A longitudinal study of within-person trajectories in quality of life in patients receiving early palliative care.

PURPOSE: To reveal the within-person trajectories in quality of life (QOL) in patients receiving early palliative care. Previous studies have mostly focused aggregated trajectories, based on all research participants combined, whereas this study focused on within-person trajectories in QOL and on whether the variability in QOL trajectories across patients is substantial enough to raise doubts about aggregated trajectories. METHODS: Twenty-five older persons in early palliative care completed the McGill Quality of Life Questionnaire multiple times. Reliable change analyses provided estimates of the occurrence of statistically significant within-person change. RESULTS: There was reliable, within-person variation in QOL scores across time, more so for physical than for psychological aspects of well-being. Changes in QOL scores occurred for most patients but the trajectories were not linear and there was no common trend in the nonlinear patterns. CONCLUSIONS: Reliable change across time can be identified in persons receiving early palliative care. However, the trajectories are notably variable and patient-specific. The high degrees of within-person variability across time suggests the importance of repeated QOL assessments and of dynamic tailoring of clinical treatments.

This study describes the quality of life (QOL) trajectories of 25 persons in early palliative care for life-limiting chronic conditions. Previous studies have mostly focused on aggregated trajectories for all research participants combined. In contrast, this study focused on within-person trajectories in QOL and on whether the variability in QOL trajectories across patients is substantial enough to question the meaningfulness of aggregated trajectories. There was both between-patient and within-person variation in QOL scores across time and no common trend. For some patients, the change was for improving scores across time. For other patients the change was for worsening scores across time. And for still other patients, the changes were reliable but not linear. The trajectories are thus quite variable and patient-specific. The variability in QOL trajectories is substantial enough to raise concerns about aggregated trajectories. The high degrees of within-person variability across time suggests the importance of repeated QOL assessments and of dynamic tailoring of clinical treatments.

Granzyme F: Exhaustion Marker and Modulator of Chimeric Antigen Receptor T Cell-Mediated Cytotoxicity.

Granzymes are a family of proteases used by CD8 T cells to mediate cytotoxicity and other less-defined activities. The substrate and mechanism of action of many granzymes are unknown, although they diverge among the family members. In this study, we show that mouse CD8+ tumor-infiltrating lymphocytes (TILs) express a unique array of granzymes relative to CD8 T cells outside the tumor microenvironment in multiple tumor models. Granzyme F was one of the most highly upregulated genes in TILs and was exclusively detected in PD1/TIM3 double-positive CD8 TILs. To determine the function of granzyme F and to improve the cytotoxic response to leukemia, we constructed chimeric Ag receptor T cells to overexpress a single granzyme, granzyme F or the better-characterized granzyme A or B. Using these doubly recombinant T cells, we demonstrated that granzyme F expression improved T cell-mediated cytotoxicity against target leukemia cells and induced a form of cell death other than chimeric Ag receptor T cells expressing only endogenous granzymes or exogenous granzyme A or B. However, increasing expression of granzyme F also had a detrimental impact on the viability of the host T cells, decreasing their persistence in circulation in vivo. These results suggest a unique role for granzyme F as a marker of terminally differentiated CD8 T cells with increased cytotoxicity, but also increased self-directed cytotoxicity, suggesting a potential mechanism for the end of the terminal exhaustion pathway.

Managing With Atrial Fibrillation: An Exploratory Model-Based Cluster Analysis of Clinical and Personal Patient Characteristics.

Background: Examining characteristics of patients with atrial fibrillation (AF) has the potential to help in identifying groups of patients who might benefit from different management approaches. Methods: Secondary analysis of online survey data was combined with clinic referral data abstraction from 196 patients with AF attending an AF specialty clinic. Cluster analyses were performed to identify distinct, homogeneous clusters of AF patients defined by 11 relevant variables: CHA2DS2-VASc score, age, AF symptoms, overall health, mental health, AF knowledge, perceived stress, household and recreation activity, overall AF quality of life, and AF symptom treatment satisfaction. Follow-up analyses examined differences between the cluster groups in additional clinical variables. Results: Evidence emerged for both 2- and 4-cluster solutions. The 2-cluster solution involved a contrast between patients who were doing well on all variables (n = 129; 66%) vs those doing less well (n = 67; 34%). The 4-cluster solution provided a closer-up view of the data, showing that the group doing less well was split into 3 meaningfully different subgroups of patients who were managing in different ways. The final 4 clusters produced were as follows: (i) doing well; (ii) stressed and discontented; (iii) struggling and dissatisfied; and (iv) satisfied and complacent. Conclusions: Patients with AF can be accurately classified into distinct, natural groupings that vary in clinically important ways. Among the patients who were not managing well with AF, we found 3 distinct subgroups of patients who may benefit from tailored approaches to AF management and support. The tailoring of treatment approaches to specific personal and/or behavioural patterns, alongside clinical patterns, holds potential to improve patient outcomes (eg, treatment satisfaction).

Contexte: L'examen des caractéristiques des patients atteints de fibrillation auriculaire (FA) pourrait permettre de mieux cerner les groupes qui pourraient bénéficier de différentes approches de prise en charge. Méthodologie: Nous avons combiné une analyse secondaire de données issues d'un sondage en ligne et les données issues de l'orientation clinique de 196 patients atteints de FA d'une clinique spécialisée en FA. Des analyses par grappes ont été réalisées pour cerner des groupes homogènes et distincts de patients atteints de FA, définis grâce à 11 variables pertinentes : score CHA2DS2-VASc, âge, symptômes de FA, état de santé général, état de santé mentale, niveau de connaissances sur la FA, niveau de stress perçu, activités récréatives et domestiques, qualité de vie générale avec la FA, et satisfaction concernant le traitement des symptômes de FA. Des ana-lyses ultérieures ont permis de se pencher sur les différences entre les groupes pour d'autres variables cliniques. Résultats: Deux solutions de regroupement des patients sont apparues possibles à l'analyse : en 2 groupes ou en 4 groupes. Le regroupement en 2 groupes mettait en relief le contraste entre les patients qui avaient des résultats favorables pour tous les paramètres (n = 129; 66 %) et ceux qui avaient des résultats moins favorables (n = 67; 34 %). Le regroupement en 4 groupes permettait d'observer les données plus en détail, et démontrait que le groupe avec des résultats moins favorables se subdivisait en 3 sous-groupes avec des distinctions pertinentes, qui vivaient leur maladie de façon différente. Les 4 groupes finaux étaient les suivants : (i) patients avec une expérience positive; (ii) patients vivant du stress et du mécontentement; (iii) patients vivant des difficultés et une insatisfaction; et (iv) patients vivant une satisfaction complaisante. Conclusions: Les patients atteints de FA peuvent être classés avec exactitude dans des groupes naturels distincts dont les différences sont d'intérêt clinique. Parmi les patients chez qui la prise en charge de la FA n'est pas optimale, il existe 3 sous-groupes différents qui pourraient tirer profit d'une approche de soutien et de prise en charge adaptée à leur profil. La personnalisation des approches thérapeutiques selon le type de comportements et de traits de personnalité, en plus du tableau clinique, pourrait permettre d'améliorer les résultats des patients (p. ex. la satisfaction par rapport au traitement).

Quality of life among patients with atrial fibrillation: A theoretically-guided cross-sectional study.

BACKGROUND: Patients with atrial fibrillation (AF) have significantly lower health-related quality of life (HRQoL) compared to the general population and patients with other heart diseases. The research emphasis on the influence of AF symptoms on HRQoL overshadows the role of individual characteristics. To address this gap, this study's purpose was to test an incremental predictive model for AF-related HRQoL following an adapted HRQoL conceptual model that incorporates both symptoms and individual characteristics. METHODS: Patients attending an AF specialty clinic were invited to complete an online survey. Hierarchical regression analyses were conducted to examine whether individual characteristics (overall mental health, perceived stress, sex, age, AF knowledge, household and recreational physical activity) incremented prediction of HRQoL and AF treatment satisfaction beyond AF symptom recency and overall health. RESULTS: Of 196 participants (mean age 65.3 years), 63% were male and 90% were Caucasian. Most reported 'excellent' or 'good' overall and mental health, had high overall AF knowledge scores, had low perceived stress scores, and had high household and recreation physical activity. The mean overall AF Effect On Quality-Of-Life Questionnaire (AFEQT) and AF treatment satisfaction scores were 70.62 and 73.84, respectively. Recency of AF symptoms and overall health accounted for 29.6% of the variance in overall HRQoL and 20.2% of the variance in AF treatment satisfaction. Individual characteristics explained an additional 13.6% of the variance in overall HRQoL and 7.6% of the variance in AF treatment satisfaction. Perceived stress and household physical activity were the largest contributors to overall HRQoL, whereas age and AF knowledge made significant contributions to AF treatment satisfaction. CONCLUSIONS: Along with AF symptoms and overall health, individual characteristics are important predictors of HRQoL and AF treatment satisfaction in AF patients. In particular, perceived stress and household physical activity could further be targeted as potential areas to improve HRQoL.

Usability and Feasibility Testing of an Atrial Fibrillation Educational Website with Patients Referred to an Atrial Fibrillation Specialty Clinic.

BACKGROUND: The purpose of this study was to design, usability test, and explore the feasibility of a web-based educational platform/intervention for patients with atrial fibrillation (AF) as part of their virtual AF care. METHODS: Participants were patients attending a specialized AF clinic. The multiple mixed-methods design included website design, think-aloud usability test, 1-month unstructured pre-testing analysis using Google Analytics, follow-up interviews, and a non-randomized one-group feasibility test using pre/post online surveys and Google Analytics. RESULTS: Usability testing participants (n = 2) guided adjustments for improving navigation. Pre-testing participants' (n = 9) website activity averaged four sessions (SD = 2.6) at 10 (SD 8) minutes per session during a 1-month study period. In the feasibility test, 30 patients referred to AF specialty clinic care completed the baseline survey, and 20 of these completed the 6-month follow-up survey. A total of 19 patients accessed the website over the 6 months, and all 30 participants were sent email prompts containing information from the website. Health-related quality of life, treatment satisfaction, household activity, and AF knowledge scores were higher at follow-up than baseline. There was an overall downward trend in self-reported healthcare utilization at follow-up. CONCLUSIONS: Access to a credible education website for patients with AF has great potential to complement virtual and hybrid models of care.

Telehealth Satisfaction in Patients Receiving Virtual Atrial Fibrillation Care: Quantitative Exploratory Study.

BACKGROUND: Telehealth can optimize access to specialty care for patients with atrial fibrillation (AF). Virtual AF care, however, may not fit with the complex needs of patients with AF. OBJECTIVE: This study aims to explore the correlation among attitudes toward health care technologies, self-efficacy, and telehealth satisfaction as part of the future planning of virtual AF clinic care. METHODS: Patients with AF older than 18 years from an urban-based, highly specialized AF clinic who had an upcoming telehealth visit were invited to participate in a web-based survey. The survey asked about demographic characteristics; use of technology; general, computer, and health care technology self-efficacy (HTSE) and health care technology attitudes, using a validated 30-item tool; and telehealth satisfaction questionnaire using a validated 14-item questionnaire. Data were analyzed with descriptive statistics, correlational analyses, and linear regression modeling. RESULTS: Participants (n=195 of 579 invited, for a 34% response rate) were primarily older, male, and White, had postsecondary schooling or more, and had high self-reported overall and mental health ratings. A variety of technologies were used in their daily lives and for health care, with the majority of technologies comprising desktop and laptop computers, smartphones, and tablets. Self-efficacy and telehealth satisfaction questionnaire scores were high overall, with male participants having higher general self-efficacy, computer self-efficacy, HTSE, and technology attitude scores. After controlling for age and sex, only HTSE was significantly related to individuals' attitudes toward health care technology. Both general self-efficacy and attitude toward health care technology were positively related to telehealth satisfaction. CONCLUSIONS: Consistent with a previous study, only HTSE significantly influenced attitudes toward health care technology. This finding confirms that, in this regard, self-efficacy is not a general perception but is domain specific. Considering participants' predominant use of the telephone for virtual care, it follows that general self-efficacy and attitude toward health care technology were significant contributors to telehealth satisfaction. Given our patients' frequent use of technology and high computer self-efficacy and HTSE scores, the use of video for telehealth appointments could be supported.

Multi-disciplinary community-based group intervention for fibromyalgia: a pilot randomized controlled trial.

Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances, mood disturbances, and cognitive impairment. Most individuals with fibromyalgia experience poorly managed symptoms and increased healthcare service use. Multicomponent therapies, with a focus on nonpharmacological modalities, are increasingly supported in the literature. However, given the limited resources available, implementation in smaller communities remains a challenge. This research tested a community-based multidisciplinary group intervention for individuals diagnosed with FM living in a small urban centre. The primary outcome was perceptions of quality of care and secondary outcomes included disease-related functioning, anxious and depressive symptoms, pain beliefs, and health service utilization. A pilot randomized control trial was conducted in which 60 patients diagnosed with fibromyalgia were randomized into a 10-week community-based multidisciplinary group intervention program or usual care. Treatment components included twice-weekly exercise sessions and weekly education sessions (e.g., pain education, cognitive behavioral strategies for stress, nutrition, peer support). The trial (NCT03270449) was registered September 1 2017. Statistically significant post-intervention improvements were found in the primary outcome, perceived quality of care (Cohen's d = 0.61, 0.66 for follow up care and goal setting, respectively). Secondary outcomes showing statistically significant improvements were disease-related daily functioning (Cohen's d = 0.70), depressive symptoms (Cohen's d = 0.87), and pain beliefs (Cohen's d = 0.61, 0.67, 0.82 for harm, disability and control, respectively). No adverse events were reported. Community-based multidisciplinary group interventions for fibromyalgia show promise for improving satisfaction with quality of care, disease-related functioning, and depression, and fostering more adaptive pain beliefs.

Myelodysplastic neoplasm-associated U2AF1 mutations induce host defense defects by compromising neutrophil chemotaxis.

Myelodysplastic neoplasm (MDS) is a hematopoietic stem cell disorder that may evolve into acute myeloid leukemia. Fatal infection is among the most common cause of death in MDS patients, likely due to myeloid cell cytopenia and dysfunction in these patients. Mutations in genes that encode components of the spliceosome represent the most common class of somatically acquired mutations in MDS patients. To determine the molecular underpinnings of the host defense defects in MDS patients, we investigated the MDS-associated spliceosome mutation U2AF1-S34F using a transgenic mouse model that expresses this mutant gene. We found that U2AF1-S34F causes a profound host defense defect in these mice, likely by inducing a significant neutrophil chemotaxis defect. Studies in human neutrophils suggest that this effect of U2AF1-S34F likely extends to MDS patients as well. RNA-seq analysis suggests that the expression of multiple genes that mediate cell migration are affected by this spliceosome mutation and therefore are likely drivers of this neutrophil dysfunction.

Concerning the eXclusion in human genomics: the choice of sex chromosome representation in the human genome drastically affects the number of identified variants.

Over the past 30 years, a community of scientists has pieced together every base pair of the human reference genome from telomere to telomere. Interestingly, most human genomics studies omit more than 5% of the genome from their analyses. Under "normal" circumstances, omitting any chromosome(s) from an analysis of the human genome would be a cause for concern, with the exception being sex chromosomes. Sex chromosomes in eutherians share an evolutionary origin as an ancestral pair of autosomes. In humans, they share 3 regions of high-sequence identity (∼98-100%), which, along with the unique transmission patterns of the sex chromosomes, introduce technical artifacts in genomic analyses. However, the human X chromosome bears numerous important genes, including more "immune response" genes than any other chromosome, which makes its exclusion irresponsible when sex differences across human diseases are widespread. To better characterize the possible effect of the inclusion/exclusion of the X chromosome on variants called, we conducted a pilot study on the Terra cloud platform to replicate a subset of standard genomic practices using both the CHM13 reference genome and the sex chromosome complement-aware reference genome. We compared the quality of variant calling, expression quantification, and allele-specific expression using these 2 reference genome versions across 50 human samples from the Genotype-Tissue Expression consortium annotated as females. We found that after correction, the whole X chromosome (100%) can generate reliable variant calls, allowing for the inclusion of the whole genome in human genomics analyses as a departure from the status quo of omitting the sex chromosomes from empirical and clinical genomics studies.

Building a collaborative cloud platform to accelerate heart, lung, blood, and sleep research.

Research increasingly relies on interrogating large-scale data resources. The NIH National Heart, Lung, and Blood Institute developed the NHLBI BioData CatalystⓇ (BDC), a community-driven ecosystem where researchers, including bench and clinical scientists, statisticians, and algorithm developers, find, access, share, store, and compute on large-scale datasets. This ecosystem provides secure, cloud-based workspaces, user authentication and authorization, search, tools and workflows, applications, and new innovative features to address community needs, including exploratory data analysis, genomic and imaging tools, tools for reproducibility, and improved interoperability with other NIH data science platforms. BDC offers straightforward access to large-scale datasets and computational resources that support precision medicine for heart, lung, blood, and sleep conditions, leveraging separately developed and managed platforms to maximize flexibility based on researcher needs, expertise, and backgrounds. Through the NHLBI BioData Catalyst Fellows Program, BDC facilitates scientific discoveries and technological advances. BDC also facilitated accelerated research on the coronavirus disease-2019 (COVID-19) pandemic.

Standardization of flow cytometry and cell sorting to enable a transcriptomic analysis in a multi-site sarcoidosis study.

The contribution and regulation of various CD4+ T cell lineages that occur with remitting vs progressive courses in sarcoidosis are poorly understood. We developed a multiparameter flow cytometry panel to sort these CD4+ T cell lineages followed by measurement of their functional potential using RNA-sequencing analysis at six-month intervals across multiple study sites. To obtain good quality RNA for sequencing, we relied on chemokine receptor expression to identify and sort lineages. To minimize gene expression changes induced by perturbations of T cells and avoid protein denaturation caused by freeze/thaw cycles, we optimized our protocols using freshly isolated samples at each study site. To accomplish this study, we had to overcome significant standardization challenges across multiple sites. Here, we detail standardization considerations for cell processing, flow staining, data acquisition, sorting parameters, and RNA quality control analysis that were performed as part of the NIH-sponsored, multi-center study, BRonchoscopy at Initial sarcoidosis diagnosis Targeting longitudinal Endpoints (BRITE). After several rounds of iterative optimization, we identified the following aspects as critical for successful standardization: 1) alignment of PMT voltages across sites using CS&T/rainbow bead technology; 2) a single template created in the cytometer program that was used by all sites to gate cell populations during data acquisition and cell sorting; 3) use of standardized lyophilized flow cytometry staining cocktails to reduce technical error during processing; 4) development and implementation of a standardized Manual of Procedures. After standardization of cell sorting, we were able to determine the minimum number of sorted cells necessary for next generation sequencing through analysis of RNA quality and quantity from sorted T cell populations. Overall, we found that implementing a multi-parameter cell sorting with RNA-seq analysis clinical study across multiple study sites requires iteratively tested standardized procedures to ensure comparable and high-quality results.

Concerning the eXclusion in human genomics: The choice of sex chromosome representation in the human genome drastically affects number of identified variants.

Over the past 30 years, a community of scientists have pieced together every base pair of the human reference genome from telomere-to-telomere. Interestingly, most human genomics studies omit more than 5% of the genome from their analyses. Under 'normal' circumstances, omitting any chromosome(s) from analysis of the human genome would be reason for concern-the exception being the sex chromosomes. Sex chromosomes in eutherians share an evolutionary origin as an ancestral pair of autosomes. In humans, they share three regions of high sequence identity (~98-100%), which-along with the unique transmission patterns of the sex chromosomes-introduce technical artifacts into genomic analyses. However, the human X chromosome bears numerous important genes-including more "immune response" genes than any other chromosome-which makes its exclusion irresponsible when sex differences across human diseases are widespread. To better characterize the effect that including/excluding the X chromosome may have on variants called, we conducted a pilot study on the Terra cloud platform to replicate a subset of standard genomic practices using both the CHM13 reference genome and sex chromosome complement-aware (SCC-aware) reference genome. We compared quality of variant calling, expression quantification, and allele-specific expression using these two reference genome versions across 50 human samples from the Genotype-Tissue-Expression consortium annotated as females. We found that after correction, the whole X chromosome (100%) can generate reliable variant calls-allowing for the inclusion of the whole genome in human genomics analyses as a departure from the status quo of omitting the sex chromosomes from empirical and clinical genomics studies.

Low TCR Binding Strength Results in Increased Progenitor-like CD8+ Tumor-Infiltrating Lymphocytes.

T-cell receptor (TCR) binding strength to peptide-MHC antigen complex influences numerous T-cell functions. However, the vast diversity of a polyclonal T-cell repertoire for even a single antigen greatly increases the complexity of studying the impact of TCR affinity on T-cell function. Here, we determined how TCR binding strength affected the protein and transcriptional profile of an endogenous, polyclonal T-cell response to a known tumor-associated antigen (TAA) within the tumor microenvironment (TME). We confirmed that the staining intensity by flow cytometry and the counts by sequencing from MHC-tetramer labeling were reliable surrogates for the TCR-peptide-MHC steady-state binding affinity. We further demonstrated by single-cell RNA sequencing that tumor-infiltrating lymphocytes (TIL) with high and low binding affinity for a TAA can differentiate into cells with many antigen-specific transcriptional profiles within an established TME. However, more progenitor-like phenotypes were significantly biased towards lower affinity T cells, and proliferating phenotypes showed significant bias towards high-affinity TILs. In addition, we found that higher affinity T cells advanced more rapidly to terminal phases of T-cell exhaustion and exhibited better tumor control. We confirmed the polyclonal TIL results using a TCR transgenic mouse possessing a single low-affinity TCR targeting the same TAA. These T cells maintained a progenitor-exhausted phenotype and exhibited impaired tumor control. We propose that high-affinity TCR interactions drive T-cell fate decisions more rapidly than low-affinity interactions and that these cells differentiate faster. These findings illustrate divergent forms of T-cell dysfunction based on TCR affinity which may impact TIL therapies and antitumor responses.

Review of the Cardiovascular Implications of the Social and Religious Practices Associated with Donning Phylacteries.

We previously published a manuscript suggesting that use of phylacteries, ritual straps worn during Jewish prayer services, affects cardiovascular and inflammatory function (Owens et al., Am J Physiol-Heart Circ Physiol, 315(6):H1748-H1758, 2018). Observed physiologic changes were associated with improved cardiac outcomes, though a direct link between phylactery use and improved cardiovascular outcomes is difficult to prove as there are a number of associated religious and spiritual practices that may confound the observed effects. In this review, we assess the scientific literature regarding religious and spiritual practices associated with phylactery in order to better understand the cardiovascular implications of the practice of donning phylacteries. We focus on key aspects traditionally associated with donning phylacteries including gathering in groups, meditation and prayer.

Society for Cardiovascular Magnetic Resonance 2021 cases of SCMR and COVID-19 case collection series.

The Society for Cardiovascular Magnetic Resonance (SCMR) is an international society focused on the research, education, and clinical application of cardiovascular magnetic resonance (CMR). "Cases of SCMR" is a case series hosted on the SCMR website ( https://www.scmr.org ) that demonstrates the utility and importance of CMR in the clinical diagnosis and management of cardiovascular disease. The COVID-19 Case Collection highlights the impact of coronavirus disease 2019 (COVID-19) on the heart as demonstrated on CMR. Each case in series consists of the clinical presentation and the role of CMR in diagnosis and guiding clinical management. The cases are all instructive and helpful in the approach to patient management. We present a digital archive of the 2021 Cases of SCMR and the 2020 and 2021 COVID-19 Case Collection series of nine cases as a means of further enhancing the education of those interested in CMR and as a means of more readily identifying these cases using a PubMed or similar literature search engine.

Inverting the model of genomics data sharing with the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space.

The NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL; https://anvilproject.org) was developed to address a widespread community need for a unified computing environment for genomics data storage, management, and analysis. In this perspective, we present AnVIL, describe its ecosystem and interoperability with other platforms, and highlight how this platform and associated initiatives contribute to improved genomic data sharing efforts. The AnVIL is a federated cloud platform designed to manage and store genomics and related data, enable population-scale analysis, and facilitate collaboration through the sharing of data, code, and analysis results. By inverting the traditional model of data sharing, the AnVIL eliminates the need for data movement while also adding security measures for active threat detection and monitoring and provides scalable, shared computing resources for any researcher. We describe the core data management and analysis components of the AnVIL, which currently consists of Terra, Gen3, Galaxy, RStudio/Bioconductor, Dockstore, and Jupyter, and describe several flagship genomics datasets available within the AnVIL. We continue to extend and innovate the AnVIL ecosystem by implementing new capabilities, including mechanisms for interoperability and responsible data sharing, while streamlining access management. The AnVIL opens many new opportunities for analysis, collaboration, and data sharing that are needed to drive research and to make discoveries through the joint analysis of hundreds of thousands to millions of genomes along with associated clinical and molecular data types.

Chromodomain helicase DNA-binding 4 (CHD4) regulates early B cell identity and V(D)J recombination.

B lymphocytes develop from uncommitted precursors into immunoglobulin (antibody)-producing B cells, a major arm of adaptive immunity. Progression of early progenitors to antibody-expressing cells in the bone marrow is orchestrated by the temporal regulation of different gene programs at discrete developmental stages. A major question concerns how B cells control the accessibility of these genes to transcription factors. Research has implicated nucleosome remodeling ATPases as mediators of chromatin accessibility. Here, we describe studies of chromodomain helicase DNA-binding 4 (CHD4; also known as Mi-2ß) in early B cell development. CHD4 comprises multiple domains that function in nucleosome mobilization and histone binding. CHD4 is a key component of Nucleosome Remodeling and Deacetylase, or NuRD (Mi-2) complexes, which assemble with other proteins that mediate transcriptional repression. We review data demonstrating that CHD4 is necessary for B lineage identity: early B lineage progression, proliferation in response to interleukin-7, responses to DNA damage, and cell survival in vivo. CHD4-NuRD is also required for the Ig heavy-chain repertoire by promoting utilization of distal variable (VH ) gene segments in V(D)J recombination. In conclusion, the regulation of chromatin accessibility by CHD4 is essential for production of antibodies by B cells, which in turn mediate humoral immune responses to pathogens and disease.

Dimensionality, Item Response Theory, Effect Size Attenuation, and Test Bias Analyses of the Self-Importance of Moral Identity Scale (SIMIS).

The extent to which morality and being a moral person are important to one's identity is most commonly assessed using Aquino and Reed's (2002) Self-Importance of Moral Identity Scale (SIMIS). This study provided detailed psychometric examinations of the structure and discrimination levels of the SIMIS in a large (N = 2108) and heterogeneous sample. Results indicated that the SIMIS is clearly 2-dimensional, as expected. The Internalization and Symbolization subscales provided sufficient, and sometimes high levels of test information across the latent trait continuums. There were no redundant items and no bias based on gender. The most notable, albeit minor, shortcomings were that there are too many response options and that test information (discrimination power) was diminished at high levels of the Internalization latent trait continuum, apparently due to skewness. The fluctuating levels of measurement precision resulted in slightly greater attenuations in effect sizes for Internalization than for Symbolization across data for 31 other measures. The present findings from a large dataset and a variety of modern, revealing statistical methods provided relatively consistent, favorable findings for the measure.