Invited Review: The role and contribution of transcriptional enhancers in brain cancer.

Genetic alterations identified across several paediatric and adult brain tumours reveal recurrent disruption of active chromatin landscapes and dysregulation of transcriptional programmes. Noncoding elements, specifically enhancers, are central to these mechanisms, and are influenced by developmental and neural gene regulatory signatures. Epigenomic and transcriptomic methods and techniques have facilitated detection of active enhancers, and characterization of brain tumours integrated with genomic structural information. These datasets have provided new insights into the mechanisms of transcriptional control that are profoundly altered in childhood and adult brain cancer; offering new ideas and molecular targets for therapeutic intervention. This review summarizes recent advances in our understanding of active transcriptional programmes of brain cancer, their impact on tumour development, and research areas for further exploration.

Weighing ependymoma as an epigenetic disease.

INTRODUCTION: Ependymoma is the third most common malignant pediatric brain tumor. Although the biology that drives ependymoma is slowly being unraveled, the ability to translate these findings to clinical care remains an ongoing challenge. Epigenetic alterations appear to play a central role in the development of molecular classification of ependymoma. METHODS: We reviewed the published literature available describing genetic and epigenetic underpinnings of ependymoma that have been reported to date and have summarized the information regarding genetic drivers of ependymoma that may point us toward therapeutic strategies. RESULTS: Ependymoma is a molecularly heterogeneous disease which has now been divided into at least nine distinct molecular subtypes based on DNA methylation and gene expression profiling. DNA methylation has emerged as an effective tool for classification of brain tumors alongside histopathology and other molecular diagnostics. There have been large retrospective cohorts describing molecular subgroup identity as a powerful independent predictor of outcome. There is limited published data on prospective trials to date however this is forthcoming which will lead to molecular stratification in the next generation of clinical studies. CONCLUSION: This is a review of recent advancements in our understanding of the epigenetic basis of ependymoma and discussion of how these findings reveal potential therapeutic opportunities.

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Significant variation between SNP-based HLA imputations in diverse populations: the last mile is the hardest.

Four single nucleotide polymorphism (SNP)-based human leukocyte antigen (HLA) imputation methods (e-HLA, HIBAG, HLA*IMP:02 and MAGPrediction) were trained using 1000 Genomes SNP and HLA genotypes and assessed for their ability to accurately impute molecular HLA-A, -B, -C and -DRB1 genotypes in the Human Genome Diversity Project cell panel. Imputation concordance was high (>89%) across all methods for both HLA-A and HLA-C, but HLA-B and HLA-DRB1 proved generally difficult to impute. Overall, <27.8% of subjects were correctly imputed for all HLA loci by any method. Concordance across all loci was not enhanced via the application of confidence thresholds; reliance on confidence scores across methods only led to noticeable improvement (+3.2%) for HLA-DRB1. As the HLA complex is highly relevant to the study of human health and disease, a standardized assessment of SNP-based HLA imputation methods is crucial for advancing genomic research. Considerable room remains for the improvement of HLA-B and especially HLA-DRB1 imputation methods, and no imputation method is as accurate as molecular genotyping. The application of large, ancestrally diverse HLA and SNP reference data sets and multiple imputation methods has the potential to make SNP-based HLA imputation methods a tractable option for determining HLA genotypes.

Impact of radiation therapy and extent of resection for ependymoma in young children: A population-based study.

BACKGROUND: Young children with posterior fossa ependymoma (PF-EPN) have a worse prognosis than older children, and they have a unique molecular profile (PF-EPN-A subtype). Alternative treatment strategies are often used in these young patients, and their prognostic factors are less clear. METHODS: We characterized the prognostic factors and treatment outcomes of 482 patients between ages 0 and 3 years with the diagnosis of ependymoma identified from the Surveillance, Epidemiology, and End Results registry (1973-2013). RESULTS: Radiation therapy (RT) was delivered to 52.3% of patients, and gross total resection (GTR) was performed in 51.0% of patients. Overall survival (OS) at 10 years was 48.4% with median follow-up of 3.3 years. WHO grade was not predictive of OS. Extent of resection was significant for survival; the 10-year OS with GTR was 61.0%, and with subtotal resection (STR) and biopsy was 38.2% and 35.0%, respectively (P < 0.001). RT significantly benefitted OS for both grades II and III. The 10-year OS for grade II was 50.5% with RT and 43.4% without (P = 0.030); 10-year OS for grade III was 66.0% with RT and 40.0% without (P = 0.002). Multivariate analysis showed significantly improved OS with RT (hazard ratio [HR] 0.601, 95% CI: 0.439-0.820, P = 0.001) and GTR (HR 0.471, 95% CI: 0.328-0.677, P < 0.0001). CONCLUSIONS: Ependymoma outcomes in patients within 0-3 years of age significantly improved with RT and GTR. Histopathologic grading of ependymoma demonstrated no prognostic significance. Given the poor OS for this population and unique genetic profile, future prospective studies with molecular-based stratification should be performed to evaluate additional prognostic factors.

Emergence of the persistent spin helix in semiconductor quantum wells.

According to Noether's theorem, for every symmetry in nature there is a corresponding conservation law. For example, invariance with respect to spatial translation corresponds to conservation of momentum. In another well-known example, invariance with respect to rotation of the electron's spin, or SU(2) symmetry, leads to conservation of spin polarization. For electrons in a solid, this symmetry is ordinarily broken by spin-orbit coupling, allowing spin angular momentum to flow to orbital angular momentum. However, it has recently been predicted that SU(2) can be achieved in a two-dimensional electron gas, despite the presence of spin-orbit coupling. The corresponding conserved quantities include the amplitude and phase of a helical spin density wave termed the 'persistent spin helix'. SU(2) is realized, in principle, when the strengths of two dominant spin-orbit interactions, the Rashba (strength parameterized by alpha) and linear Dresselhaus (beta(1)) interactions, are equal. This symmetry is predicted to be robust against all forms of spin-independent scattering, including electron-electron interactions, but is broken by the cubic Dresselhaus term (beta(3)) and spin-dependent scattering. When these terms are negligible, the distance over which spin information can propagate is predicted to diverge as alpha approaches beta(1). Here we report experimental observation of the emergence of the persistent spin helix in GaAs quantum wells by independently tuning alpha and beta(1). Using transient spin-grating spectroscopy, we find a spin-lifetime enhancement of two orders of magnitude near the symmetry point. Excellent quantitative agreement with theory across a wide range of sample parameters allows us to obtain an absolute measure of all relevant spin-orbit terms, identifying beta(3) as the main SU(2)-violating term in our samples. The tunable suppression of spin relaxation demonstrated in this work is well suited for application to spintronics.

Simultaneous optimization method for absorption spectroscopy postprocessing.

A simultaneous optimization method is proposed for absorption spectroscopy postprocessing. This method is particularly useful for thermometry measurements based on congested spectra, as commonly encountered in combustion applications of H2O absorption spectroscopy. A comparison test demonstrated that the simultaneous optimization method had greater accuracy, greater precision, and was more user-independent than the common step-wise postprocessing method previously used by the authors. The simultaneous optimization method was also used to process experimental data from an environmental chamber and a constant volume combustion chamber, producing results with errors on the order of only 1%.

Demonstration of temperature imaging by H2O absorption spectroscopy using compressed sensing tomography.

This paper introduces temperature imaging by total-variation-based compressed sensing (CS) tomography of H2O vapor absorption spectroscopy. A controlled laboratory setup is used to generate a constant two-dimensional temperature distribution in air (a roughly Gaussian temperature profile with a central temperature of 677 K). A wavelength-tunable laser beam is directed through the known distribution; the beam is translated and rotated using motorized stages to acquire complete absorption spectra in the 1330-1365 nm range at each of 64 beam locations and 60 view angles. Temperature reconstructions are compared to independent thermocouple measurements. Although the distribution studied is approximately axisymmetric, axisymmetry is not assumed and simulations show similar performance for arbitrary temperature distributions. We study the measurement error as a function of number of beams and view angles used in reconstruction to gauge the potential for application of CS in practical test articles where optical access is limited.

Absolute pulse energy measurements of soft x-rays at the Linac Coherent Light Source.

This paper reports novel measurements of x-ray optical radiation on an absolute scale from the intense and ultra-short radiation generated in the soft x-ray regime of a free electron laser. We give a brief description of the detection principle for radiation measurements which was specifically adapted for this photon energy range. We present data characterizing the soft x-ray instrument at the Linac Coherent Light Source (LCLS) with respect to the radiant power output and transmission by using an absolute detector temporarily placed at the downstream end of the instrument. This provides an estimation of the reflectivity of all x-ray optical elements in the beamline and provides the absolute photon number per bandwidth per pulse. This parameter is important for many experiments that need to understand the trade-offs between high energy resolution and high flux, such as experiments focused on studying materials via resonant processes. Furthermore, the results are compared with the LCLS diagnostic gas detectors to test the limits of linearity, and observations are reported on radiation contamination from spontaneous undulator radiation and higher harmonic content.

[Mental disorders in the general population : Study on the health of adults in Germany and the additional module mental health (DEGS1-MH)]. / Psychische Störungen in der Allgemeinbevölkerung : Studie zur Gesundheit Erwachsener in Deutschland und ihr Zusatzmodul Psychische Gesundheit (DEGS1-MH).

BACKGROUND AND OBJECTIVES: The German health interview and examination survey for adults (DEGS1) with the mental health module (DEGS1-MH) is the successor to the last survey of mental disorders in the general German population 15 years ago (GHS-MHS). This paper reports the basic findings on the 12-month prevalence of mental disorders, associated disabilities and self-reported healthcare utilization. METHODS: A representative national cohort (age range 18-79 years, n = 5,317) was selected and individuals were personally examined (87.5 % face to face and 12.5 % via telephone) by a comprehensive clinical interview using the composite international diagnostic interview (CIDI) questionnaire. RESULTS: The overall 12-month prevalence of mental disorders was 27.7 % with substantial differences between subgroups (e.g. sex, age, socioeconomic status). Mental disorders were found to be particularly impairing (elevated number of disability days). Less than 50 % of those affected reported to be in contact with health services due to mental health problems within the last 12 months (range 10-40 % depending on the number of diagnoses). CONCLUSIONS: Mental disorders were found to be commonplace with a prevalence level comparable to that found in the 1998 predecessor study but several further adjustments will have to be made for a sound methodological comparison between the studies. Apart from individual distress, elevated self-reported disability indicated a high societal disease burden of mental disorders (also in comparison with many somatic diseases). Despite a relatively comprehensive and well developed mental healthcare system in Germany there are still optimisation needs for treatment rates.

Assessing Growth of BACB Certificants (1999-2019).

Geographic distribution patterns of board certified behavior analysts may be useful in analyzing the growth of the field. First, we present an international snapshot of Behavior Analyst Certification Board (BACB) certificants, then analyze relative growth rates between countries from 1999 to 2019. This is followed by an in depth review of certificant distribution patterns in the United States and Canada, as well as the ratios of experienced behavior analysts to new certificants. These data highlight regions with a potential deficit of qualified supervisors. There are factors that influence different dispersal patterns, and without drilling deeper into the data we may be unable to effectively identify or influence them in order meet the specific needs of a geographic region. Supplementary Information: The online version contains supplementary material available at 10.1007/s40614-023-00370-5.

Genotype List String: a grammar for describing HLA and KIR genotyping results in a text string.

Knowledge of an individual's human leukocyte antigen (HLA) genotype is essential for modern medical genetics, and is crucial for hematopoietic stem cell and solid-organ transplantation. However, the high levels of polymorphism known for the HLA genes make it difficult to generate an HLA genotype that unambiguously identifies the alleles that are present at a given HLA locus in an individual. For the last 20 years, the histocompatibility and immunogenetics community has recorded this HLA genotyping ambiguity using allele codes developed by the National Marrow Donor Program (NMDP). While these allele codes may have been effective for recording an HLA genotyping result when initially developed, their use today results in increased ambiguity in an HLA genotype, and they are no longer suitable in the era of rapid allele discovery and ultra-high allele polymorphism. Here, we present a text string format capable of fully representing HLA genotyping results. This Genotype List (GL) String format is an extension of a proposed standard for reporting killer-cell immunoglobulin-like receptor (KIR) genotype data that can be applied to any genetic data that use a standard nomenclature for identifying variants. The GL String format uses a hierarchical set of operators to describe the relationships between alleles, lists of possible alleles, phased alleles, genotypes, lists of possible genotypes, and multilocus unphased genotypes, without losing typing information or increasing typing ambiguity. When used in concert with appropriate tools to create, exchange, and parse these strings, we anticipate that GL Strings will replace NMDP allele codes for reporting HLA genotypes.

Common and well-documented HLA alleles: 2012 update to the CWD catalogue.

We have updated the catalogue of common and well-documented (CWD) human leukocyte antigen (HLA) alleles to reflect current understanding of the prevalence of specific allele sequences. The original CWD catalogue designated 721 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and -DPB1 loci in IMGT (IMmunoGeneTics)/HLA Database release 2.15.0 as being CWD. The updated CWD catalogue designates 1122 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and -DPB1 loci as being CWD, and represents 14.3% of the HLA alleles in IMGT/HLA Database release 3.9.0. In particular, we identified 415 of these alleles as being 'common' (having known frequencies) and 707 as being 'well-documented' on the basis of ~140,000 sequence-based typing observations and available HLA haplotype data. Using these allele prevalence data, we have also assigned CWD status to specific G and P designations. We identified 147/151 G groups and 290/415 P groups as being CWD. The CWD catalogue will be updated on a regular basis moving forward, and will incorporate changes to the IMGT/HLA Database as well as empirical data from the histocompatibility and immunogenetics community. This version 2.0.0 of the CWD catalogue is available online at cwd.immunogenomics.org, and will be integrated into the Allele Frequencies Net Database, the IMGT/HLA Database and National Marrow Donor Program's bioinformatics web pages.

Cortisol reactions to a social evaluative paradigm in 5- and 6-year-old children.

The goal of the present study was to develop a stress paradigm to elicit cortisol secretory responses in a group of 5- and 6-year-old children as a whole. To this end, we tested a paradigm containing elements of social evaluative threat, unpredictability and uncontrollability, and with a duration of 20 min. The Children's Reactions to Evaluation Stress Test is composed of three short tasks that children have to perform in front of a judge. The tasks are rigged so as to provoke (partial) failure in the child's performance. Participants were 42 children (M = 68.0 months, SD = 4.3). Six saliva samples were taken during the testing session to obtain cortisol measurements of baseline concentrations, stress reactivity, and recovery. Our findings showed that this paradigm was effective in provoking a significant increase in salivary cortisol concentration in the group as a whole, with no effects of possible confounders (child's sex, age or school, parental educational level, time of testing, sex of experimenter, and sex of judge). The mean cortisol concentration increase for the group was 127.5% (SD = 190.9); 61% of the children could be classified as reactors (mean increase of 214%, SD = 201.5), and 39% as non-reactors (mean decrease of 7.8%, SD = 16.8). To our knowledge, this is the first study in this age group that shows a significant cortisol response for the group as a whole to a standardized laboratory paradigm. As such, this paradigm is a promising tool to be used in future research on early life interactions between physiology and psychology.

16(th) IHIW: immunogenomic data-management methods. report from the immunogenomic data analysis working group (IDAWG).

SUMMARY: The goal of the immunogenomic data analysis working group (IDAWG) is to facilitate the consistent analysis of HLA and KIR data, and the sharing of those data among the immunogenomic and larger genomic communities. However, the data management approaches currently applied by immunogenomic researchers are not widely discussed or reported in the literature, and the effect of different approaches on data analyses is not known. With ASHI's support, the IDAWG developed a 45 question survey on HLA and KIR data generation, data management and data analysis practices. Survey questions detailed the loci genotyped, typing systems used, nomenclature versions reported, computer operating systems and software used to manage and transmit data, the approaches applied to resolve HLA ambiguity and the methods used for basic population-level analyses. Respondents were invited to demonstrate their HLA ambiguity resolution approaches in simulated data sets. By May 2012, 156 respondents from 35 nations had completed the survey. These survey respondents represent a broad sampling of the Immunogenomic community; 52% were European, 30% North American, 10% Asian, 4% South American and 4% from the Pacific. The project will continue in conjunction with the 17th Workshop, with the aim of developing community data sharing standards, ambiguity resolution documentation formats, single-task data Management tools and novel data analysis methods and applications. While additional project details and plans for the 17th IHIW will be forthcoming, we welcome the input and participation in these projects from the histocompatibility and immunogenetics community.

16(th) IHIW: extending the number of resources and bioinformatics analysis for the investigation of HLA rare alleles.

Continuing a project presented at the 15th International HLA and Immunogenetics Workshop (IHIWS) on the rarity of HLA alleles, we sought to expand the number of data sources and bioinformatics tools available in the Allele Frequencies Net Database website (AFND, www.allelefrequencies.net). In this 16th IHIWS Rare Alleles project, HLA alleles described in the latest IMGT/HLA Database (release 3.8.0) were queried against different sources including data from registries (stem cell) and from 74 different laboratories around the world. We demonstrated that approximately 40% of the alleles officially named in the IMGT/HLA Database have been reported only once across all different sources. To facilitate the large-scale analysis of rare alleles, we have produced an online tool called the Rare Allele Detector that simplifies the detection of alleles that are considered to be 'very rare', 'rare' or 'frequent'. Tools and associated data can be accessed via the www.allelefrequencies.net website.

Learning Disability Liaison Nursing Services in south-east Scotland: a mixed-methods impact and outcome study.

BACKGROUND: There have been significant concerns about the care and treatment of people with intellectual disabilities (ID) when attending general hospitals, which have led to inquiries that highlight service and systems failures. One response has been the development of Learning Disability Liaison Nursing (LDLN) Services across the UK that aim to ensure that additional, specialist support is available for patients, their carers and general healthcare professionals. METHODS: A mixed-methods study to investigate the impact of LDLN Services across four Scottish NHS boards was undertaken. In total, 323 referrals made over 18 months were analysed along with qualitative data drawn from interviews and focus groups with a sample of 85 participants including patients with ID (n = 5), carers (n = 16), primary care healthcare professionals (n = 39) and general hospital professionals (n = 19) and learning disability liaison nurses (n = 6). RESULTS: The referral patterns to the four liaison nursing services closely matched the known health needs of adults with ID, with common admissions being due to neurological, respiratory and gastrointestinal issues. The LDLN role was seen to be complex and impacted on three key areas: (i) clinical patient care; (ii) education and practice development; and (iii) strategic organisational developments. Specific patient outcomes were linked to issues relating to capacity and consent to treatment, fostering person-centred adjustments to care, augmenting communication and the liaison nurses acting as positive role models and ambassadors for people with ID. CONCLUSIONS: The LDLN Services were valued by stakeholders by achieving person-centred outcomes. With their expert knowledge and skills, the liaison nurses had an important role in developing effective systems and processes within general hospital settings. The outcomes highlight the importance of supporting and promoting LDLN Services and the challenges in delivering the multifaceted elements of the role. There is a need to take account of the complex and multidimensional nature of the LDLN role and the possible tensions between achieving clinical outcomes, education and practice developments and organisational strategic initiatives.

Building a Social Justice Framework for Cultural and Linguistic Diversity in ABA.

ABA may be uniquely positioned to have broader impacts with culturally and linguistically diverse (CLD) client populations, not only due to its growth and increased social acceptability, but also because a segment of the field practices within the education system. Decades of misinformation have potentially reduced the widespread reliance on learning pedagogies derived from behavior analytic research. Disseminating ABA technologies depends on an advocacy-based approach to close gaps from research-to-practice. Social justice is both an approach and a framework that can be integrated into our strategic planning for the field. This article describes how to apply social justice guidelines when working with CLD students and families. There are culturally relevant considerations that can be included in our research, training, and service delivery, in particular if we want the field to grow in a sustainable fashion. Behavior analysts must consider it an ongoing long-term objective to engage in culturally informed assessment, culturally and linguistically relevant intervention, culturally focused advocacy and collaboration with families, and use self-assessment of their cultural competence.

Statistical Decision-Making Accuracies for Some Overlap- and Distance-based Measures for Single-Case Experimental Designs.

Selecting a quantitative measure to guide decision making in single-case experimental designs (SCEDs) is complicated. Many measures exist and all have been rightly criticized. The two general classes of measure are overlap-based (e.g., percentage nonoverlapping data) and distance-based (e.g., Cohen's d). We compare several measures from each category for Type I error rate and power across a range of designs using equal numbers of observations (i.e., 3-10) in each phase. Results showed that Tau and the distance-based measures (i.e., RD and g) provided the highest decision accuracies. Other overlap-based measures (e.g., PND, dual-criterion method) did not perform as well. It is recommended that Tau be used to guide decision making about the presence/absence of a treatment effect, and RD or g be used to quantify the magnitude of the treatment effect. Supplementary Information: The online version contains supplementary material available at 10.1007/s40614-021-00317-8.

Reconsideration of the type I error rate for psychological science in the era of replication.

Careful consideration of the tradeoff between Type I and Type II error rates when designing experiments is critical for maximizing statistical decision accuracy. Typically, Type I error rates (e.g., .05) are significantly lower than Type II error rates (e.g., .20 for .80 power) in psychological science. Further, positive findings (true effects and Type I errors) are more likely to be the focus of replication. This conventional approach leads to very high rates of Type II error. Analyses show that increasing the Type I error rate to .10, thereby increasing power and decreasing the Type II error rate for each test, leads to higher overall rates of correct statistical decisions. This increase of Type I error rate is consistent with, and most beneficial in the context of, the replication and "New Statistics" movements in psychology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).