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Correlated oxides are known to have remarkable properties, with a range of electronic, magnetic, optoelectronic, and photonic functionalities. A key ingredient in realizing these properties into practical technology is the effective and scalable integration of oxides with conventional semiconductors. Unlocking the full spectrum of functionality requires atomically abrupt oxide-semiconductor interfaces and intimate knowledge of their potential landscape and charge transport. In this study, we investigated the electrical properties of epitaxial SrTiO 3 /GaAs heterostructures by examining the band alignment and transport behavior at the interface. We employ X-ray photoelectron spectroscopy (XPS) to measure the barriers for electrons and holes across the interface and, through them, explain the transport behavior for junctions with n- and p-type GaAs. We further show qualitative evidence of the strong photoresponse of these structures, illustrating the potential of these structures in optoelectronic devices. These results establish the fundamental groundwork for utilizing these interfaces toward new devices and define their design space., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background and Purpose: Multiple studies demonstrated hypothalamic-pituitary dysfunction in survivors of pediatric brain tumors. However, few studies investigated the trajectories of pituitary height in these patients and their associations with pituitary function. We aimed to evaluate longitudinal changes of pituitary height in children and adolescents with brain tumors, and their association with endocrine deficiencies., Materials and Methods: We conducted a retrospective analysis of 193 pediatric patients (54.9% male) diagnosed with brain tumors from 2002 to 2018, with a minimum of two years of radiological follow-up. Pituitary height was measured using MRI scans at diagnosis and at 2, 5, and 10 years post-diagnosis, with clinical data sourced from patient charts., Results: Average age at diagnosis was 7.6 ± 4.5 years, with a follow-up of 6.1 ± 3.4 years. 52.8% underwent radiotherapy and 37.8% experienced pituitary hormone deficiency. Radiation treatment was a significant predictor of decreased pituitary height at all observed time points (p = 0.016, p < 0.001, p = 0.008, respectively). Additionally, chemotherapy (p = 0.004) or radiotherapy (p = 0.022) history and pituitary height at 10 years (p = 0.047) were predictors of endocrine deficiencies. ANOVA revealed an expected increase in pituitary height over time in pediatric patients, but this growth was significantly impacted by radiation treatment and gender (p for interaction = 0.005 and 0.025, respectively)., Conclusion: Cranial irradiation in pediatric patients is associated with impairment of the physiologic increase in pituitary size; in turn, decreased pituitary height is associated with endocrine dysfunction. We suggest that pituitary gland should be evaluated on surveillance imaging of pediatric brain tumor survivors, and if small for age, clinical endocrine evaluation should be pursued., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD., Methods: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions., Findings: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions., Interpretation: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD., Funding: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center., Competing Interests: Declaration of interests ALa reports payment from Alexion, support from Servier and stock from Gilead, outside of the submitted work. AV is co-lead role of the Consortium for Childhood Cancer Predisposition, outside of the submitted work. BH reports payment and stock from Invitae, outside of the submitted work. BC reports participation as data safety and monitoring board member in ReRad Study, participation in the chapter advisory board for Make a Wish Canada Nova Scotia, and participation in the medical advisory committee for Make a Wish Canada, outside of the submitted work. CCP reports grants from St Baldrick's Foundation, outside of the submitted work. DSZ reports consulting fees for Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Alexion, Amgen, and Norgine, outside of the submitted work. DTB reports grants from MSD and Novocure, consulting fees from Nanocarry Therapeutics and Servier, and payment from Servier, outside of the submitted work. EO reports payment and support from Alexion for educational event, outside of the submitted work. EB reports grants from Roche and board participation for Novartis, Alexion and Gilead, outside of the submitted work. FC reports grants from Hall Hunter Foundation (UK), outside of the submitted work. HBF reports payments from Illumina and Sanofi Genzyme, support from Illumina, participation as scientific advisory committee for Sanofi Genzyme, International Gaucher Alliance and Igentify, stock from Igentify, and receipt of materials from Illumina, outside of the submitted work. IW reports grants from Chimerix and payment from COG Partners, outside of the submitted work. IS reports grants from Fondation Saint-Luc and FNRS-CDR, outside of the submitted work. JK reports other financial interests at Servier and PRA Health Sciences, outside of the submitted work. JRG-S reports participation on the board of the Philippine Society of Pediatric Oncology and Philippine Board of Pediatric Oncology, and stock in Macrogenics, Moderna, Mirati Therapeutics, CRISPR Therapeutics, Repligen, Quidelortho, and Shockwave Medical, outside of the submitted work. KJB reports consulting fees from US WorldMeds, Springworks Therapeutics, Alexion, and YmAbs, and payment from Alexion, outside of the submitted work. MS reports grants and support from the Swedish Childhood Cancer Fund, participation as a data safety and monitoring board member for clinical trial NCT05230758, and participation in the Swedish Pediatric CNS tumour group, outside of the submitted work. MAC reports financial support from SUNY Upstate Department of Pediatrics and board participation for Paige's Butterfly Run, outside of the submitted work. MO reports payment from Aptitude Health and participation on a data safety monitoring board or advisory board for Ultragenyx and Abeona, outside of the submitted works. MZ reports payment and support from and board participation for AstraZeneca. NW reports grants from CANSEARCH Foundation, Childhood Cancer Research Switzerland, and the Foundation for Children and Adolescents with Cancer; payment, support, and advisory board participation for Swedish Orphan Biovitrum; and board participation for Childhood Cancer Switzerland, outside of the submitted work. NH reports grants from the National Institutes of Health (NIH) and board participation for Incyte and Pfizer, outside of the submitted work. PCN reports grants from the Canadian Institutes for Health Research (CIHR) Foundation, US Department of Defense, and Garron Family Cancer Centre, outside of the submitted work. RP reports participation in the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer, outside of the submitted work. RT reports consulting fees from Fennec Pharmaceuticals and Day One Biopharmaceuticals and payment from Fennec Pharmaceuticals, outside of the submitted work. SS reports payments from Sanofi Pharmaceuticals and Mylan Pharmaceutical, and board participation for Sanofi Pharmaceuticals, outside of the submitted work. SB reports consulting fees from Hoffmann-La Roche, YmAbs, MAP Biopharma and SERB SAS, and payment from Zschimmer & Schwarz Mohsdorf, outside of the submitted work. UI reports board participation in Pakistan Society of Pediatric Oncology, outside of the submitted work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Endocrine deficiencies, including hypothalamic-pituitary-gonadal axis (HPGA) impairment, are common in survivors of childhood and adolescent medulloblastoma. Still, data regarding pubertal development and fecundity are limited, and few studies assessed HPGA function in males. We aimed to describe HPGA function in a large cohort of patients with medulloblastoma., Methods: A retrospective study comprising all 62 medulloblastoma patients treated in our center between 1987 and 2021, who were at least 2 years from completion of therapy. HPGA function was assessed based on clinical data, biochemical markers, and questionnaires., Results: Overall, 76% of female patients had clinical or biochemical evidence of HPGA dysfunction. Biochemical evidence of diminished ovarian reserve was seen in all prepubertal girls (n = 4). Among the males, 34% had clinical or biochemical evidence of gonadal dysfunction, 34% had normal function, and 29% were age-appropriately clinically and biochemically prepubertal. The difference between males and females was significant (P = .003). Cyclophosphamide-equivalent dose was significantly associated with HPGA function in females, but not in males. There was no association between HPGA dysfunction and other endocrine deficiencies, length of follow-up, weight status, and radiation treatment protocol. Two female and 2 male patients achieved successful pregnancies, resulting in 6 live births., Conclusions: HPGA dysfunction is common after treatment for childhood medulloblastoma. This is seen more in females, likely due to damage to the ovaries from spinal radiotherapy. Our findings may assist in counseling patients and their families regarding risk to future fertility and need for fertility preservation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Vaccine hesitancy is increasing. We assessed attitudes toward influenza and COVID-19 vaccines and the relation between hesitancy to influenza vaccine and hesitancy towards COVID-19 vaccines., Methods: A structured questionnaire administered during September 2020 to a representative sample of the Jewish Israeli population assessed attitudes and acceptance of influenza and COVID-19 vaccines. Factors for vaccine hesitancy were determined using logistic regression. Questionnaires were administered prior to the release of clinical data regarding efficacy and safety of COVID-19 vaccines and prior to vaccine rollout., Results: We approached 10,625 people, of these 2,080 responded (19%), and 2,024 completed the questionnaire (97.3%), 64.9% aged 15-64 years and 35.1% aged ≥65 years. 37% had co-morbidities. 43.5% experienced financial deterioration due to the pandemic. 65.9% received influenza vaccine ≥1 time in the past. Influenza vaccination rates were higher in the elderly (81.8%). Reasons for influenza vaccine hesitancy were opinions that the vaccine is ineffective (27.1%), and fear of side effects (29.3%). 8.2% of people aged 16-64 and 13.8% of people aged≥65 refused to be vaccinated at least once over the course of one's lifetime. Percent of responders willing to receive a COVID-19 vaccine were higher than percent of responders willing to receive the influenza vaccine both in people aged 16-64 years (942 (72.3%) vs. 38.4%, respectively) and in people 65 years and older (84.0% vs. 76.8%, respectively). Hesitancy towards COVID-19 vaccine was associated with hesitancy towards other vaccines. Only 26.8% would participate in a COVID-19 vaccine trial., Conclusions: Willingness to receive COVID-19 vaccine was higher than willingness to receive influenza vaccine. The results point to areas of fear from influenza vaccines side effects and lack of knowledge regarding influenza vaccines effectiveness that can be addressed to increase acceptance. Hesitancy towards other vaccines was associated with hesitancy towards COVID-19 vaccination., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: YM receiving grant funding and lecture fees from Pfizer, and lecture fees from MSD. There are no patents, products in development or marketing products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. SC has no competing interests.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., (© 2022. The Author(s).)

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals., Patients and Methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation., Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years., Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD., Competing Interests: Hagit N. BarisConsulting or Advisory Role: Sanofi, Igentify LtdSpeakers' Bureau: Sanofi, Takeda, Pfizer Donald BaselHonoraria: BioMarinConsulting or Advisory Role: iQvia Deborah T. BlumenthalConsulting or Advisory Role: AstraZeneca, Novocure, Takeda Miriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmune Sara RhodeHonoraria: Myriad GeneticsSpeakers' Bureau: Myriad GeneticsTravel, Accommodations, Expenses: Myriad Genetics Roula FarahHonoraria: Novo NordiskConsulting or Advisory Role: Novo Nordisk William D. FoulkesResearch Funding: AstraZeneca David GassEmployment: X4 PharmaceuticalsHonoraria: X4 PharmaceuticalsSpeakers' Bureau: Precisionscientia Heather HampelStock and Other Ownership Interests: Genome MedicalConsulting or Advisory Role: InVitae, Genome Medical, Promega, 23andMe Jordan R. HansfordConsulting or Advisory Role: Bayer Craig HarlosTravel, Accommodations, Expenses: GlaxoSmithKline Nobuko HijiyaHonoraria: NovartisConsulting or Advisory Role: Novartis, IncyteResearch Funding: Pfizer Junne KamiharaStock and Other Ownership Interests: PanTher Therapeutics, ROME Therapeutics, TellBioHonoraria: Pfizer, NanoString Technologies, Third Rock Ventures, Foundation MedicineConsulting or Advisory Role: ROME Therapeutics, Third Rock VenturesResearch Funding: PureTech, Ribon Therapeutics, ACD BiotechnePatents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics, Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics, Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc Jeffrey KnipsteinEmployment: PRA Health SciencesConsulting or Advisory Role: Atheneum Alvaro LassalettaStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche, ServierTravel, Accommodations, Expenses: Shire, Gilead Sciences Simon C. LingHonoraria: AbbvieResearch Funding: Abbvie, Gilead Sciences Michael P. LinkConsulting or Advisory Role: Incyte, ADC Therapeutics, Lilly, Steba Biotech, Mesoblast, GlaxoSmithKline, SyndaxResearch Funding: Seattle Genetics, Janssen Oncology Rebecca Loret de MolaEmployment: Huron Consulting Maura MassiminoConsulting or Advisory Role: Oncoscience, Novartis Gary MasonEmployment: Janssen Research & Development, MerckStock and Other Ownership Interests: Johnson & Johnson, MerckTravel, Accommodations, Expenses: Janssen Research & Development Kim E. NicholsStock and Other Ownership Interests: IncyteResearch Funding: Incyte/Novartis, Alpine Immune Sciences Enrico OpocherConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca Michael OsbornTravel, Accommodations, Expenses: Amgen, Pfizer Benjamin OshrineHonoraria: Mesoblast Alyssa ReddyConsulting or Advisory Role: Novartis, AstraZeneca Lara ReichmanResearch Funding: Illumina Marc RemkeStock and Other Ownership Interests: Bayer, BB Biotech Ventures, BioNTech AG, InVitae, IDEXX Laboratories Kami Wolfe SchneiderOther Relationship: Journal of Genetic Counseling Duncan StearnsConsulting or Advisory Role: AstraZenecaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/792397 Patrick TombocHonoraria: Unicare Health PlanConsulting or Advisory Role: UniCare Health Plan An Van DammeConsulting or Advisory Role: Octapharm, Pfizer, BayerResearch Funding: Johnson & JohnsonTravel, Accommodations, Expenses: Pfizer, Sobi, Shire, Roche Ira WinerResearch Funding: Oncoceutics David S. ZieglerConsulting or Advisory Role: Bayer, AmgenTravel, Accommodations, Expenses: Bayer Cynthia HawkinsConsulting or Advisory Role: BayerPatents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel David MalkinConsulting or Advisory Role: Bayer Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche, Bristol Myers SquibbNo other potential conflicts of interest were reported.

Targeted medications and immunotherapies are being developed to specifically target the pathways involved in tumours. There is limited experience with these new medications and their cutaneous side-effects in the paediatric population. A retrospective study of all paediatric oncological patients treated with targeted therapies and immunotherapies between 1 January 2013 and 1 August 2020 was carried out in 2 haemato-oncological referral centres. A total of 103 children were included in the study. The median (interquartile range) age was 13 years (8.4-16.9), male:female ratio 1.5:1, median (interquartile range) follow-up was 7 months (2-18). Fifty (48%) of the children developed cutaneous adverse events. Treatment was discontinued in only 3 (6%) cases and was altered in only (2%) 1 case due to a cutaneous adverse event. When targeted therapies and immunotherapies for tumours in children are used, there is an increased incidence of cutaneous adverse events. Nevertheless, treatment modification or discontinuation due to cutaneous side-effects is rarely needed.

Introduction: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment., Method: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication., Results: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy., Conclusion: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK ( n = 31), NTRK1/2/3 ( n = 21), ROS1 ( n = 9), and MET ( n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1 , or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype. See related commentary by Szulzewsky and Cimino, p. 904 . This article is highlighted in the In This Issue feature, p. 890 ., (©2020 American Association for Cancer Research.)

Objectives: Adverse events in blood collection procedures such as mismatched or unlabeled samples may have critical implications on patient safety (such as wrong diagnosis and treatments). The current study examined blood collection procedures in an emergency department before and after the application of a human factors approach for improving performance quality and preventing adverse events., Methods: In the emergency department of a community care hospital, 190 blood collection events were observed in 2 phases: preintervention and postintervention. Two quality measures were tested as follows: quality measure 1, performing all 7 stages in the procedure of blood collection according to protocol, and quality measure 2, performing the stages of the procedure in the correct sequence according to the protocol. In addition, medical staff anonymously answered questionnaires about their procedure for collecting blood., Results: Analyses of data collected before the intervention revealed only 2 events in which all 7 stages in the protocol of the procedure were performed and only 1 event in which the 7 stages of the procedure were performed in the correct sequence. In 91% of the events, the patient was not fully identified. Based on these findings, we developed an intervention using a human factors approach to improve the quality of performance. Analyses of data collected after the intervention revealed significant differences (t188 = -14.9, ρ < 0.01) in quality measure 1 before (mean [SD], 4.8 [0.6]) and after (mean [SD], 6.4 [0.8]) the intervention was initiated, which implies improvement on efficiency subsequent to the implementation of the intervention. Improvement also appeared in quality measure 2., Conclusions: This study illustrates the nature of potential errors in blood collection performance, offering a proactive approach to improve the rate of proper performance.

Background: Germline mutations in the DNA polymerase genes POLD1 and POLE confer high risk for multiple colorectal adenomas and colorectal cancer. However, prevalence and the clinical phenotype of mutation carriers are still not fully characterized., Objective: The purpose of this study was to assess the prevalence of germline mutations and to describe the genotype-phenotype correlation in POLD1 and POLE genes in Jewish subjects with multiple colorectal adenomas and/or early-onset mismatch repair proficient colorectal cancers., Design: This study is a comparison of genetic and clinical data from affected and control groups., Settings: The study was conducted at a high-volume tertiary referral center., Patients: The study cohort included 132 subjects: 68 with multiple colorectal adenomas and 64 with early-onset mismatch repair proficient colorectal cancers. The control group included 5685 individuals having no colorectal cancer or colorectal adenomas., Main Outcome Measures: Study and control subjects were tested for POLD1 and POLE mutations and a clinical correlation was assessed., Results: Eleven of the 132 study subjects (8.3%) carried either a POLD1 or a POLE mutation: 7 of 68 (10.3%) subjects with multiple colorectal adenomas and 4 of 64 (6.2%) subjects with early-onset mismatch repair proficient colorectal cancer. Three mutations were detected, showing statistical significance in frequency between study and control groups (p < 0.001). Eight of the 11 mutation carriers were Ashkenazi Jews carrying the same POLD1 mutation (V759I), implicating it as a possible low-to-moderate risk founder mutation. Phenotype of mutation carriers was notable for age under 50 at diagnosis, a propensity toward left-sided colorectal cancer, and extracolonic tumors (64%, 100%, and 27% of cases)., Limitations: The study cohort was limited by its relatively small size., Conclusions: Germline mutations in POLD1 and POLE were found to be relatively frequent in our Jewish cohorts. Further studies are needed to clarify the importance of POLD1 and POLE mutations and to define the most suitable surveillance program for Jewish and other POLD1 and POLE mutation carriers. See Video Abstract at http://links.lww.com/DCR/A658.

Background: Acute musculoskeletal pain is one of the most commonly reported symptoms among patients visiting the emergency department (ED). Treatment with over-the-counter pain medications, given by nurses, results in improved pain management and reduces the waiting time to drug administration without significant side effects. Opioid analgesics are extensively used for acute pain in the ED. Compared to morphine, oxycodone has a much more specific pharmacological activity, higher analgesic potential, and more tolerable side effects., Objectives: To assess the degree of pain reduction using different protocols, including dypirone and oxycodone given by nurses, in treating acute musculoskeletal pain in the emergency department (primary outcome) and to evaluate the need for rescue medications (secondary outcome)., Methods: This observational prospective clinical trial compared two groups of 50 patients, each one visiting the ED due to musculoskeletal pain. One group was treated with dipyrone syrup and the other was treated with oxycodone syrup. The primary outcome was pain reduction measured by the Numeric Rating Scale (NRS). The secondary outcome was the difference in need for rescue medications., Results: The reduction in the NRS was greater in the patients treated with oxycodone. This finding was statistically and clinically significant (P < 0.001). The need for rescue medications was also significantly reduced in this group of patients (P = 0.007)., Conclusions: This study showed that the administration of over-the-counter oxycodone syrup by nurses decreases the post-treatment pain reported by patients, reduces the need for rescue medications, and increases the satisfaction of the medical staff.

Background: Length of stay (LOS) is considered a key measure of emergency department throughput, and from the perspective of the patient, it is perceived as a measure of healthcare service quality. Prolonged LOS can be caused by various internal and external factors. This study examined LOS in the emergency department and explored the main factors that influence LOS and cause delay in patient care., Methods: Observations of 105 patients were performed over a 3-month period at the emergency room of a community urban hospital. Observers monitored patients from the moment of entrance to the department until discharge or admission to another hospital ward., Results: Analysis revealed a general average total emergency department LOS of 438 min. Significant differences in average LOS were found between admitted patients (Mean = 544 min, SD = 323 min) and discharged patients (Mean = 291 min, SD = 286 min). In addition, nurse and physician change of shifts and admissions to hospital wards were found to be significant factors associated with LOS. Using an Ishikawa causal diagram, we explored various latent organizational factors that may prolong this time., Conclusions: The study identified several factors that are associated with high average emergency department LOS. High LOS may lead to increases in expenditures and may have implications for patient safety, whereas certain organizational changes, communication improvement, and time management may have a positive effect on it. Interdisciplinary methods can be used to explore factors causing prolonged emergency department LOS and contribute to a better understanding of them.

A new superconducting Electron Cyclotron Resonance Ion Source (ECRIS) is under development at LBNL to harness the winding techniques of a closed-loop sextupole coil for the next generation ECRIS and to enhance the capability of the 88-in. cyclotron facility. The proposed ECRIS will use a superconducting closed-loop sextupole coil to produce the radial field and a substantial portion of the axial field. The field strengths of the injection, central and extraction regions are adjusted by a three solenoids outside the closed-loop sextupole coil. In addition to maintaining the typical ECRIS magnetic field configuration, this new source will also be able to produce a dustpan-like minimum-B field to explore possible ECRIS performance enhancement. The dustpan-like minimum-B field configuration has about the same strengths for the maximum axial field at the injection region and the maximum radial pole fields at the plasma chamber walls but it can be substantially lower at the extraction region. The dustpan-like minimum-B will have a field maximum Bmax ≥ 2.6 T for operations up to 18 GHz with a ratio of Bmax/Bres ≥ 4 and higher ratios for lower frequencies. The field maxima of this new source can reach over 3 T both at the injection and the plasma chamber walls which could also support operation at 28 GHz. The source will be built of cryogen-free with the magnets directly cooled by cryo-coolers to simplify the cryostat structure. The source design features will be presented and discussed.

This work combines the monitoring of two incidents of spring water pollution in the Western Galilee region of Israel, together with artificial tracer tests that provided valuable information regarding karst system connections and direct estimation of groundwater velocities. Almost simultaneous contamination of seven springs endangered the water supply for the region. The variations over time in contaminant concentration in the different springs were not similar, indicating more than one contamination source. Tracer tests revealed two different pollution sources that contributed to two different conduit pathways in the karst system. Breakthrough data for the tracers were modeled by a two-region non-equilibrium transport model, which provided the transport parameters of the karst conduit. Groundwater velocities in the conduits were found to be in a range of 2-3 km/day. The rapid response of the system was also demonstrated by the short recovery time of the springs, where, after the elimination of the pollution source, most water quality parameters reverted to their background concentrations in less than 3 months. The coexistence of highly polluted springs and uncontaminated groundwater in boreholes penetrating into the same aquifer demonstrates the complexity of groundwater flow in karst systems. In such systems, the fast groundwater flow in localized karst conduits seems to coexist with a slower flow within other portions of the aquifer., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A fourth generation electron cyclotron resonance ion source with an operating frequency between 40 and 56 GHz has the potential to quadruple the heavy-ion beam currents and provide a cost effective upgrade path for heavy ion drivers in use or in the planning stage at radioactive beam facilities. Design studies show it is feasible to produce the required magnetic fields in the plasma chamber, 7 T axially and 4 T in the radial direction with a magnetic structure using commercially available Nb(3)Sn superconducting materials. In this paper we describe the design of such a magnet structure including a 3D analysis of the Lorentz forces generated by the magnetic fields and the necessary clamping structure to stabilize the conductor against these forces.

Electron cyclotron resonance (ECR) ion sources are an essential component of heavy-ion accelerators. Over the past few decades advances in magnet technology and an improved understanding of the ECR ion source plasma physics have led to remarkable performance improvements of ECR ion sources. Currently third generation high field superconducting ECR ion sources operating at frequencies around 28 GHz are the state of the art ion injectors and several devices are either under commissioning or under design around the world. At the same time, the demand for increased intensities of highly charged heavy ions continues to grow, which makes the development of even higher performance ECR ion sources a necessity. To extend ECR ion sources to frequencies well above 28 GHz, new magnet technology will be needed in order to operate at higher field and force levels. The superconducting magnet program at LBNL has been developing high field superconducting magnets for particle accelerators based on Nb(3)Sn superconducting technology for several years. At the moment, Nb(3)Sn is the only practical conductor capable of operating at the 15 T field level in the relevant configurations. Recent design studies have been focused on the possibility of using Nb(3)Sn in the next generation of ECR ion sources. In the past, LBNL has worked on the VENUS ECR, a 28 GHz source with solenoids and a sextupole made with NbTi operating at fields of 6-7 T. VENUS has now been operating since 2004. We present in this paper the design of a Nb(3)Sn ECR ion source optimized to operate at an rf frequency of 56 GHz with conductor peak fields of 13-15 T. Because of the brittleness and strain sensitivity of Nb(3)Sn, particular care is required in the design of the magnet support structure, which must be capable of providing support to the coils without overstressing the conductor. In this paper, we present the main features of the support structure, featuring an external aluminum shell pretensioned with water-pressurized bladders, and we analyze the expected coil stresses with a two-dimensional finite element mechanical model.

The concepts and technical challenges related to developing a fourth generation electron cyclotron resonance (ECR) ion source with a rf frequency greater than 40 GHz and magnetic confinement fields greater than twice B(ECR) will be explored in this article. Based on the semiempirical frequency scaling of ECR plasma density with the square of operating frequency, there should be significant gains in performance over current third generation ECR ion sources, which operate at rf frequencies between 20 and 30 GHz. While the third generation ECR ion sources use NbTi superconducting solenoid and sextupole coils, the new sources will need to use different superconducting materials, such as Nb(3)Sn, to reach the required magnetic confinement, which scales linearly with rf frequency. Additional technical challenges include increased bremsstrahlung production, which may increase faster than the plasma density, bremsstrahlung heating of the cold mass, and the availability of high power continuous wave microwave sources at these frequencies. With each generation of ECR ion sources, there are new challenges to be mastered, but the potential for higher performance and reduced cost of the associated accelerator continues to make this a promising avenue for development.

PrPSc, an abnormal conformational isoform of the normal prion protein, PrPC, is the only known component of the prion, a proteinacious agent that causes fatal neurodegenerative disorders in humans and other animals. The hallmark properties of PrPSc are its insolubility in nondenaturing detergents and its resistance to digestion by proteases. Anions such as Congo red (CR) have been shown to reduce the accumulation of PrPSc in a neuroblastoma cell line permanently infected with prions as well as to delay disease onset in rodents when administrated prophylactically. The mechanism by which such anti-prion agents operate is unknown. We show here that in vitro incubation with CR renders native PrPSc resistant to denaturation by boiling SDS. This resulted from PrPSc conformation, since neither the properties of PrPC nor those of predenatured PrPSc were changed by the addition of CR. CR-PrPSc could only be denatured by the addition of acidic 3 M guanidine thiocyanate. Since in vitro conversion experiments have suggested that partial denaturation may be required for PrPSc to serve as template in the PrPC --> PrPSc conversion, we propose that CR inhibits prion propagation by overstabilizing the conformation of PrPSc molecules.