, 0.7-3.5 mm). Expected maximal PD diameter in any segment, in terms of the 5th and 95th percentile values of observers' mean measurements, was 1.4-2.3 mm; the prediction interval's upper limit increased from age 5 to 17 from 2.1 to 2.5 mm. All observers reported CBD visibility in all patients. Mean CBD diameter across observers was 3.1 mm (range across observers, 2.9-3.4 mm). Expected CBD diameter, in terms of the 5th and 95th percentile values of observers' mean measurements, was 2.3-4.9 mm; the prediction interval's upper limit increased from age 5 to 17 from 3.9 to 5.0 mm. Conclusion: We report expected upper limits for PD and CBD measurements on 2D MR images in children without evidence of pancreaticobiliary disease. Clinical Impact: These findings may aid radiologists' identification of pancreaticobiliary duct abnormalities on routine abdominal MRI examinations.

Machine Learning Diagnosis of Small-Bowel Crohn Disease Using T2-Weighted MRI Radiomic and Clinical Data.

BACKGROUND. Radiologists have variable diagnostic performance and considerable interreader variability when interpreting MR enterography (MRE) examinations for suspected Crohn disease (CD). OBJECTIVE. The purposes of this study were to develop a machine learning method for predicting ileal CD by use of radiomic features of ileal wall and mesenteric fat from noncontrast T2-weighted MRI and to compare the performance of the method with that of expert radiologists. METHODS. This single-institution study included retrospectively identified patients who underwent MRE for suspected ileal CD from January 1, 2020, to January 31, 2021, and prospectively enrolled participants (patients with newly diagnosed ileal CD or healthy control participants) from December 2018 to October 2021. Using axial T2-weighted SSFSE images, a radiologist selected two slices showing greatest terminal ileal wall thickening. Four ROIs were segmented, and radiomic features were extracted from each ROI. After feature selection, support-vector machine models were trained to classify the presence of ileal CD. Three fellowship-trained pediatric abdominal radiologists independently classified the presence of ileal CD on SSFSE images. The reference standard was clinical diagnosis of ileal CD based on endoscopy and biopsy results. Radiomic-only, clinical-only, and radiomic-clinical ensemble models were trained and evaluated by nested cross-validation. RESULTS. The study included 135 participants (67 female, 68 male; mean age, 15.2 ± 3.2 years); 70 were diagnosed with ileal CD. The three radiologists had accuracies of 83.7% (113/135), 88.1% (119/135), and 86.7% (117/135) for diagnosing CD; consensus accuracy was 88.1%. Interradiologist agreement was substantial (κ = 0.78). The best-performing ROI was bowel core (AUC, 0.95; accuracy, 89.6%); other ROIs had worse performance (whole-bowel AUC, 0.86; fat-core AUC, 0.70; whole-fat AUC, 0.73). For the clinical-only model, AUC was 0.85 and accuracy was 80.0%. The ensemble model combining bowel-core radiomic and clinical models had AUC of 0.98 and accuracy of 93.5%. The bowel-core radiomic-only model had significantly greater accuracy than radiologist 1 (p = .009) and radiologist 2 (p = .02) but not radiologist 3 (p > .99) or the radiologists in consensus (p = .05). The ensemble model had greater accuracy than the radiologists in consensus (p = .02). CONCLUSION. A radiomic machine learning model predicted CD diagnosis with better performance than two of three expert radiologists. Model performance improved when radiomic data were ensembled with clinical data. CLINICAL IMPACT. Deployment of a radiomic-based model including T2-weighted MRI data could decrease interradiologist variability and increase diagnostic accuracy for pediatric CD.

Domestically Acquired NDM-1-Producing Pseudomonas aeruginosa, Southern California, USA, 2023.

We describe a case of New Delhi metallo-ß-lactamase 1-producing carbapenem-resistant Pseudomonas aeruginosa (CRPA) in a transplant patient with multiple hospitalizations in California, USA. Whole-genome sequencing revealed the isolate was genetically distinctive, despite ≈95% similarity to other global strains. The patient's lack of international travel suggests this CRPA was acquired domestically.

Imaging of pediatric renal tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper focused on Wilms tumor and nephrogenic rests.

Malignant renal tumors account for approximately 6% of pediatric malignancies, with Wilms tumor (WT) representing approximately 90% of pediatric renal tumors. This paper provides consensus-based imaging guidelines for the initial evaluation of a child with suspected WT and follow-up during and after therapy co-developed by the Children's Oncology Group (COG) Diagnostic Imaging and Society for Pediatric Radiology (SPR) oncology committees. The guidelines for Wilms Tumor Imaging in the Society of International Pediatric Oncology (SIOP) are briefly discussed to highlight some of the differences in imaging approach.

Similarities and controversies in imaging of pediatric renal tumors: A SIOP-RTSG and COG collaboration.

Malignant renal tumors are rare in children, and Wilms tumors (WTs) are the most common subtype. Imaging plays an essential role in the diagnosis, staging, and follow-up of these patients. Initial workup for staging is mainly performed by cross-sectional imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI). Imaging approach within the two core international groups, the Children's Oncology Group (COG, North America) and the International Society of Pediatric Oncology - Renal Tumor Study Group (SIOP-RTSG, Europe), differs. Whereas abdominal ultrasound (US) is used for the initial diagnosis of a suspected pediatric renal tumor globally, COG protocols support the use of CT or MRI for locoregional staging, contrary to the preference for MRI over CT for abdominopelvic evaluation within the SIOP-RTSG. The purpose of this manuscript is to summarize current imaging approaches, highlighting differences and similarities within these core international groups, while focusing on future innovative efforts and collaboration within the HARMONICA initiative.

The Simplified MR Index of Activity Score in Pediatric Small-Bowel Crohn Disease: An Interreader Agreement and Responsiveness Study.

BACKGROUND. The simplified MR index of activity (MaRIA) score is used to assess the severity of small-bowel inflammation without use of IV contrast material. OBJECTIVE. The purposes of this study were to assess interreader agreement on the use of simplified MaRIA scores for evaluation of the inflammatory activity of terminal ileal Crohn disease in children and young adults and to assess whether simplified MaRIA scores change after biologic medical therapy. METHODS. This analysis was ancillary to a previously reported primary prospective research investigation. The study included 20 children and young adults with newly diagnosed ileal Crohn disease and 15 healthy control participants who underwent research small-bowel MRI examinations between December 2018 and October 2021. The participants with Crohn disease underwent baseline MRI and MRI 6 weeks and 6 months after beginning anti-tumor necrosis factor α-treatment as well as weighted pediatric Crohn disease activity index (wPCDAI) and C-reactive protein (CRP) assessment on the day of each examination. Control participants underwent one MRI examination. Four pediatric radiologists independently assigned simplified MaRIA scores using axial and coronal T2-weighted SSFSE images. Median simplified MaRIA score among readers was computed. Interreader agreement was assessed with Fleiss kappa coefficients and intra-class correlation coefficient (ICC). Analysis included the Mann-Whitney U test, Friedman test, and Spearman rank correlation. RESULTS. Simplified MaRIA scores (across time points and study groups) had substantial interreader agreement (κ = 0.65 [95% CI, 0.56-0.74]; ICC, 0.71 [95% CI, 0.63-0.78]). Median scores were higher in participants with Crohn disease at baseline than in healthy control participants (3.5 [IQR, 2.5-4.9] vs 0.5 [IQR, 0-2.0]; p < .001). Scores decreased after medical treatment in participants with Crohn disease (p = .005). The median score was 3.5 (IQR, 2.5-4.9) at baseline, 2.3 (IQR, 1.6-3.9) at 6 weeks, and 2.0 (IQR, 0.5-2.5) at 6 months. In participants with Crohn disease, median scores had significant correlations with wPCDAI (ρ = 0.46 [95% CI, 0.18-0.64]; p < .001) and CRP level (ρ = 0.48 [95% CI, 0.27-0.65]; p < .001). CONCLUSION. Radiologists had substantial agreement in use of simplified MaRIA scores to assess intestinal inflammation in ileal Crohn disease. Scores changed over time after medical therapy. CLINICAL IMPACT. The results support the simplified MaRIA score as an objective MRI-based clinical measure of intestinal inflammation in children and young adults with Crohn disease.

Secondary mathematics teachers' descriptions of student engagement.

There is a need for a more robust conceptualization of engagement in mathematics education research. Investigating how teachers describe engagement can provide insight into relationships between purposes of engagement and dimensions of engagement. In this exploratory study, we examined how 28 secondary mathematics teachers in two states in the USA talked about their students' engagement. During interviews, we asked teachers to provide their definitions for engagement, describe their teaching strategies for engaging students, and describe their observations of engagement during a video clip from their own classroom. We interpreted teachers' talk to identify how they described the nature of mathematics engagement (dimensions such as behavioral, cognitive, affective, and/or social engagement) and purposes of engagement (engagement in learning or in schooling [Harris, 2011]). When teachers described the purpose of engagement as engagement in learning, they also tended to describe the nature of engagement with cognitive and social dimensions and with multiple dimensions of engagement.

Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease.

Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Therapeutics that lower HTT have shown preclinical promise and are being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. We have reported that mutant HTT (mHTT) in the CSF of HD patients correlates with clinical measures, including disease burden as well as motor and cognitive performance. We have also shown that lowering HTT in the brains of HD mice results in correlative reduction of mHTT in the CSF, prompting the use of this measure as an exploratory marker of target engagement in clinical trials. In this study, we investigate the mechanisms of mHTT clearance from the brain in adult mice of both sexes to elucidate the significance of therapy-induced CSF mHTT changes. We demonstrate that, although neurodegeneration increases CSF mHTT concentrations, mHTT is also present in the CSF of mice in the absence of neurodegeneration. Importantly, we show that secretion of mHTT from cells in the CNS followed by glymphatic clearance from the extracellular space contributes to mHTT in the CSF. Furthermore, we observe secretion of wild type HTT from healthy control neurons, suggesting that HTT secretion is a normal process occurring in the absence of pathogenesis. Overall, our data support both passive release and active clearance of mHTT into CSF, suggesting that its treatment-induced changes may represent a combination of target engagement and preservation of neurons.SIGNIFICANCE STATEMENT: Changes in CSF mutant huntingtin (mHTT) are being used as an exploratory endpoint in HTT lowering clinical trials for the treatment of Huntington disease (HD). Recently, it was demonstrated that intrathecal administration of a HTT lowering agent leads to dose-dependent reduction of CSF mHTT in HD patients. However, little is known about how HTT, an intracellular protein, reaches the extracellular space and ultimately the CSF. Our findings that HTT enters CSF by both passive release and active secretion followed by glymphatic clearance may have significant implications for interpretation of treatment-induced changes of CSF mHTT in clinical trials for HD.

In-Depth Mass Spectrometry-Based Proteomics of Formalin-Fixed, Paraffin-Embedded Tissues with a Spatial Resolution of 50-200 µm.

Formalin-fixed, paraffin-embedded (FFPE) tissues are banked in large repositories to cost-effectively preserve valuable specimens for later study. With the rapid growth of spatial proteomics, FFPE tissues can serve as a more accessible alternative to more commonly used frozen tissues. However, extracting proteins from FFPE tissues is challenging due to cross-links formed between proteins and formaldehyde. Here, we have adapted the nanoPOTS sample processing workflow, which was previously applied to single cells and fresh-frozen tissues, to profile protein expression from FFPE tissues. Following the optimization of extraction solvents, times, and temperatures, we identified an average of 1312 and 3184 high-confidence master proteins from 10 µm thick FFPE-preserved mouse liver tissue squares having lateral dimensions of 50 and 200 µm, respectively. The observed proteome coverage for FFPE tissues was on average 88% of that achieved for similar fresh-frozen tissues. We also characterized the performance of our fully automated sample preparation and analysis workflow, termed autoPOTS, for FFPE spatial proteomics. This modified nanodroplet processing in one pot for trace samples (nanoPOTS) and fully automated processing in one pot for trace sample (autoPOTS) workflows provides the greatest coverage reported to date for high-resolution spatial proteomics applied to FFPE tissues. Data are available via ProteomeXchange with identifier PXD029729.

Extracellular vesicle-associated cytokines in sport-related concussion.

Growing evidence suggests that sport-related concussion results in a robust inflammatory response that can be measured in serum or plasma and is predictive of symptom recovery. Recently, extracellular vesicles (EV) derived from serum or plasma have emerged as a promising source of biomarkers for neurological disorders like concussion because they may better reflect central immunological activity. However, the association of acute concussion with EV-associated cytokines has not yet been systematically studied in humans. We tested the hypothesis that EV-associated cytokines are elevated acutely and predictive of symptom duration following concussion in a cohort of high-school and collegiate football players. Players were enrolled and provided serum samples at a preseason baseline visit (N = 857). An additional blood draw was obtained in players that subsequently suffered a concussion (N = 23) within 6-hours post-injury and in matched, uninjured players (N = 44). Concentrations of Interleukin-6 (IL-6), IL-1ß, IL-1 receptor antagonist (IL-1RA), IL-10, and tumor necrosis factor were measured in EV and EV-depleted serum samples. EV-associated IL-6 was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). In EV-depleted samples, IL-1RA was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). Time-to-event analyses showed that post-injury EV-associated IL-6 levels were positively associated with the number of days that injured athletes reported symptoms (p < 0.05). These results highlight the potential of EV-associated cytokines as biomarkers of concussion.

Metastatic neuroblastoma masquerading as infantile hemangioma in a 4-month-old child.

INTRODUCTION: Diffuse liver lesions in an infant have a differential diagnosis including infantile hemangioma (IH), which is common in the first year of life, and neuroblastoma (NBL) which presents at a median age of 18 months. RESULTS: We describe the case of a 4-month-old girl with a known superficial/deep IH who presented with new axillary nodules and hepatosplenomegaly, initially suspected to reflect IH but later determined to be widely metastatic NBL. CONCLUSION: Hepatic IH and metastatic NBL can present similarly. Clinicians must maintain a broad differential when evaluating new findings in a patient with previously diagnosed IH.

Pharmacist driven antibiotic redosing in the emergency department.

STUDY OBJECTIVE: Determine whether an expanded emergency medicine (EM) pharmacist scope of practice reduces the frequency of major delays in subsequent antibiotic administration in patients boarded in the emergency department (ED). METHODS: A pre-post, quasi-experimental study conducted from November 2019-March 2020 at a single-center tertiary academic medical center following the implementation of an expanded EM pharmacist scope of practice. Adult patients were included if they received an initial antibiotic dose in the ED and deemed to be high-risk. Subsequent antibiotic doses were reordered by EM pharmacists for up to 24-h after the initial order pending ED length of stay (LOS). The historical control group consisted of retrospective chart review of cases from the previous year. RESULTS: The study identified that of the 181 participants enrolled, major delays in subsequent antibiotic administration occurred in 13% of the intervention group and 48% of the control group (p < 0.01). When compared to the control group, the intervention group had a significant decrease in the number of delays among antibiotics dosed at 6-h (39% vs 13%) and 8-h (60% vs 8%) intervals. For antibiotics dosed at 12-h intervals, no statistically significant difference was observed between the control and intervention groups respectively (19% vs 5%). A statistically significant lower incidence of in-hospital mortality was observed in the intervention group (3% vs 11%, p = 0.02). In the intervention group, 97% of patients received subsequent antibiotic doses while boarded in the ED, compared to 65% in the control group (<0.01). CONCLUSION: Expanding EM pharmacist scope of practice was associated with a significant reduction in the frequency of major delays in subsequent antibiotic administration as well as a decreased incidence of hospital mortality.

Clinical utility and economic impact of routine delayed follow-up radiographs in children with uncomplicated distal radius Salter-Harris 2 fractures.

BACKGROUND: Salter-Harris 2 fractures of the distal radius are common in pediatrics. Children with these fractures have a theoretical risk of developing a physeal bridge with subsequent growth disturbance. OBJECTIVE: The purpose of this study was to investigate the clinical utility and economic impact of obtaining routine delayed radiographs in asymptomatic patients with uncomplicated Salter-Harris 2 fractures of the distal radius. MATERIALS AND METHODS: Radiology records were searched retrospectively between Jan. 1, 2016, and Jan. 1, 2018, to identify patients with an acute Salter-Harris type 2 fracture of the distal radius and delayed wrist radiography 3 to 8 months after the injury. Exclusion criteria included distal radius surgery, clinical symptoms, secondary wrist trauma or a history of infection. The financial cost associated with follow-up imaging was determined based on standard charges associated with wrist/forearm radiography, wrist magnetic resonance imaging (MRI) and orthopedic clinical care. RESULTS: A total of 381 children with Salter-Harris 2 fractures of the distal radius and delayed radiographs were identified, 56% male (ages 1-18 years, mean: 9.8 years). Four children were excluded because of surgical intervention or clinical symptoms to the same wrist resulting in 377 subjects. There were five confirmed positive cases (1.3%) of distal radius physeal bridge formation, with four cases confirmed on MRI and one case confirmed clinically and radiographically. Based on routine institutional charges for the wrist/forearm radiographs and orthopedic clinic visits, the total billed charges for the 377 patients would equal $245,804, or $49,161 in billed charges per identified physeal bridge. Only three of the five positive cases of confirmed physeal bridge went on to surgical treatment. The billed charges per identified physeal bridge requiring surgery were $81,935. CONCLUSION: In asymptomatic children with uncomplicated Salter-Harris 2 fractures of the distal radius, detection of a physeal bridge on delayed radiographs is rare. The financial burden of routine delayed follow-up in asymptomatic patients, a common clinical practice, is an important consideration.

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone. METHODS: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867. FINDINGS: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related. INTERPRETATION: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up. FUNDING: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.

Compassionate Use of Tocilizumab for Treatment of SARS-CoV-2 Pneumonia.

BACKGROUND: Preliminary data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients indicate that a cytokine storm may increase morbidity and mortality. Tocilizumab (anti-IL-6R) is approved by the Food and Drug Administration for treatment of cytokine storm associated with chimeric antigen receptor T-cell therapy. Here we examined compassionate use of tocilizumab in patients with SARS-CoV-2 pneumonia. METHODS: We report on a single-center study of tocilizumab in hospitalized patients with SARS-CoV-2 pneumonia. All patients had confirmed SARS-CoV-2 pneumonia and oxygen saturations <90% on oxygen support with most intubated. We examined clinical and laboratory parameters including oxygen and vasopressor requirements, cytokine profiles, and C-reactive protein (CRP) levels pre- and post-tocilizumab treatment. RESULTS: Twenty-seven SARS-CoV-2 pneumonia patients received one 400 mg dose of tocilizumab. Interleukin (IL)-6 was the predominant cytokine detected at tocilizumab treatment. Significant reductions in temperature and CRP were seen post-tocilizumab. However, 4 patients did not show rapid CRP declines, of whom 3 had poorer outcomes. Oxygen and vasopressor requirements diminished over the first week post-tocilizumab. Twenty-two patients required mechanical ventilation; at last follow-up, 16 were extubated. Adverse events and serious adverse events were minimal, but 2 deaths (7.4%) occurred that were felt unrelated to tocilizumab. CONCLUSIONS: Compared to published reports on the morbidity and mortality associated with SARS-CoV-2, tocilizumab appears to offer benefits in reducing inflammation, oxygen requirements, vasopressor support, and mortality. The rationale for tocilizumab treatment is supported by detection of IL-6 in pathogenic levels in all patients. Additional doses of tocilizumab may be needed for those showing slow declines in CRP. Proof of efficacy awaits randomized, placebo-controlled clinical trials.

Secretin Improves Visualization of Nondilated Pancreatic Ducts in Children Undergoing MRCP.

OBJECTIVE. The objective of our study was to assess whether secretin improves visualization of a nondilated pancreatic duct and whether it increases identification of variant duct anatomy on MRCP in pediatric patients. MATERIALS AND METHODS. This study is a delayed retrospective review of MRCP images that were prospectively obtained of 50 volunteers without a history of pancreatic disease who ranged in age from 6 to 15 years old. MRCP images (coronal 3D fast recovery fast spin-echo [FSE] and coronal single-shot FSE fat-saturated sequences) obtained before and after secretin administration were separated for review by three radiologists (reviewers 1-3). The reviewers were blinded to the purpose of the study and to secretin administration. Reviewers ranked subjective image quality (Likert scale, 1-5 points) and reported pancreaticobiliary duct anatomy and duct visibility (yes or no). Paired t tests were used for comparison of means, and the chi-square test or Fisher exact test was used for comparison of frequencies. Sensitivity and specificity of MRCP images obtained before secretin administration were judged against MRCP images obtained after secretin administration as the reference standard. RESULTS. The frequency of image quality scores of 4 or greater assigned to 3D MRCP images was statistically significantly greater after secretin administration for reviewer 2 (p < 0.0001) and reviewer 3 (p = 0.005) and approached statistical significance for reviewer 1 (p = 0.052). Mean number of visible pancreatic duct segments (head and uncinate, body, tail) was significantly greater on the MRCP images obtained after secretin administration than on those obtained before secretin administration for all reviewers (reviewer 1, 1.9 vs 1.3; reviewer 2, 1.9 vs 1.2; reviewer 3, 1.4 vs 0.8; all, p < 0.01). For all three reviewers, the sensitivity of MRCP images obtained before secretin administration was poor for variant pancreatic ductal anatomy (reviewer 1, 37.5%; reviewer 2, 50.0%; reviewer 3, 40.0%). CONCLUSION. Secretin administration improved subjective MRCP image quality, improved subjective visualization of the pancreatic duct, and provided greater sensitivity for anatomic variants such as pancreas divisum in a cohort of children with nondilated pancreatic ducts.