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Abstract Introduction Food allergies (FA) can detrimentally impact physical, emotional, and psychological quality of life (QoL) among pediatric patients. Given the changes from childhood into adolescence, the impact of FA on QoL likely evolves with age. The purpose of this study was to determine whether QoL differed between adolescents and children with FA who participated in a Food Allergy Symposium (FAS). Methods Patients with confirmed FA were recruited at an educational community symposium in September 2018 and September 2019. Patients and/or their parents were invited to complete the Food Allergy Quality of Life Questionnaires (FAQLQ). The Food Allergy Independent Measure (FAIM) reflects concerns about accidental food exposure and disease severity. Higher FAIM and FAQLQ scores reflect worse QoL. Summary scores were compared using the Wilcoxon rank sum test, Fisher’s exact test, or the Chi-square test. Results Seventy-four surveys (82% children, 18% adolescents) were included. The FAQLQ total score was higher among adolescents than children (median 5.2 vs 4.2; p = 0.045), and the FAIM was lower in adolescents (median 2.2 vs 2.8; p = 0.037). More adolescents reported previous anaphylaxis than children (91.7% vs 51.8%; p = 0.011). The percentage reassured by having epinephrine was higher in adolescents (81.8% vs 45.8%; p = 0.046). No other QoL scores and survey responses were significantly different. Discussion In this study, adolescents were more concerned about their disease and more reassured by epinephrine carriage than younger children, which may reflect increased autonomy and responsibility. Community events are an important way to assess QoL and provide FA-related education to pediatric patients.

Nuclear factor κappa-B (NFκB) is a family of transcription factors involved in regulating inflammation and immunity. Mutations in the NFκB1 pathway are associated with primary immune defects and underlie the most common monogenic etiology of common variable immunodeficiency (CVID). However, little is known about how NFκB1 defects or primary immunodeficiency (PID) complicate pregnancy. We present a previously healthy 34-year-old patient who suffered from poor wound healing and sterile sepsis during the post-partum period of each of her three pregnancies. She was otherwise asymptomatic, but her daughter developed Evans Syndrome (ES) with hypogammaglobulinemia prompting expanded genetic testing which revealed a novel monoallelic variant in NFκB1. This case highlights that pregnancy-related complications of PID can be difficult to recognize and may portend adverse patient outcomes. For these reasons, guidance regarding diagnosis and management of women of childbearing age with PID is warranted.

Introduction: Food allergies (FA) can detrimentally impact physical, emotional, and psychological quality of life (QoL) among pediatric patients. Given the changes from childhood into adolescence, the impact of FA on QoL likely evolves with age. The purpose of this study was to determine whether QoL differed between adolescents and children with FA who participated in a Food Allergy Symposium (FAS). Methods: Patients with confirmed FA were recruited at an educational community symposium in September 2018 and September 2019. Patients and/or their parents were invited to complete the Food Allergy Quality of Life Questionnaires (FAQLQ). The Food Allergy Independent Measure (FAIM) reflects concerns about accidental food exposure and disease severity. Higher FAIM and FAQLQ scores reflect worse QoL. Summary scores were compared using the Wilcoxon rank sum test, Fisher's exact test, or the Chi-square test. Results: Seventy-four surveys (82% children, 18% adolescents) were included. The FAQLQ total score was higher among adolescents than children (median 5.2 vs 4.2; p = 0.045), and the FAIM was lower in adolescents (median 2.2 vs 2.8; p = 0.037). More adolescents reported previous anaphylaxis than children (91.7% vs 51.8%; p = 0.011). The percentage reassured by having epinephrine was higher in adolescents (81.8% vs 45.8%; p = 0.046). No other QoL scores and survey responses were significantly different. Discussion: In this study, adolescents were more concerned about their disease and more reassured by epinephrine carriage than younger children, which may reflect increased autonomy and responsibility. Community events are an important way to assess QoL and provide FA-related education to pediatric patients. [ABSTRACT FROM AUTHOR]

Anaphylaxis, desensitization, food allergen, food allergy, omalizumab, oral immunotherapy, shellfish allergy, shrimp allergy, sustained unresponsiveness In addition, commercial shrimp extracts are heterogeneous with variable allergen representation.11 The differing allergens may result in varied responses in SPT and IgE results, which may explain Patient B's apparent negative shrimp IgE test. Keywords: anaphylaxis; desensitization; food allergen; food allergy; omalizumab; oral immunotherapy; shellfish allergy; shrimp allergy; sustained unresponsiveness EN anaphylaxis desensitization food allergen food allergy omalizumab oral immunotherapy shellfish allergy shrimp allergy sustained unresponsiveness 1 4 4 01/05/22 20220101 NES 220101 AUTHOR CONTRIBUTIONS B Diem-Tran Nguyen: b Data curation (equal); Investigation (equal); Project administration (lead); Visualization (lead); Writing-original draft (lead); Writing-review & editing (equal). [Extracted from the article]

Current synthesis methods of nanoporous Cu–C composites offer limited control of the material composition, structure, and properties, particularly for large Cu loadings of ≳20 wt%. Here, we describe two related approaches to realize novel nanoporous Cu–C composites based on the templating of recently developed carbon-nanotube aerogels (CNT-CAs). Our first approach involves the trapping of Cu nanoparticles while CNT-CAs undergo gelation. This method yields nanofoams with relatively high densities of ≳65 mg cm−3 for Cu loadings of ≳10 wt%. Our second approach overcomes this limitation by filling the pores of undoped CNT-CA monoliths with an aqueous solution of CuSO4 followed by (i) freeze-drying to remove water and (ii) thermal decomposition of CuSO4. With this approach, we demonstrate Cu–C composites with a C matrix density of ∼25 mg cm−3 and Cu loadings of up to 70 wt%. These versatile methods could be extended to fabricate other nanoporous metal–carbon composite materials geared for specific applications. [ABSTRACT FROM AUTHOR]

Androgen receptor splicing variant 7 (AR-V7) is a truncated variant of the AR mRNA that may be a predictive biomarker for AR-targeted therapy. AR-V7 has been described in prostate, breast, salivary duct, and hepatocellular carcinomas as well as mammary and extra-mammary Paget disease. We report 2 gynecologic cancers occurring in the lower uterine segment and ovary and both harboring AR-V7 by targeted RNA sequencing. The uterine tumor was an undifferentiated carcinoma consisting of epithelioid cells and focally spindled cells arranged in sheets, nests, and cords associated with brisk mitotic activity and tumor necrosis. The ovarian tumor consisted of glands with cribriform and solid architecture and uniform cytologic atypia. ER and PR were positive in the ovarian tumor and negative in the uterine tumor. Both were positive for AR and negative for HER2, GATA3, and NKX3.1. DNA methylation profiling showed epigenetic similarity of the AR-V7-positive gynecologic cancers to AR-V7-positive breast cancers rather than to prostate cancers. AR-V7 may underpin rare gynecologic carcinomas with undifferentiated histology or cribriform growth reminiscent of prostatic adenocarcinoma and breast invasive ductal carcinoma., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

Objective: Social interactions and experiences are increasingly occurring online, including for young adults with psychosis. Healthy social interactions and experiences are widely recognized as a critical component of social recovery, yet research thus far has focused predominantly on offline interactions with limited understanding of these interactions online. We developed the Social Media and Internet sociaL Engagement (SMILE) questionnaire to assess the type, frequency, and nature of online social interactions and experiences among young adults with early psychosis to better assess online social activity and ultimately support personalized interventions., Methods: Participants ( N  = 49) completed the SMILE questionnaire which asked about online platforms used, frequency of use, and if positive and negative experiences were more likely to happen online or offline. Participants completed additional self-report measures of victimization, positive psychotic symptoms, social functioning, and demographics. Exploratory factor analysis and correlations between identified factors and clinical measures of interest were completed., Results: Exploratory factor analysis revealed three factors: positive engagement, victimization, and internalizing experiences. Most participants (6%-37%) experienced positive engagement offline. Victimization occurred equally online and offline (8%-27% and 4%-24%, respectively). Most participants (37%-51%) endorsed internalizing experiences as occurring equally offline and online, but approximately a third of participants reported internalizing experiences more frequently offline (20%-35%). Victimization was moderately (r =  0.34) correlated with overall online social experiences, suggesting more online time may increase the likelihood of victimization. Age was inversely related to the frequency of overall online social experiences., Conclusion: Young adults with early psychosis experience positive and negative social experiences online and offline. New scales and measures to comprehensively assess the nature and function of online social interactions and experiences are needed., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

With the rise of anti-Asian racism and discrimination that followed the onset of the COVID-19 pandemic, the need to improve Asian Americans' (AA) connection to and experiences with clinical care is critical. AA at risk for or experiencing psychosis represent a particularly vulnerable subset of a population that already exhibits low service utilization and a multitude of barriers to mental health care treatment. Considering that victimization and discrimination were well-documented factors that exacerbate psychotic symptoms prepandemic, preparing clinicians to adequately support this already hard-to-reach population warrants special attention. In this article, we argue for the importance of addressing the unique needs of this population in an acute time of need. We outline three main considerations for working with AA across the psychosis spectrum, including actionable steps clinicians can implement related to (a) the variability in AA identities, (b) the relationship between victimization and psychosis, and (c) improving access to culturally sensitive mental health care treatment. By considering the diverse needs of AA at risk for or living with psychosis, clinicians across professional levels and contexts can better serve this vulnerable population. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Electrodeposited amorphous hydrated iridium oxide (IrOx) is a promising material for pH sensing due to its high sensitivity and the ease of fabrication. However, durability and variability continue to restrict the sensor's effectiveness. Variation in probe films can be seen in both performance and fabrication, but it has been found that performance variation can be controlled with potentiostatic conditioning (PC). To make proper use of this technique, the morphological and chemical changes affecting the conditioning process must be understood. Here, a thorough study of this material, after undergoing PC in a pH-sensing-relevant potential regime, was conducted by voltammetry, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Fitting of XPS data was performed, guided by raw trends in survey scans, core orbitals, and valence spectra, both XPS and UPS. The findings indicate that the PC process can repeatably control and conform performance and surface bonding to desired calibrations and distributions, respectively; PC was able to reduce sensitivity and offset ranges to as low as ±0.7 mV/pH and ±0.008 V, respectively, and repeat bonding distributions over ~2 months of sample preparation. Both Ir/O atomic ratios (shifting from 4:1 to over 4.5:1) and fitted components assigned hydroxide or oxide states based on the literature (low-voltage spectra being almost entirely with suggested hydroxide components, and high-voltage spectra almost entirely with suggested oxide components) trend across the polarization range. Self-consistent valence, core orbital, and survey quantitative trends point to a likely mechanism of ligand conversion from hydroxide to oxide, suggesting that the conditioning process enforces specific state mixtures that include both theoretical Ir(III) and Ir(IV) species, and raising the conditioning potential alters the surface species from an assumed mixture of Ir species to more oxidized Ir species.

For the US Food and Drug Administration's (FDA) mycotoxin program, the desired application of certified reference materials (CRMs) is primarily for validating methods for the determination of mycotoxins in foods and establishing metrological traceability of measurement results generated by such validated methods. The latter has been an important but insufficiently addressed challenge due to the lack of appropriate protocols and CRMs. Taking advantage of two recently available mycotoxin CRMs, OTAN-1 and Standard Reference Material (SRM) 1565, a protocol was developed for systematically examining uncertainty and establishing metrological traceability of measurement results of ochratoxin A (OTA) in corn through a series of calibration operations using the two CRMs. Instrument and method calibrations were performed using OTAN-1 and SRM 1565. The OTA value and its standard and expanded (k = 2, approximately 95% confidence) uncertainties were estimated from the calibration data and documented. These results demonstrate that the major contributing source of uncertainty is the sample matrix, highlighting the important role of the certified matrix reference material in method calibration. The value of OTA (38.5 ± 7.2 µg/g; 95% confidence interval) in the incurred sample was metrologically traceable to the International System of Units through two CRMs using the multi-laboratory validated liquid chromatography-mass spectrometry FDA compendial method. In addition, an alternative estimation of uncertainty was conducted using a one-point calibration, resulting in comparable uncertainty., (© 2023 Institute of Food Technologists. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Pilocytic astrocytomas are the most common pediatric brain tumors, typically presenting as low-grade neoplasms. We report two cases of pilocytic astrocytoma with atypical tumor progression. Case 1 involves a 12-yr-old boy with an unresectable suprasellar tumor, negative for BRAF rearrangement but harboring a BRAF p.V600E mutation. He experienced tumor size reduction and stable disease following dabrafenib treatment. Case 2 describes a 6-yr-old boy with a thalamic tumor that underwent multiple resections, with no actionable driver detected using targeted next-generation sequencing. Whole-genome and RNA-seq analysis identified an internal tandem duplication in FGFR1 and RAS pathway activation. Future management options include FGFR1 inhibitors. These cases demonstrate the importance of escalating molecular diagnostics for pediatric brain cancer, advocating for early reflexing to integrative whole-genome sequencing and transcriptomic profiling when targeted panels are uninformative. Identifying molecular drivers can significantly impact treatment decisions and improve patient outcomes., (© 2023 Al Assaad et al.; Published by Cold Spring Harbor Laboratory Press.)

DNA methylation is an essential molecular assay for central nervous system (CNS) tumor diagnostics. While some fusions define specific brain tumors, others occur across many different diagnoses. We performed a retrospective analysis of 219 primary CNS tumors with whole genome DNA methylation and RNA next-generation sequencing. DNA methylation profiling results were compared with RNAseq detected gene fusions. We detected 105 rare fusions involving 31 driver genes, including 23 fusions previously not implicated in brain tumors. In addition, we identified 6 multi-fusion tumors. Rare fusions and multi-fusion events can impact the diagnostic accuracy of DNA methylation by decreasing confidence in the result, such as BRAF, RAF, or FGFR1 fusions, or result in a complete mismatch, such as NTRK, EWSR1, FGFR, and ALK fusions., Implications: DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions., (©2023 American Association for Cancer Research.)

Endometrial/endometrioid stromal tumors are rare and morphologically heterogenous, and their diagnosis may be challenging. We identified 3 endometrial/endometrioid stromal tumors with identical and previously undescribed histologic features and herein report their morphologic, immunohistochemical, and molecular profiles. Patients were 53, 62, and 79 years. Tumors were well-circumscribed, tan-yellow solid masses measuring 10.0, 11.0, and 18.7 cm, and were intramyometrial (n=2) or in the broad ligament (n=1). All showed small, tight whorls of epithelioid to slightly spindled tumor cells with minimal cytoplasm and negligible mitoses, multifocally associated with hyalinization and myxoid change set in a loose fibroblastic background with small, delicate vessels. This morphology was seen throughout in 1 tumor and in ∼20% and 70% of the 2 others with the remaining areas showing sex cord-like differentiation. Tumor cells expressed CD10 (3/3, 1 focal), calretinin (3/3 diffuse), WT1 (3/3 diffuse), estrogen receptor (1/1, diffuse). RNA-sequencing was successful in 1 tumor and revealed a GREB1-CTNNB1 in-frame fusion. All 3 tumors harbored a CTNNB1 translocation by fluorescence in situ hybridization correlating with nuclear β-catenin expression. Whole-genome DNA methylation analysis classified all 3 tumors within the low-grade endometrial stromal sarcoma reference class with flat copy number profiles. One patient (79-y-old) died of unrelated causes 2 months after surgery and the other 2 were alive without disease after 13 and 75 months. We have described a rare subset of endometrial/endometrioid stromal tumors with extensive whorling and a CTNNB1 translocation, expanding the morphologic and molecular spectrum of these neoplasms., Competing Interests: Conflicts of Interest and Source of Funding: B.W. reports research funding from Repare Therapeutics, outside the scope of this study. For the remaining authors none were declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Next-generation sequencing (NGS) studies have demonstrated that co-occurring sporadic endometrioid endometrial carcinoma (EEC) and endometrioid ovarian carcinoma (EOC) are clonally related, suggesting that they originate from a single primary tumor. Despite clonality, synchronous EEC and EOC when diagnosed at early stage behave indolently, similar to isolated primary EEC or isolated primary EOC. In the present study, we compared the DNA methylation signatures of co-occurring EEC and EOC with those of isolated primary EEC and isolated primary EOC. We also performed targeted NGS to assess the clonal relatedness of 7 co-occurring EEC and EOC (4 synchronous EEC and EOC and 3 metastatic EEC based on pathologic criteria). NGS confirmed a clonal relationship in all co-occurring EEC and EOC. DNA methylation profiling showed distinct epigenetic signatures of isolated primary EEC and isolated primary EOC. Endometrial tumors from co-occurring EEC and EOC clustered with isolated primary EEC while their ovarian counterparts clustered with isolated primary EOC. Three co-occurring EEC and EOC cases with peritoneal lesions showed a closer epigenetic signature and copy number variation profile between the peritoneal lesion and EOC than EEC. In conclusion, synchronous sporadic EEC and EOC are clonally related but demonstrate a shift in DNA methylation signatures between ovarian and endometrial tumors as well as epigenetic overlap between ovarian and peritoneal tumors. Our results suggest that tumor microenvironment in the ovary may play a role in epigenetic modulation of metastatic EEC., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Triple-negative breast cancers (TNBC) include diverse carcinomas with heterogeneous clinical behavior. DNA methylation is a useful tool in classifying a variety of cancers. In this study, we analyzed TNBC using DNA methylation profiling and compared the results to those of mutational analysis. DNA methylation profiling (Infinium MethylationEPIC array, Illumina) and 50-gene panel-targeted DNA sequencing were performed in 44 treatment-naïve TNBC. We identified 3 distinct DNA methylation clusters with specific clinicopathologic and molecular features. Cluster 1 (phosphoinositide 3-kinase/protein kinase B-enriched cluster; n = 9) patients were significantly older (mean age, 71 years; P = .008) with tumors that were more likely to exhibit apocrine differentiation (78%; P < .001), a lower grade (44% were grade 2), a lower proliferation index (median Ki-67, 15%; P = .002), and lower tumor-infiltrating lymphocyte fractions (median, 15%; P = .0142). Tumors carried recurrent PIK3CA and AKT1 mutations and a higher percentage of low HER-2 expression (89%; P = .033). Cluster 3 (chromosomal instability cluster; n = 28) patients were significantly younger (median age, 57 years). Tumors were of higher grade (grade 3, 93%), had a higher proliferation index (median Ki-67, 75%), and were with a high fraction of tumor-infiltrating lymphocytes (median, 30%). Ninety-one percent of the germline BRCA1/2 mutation carriers were in cluster 3, and these tumors showed the highest level of copy number alterations. Cluster 2 represented cases with intermediate clinicopathologic characteristics and no specific molecular profile (no specific molecular profile cluster; n = 7). There were no differences in relation to stage, recurrence, and survival. In conclusion, DNA methylation profiling is a promising tool to classify patients with TNBC into biologically relevant groups, which may result in better disease characterization and reveal potential targets for emerging therapies., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF have been described to harbor distinct histological features and frequent loss of CDKN2A/B. However, histological evaluation may be rater-dependent, and detailed knowledge about the molecular mechanisms of malignant transformation is scarce. In general, malignant transformation can be accompanied by significant epigenetic changes, and global DNA methylation profiling is able to differentiate relevant tumor subgroups. Therefore, epigenetic profiling might provide a valuable tool to distinguish and characterize ANF with differing extent of histopathological atypia from neurofibromas and MPNST., Methods: We investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors., Results: Unsupervised class discovery and t-SNE analysis indicated that 36/40 ANF cluster with benign peripheral nerve sheath tumors with clear separation from MPNST. 21 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors in this cluster had a frequent heterozygous or homozygous loss of CDKN2A/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions., Conclusions: Our data suggest that ANF with varying histological morphology show distinct epigenetic similarities and cluster in proximity to benign peripheral nerve sheath tumor entities. Future investigations should pay special respect to correlating this methylation pattern to clinical outcomes., (© 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.)

Neuropsychiatric disorders, such as major depression, anxiety disorders, and post-traumatic stress disorder, tend to be long-term conditions in whose development and maintenance stress are central pathogenic factors. Translational mouse models are widely used in neuropsychiatric research, exploiting social and non-social stressors to investigate the mechanisms underlying their detrimental effects. However, most studies focus on the short-term consequences of chronic stress, whereas only a few are interested in the long-term course. This is counterintuitive given the human conditions that preclinical models are designed to mimic. In this review, we have summarized the limited work to date on long-term effects of chronic stress in mice models. First, the different models are presented and a definition of short- vs. long-term sequelae is proposed. On this basis, behavioral, endocrine, and vegetative effects are addressed before examining data on cellular and molecular alterations in the brain. Finally, future directions for research on the long-term effects of stress are discussed., (© 2023. The Author(s).)

Physical therapists in the military are allowed some of the widest scope-of-practice privileges in the USA. These privileges include ordering imaging, making direct referrals, and serving as direct-access providers. This independent functioning model may help contribute to more efficient and effective patient care. In this study, two cases are presented to highlight the decision-making process of physical therapists who were able to order imaging and make direct referrals that contributed to successful patient outcomes. The purpose of this study is 2-fold: (1) to highlight physical therapists ordering diagnostic imaging and (2) to correlate physical therapists making direct referrals. The first case involves an active duty military female who sustained an ankle injury. She was referred to physical therapy and underwent conservative treatment with minimal progress. The physical therapist used her privileges to order imaging, interpreted the findings, and referred the patient to an experienced podiatric surgeon. The second case involves an active duty military male who sustained a knee injury. He was referred directly to physical therapy by the hospital urgent care. The military physical therapist evaluated him and determined that an orthopedic referral was necessary. Both of the prior mentioned cases resulted in successful outcomes, with patients returning to their prior level of function. In the military healthcare setting, physical therapists have a unique set of practice privileges that can contribute to timely patient management, improved patient satisfaction, and more efficient and effective care. This healthcare model may be considered in civilian settings in the future as well., (© The Association of Military Surgeons of the United States 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sample homogeneity dictates whether analyzing a test portion of an entire sample can provide representative information about incurred mycotoxins. In this study, we evaluated particle-size-distribution-based homogeneity of laboratory mycotoxin samples using laser diffraction particle size analysis and International Organization for Standardization (ISO) Guide 35: 2017. Incurred whole corn, compound feed, peanut butter, and wheat flour (500 g each) were comminuted using wet, cryogenic, or dry milling. We used a sample dividing (riffling) device to obtain representative subsamples (25 g each) and developed a laser diffraction particle size analysis procedure by optimizing key parameters such as the refractive index, absorption, and stirring rate. The homogeneity of the particle size distribution within laboratory subsamples was characterized using the optimized laser diffraction procedure. An assessment of homogeneity was also performed for individual mycotoxins in each incurred matrix sample following the procedure described in ISO Guide 35. The concentrations of the incurred mycotoxins were determined using liquid chromatography-mass spectrometry (LC-MS). Within- and between-subsample variances of incurred aflatoxin B1 in peanut butter; deoxynivalenol in corn, compound feed, and wheat flour; and fumonisins in compound feed corroborated that when the particle size measurements were less than 850 µm, mycotoxins concentrations were consistent across independent test portions, which was confirmed using an analysis of variance (F-test). This study highlights the benefits of laser diffraction particle size analysis and suggests its use as a test procedure to evaluate homogeneity in new sample commodities.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis., Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility., Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases., Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design., Competing Interests: M.S. is scientific advisor and shareholder of C2i Genomics, Heidelberg Epignostix and Halo Dx, and a scientific advisor of Arima Genomics, and received research funding from Lilly USA. Other authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Isocitrate dehydrogenase (IDH) mutations are thought to represent an early oncogenic event in glioma evolution, found with high penetrance across tumor cells; however, in rare cases, IDH mutation may exist only in a small subset of the total tumor cells (subclonal IDH mutation)., Methods: We present 2 institutional cases with subclonal IDH1 R132H mutation. In addition, 2 large publicly available cohorts of IDH-mutant astrocytomas were mined for cases harboring subclonal IDH mutations (defined as tumor cell fraction with IDH mutation ≤0.67) and the clinical and molecular features of these subclonal cases were compared to clonal IDH-mutant astrocytomas., Results: Immunohistochemistry (IHC) performed on 2 institutional World Health Organization grade 4 IDH-mutant astrocytomas revealed only a minority of tumor cells in each case with IDH1 R132H mutant protein, and next-generation sequencing (NGS) revealed remarkably low IDH1 variant allele frequencies compared to other pathogenic mutations, including TP53 and/or ATRX . DNA methylation classified the first tumor as high-grade IDH-mutant astrocytoma with high confidence (0.98 scores). In the publicly available datasets, subclonal IDH mutation was present in 3.9% of IDH-mutant astrocytomas (18/466 tumors). Compared to clonal IDH-mutant astrocytomas (n = 156), subclonal cases demonstrated worse overall survival in grades 3 ( P = .0106) and 4 ( P = .0184)., Conclusions: While rare, subclonal IDH1 mutations are present in a subset of IDH-mutant astrocytomas of all grades, which may lead to a mismatch between IHC results and genetic/epigenetic classification. These findings suggest a possible prognostic role of IDH mutation subclonality, and highlight the potential clinical utility of quantitative IDH1 mutation evaluation by IHC and NGS., Competing Interests: The authors have no conflict of interest to report. Competing interests: The results presented in this paper have not been published previously in whole or part. The authors declare that they have no competing interests., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

A small subset of male germ cell tumors (GCT) demonstrates overgrowth of histologic components that resemble somatic malignancies (e.g., sarcoma, carcinoma). The presence of so-called "somatic-type" malignancies (SM) in GCT has been associated with chemotherapy-resistance and poor clinical outcomes in prior studies. However, the molecular characteristics of these tumors remain largely undescribed. In this study, we performed a multi-platform molecular analysis of GCTs with SM diagnosed in 36 male patients (primary site: testis, 29 and mediastinum, 7). The most common histologic types of SM were sarcoma and embryonic-type neuroectodermal tumor (ENT, formerly known as "PNET"), present in 61% and 31% of cases, respectively. KRAS and TP53 mutations were identified by DNA sequencing in 28% of cases each, with enrichment of TP53 mutations in mediastinal tumors (86%). Gains in the short arm of chromosome 12 were seen in 91% of cases, likely reflecting the presence of isochromosome 12p. Numerous copy number changes indicative of widespread aneuploidy were found in 94% of cases. Focal homozygous deletions and amplifications were also detected, including MDM2 amplifications in 16% of cases. Sequencing of paired samples in 8 patients revealed similar mutational and copy number profiles in the conventional GCT and SM components. Oncogenic gene fusions were not detected using RNA sequencing of SM components from 9 cases. DNA methylation analysis highlighted the distinct methylation profile of SM components that sets them apart from conventional GCT components. In conclusion, GCT with SM are characterized by widespread aneuploidy, a distinct epigenetic signature and the presence of mutations that are otherwise rare in testicular GCT without SM. The similarity of the mutational and DNA methylation profiles of different histologic types of SM suggests that the identification of SM components could be more important than their precise histologic subclassification, pending confirmation by further studies., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

A subset of testicular sex cord-stromal tumors (SCST), which includes neoplasms with mixed histology, cannot be classified into a specific histologic subtype. This study evaluated the clinicopathologic, immunophenotypic and molecular features of 26 SCST not amenable to specific classification by expert uropathologists. Median age at diagnosis was 43 years and median tumor size was 2.4 cm. Follow-up information was available for 18 (69%) patients, with evidence of an aggressive clinical course in 6 patients (4 alive with disease, 2 dead of disease 3 months and 6 months after orchiectomy). Microscopically, SCST not amenable to specific classification demonstrated monophasic epithelioid (9/26, 35%), monophasic spindle cell (5/26, 19%), and biphasic or mixed histology (12/26, 46%). One or more aggressive histopathologic features were seen in 11 cases. DNA sequencing was successful in 22 tumors. Pathogenic CTNNB1 and APC alterations were seen in 7 (33%) and 2 (10%) cases, respectively, with additional variants (e.g., CDKN2A, RB1, TP53, BRCA2) being identified in individual cases. Combined evaluation of morphology, sequencing data and beta-catenin immunohistochemistry resulted in reclassification of 6 (23%) tumors as Sertoli cell tumor, not otherwise specified. This was supported by comparing the methylation profiles of a subset of these tumors and those of typical Sertoli cell tumors. Additionally, a subset of 5 neoplasms (19%) with spindle cell or biphasic histology and SMA expression was characterized by hyperdiploid genomes with recurrent chromosomal gains and absence of driver mutations, possibly representing a distinct tumor type. The SCST that remained not amenable to specific histologic classification (15/26, 58%) were enriched for aggressive histologic features and malignant clinical behavior. In conclusion, this study demonstrated that a subset of testicular SCST that were originally not amenable to specific classification could be reclassified by combined evaluation of morphology, immunohistochemistry and molecular data., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Background: Hyperglycemia has been associated with worse survival in glioblastoma. Attempts to lower glucose yielded mixed responses which could be due to molecularly distinct GBM subclasses., Methods: Clinical, laboratory, and molecular data on 89 IDH-wt GBMs profiled by clinical next-generation sequencing and treated with Stupp protocol were reviewed. IDH-wt GBMs were sub-classified into RTK I (Proneural), RTK II (Classical) and Mesenchymal subtypes using whole-genome DNA methylation. Average glucose was calculated by time-weighting glucose measurements between diagnosis and last follow-up., Results: Patients were stratified into three groups using average glucose: tertile one (<100 mg/dL), tertile two (100-115 mg/dL), and tertile three (>115 mg/dL). Comparison across glucose tertiles revealed no differences in performance status (KPS), dexamethasone dose, MGMT methylation, or methylation subclass. Overall survival (OS) was not affected by methylation subclass ( P = .9) but decreased with higher glucose ( P = .015). Higher glucose tertiles were associated with poorer OS among RTK I ( P = .08) and mesenchymal tumors ( P = .05), but not RTK II ( P = .99). After controlling for age, KPS, dexamethasone, and MGMT status, glucose remained significantly associated with OS (aHR = 5.2, P = .02). Methylation clustering did not identify unique signatures associated with high or low glucose levels. Metabolomic analysis of 23 tumors showed minimal variation across metabolites without differences between molecular subclasses., Conclusion: Higher average glucose values were associated with poorer OS in RTKI and Mesenchymal IDH-wt GBM, but not RTKII. There were no discernible epigenetic or metabolomic differences between tumors in different glucose environments, suggesting a potential survival benefit to lowering systemic glucose in selected molecular subtypes., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients' clinical course are unknown., Methods: We assembled a cohort of 185 tumors classified as MPE based on DNA methylation. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPE-B, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors., Results: MPE-A occurred at a median age of 27 years and were enriched with tumors demonstrating papillary morphology and MGMT promoter hypermethylation. Half of these tumors could not be totally resected, and 85% relapsed within 10 years. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. MPE-B occurred at a median age of 45 years and included many tumors with a histological diagnosis of WHO grade II and tanycytic morphology. Patients within this subtype had a significantly better outcome with a relapse rate of 33% in 10 years (P = 3.4e-06)., Conclusions: We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment., (© The Author(s) 2022. 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.)

Paired-like homeobox 2b (PHOX2B) is an established immunomarker for peripheral neuroblastoma and autonomic nervous system cells. We aimed to evaluate the utility of PHOX2B immunostaining in central nervous system (CNS) tumors with embryonal morphology. Fifty-one tumors were stained with PHOX2B and submitted for whole slide image analysis: 35 CNS tumors with embryonal morphology (31 CNS embryonal tumors and four gliomas); and 16 peripheral neuroblastomas were included for comparison. Diffuse nuclear immunopositivity was observed in all (16/16) neuroblastomas (primary and metastatic). Among CNS embryonal tumors, focal immunoreactivity for PHOX2B was observed in most (5/7) embryonal tumors with multilayered rosettes (ETMR) and a single high-grade neuroepithelial tumor (HGNET) with PLAGL2 amplification; the remaining 27 CNS tumors were essentially immunonegative (<0.05% positive). Among ETMR, PHOX2B expression was observed in a small overall proportion (0.04%-4.94%) of neoplastic cells but focally reached up to 39% in 1 mm 'hot spot' areas. In the PLAGL2-amplified case, 0.09% of the total neoplastic population was immunoreactive, with 0.53% in the 'hot spot' area. Care should be taken in interpreting PHOX2B immunopositivity in a differential diagnosis that includes metastatic neuroblastoma and CNS tumors; focal or patchy expression should not be considered definitively diagnostic of metastatic peripheral neuroblastoma., (© 2022 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Chordoid meningioma is a morphological variant of meningioma designated as WHO grade 2. However, the recurrence rates varied widely in different case series, and to date, a unifying molecular genetic signature has not been identified. Among 1897 meningiomas resected at our institution, we identified 12 primary chordoid meningiomas from 12 patients. Histologically, all 12 cases had predominant (> 50%) chordoid morphology. Ten were otherwise grade 1, and two were also atypical. We performed DNA global methylation profile, copy number variation analysis, and targeted next-generation sequencing on 11 chordoid meningiomas, and compared to those of 51 non-chordoid, mostly high grade meningiomas. The chordoid meningiomas demonstrated a unique methylation profile in tSNE, UMAP, and hierarchical heatmap clustering analyses of the most differentially methylated CpGs. The most common copy number variation in chordoid meningioma was loss of 1p (7/11, 64%). Three chordoid meningiomas had 2p loss, which was significantly higher than the non-chordoid control cohort (27% vs 7.2%, p = 0.035). 22q loss was only seen in the two cases with additional atypical histological features. Chordoid meningiomas were enriched in mutations in chromatin remodeling genes EP400 (8/11,73%) KMT2C (4/11, 36%) and KMT2D (4/11, 36%), and showed low or absent NF2, TERT, SMO, and AKT1 mutations. Prognosis wise, only one case recurred. This case had atypical histology and high-grade molecular features including truncating NF2 mutation, 1p, 8p, 10, 14, 22q loss, and homozygous deletion of CDKN2A/B. Progression free survival of chordoid, otherwise grade 1 meningioma was comparable to non-chordoid WHO grade 1 meningioma (p = 0.75), and significantly better than chordoid WHO grade 2 meningioma (p = 0.019). Conclusion: the chordoid histology alone may not justify a universal WHO grade 2 designation. Screening for additional atypical histological or molecular genetic features is recommended., (© 2022. The Author(s).)

Greenspace exposure is associated with psychological benefits. In this systematic review, we summarized and critically evaluated the literature on the relationship between greenspace exposure (i.e., objective and subjective assessments of interactions with nature) and psychopathology incidence and symptom severity in those with and without a clinical diagnosis. A secondary aim of our review was to examine potential interactions between greenspace exposure and urban environmental features (e.g., pollution, population density) associated with poorer mental health. We identified 40 studies published between January 1, 1981, and July 31, 2020, from PubMed and PsycINFO electronic database search. Although heterogeneous in assessments of greenspace exposure and psychopathology symptom domain, the majority of cross-sectional and longitudinal evidence found that objectively assessed greenspace exposure (e.g., satellite measures of greenery) was related to less severe symptoms and lower incidence of psychopathology in children (e.g., attention-deficit/hyperactivity disorder symptoms) and adults (e.g., depression symptoms). In addition, five studies that assessed urban environmental features suggest that greenspace exposure may show a net positive relationship with psychopathology over and above the absence of urban features. We discuss limitations of the literature and future directions, including more mechanistic work to delineate the potential cognitive, affective, and behavioral factors that may contribute to the beneficial relationship between greenspace exposure and psychological health., (© 2022 The Authors.)

Background: Preliminary evidence suggests that aerobic exercise may augment the effects of cognitive remediation on improving cognitive functioning in severe mental illness. It has also been hypothesized that increases in cognitive functioning associated with adding exercise are mediated by increases in brain derived neurotrophic factor (BDNF). However, rigorous controlled trials are lacking., Methods: A randomized controlled trial was conducted to explore whether adding a 30-h aerobic exercise program over 10 weeks to an equally intensive cognitive remediation program (CR + E) improved cognitive functioning more than cognitive remediation alone (CR-Only). Thirty-four participants with schizophrenia or bipolar disorder were randomly assigned to CR + E or CR-Only, and cognitive functioning was assessed at baseline and post-treatment. Total and mature BDNF were measured in blood serum at baseline, Week-5 pre- and post-exercise, and Week-10 pre- and post-exercise., Results: Participants in both conditions had high levels of engagement in the interventions and improved significantly in cognitive functioning, but did not differ in amount of cognitive change. The groups also did not differ in changes in BDNF from pre-to post-exercise at Weeks 5 or 10, nor in resting BDNF levels. Exploratory analyses indicated that higher body mass index (BMI) significantly predicted attenuated improvement in cognitive functioning for both groups., Discussion: Exercise did not augment the effects of cognitive remediation in persons with severe mental illness, possibly because the cognitive remediation program resulted in strong gains in cognitive functioning. Moderate aerobic exercise does not appear to reliably increase BDNF levels in persons with severe mental illness. CLINICALTRIALS., Gov Identifier: NCT02326389., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM) is the most common malignant primary central nervous system (CNS) neoplasm in adults, and has an almost universally poor prognosis. Recently, an emphasis on genetic and epigenetic profiling has revealed a number of molecular features useful in the diagnostic and prognostic classification of GBM, advancing our understanding of the underlying features that make these tumors so aggressive and providing the rationale for the creation of better targeted therapeutics. One such method, DNA methylation profiling, has recently emerged as an important technique for the classification of CNS tumors, with diagnostic accuracy in some cases surpassing traditional methods. However, how DNA methylation profiles change with the course of the disease remains less understood. Here, we present a case of a 30-year-old male with primary IDH-mutant GBM with widespread recurrence and death two years later. Using unsupervised hierarchical clustering of methylation probes, we created a phylogenetic map to trace the tumor path as it spread from the initial biopsy site throughout the right hemisphere, across the corpus callosum to the contralateral hemisphere, and into the brainstem. We identified molecular divergence between the right and left hemisphere GBM samples marked by distinct copy number profile alterations, alterations in specific methylation sites, and regional loss of MGMT promoter methylation, providing a potential mechanism for treatment resistance in this case. In summary, this case both highlights the molecular diversity in GBM, and illustrates a novel use for methylation profiling in establishing a phylogenetic profile to allow for spatial mapping of tumor progression.

Formalin-fixed, paraffin-embedded (FFPE) tissue is the most commonly used material for tumor molecular profiling, therapy selection, and prognostication. Tumor tissue enrichment by tissue dissection is highly recommended to generate quality data reproducibly for use in downstream assays, such as real-time PCR and next-generation sequencing. The aim of this study was to evaluate the performance of the automated tissue dissection tool AVENIO Millisect System compared with a manual dissection method using 18 FFPE tissue specimens. The study assessed performance of these two methods with paraffinized and deparaffinized sections at 5- and 10-μm thickness as well as at low (5% to 10%) and high (>50%) tumor content. In addition, compatibility with various nucleic acid and protein extraction methods was assessed. Overall, dissection by Millisect resulted in statistically significantly higher yields of nucleic acids and protein compared with manual dissection (P = 0.00524). In downstream analysis on a statistically nonpowered sample set, EGFR mutation testing by PCR led to highly concordant results, and next-generation sequencing testing yielded significantly higher allelic frequencies when tissue was dissected by Millisect compared with manual scraping, demonstrating noninferiority of the automated method. In summary, the AVENIO Millisect System may replace manual labor and support automation of FFPE tumor tissue workflows in clinical molecular laboratories with high testing volumes with adequate validation., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Microplastic pollutants in oceans and food chains are concerning to public health. Common plasticizing compounds Bisphenol-A (BPA) and Styrene-7,8-Oxide (SO) are now labeled as carcinogens. We show that BPA and SO cause deoxyribonucleic acid damage and mutagenesis in human cells, and analyze the genome-wide point mutation and genomic rearrangement patterns associated with BPA and SO exposure. A subset of the single- and doublet base substitutions shows mutagenesis near or at guanine, consistent with these compounds' preferences to form guanosine adducts. Presence of other mutational signatures suggest additional mutagenesis probably due to complex effects of BPA and SO on diverse cellular processes. Analyzing data for 19 cancer cohorts, we find that tumors of digestive and urinary organs show relatively high similarity in mutational profiles, and the burden of such mutations increases with age. Even within the same cancer type, proportions of corresponding mutational patterns vary among the cohorts from different countries, as does the amount of microplastic waste in ocean waters. BPA and SO are relatively mild mutagens, and other environmental agents can also potentially generate similar, complex mutational patterns in cancer genomes. Nonetheless, our findings call for systematic evaluation of public health consequences of microplastic exposure worldwide., (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.)

Background: The impact of different disease stages and treatment for human epidermal growth factor 2 positive (HER2-positive) breast cancer (BC) on work productivity and health-related quality of life (HRQoL) is poorly understood., Methods: This was a UK cross-sectional study of 299 adult patients with HER2-positive early or metastatic BC (NCT03099200). Productivity was assessed using the work productivity and activity impairment scale; HRQoL was measured using EuroQol-5 Dimensions-5 levels (EQ-5D-5L), and Functional Assessment of Cancer Therapy Breast (FACT-G and -B) instruments. Three balanced patient groups were recruited: (1) early BC on treatment post-surgery, (2) early BC after completion of adjuvant treatment, (3) during metastatic BC treatment. Between-group comparisons were performed using an analysis of variance., Results: Group 1 comprised 89 patients, Group 2, 108 and Group 3, 102. Age, ethnicity and comorbidities were similar across groups. Patients in Group 3 reported more often being unable to work (significant Bonferroni adjusted p < 0.003). Proportions of employed patients were 50.6%, 50.9% and 27.5% in Groups 1, 2 and 3, respectively. For patients in part-time employment, the number of hours worked was significantly higher in Group 2 patients versus Group 3 (p = 0.002). Group 2 also had significantly lower levels of work absenteeism and overall work impairment compared with Group 1 (p < 0.001). Patients in Group 3 reported worse health utility scores (p ≤ 0.002), moderate or worse problems in the EQ-5D-5L self-care and usual activity domains (p ≤ 0.001), and lower HRQoL as assessed by FACT summary scores (p < 0.001 for FACT-B and -G) than Groups 1 and 2. Poorer HRQoL was significantly associated with higher work impairment (p < 0.001), with the strongest relationships being observed between activity impairment and HRQoL (Pearson's r: 0.67)., Conclusions: Metastatic disease and treatment of HER2-positive BC adversely impacted on work productivity and HRQoL. The results of this study support the idea that being able to delay or prevent the metastatic recurrence of BC, for example by extending the time patients are in remission or at early stage of BC, has wider benefits in terms of patient productivity and HRQoL.

Background: Various self-reported or clinician-reported (as a proxy) measures exist to quantify the burden of schizophrenia on patients. Evidence of the psychometric relationship between these measures to inform their practical use is limited., Objectives: Our objective was to conduct an exploratory analysis of the construct validity of patient-reported (EQ-5D, SF-6D, WEMWBS, SQLS subscales of Psychosocial, Motivation, Symptoms) versus clinician-reported measures (PANSS, CGI-SCH, NSA-4, HoNOS-PbR) to inform future use of patient-reported measures for burden-of-illness assessment and/or economic evaluation., Methods: In an adult patient population with schizophrenia, construct validity was assessed in relation to convergent and known-group validity. Convergent validity was assessed using Spearman's rank absolute correlation strength (ACS: weak ≤ 0.3, moderate = 0.3 < 0.5, strong ≥ 0.5) and graphically using locally weighted scatterplot smoothing (LOWESS) techniques. Known-group validity was assessed using Cohen's d absolute effect size (AES: small ≤ 0.5, moderate = 0.5 < 0.8, large ≥ 0.8). Floor and ceiling effects were assessed as a proxy of sensitivity in this cross-sectional study. Statistical significance was assessed at the 5% threshold level (p < 0.05). Across head-to-head assessments, the frequency of producing the strongest ACS, largest AES, and statistically significant results determined the best overall construct validity., Results: Overall, 304 patients consented to the study. In relation to statistically significant results, the SF-6D most frequently exhibited the strongest ACS and largest AES against the clinician-reported measure scores (ACS range 0.084-0.436; AES range 0.043-0.746), and the SQLS Motivation subscale most frequently exhibited the weakest/smallest values (ACS range 0.009-0.157; AES range 0.002-0.397), although these results were mixed according to the clinician-reported measure used for comparative analysis (ACS range 0.009-0.529; AES range 0.002-0.934)., Conclusion: The SF-6D indicated the best (mostly moderate) construct validity but still missed the negative symptoms of the condition. Although further evidence is required to confirm or refute these exploratory results, compared with the EQ-5D, the SF-6D can be self-reported to better capture generic health-related quality-of-life aspects of schizophrenia for the purpose of economic evaluation. The lack of construct validity for SQLS Motivation and Symptoms subscales were hypothesized post-hoc to be representative of the complementary information elicited by the subscales not captured by the clinician-reported measures. Therefore, the SQLS can be self-reported to capture complementary (i.e., additional) information relative to clinician-reported measures.

Aim: This review aims to assist physicians and payers in assessing the efficacy and safety of bevacizumab in real-world clinical practice by identifying evidence on the comparative effectiveness and safety of bevacizumab in its most frequent indications. Materials & methods: In a systematic review of the published literature, electronic databases (Embase ® , MEDLINE ® and the Cochrane Library) were searched in May 2016 and updated in January 2017; 20 scientific congresses were searched in 2014-2017., Results: Of 61 included publications, 49, eight, four and 0 concerned metastatic colorectal cancer, metastatic breast cancer, advanced ovarian cancer and cervical cancer, respectively. Fifteen publications (metastatic colorectal cancer) reported on factors predictive of response to therapy., Conclusion: Effectiveness findings from real-world studies broadly supported results from registration studies.

Notch1 signaling must elevate to high levels in order to drive the proliferation of CD4 - CD8 - double-negative (DN) thymocytes and progression to the CD4 + CD8 + double-positive (DP) stage through β-selection. During this critical phase of pre-T-cell development, which is also known as the DN-DP transition, it is unclear whether the Notch1 transcriptional complex strengthens its signal output as a discrete unit or through cofactors. We previously showed that the protein inhibitor of activated STAT-like coactivator Zmiz1 is a context-dependent cofactor of Notch1 in T-cell leukemia. We also showed that withdrawal of Zmiz1 generated an early T-lineage progenitor (ETP) defect. Here, we show that this early defect seems inconsistent with loss-of-Notch1 function. In contrast, at the later pre-T-cell stage, withdrawal of Zmiz1 impaired the DN-DP transition by inhibiting proliferation, like withdrawal of Notch. In pre-T cells, but not ETPs, Zmiz1 cooperatively regulated Notch1 target genes Hes1 , Lef1 , and Myc. Enforced expression of either activated Notch1 or Myc partially rescued the Zmiz1-deficient DN-DP defect. We identified residues in the tetratricopeptide repeat (TPR) domain of Zmiz1 that bind Notch1. Mutating only a single residue impaired the Zmiz1-Notch1 interaction, Myc induction, the DN-DP transition, and leukemic proliferation. Similar effects were seen using a dominant-negative TPR protein. Our studies identify stage-specific roles of Zmiz1. Zmiz1 is a context-specific cofactor for Notch1 during Notch/Myc-dependent thymocyte proliferation, whether normal or malignant. Finally, we highlight a vulnerability in leukemic cells that originated from a developmentally important Zmiz1-Notch1 interaction that is hijacked during transformation from normal pre-T cells., (© 2018 by The American Society of Hematology.)

Objectives: The effects of acute coronary syndrome (ACS) events on health-related quality-of-life (HRQoL) and the time dependency of these effects are unknown. This study aimed to characterize health utilities in ACS patients to aid development of future economic models estimating the cost per quality-adjusted life-year impact of ACS events and potential treatments., Methods: Multi-center, non-interventional, longitudinal evaluation of health utility in patients experiencing ACS or stroke events. EuroQol-5 dimension 3 level (EQ-5D-3L) surveys were sent to patients (≥18 years) from three UK centers, 1 month after hospital discharge for myocardial infarction (MI), unstable angina (UA), or stroke. Patient demographics, lifestyle, and baseline utility score were collected in the first survey. Follow-up surveys were sent at 6, 12, 18, and 24 months to prospectively capture utility and subsequent health events. Two methods of patient identification were adopted-prospective, where the patient's qualifying events occurred after the study index date, and retrospective, where the patient's qualifying event occurred prior to the study index date. General healthy population utility values were assumed for pre-event HRQoL., Results: Between January 2011 and March 2014, 2,103 prospectively (n = 1,350)/retrospectively (n = 753) identified patients (mean age = 68.3 years; 67.9% male) responded: MI = 55.9% (n = 1,176), UA = 42.7% (n = 898), stroke = 1.4% (n = 29); 24% had type 2 diabetes. Post-event utility values were lower than general healthy population values, although significant differences in utility between subsequent 6 (n = 1,031, change = -0.002), 12 (n = 1,096, change = -0.008), 18 (n = 1,246, change = -0.007), and 24 (n = 1,277, change = -0.004) month timepoints were not detected. Through multivariate regression analyses, wheelchair use, current smoking, and secondary mental and joint health events were associated with the greatest statistically significant utility decrements., Conclusions: This study indicates that health utility decreases following a cardiovascular event and, although some improvement occurs over the subsequent 24 months, general healthy population utility is not necessarily attained.

Catalytic substrate, which is devoid of expensive noble metals and enzymes for hydrogen peroxide (H₂O₂), reduction reactions can be obtained via nitrogen doping of graphite. Here, we report a facile fabrication method for obtaining such nitrogen doped graphitized carbon using polyacrylonitrile (PAN) mats and its use in H₂O₂ sensing. A high degree of graphitization was obtained with a mechanical treatment of the PAN fibers embedded with carbon nanotubes (CNT) prior to the pyrolysis step. The electrochemical testing showed a limit of detection (LOD) 0.609 µM and sensitivity of 2.54 µA cm -2 mM -1 . The promising sensing performance of the developed carbon electrodes can be attributed to the presence of high content of pyridinic and graphitic nitrogens in the pyrolytic carbons, as confirmed by X-ray photoelectron spectroscopy. The reported results suggest that, despite their simple fabrication, the hydrogen peroxide sensors developed from pyrolytic carbon nanofibers are comparable with their sophisticated nitrogen-doped graphene counterparts., Competing Interests: The authors declare no conflict of interest.

We evaluated the microbiological performance of an ultraviolet (UV) light-based peritoneal dialysis catheter connection system. The system includes a UV light-generating device combined with a UV transmissive window incorporated into the transfer set. Each UV transparent transfer set was inoculated with 10 μL of cultured inoculum consisting of either S. aureus, E. coli, or C. albicans After being inoculated, we attached a solution set connector to the transfer catheter, and exposed that connection to a UV light dose of approximately 340 mJoules/cm 2 After exposure to UV light, we broke the seal of the solution set and opened the plunger valve on the UV transmissive transfer catheter. We then flushed 10 mL of dialysate through the connection. The flushed solution was collected, diluted, plated on agar medium, and incubated for 24 hours. Results were compared to positive controls collected in an identical manner without exposure to UV light. Thirty test samples and 3 positive controls were collected for each organism. All test samples exposed to UV light had complete kill of bacteria except 1 colony on a single plate in the S. aureus group. Mean log reduction was 4.03 for C. albicans, 4.73 for S. aureus, and 5.29 for E. coli All positive control samples had significant bacterial growth. Our results demonstrate that the application of UV light within a UV transmissive transfer catheter window produces a germicidal effect upon microorganisms known to be associated with peritonitis., (Copyright © 2017 International Society for Peritoneal Dialysis.)

Environmental heterogeneity helps maintain genetic variation in fitness. Therefore, one might predict that populations living in heterogeneous environments have higher adaptive potential than populations living in homogeneous environments. Such a prediction could be useful in guiding conservation priorities without requiring detailed genetic studies. However, this prediction will be true only if the additional genetic variation maintained by environmental heterogeneity can be used to respond to novel selection. Here we examine the effect of environmental heterogeneity on future adaptability using replicated experimental Drosophila melanogaster populations that had previously evolved for ∼100 generations under one of four selective regimes: constant salt-enriched larvae medium, constant cadmium-enriched larvae medium, and two heterogeneous regimes that vary either temporally or spatially between the two media. Replicates of these experimental populations were subjected to a novel heat stress while being maintained in their original larval diet selection regimes. Adaptation to increased temperature was measured with respect to female productivity and male siring success after ∼20 generations. For female productivity, there was evidence of adaptation overall and heterogeneous populations had a larger adaptive response than homogeneous populations. There was less evidence of adaptation overall for male siring success and no support for faster adaptation in heterogeneous populations.

Purpose: The purpose of this study was to use a cross-sectional prevalence-based health care economic survey to ascertain the annual, incremental, societal ophthalmic costs associated with neovascular age-related macular degeneration., Methods: Consecutive patients (n = 200) with neovascular age-related macular degeneration were studied. A Control Cohort included patients with good (20/20-20/25) vision, while Study Cohort vision levels included Subcohort 1: 20/30 to 20/50, Subcohort 2: 20/60 to 20/100, Subcohort 3: 20/200 to 20/400, and Subcohort 4: 20/800 to no light perception. An interviewer-administered, standardized, written survey assessed 1) direct ophthalmic medical, 2) direct nonophthalmic medical, 3) direct nonmedical, and 4) indirect medical costs accrued due solely to neovascular age-related macular degeneration., Results: The mean annual societal cost for the Control Cohort was $6,116 and for the Study Cohort averaged $39,910 (P < 0.001). Study Subcohort 1 costs averaged $20,339, while Subcohort 4 costs averaged $82,984. Direct ophthalmic medical costs comprised 17.9% of Study Cohort societal ophthalmic costs, versus 74.1% of Control Cohort societal ophthalmic costs (P < 0.001) and 10.4% of 20/800 to no light perception subcohort costs. Direct nonmedical costs, primarily caregiver, comprised 67.1% of Study Cohort societal ophthalmic costs, versus 21.3% ($1,302/$6,116) of Control Cohort costs (P < 0.001) and 74.1% of 20/800 to no light perception subcohort costs., Conclusion: Total societal ophthalmic costs associated with neovascular age-related macular degeneration dramatically increase as vision in the better-seeing eye decreases.

Cigarette smoke (CS) exposure is known to induce proteostasis imbalance that can initiate accumulation of ubiquitinated proteins. Therefore, the primary goal of this study was to determine if first- and secondhand CS induces localization of ubiquitinated proteins in perinuclear spaces as aggresome bodies. Furthermore, we sought to determine the mechanism by which smoke-induced aggresome formation contributes to chronic obstructive pulmonary disease (COPD)-emphysema pathogenesis. Hence, Beas2b cells were treated with CS extract (CSE) for in vitro experimental analysis of CS-induced aggresome formation by immunoblotting, microscopy, and reporter assays, whereas chronic CS-exposed murine model and human COPD-emphysema lung tissues were used for validation. In preliminary analysis, we observed a significant (P < 0.01) increase in ubiquitinated protein aggregation in the insoluble protein fraction of CSE-treated Beas2b cells. We verified that CS-induced ubiquitin aggregrates are localized in the perinuclear spaces as aggresome bodies. These CS-induced aggresomes (P < 0.001) colocalize with autophagy protein microtubule-associated protein 1 light chain-3B(+) autophagy bodies, whereas U.S. Food and Drug Administration-approved autophagy-inducing drug (carbamazepine) significantly (P < 0.01) decreases their colocalization and expression, suggesting CS-impaired autophagy. Moreover, CSE treatment significantly increases valosin-containing protein-p62 protein-protein interaction (P < 0.0005) and p62 expression (aberrant autophagy marker; P < 0.0001), verifying CS-impaired autophagy as an aggresome formation mechanism. We also found that inhibiting protein synthesis by cycloheximide does not deplete CS-induced ubiquitinated protein aggregates, suggesting the role of CS-induced protein synthesis in aggresome formation. Next, we used an emphysema murine model to verify that chronic CS significantly (P < 0.0005) induces aggresome formation. Moreover, we observed that autophagy induction by carbamazepine inhibits CS-induced aggresome formation and alveolar space enlargement (P < 0.001), confirming involvement of aggresome bodies in COPD-emphysema pathogenesis. Finally, significantly higher p62 accumulation in smokers and severe COPD-emphysema lungs (Global Initiative for Chronic Obstructive Lung Disease Stage III/IV) as compared with normal nonsmokers (Global Initiative for Chronic Obstructive Lung Disease Stage 0) substantiates the pathogenic role of autophagy impairment in aggresome formation and COPD-emphysema progression. In conclusion, CS-induced aggresome formation is a novel mechanism involved in COPD-emphysema pathogenesis.

Purpose: To quantify the burden of illness for incident branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) in a commercially insured working-age (commercial) and Medicare US population., Methods: Retrospective cohort analysis of health care claims from 2003 through 2008 from commercial and Medicare patients with ≥2 outpatient diagnoses for BRVO or CRVO. The index date was the first retinal vein occlusion diagnosis. Patients with medical and pharmacy benefits were followed ≥1 year preindex and then between 1 year and 3 years postindex. Incidence and prevalence of retinal vein occlusion was determined. Burden of illness was compared with matched control subjects without retinal vein occlusion., Results: The commercial sample comprised 1,188 CRVO and 2,252 BRVO cases, whereas the Medicare sample had 2,739 CRVO and 4,573 BRVO cases. Adjusted ratio of case-to-control, all-cause expenditures for commercial patients at 1 year and 3 years postindex were 1.88 and 1.68, respectively, for BRVO and 1.42 and 1.36, respectively, for CRVO. For Medicare patients, these were 1.29 and 1.13, respectively, for BRVO and 1.23 and 1.14, respectively, for CRVO. All comparisons were significant (P < 0.001)., Conclusion: Health care utilization and expenditures for commercially insured working-age and Medicare patients with BRVO or CRVO were significantly greater than those for control subjects. Retinal vein occlusion development may be a marker for the increased severity of systemic vascular disease.