A high tumour mutational burden (hypermutation) is observed in some gliomas
; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly ...understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
Teen readiness assessments may provide a developmental indicator of the transfer of responsibility for health self-management from caregivers to teens. Among urban adolescents with asthma, we aimed ...to describe teen readiness for talking with providers and identify how readiness relates to responsibility for asthma management, medication beliefs, and clinical outcomes.
Teens and caregivers enrolled in the school-based asthma care for teen's trial in Rochester, NY completed in-home surveys. We classified ready teens as those reporting a score of five on both items of the transition readiness assessment questionnaire talking with providers subscale. We performed bivariate analyses to detect differences between ready teens and other teens in teen- and caregiver-reported responsibility, teen medication beliefs, and clinical outcomes (medication adherence over the past 2 weeks, and healthcare use over the past year).
Among this sample of 251 adolescents (mean age: 13.4 years), 35% were classified as "Ready." Ready teens were more likely than other teens to want to use a controller medication independently (7.6 vs. 6.5 out of 10, p < .01) and to have confidence in this ability (8.4 vs. 7.6 out of 10, p = .02). Teens reported poor adherence (missed 52.9% of prescribed controller doses), with no differences in responsibility or clinical outcomes based on level of teen readiness for talking with providers.
In urban adolescents with poorly controlled asthma, a higher level of teen readiness for talking with providers is associated with higher perceptions of independence in medication taking, but does not appear to relate to clinical outcomes.
To understand existing care practices and policies, and potential enhancements, to improve the effectiveness of the US Department of Veterans Affairs (VA) Supportive Services for Veteran Families ...(SSVF) Health Care Navigators (HCN) in linking Veterans experiencing housing instability in rural areas with health care services.
We used primary data collected during semistructured interviews with HCNs (n = 21) serving rural areas across the United States during Spring 2022.
We applied the Consolidated Framework for Implementation Research (CFIR) 2009 and the Social Ecological Model (SEM) to the collection and analysis of qualitative data to understand how HCNs administer services within SSVF and the larger community.
We used rapid qualitative methods to summarize and analyze data. Templated matrix summaries identified facilitators and barriers to linking Veterans with health care services and policy and practice implications.
Using CFIR 2009, we identified contextual factors affecting successful implementation of HCN services within SSVF; we offer a crosswalk between CFIR 2009 and the version updated in 2022. Framing facilitators and barriers within the SEM provided insight into whether implementation strategies should be addressed at a community, interpersonal, or intrapersonal level within the SEM. Facilitators included sufficient knowledge, training, and mentorship opportunities for HCNs and their capacity to collaborate within their organization and with other community-based organizations. Barriers included lack of local technology and housing resources, inadequate understanding of Veterans' service eligibilities and pathways to access those services, and deficient collaboration with the VA.
Understanding facilitators and barriers experienced by HCN when linking unstably housed Veterans in rural areas with health care services can inform future strategies, including policy changes such as increased training to support HCNs' understanding of eligibility, benefits, and entitlements as well as improving communication and collaboration between VA and community partners.
Recent media reports suggest that teachers and teacher educators are using the three-cueing system model to justify an overemphasis on context to help students read unfamiliar words. In this ...conceptual article, the authors argue that although these critiques are exaggerated, the current climate provides an opportunity for teacher educators to reflect on their ways of talking about word reading with teachers. The authors propose answers to nine questions, derived from recent conversations with teachers as they navigate conflicting messages about reading. To answer these questions, the authors describe a model of word reading, the Sound-Spelling-Meaning (SSM) model, and related instructional routines that are consistent with current evidence. The SSM model offers teachers and teacher educators a consistent language for talking and learning about word reading processes. It can be useful in teacher education to guide discussions of how words eventually become effortless for readers, the pivotal role of spelling in reading development, and the role of context in word recognition.
In classrooms, reading and responding to literature has been identified as a powerful method for dealing with critical social issues, including bullying and racism. The purpose of this article is to ...analyze children’s literature published from 1997 to 2017 that highlights the intersection of bullying and racism. Our article begins with a description of how critical race theory is foundational to our understanding and how research on bullying illuminates our analysis of children’s literature. Using critical content analysis), we analyze relevant picturebooks to address how racism can influence bullying behavior. Finally, this article concludes with implications for classroom practices and ideas for future directions.
Objectives/Hypothesis
Chronic Rhinosinusitis (CRS) is accompanied by evidence of a vigorous adaptive immune response, and emerging studies demonstrate that some nasal polyps manifest a polyclonal ...autoantibody response. We previously found that antibodies against BP180, a component of the hemidesmosome complex and the dominant epitope in autoimmune bullous pemphigoid, were found at elevated levels in nasal polyp tissue. Given the critical role of hemidesmosomes in maintaining epithelial integrity, we sought to investigate the distribution of BP180 in nasal tissue and evaluate for evidence of systemic autoimmunity against this antigen in CRS.
Study Design
Case‐control experimental study.
Methods
The expression and distribution of BP180 in cultured nasal epithelial cells and normal nasal tissue were confirmed using real‐time polymerase chain reaction (PCR), Western immunoblotting, immunofluorescence and immunohistochemistry. Sera were collected from three groups: control, CRSsNP, and CRSwNP. A commercially available ELISA was utilized to compare anti‐BP180 autoantibody levels in sera.
Results
BP180 is expressed in nasal epithelium, but is not confined to the basement membrane as it is in human skin. In cultured nasal epithelial cells, confocal immunofluorescence showed a punctate distribution of BP180 along the basal surface, consistent with its distribution in epithelial keratinocytes. There are significantly higher levels of circulating nonpathologic anti‐BP180 autoantibodies in CRS patients compared with normal controls (P <0.05).
Conclusions
BP180 is more widely expressed in nasal epithelium versus skin, although it appears to play a similar role in the formation of hemidesmosomes along the basement membrane. Further investigations are ongoing to characterize the pathogenicity of the anti‐epithelial antibody response in CRS.
Level of Evidence
N/A. Laryngoscope, 123:2104–2111, 2013
Purpose
Chordomas account for 1% to 4% of all bone malignancies and 0.5% of all primary intracranial central nervous system tumors. Prior epidemiologic literature is based on limited population data. ...The purpose of this study is to provide the largest and most inclusive population based study of the descriptive epidemiology of chordomas.
Methods
The Centers for Disease Control and Prevention and National Program of Cancer Registries were queried for chordoma in all locations. Age-adjusted incidence per 100,000 persons was calculated by age, sex, race, and ethnicity. Annual percentage change was calculated using Joinpoint.
Results
From 2004 to 2014, a total of 3670 chordomas were diagnosed in the US. The most common location was cranial (38.7%), followed by sacral (34.3%) and spinal (27.0%). The average age-adjusted incidence rate was 0.088 per 100,000 persons per year (95% CI 0.086–0.091), with an annual percentage change of 1.29% (95% CI 0.31–2.28%). For all chordomas, the incidence peaks in the 75–84 year age group. The male-to-female incidence rate ratio is 1.54 (p < 0.001). American Indian/Alaskan Native and Black patients had a statistically lower incidence rate than White and Asian/Pacific Islander patients.
Conclusion
Approximately 0.088 chordomas per 100,000 persons are newly diagnosed in the US each year, with cranial location being the most common, followed by sacral and spinal. Incidence increases with age, and men are at a significantly higher risk than women. This investigation represents the largest population-based epidemiologic study of chordomas in the US.
Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.
Metabolic analysis was performed on blood samples from 30 mothers of young ...children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.
Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules. Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.
Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.
Introduction
Central neurocytoma (CN) and extraventricular neurocytoma (EVN) are rare intracranial tumors. There is a paucity of studies reporting the population-based incidence of these tumors. We ...used the Central Brain Tumor Registry of the United States (CBTRUS), which contains the largest aggregation of population-based data on the incidence of primary central nervous system tumors in the United States to describe these tumors.
Methods
The CBTRUS database, provided by CDC representing approximately 100% of the US population, was queried using the following search criteria: diagnosis years 2006–2014, ICD-0-3 histology codes (9506/0: central neurocytoma, benign; 9506/1: central neurocytoma, uncertain). Annual age-adjusted incidence rates are presented per 100,000 population. Incidence was estimated by age, gender, race, and ethnicity.
Results
The combined overall annual incidence rate of CN and EVN was 0.032 0.030–0.034. The incidence rates were 0.022 0.021–0.024 and 0.009 0.008–0.010 for CN and EVN, respectively. The most frequently documented locations for EVN were frontal lobe and cerebellum, followed by temporal lobe. Peak incidence was found in the 20–34 years range for both CN and EVN. The incidence rate was slightly lower in males compared to females for CN and identical for EVN. The overall incidence rate of CN and EVN combined was lower in Blacks 0.026 0.021–0.032 and Hispanic Whites 0.020 0.016–0.025 compared to Non-Hispanic Whites 0.035 0.033–0.038.
Conclusion
CN and EVN are rare tumors with a peak incidence in the 20–34 years age group. This study represents the largest population-based epidemiological study on CN and EVN in the US.
To compare the abilities of teens with uncontrolled persistent asthma and their caregivers to identify inhaled medications and state correct indications for use; examine medication responsibility ...within dyads; and determine whether responsibility is associated with knowledge about inhaled therapies.
In the baseline survey for the School-Based Asthma Care for Teens (SB-ACT) trial, we separately asked caregivers and teens to: 1) identify the teen's inhaled asthma therapies by name and from a picture chart (complete matches considered “concordant”); 2) describe indications of use for each medication; and 3) describe the allocation of responsibility for medication use within dyads. We limited analyses to dyads in which either member reported at least one rescue and one inhaled controller medication; we used McNemar and Pearson chi-square tests.
A total of 136 dyads were analyzed. More caregivers than teens concordantly identified medications (63% vs 31%, P < .001). There was no difference between caregivers and teens in the ability to state correct indications for use (56% vs 54%, P = .79). More teens than caregivers endorsed “full teen responsibility” for rescue medication (65% vs 27%, P < .001) and controller medication use (50% vs 15%, P < .001). Neither concordant identification nor knowing indications for use was associated with reported medication responsibility.
Medication responsibility within dyads of caregivers and teens with persistent asthma is not associated with knowledge about inhaled therapies. Targeting both members of the dyad with education and self-management strategies before responsibility transitions start may allow providers to avoid a missed opportunity to support these emerging stakeholders to adherence.
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