Search

The recycling of depleted high global warming mixtures of fluorinated gases (F-gases) with close-boiling or azeotropic behavior requires advanced separation processes to obtain effectively the pure components. Herein, several types of PIM-1 membranes were tested for the first time towards the separation of hydrofluorocarbons and hydrofluoroolefins, showing extraordinarily high permeability coefficients for the value-added difluoromethane (R-32), up to 4100 barrer, coupled with high selectivity for the F-gas pairs of interest. Additionally, the solubility of selected F-gases in PIM-1 was measured and fitted to the dual-mode and Guggenheim, Anderson and de Boer sorption models. The separation performance of the standard PIM-1 and a highly branched PIM-1 was examined with the mixture R-410A (containing R-32 and pentafluoroethane R-125) to assess the influence of the membrane topology on the mixed-gas permeation properties over time (physical aging). Considering that the branched PIM-1 membrane was the least impacted by the aging phenomena, it was used to recover high purity R-32 (concentration in the permeate side as high as 98.9 vol % was achieved) from refrigerant gas mixtures R-410A and R-454B (mixture of R-32 and R-1234yf) in continuous long-term experiments. Results showed the great potential of PIM-1 membranes for the separation of R-32 from refrigerant mixtures collected from end-of-life equipment. This research is supported by project PID2019-105827RB-I00 funded by MCIN/AEI/10.13039/501100011033. F.P. and S.V.G.H. acknowledge the support of the Spanish State Research Agency and the Spanish Ministry of Science and Innovation (grants IJC2020-043134-I and PRE2020-093568, respectively). A.B.F and P.M.B acknowledge EPSRC Grant ep/v047078/1 (SynHiSel). P.G. is supported by Grant RYC2019-027060-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”.

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3–specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation.Significance:This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF.This article is highlighted in the In This Issue feature, p. 1

Supplementary Data from Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety

Background: Selenium may prevent colorectal cancer. However, several previous studies are small and few investigated the association between selenium and colorectal cancer among women whose selenium metabolism may differ from men. Furthermore, genetic variants in selenoenzymes may be associated with colorectal cancer risk.Methods: This nested case–control study investigated whether serum selenium concentration and genetic variants in five selenoenzymes (glutathione peroxidase 1–4 and selenoprotein P) were associated with colorectal cancer risk in 804 colorectal cancer cases and 805 matched controls from the Women's Health Initiative (WHI) Observational Study. A meta-analysis was conducted to compare the WHI result with previous studies including 12 observational studies and two clinical trials on selenium.Results: Within the WHI, selenium concentrations were relatively high (mean = 135.6 μg/L) and were not associated with colorectal cancer risk (Ptrend = 0.10); the adjusted OR comparing the fifth with first quintile was 1.26 (95% CI, 0.91–1.73). Moreover, genetic variants in selenoenzymes were not significantly associated with colorectal cancer risk. Consistent with the finding in WHI, our meta-analysis showed no association between selenium and colorectal tumor risk in women (OR = 0.97; 95% CI, 0.79–1.18) comparing the highest quantile with the lowest); however, in men, there was a significant inverse association (OR = 0.68; 95% CI, 0.57–0.82) (P = 0.01).Conclusion: Consistent with previous studies, we observed no protective effect of selenium on colorectal cancer among women.Impact: Our analyses suggest that a population with relatively high selenium concentrations, especially women, would not benefit from increasing selenium intake. Cancer Epidemiol Biomarkers Prev; 20(9); 1822–30. ©2011 AACR.

PDF file - 60K

PDF file - 71K

PDF file - 103K

PDF file - 244K

PDF file - 114K

PDF file - 86K

Physical aging of glassy polymers leads to a decrease in permeability over time when they are used in membranes. This hinders the industrial application of high free volume polymers, such as the archetypal polymer of intrinsic microporosity PIM-1, for membrane gas separation. In thin film composite (TFC) membranes, aging is much more rapid than in thicker self-standing membranes, as rearrangement within the thin active layer is relatively fast. Liquid alcohol treatment, which swells the membrane, is often used in the laboratory to rejuvenate aged self-standing membranes, but this is not easily applied on an industrial scale and is not suitable to refresh TFC membranes because of the risk of membrane delamination. In this work, it is demonstrated that a simple method of storage in an atmosphere of methanol vapor effectively retards physical aging of PIM-1 TFC membranes. The same method can also be utilized to refresh aged PIM-1 TFC membranes, and one-week methanol vapor storage is sufficient to recover most of the original CO2 permeance.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) occurs predominantly in children and is typically characterized by diffuse leptomeningeal lesions throughout the neuroaxis with focal segments of parenchymal involvement. Recent reports have identified cases without diffuse leptomeningeal involvement that retain classic glioneuronal features on histology. In this report, we present a case of a 4-year-old boy with a large cystic-solid intramedullary spinal cord lesion that on surgical biopsy revealed a biphasic astrocytic tumor with sparsely distributed eosinophilic granular bodies and Rosenthal fibers. Next-generation sequencing revealed a KIAA1549-BRAF fusion, 1p/19q codeletion, and lack of an IDH1 mutation. Methylation profiling demonstrated a calibrated class score of 0.98 for DLGNT and copy number loss of 1p. Despite the morphologic similarities to pilocytic astrocytoma and the lack of oligodendroglial/neuronal components or leptomeningeal dissemination, the molecular profile was definitive in classifying the tumor as DLGNT. This case highlights the importance of molecular and genetic testing in the characterization of pediatric central nervous system tumors.

The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) provides benefits to low-income, nutritionally at-risk women, infants, and children. To administer WIC, officials and program managers at the federal and state levels want to understand who is eligible for the program, who among the eligible population chooses to participate, and who is not accessing the program despite their eligibility. Novel individual-level data linkages between restricted-use WIC Administrative Records and the American Community Survey provide WIC access rates estimated at the state and county levels, as well as estimates disaggregated by the demographic and socioeconomic characteristics of individuals and their households. These estimates are developed by the Census-FNS-ERS Joint Project, a research partnership among the US Census Bureau, the US Department of Agriculture’s Food and Nutrition Service and Economic Research Service, and state WIC agencies that provide the requisite WIC administrative data to the Census Bureau. This article details and evaluates our current data linkage and estimation methods, reports results, and identifies areas for improvement and further research.

Background Children undergoing liver transplantation are at risk for surgical site infections (SSI). IDSA/ASHP/SIS/SHEA guidelines recommend surgical prophylaxis with a third-generation cephalosporin plus ampicillin or piperacillin-tazobactam alone. The study objectives were to describe the surgical prophylaxis used at our institution, obtain data on whether prophylactic antimicrobials are adjusted for multidrug resistant organisms and to determine whether adjustments correlate with SSI. Methods Pediatric liver transplant procedures, with associated peri-operative and intra-operative antimicrobials, were extracted from our institutions’ Anesthesia Record Keeping System (ARKS) between 2005-2022. Medical records were reviewed for demographics, microbiological data (e.g., colonization), protocol deviations and 30-day CDC/NHSN SSIs. Results Seventy-one procedures were performed in 69 patients, median age 3 years (range, 5 months- 17 years), where 89% had a pre-transplant infectious disease consultation. Variations from protocol occurred in 39% (n=28), of which 3 were consult-directed. Sixteen were colonized with an organism prior to transplant (3 MDRO and 1 Candida spp.), of which 10 had a protocol adjustment (p< 0.001). The most common additional antimicrobials were vancomycin (n=17) and fluconazole (n=8). Reasons for fluconazole were fulminant liver failure (n=2), surgeon concern (n=3), colonization or prolonged antimicrobials prior to transplant (n=2) and continuation of prophylaxis (n=1). Ten procedures were complicated by an SSI (14%). SSI rates did not differ in those with and without protocol adjustments (p=0.50). Conclusion Adjustments to guideline concordant surgical prophylaxis recommendations occurred in 39% of pediatric liver transplant procedures, with the most common being addition of vancomycin or fluconazole. Adjustments were based on a pre-transplant infectious disease consult recommendations in 11% of cases. Protocol adjustment correlated with any pretransplant microbiology culture result, but not with either MDRO colonization or subsequent SSI. Antimicrobial stewardship efforts may be indicated to address variations in antimicrobial prophylaxis in pediatric liver transplant patients. Disclosures All Authors: No reported disclosures.

Objective:To assess central venous catheter (CVC) harm in pediatric oncology patients, we explored risks for central-line–associated bloodstream infections (CLABSIs) and central-line–associated non-CLABSI complications (CLANCs).Design:Retrospective cohort study.Setting:Midwestern US pediatric oncology program.Patients:The study cohort comprised 592 pediatric oncology patients seen between 2006 and 2016.Methods:CLABSIs were defined according to Centers for Disease Control and Prevention (CDC)/National Health Safety Network (NHSN) definitions. CLANCs were classified using a novel definition requiring CVC removal. Patient-level and central-line–level risks were calculated using a negative binomial model to adjust for correlations between total events and line numbers.Results:CVCs were inserted in 62% of patients, with 175,937 total catheter days. The inpatient CLABSI and CLANC rates were 5.8 and 8.5 times higher than outpatient rates. At the patient level, shared risks included acute myeloid leukemia (AML) and age 1 lumen. AML was a CLABSI-specific risk. CLANC-specific risks included non–brain-tumor diagnosis, younger age at diagnosis or central-line placement, and age 1 lumen and for CLANC age Conclusions:Among patients with CVCs, CLABSI and CLANC rates were similar, higher among inpatients than outpatients. For both CLABSIs and CLANCs, infants and patients with AML were at higher risk. In both univariate and multivariate models, lines with >1 lumen were associated with CLABSIs and placement during infancy with CLANCs.

PIM-1/holey graphene oxide (GO) mixed matrix membranes (MMMs) have been prepared and their gas separation performance for CO2/CH4 mixtures assessed. Nanopores have been created in the basal plane of gas-impermeable GO by chemical etching reactions, and the resulting holey flakes have been further chemically functionalized, either with octadecylamine (ODA) or with PIM-1 moieties, to aid their dispersion in PIM-1. It is found that nanopores barely promote gas transport through the graphene-like nanofiller for fresh membranes (tested right after preparation); however, the prepared hybrid PIM-1/holey GO membranes exhibit higher CO2 permeability and CO2/CH4 selectivity than the pure polymer membrane 150 days after preparation and 13 and 15% higher CO2 permeability for filler contents of 0.1% of octadecylamine-functionalized holey GO and 1% of (PIM-1)-functionalized holey GO, respectively. The most significant improvement is observed for the mitigation of physical aging, as MMMs using 10% of (PIM-1)-functionalized holey GO nanofillers are capable of maintaining up to 70% of their initial CO2 permeability after 150 days, whereas only 53% is kept for pure PIM-1 after the same period. The gas permeability of the nanofiller has been rationalized with the aid of the Maxwell–Wagner–Sillars equation., The authors are grateful to EPSRC for funding under grant numbers EP/K016946/1 and EP/M01486X/1. J. M. Luque-Alled is grateful to the Department of Chemical Engineering and Analytical Science─The University of Manchester for funding his Ph.D. studies. P. Gorgojo acknowledges the Spanish Ministry of Economy and Competitiveness and the European Social Fund through the Ramon y Cajal programme (RYC2019-027060-I/AEI/10.13039/501100011033).

Experiential learning has played an integral role in curricular innovation since the inception of North American sport management education. However, internationally, work-integrated learning, and specifically cooperative education, have proven to be robust methods for preparing students for the workforce with little to no mention of these terms as applied to sport management curricula in the United States. This educational research review positions involving both of these structured pedagogies that combine classroom instruction with highly contextualized, authentic work experiences of at least two semesters to improve experiential learning and calls for more research to be done to demonstrate its efficacy. Recommendations are made to spur faculty to consider ways these pedagogies can be applied to their sport management curricula. In addition, this review addresses keys to successfully implement them on campus.

The polymer of intrinsic microporosity PIM-1 was synthesized with different topologies and negligible network content. A more rapid heating rate from room temperature yielded a predominantly di-substituted PIM-1 (D-PIM-1), whereas a marginally lower heating rate produced a more branched structure (B-PIM-1). Both polymers were acid-hydrolyzed to give carboxylic acid functionalization (cPIM-1), as indicated by FT-IR, 1H NMR, and elemental analysis. Both PIM-1 and cPIM-1 were processed into self-supported membranes and into thin film composite (TFC) membranes on a polyacrylonitrile support. For a 70% hydrolysed polymer (D-cPIM-1-70%), the initial CO2 permeance reached 7700 GPU, with ideal selectivity of 56 for CO2/N2 and 37 for CO2/CH4. D-PIM-1 and D-cPIM-1-70% showed 85% and 52% CO2 permeance drop after 60 days’ aging, respectively. B-PIM-1, with initial CO2 permeance of 3100 GPU and ideal selectivity of 19 for CO2/N2 and 11 for CO2/CH4, showed only a 65% decrease. Polymer that was both branched and hydrolysed (B-cPIM-1-73&81%), with CO2 permeance of 3200 GPU and selectivity of 64 for CO2/N2 and 45 for CO2/CH4, showed no decrease of CO2 permeance after 60 days. The branched structure is crucial for reducing membrane aging. Plasticization gave rise to reduced selectivity in mixed gas experiments, but nevertheless TFC membranes prepared from B-cPIM-1-81% were able to concentrate CO2 to 38% from a 10% CO2/90% N2 mixture at 4.8 bar.

Molecular time trees indicating that embryophytes originated around 500 million years ago (Ma) during the Cambrian are at odds with the record of fossil plants, which first appear in the mid-Silurian almost 80 million years later. This time gap has been attributed to a missing fossil plant record, but that attribution belies the case for fossil spores. Here, we describe a Tremadocian (Early Ordovician, about 480 Ma) assemblage with elements of both Cambrian and younger embryophyte spores that provides a new level of evolutionary continuity between embryophytes and their algal ancestors. This finding suggests that the molecular phylogenetic signal retains a latent evolutionary history of the acquisition of the embryophytic developmental genome, a history that perhaps began during Ediacaran-Cambrian time but was not completed until the mid-Silurian (about 430 Ma).

Supplemental Digital Content is available in the text., OBJECTIVES: Firearm-related injury is the second leading cause of injury and death for children 1–18 years old in United States. The objective of our study was to analyze the outcomes of children admitted to the PICU with firearm injuries. DESIGN: Retrospective study. SETTING: PICUs in United States contributing data to Virtual Pediatric Systems, LLC, from January 2009 to December 2017. PATIENTS: Children age 1 month to 18 years old admitted to the PICU with firearm injury, identified by external cause of injury E-codes and International Classification of Diseases, 9th Edition, and International Classification of Diseases, 10th Edition, codes were identified. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 1,447 cases identified of which 175 (12%) died in the PICU. Unintentional firearm injury (67.7%) and assault with a firearm injury (20%) comprised 90% of the cases. Males comprised 78% of the cohort (1,122) and race distribution included 45% Black (646), 27% White (390), and 12% Hispanic (178). Among the children who died in the PICU, 55% were 13–18 years old. Children attempting suicide with a firearm were more likely to die in the PICU as compared to the other causes of firearm injury. Based on their Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores at discharge, there is high morbidity in children with firearm injuries. CONCLUSIONS: Mortality rate of children with firearm injury admitted to the PICU is high. Children admitted to the PICU with suicide attempt with a firearm carried the highest mortality. Further studies may help further define the epidemiology of firearm injuries in children and plan interventions to minimize these unnecessary deaths.

BackgroundPediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target.MethodsWe investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing.ResultsWe identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2–4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed.ConclusionTaken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.

BACKGROUND Syphilis screening during pregnancy helps prevent congenital syphilis. The harms associated with false positive (FP) screens and whether screening leads to correct treatments has not been well determined. METHODS The population included mothers and infants from 75 056 pregnancies. Using laboratory-based criteria we classified initial positive syphilis screens as FP or true positive (TP) and calculated false discovery rates. For mothers and infants we determined treatments, clinical characteristics, and syphilis classifications. RESULTS There were 221 positive screens: 183 FP and 38 TP. The false discovery rate was 0.83 (95% confidence interval [CI], 0.78–0.88). False discovery rates were similar for traditional 0.83 [95% CI, 0.72–0.94] and reverse algorithms 0.83 (95% CI, 0.77–0.88), and for syphilis Immunoglobin (Ig) G 0.79 (95% CI, 0.71–0.86) and total 0.90 (95% CI, 0.82–0.97) assays. FP screens led to treatment in 2 women and 1 infant. Two high-risk women were not rescreened at delivery and were diagnosed after hospital discharge; 1 infant developed congenital syphilis. Among 15 TP women with new syphilis, the diagnosis was before the late third trimester in 14 (93%). In one-half of these women, there was concern for reinfection, treatment failure, inadequate treatment or follow-up care, or late treatment, and their infants did not achieve an optimal syphilis classification. CONCLUSIONS Syphilis screening identifies maternal syphilis, but limitations include FP screens, which occasionally lead to unnecessary treatment, inconsistent risk-based rescreening, and among TP mothers failure to optimize care to prevent birth of infants at higher risk for congenital syphilis.

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3–specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation. Significance: This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF. This article is highlighted in the In This Issue feature, p. 1

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is characterized by widespread leptomeningeal lesions with focal parenchymal involvement. We present a child with a large intramedullary spinal cord lesion, whose biopsy revealed a biphasic astrocytic tumor consistent with pilocytic astrocytoma. Next-generation sequencing revealed a KIAA1549-BRAF fusion, 1p/19q co-deletion, and no IDH1 mutation. Methylation profiling demonstrated a calibrated class score of 0.98 for DLGNT. Despite morphologic similarities to pilocytic astrocytoma and lack of oligodendroglial/neuronal components or leptomeningeal dissemination, the molecular profile definitively classified the tumor as DLGNT. This case highlights the importance of molecular and genetic testing in diagnosing pediatric central nervous system tumors.