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The Caught Being Good Game (CBGG) is an evidence-based practice used in classrooms to reduce disruptive classroom behavior. This approach to classwide intervention has been implemented and its effectiveness demonstrated across grade levels and types of disruptive behavior. Teachers report that the CBGG is an easy classroom management strategy to implement. Although several studies have been published demonstrating its utility, less research has examined how variations in the contingencies employed impact outcomes. In the current study, the CBGG was implemented across three classrooms in an effort to replicate previous findings. As well, the magnitude of reward/reinforcement was manipulated to determine whether this parameter affected intervention efficacy. Results of the study demonstrated appropriate classroom behavior increased across three elementary classrooms. The impact of magnitude of reward/reinforcement was idiosyncratic across the three classrooms, with no uniform impact of magnitude on intervention outcomes. Reasons why magnitude of reinforcement may not have impacted the efficacy of the CBGG are discussed.

BackgroundMutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion.MethodsVarious mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration.ResultsPiezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development.ConclusionsPiezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.

The diagnosis of Mendelian disorders requires labor-intensive literature research. Trained clinicians can spend hours looking for the right publication(s) supporting a single gene that best explains a patient's disease. AMELIE (Automatic Mendelian Literature Evaluation) greatly accelerates this process. AMELIE parses all 29 million PubMed abstracts and downloads and further parses hundreds of thousands of full-text articles in search of information supporting the causality and associated phenotypes of most published genetic variants. AMELIE then prioritizes patient candidate variants for their likelihood of explaining any patient's given set of phenotypes. Diagnosis of singleton patients (without relatives' exomes) is the most time-consuming scenario, and AMELIE ranked the causative gene at the very top for 66% of 215 diagnosed singleton Mendelian patients from the Deciphering Developmental Disorders project. Evaluating only the top 11 AMELIE-scored genes of 127 (median) candidate genes per patient resulted in a rapid diagnosis in more than 90% of cases. AMELIE-based evaluation of all cases was 3 to 19 times more efficient than hand-curated database-based approaches. We replicated these results on a retrospective cohort of clinical cases from Stanford Children's Health and the Manton Center for Orphan Disease Research. An analysis web portal with our most recent update, programmatic interface, and code is available at AMELIE.stanford.edu.

PurposeBoth monogenic pathogenic variant cataloging and clinical patient diagnosis start with variant-level evidence retrieval followed by expert evidence integration in search of diagnostic variants and genes. Here, we try to accelerate pathogenic variant evidence retrieval by an automatic approach.MethodsAutomatic VAriant evidence DAtabase (AVADA) is a novel machine learning tool that uses natural language processing to automatically identify pathogenic genetic variant evidence in full-text primary literature about monogenic disease and convert it to genomic coordinates.ResultsAVADA automatically retrieved almost 60% of likely disease-causing variants deposited in the Human Gene Mutation Database (HGMD), a 4.4-fold improvement over the current best open source automated variant extractor. AVADA contains over 60,000 likely disease-causing variants that are in HGMD but not in ClinVar. AVADA also highlights the challenges of automated variant mapping and pathogenicity curation. However, when combined with manual validation, on 245 diagnosed patients, AVADA provides valuable evidence for an additional 18 diagnostic variants, on top of ClinVar's 21, versus only 2 using the best current automated approach.ConclusionAVADA advances automated retrieval of pathogenic monogenic variant evidence from full-text literature. Far from perfect, but much faster than PubMed/Google Scholar search, careful curation of AVADA-retrieved evidence can aid both database curation and patient diagnosis.

BackgroundA single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia.MethodsThree families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq.ResultsGenetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10. Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3' UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS.ConclusionThese data show that PAS variants are the most common variant type in NAA10-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields.

Cancer genomes accumulate nucleotide sequence variations that number in the tens of thousands per genome. A prominent fraction of these mutations is thought to arise as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases. These enzymes, collectively called activation induced deaminase (AID)/APOBECs, deaminate cytosines located within defined DNA sequence contexts. The resulting changes of the original C:G pair in these contexts (mutational signatures) provide indirect evidence for the participation of specific cytosine deaminases in a given cancer type. The conventional method used for the analysis of mutable motifs is the consensus approach. Here, for the first time, we have adopted the frequently used weight matrix (sequence profile) approach for the analysis of mutagenesis and provide evidence for this method being a more precise descriptor of mutations than the sequence consensus approach. We confirm that while mutational footprints of APOBEC1, APOBEC3A, APOBEC3B, and APOBEC3G are prominent in many cancers, mutable motifs characteristic of the action of the humoral immune response somatic hypermutation enzyme, AID, are the most widespread feature of somatic mutation spectra attributable to deaminases in cancer genomes. Overall, the weight matrix approach reveals that somatic mutations are significantly associated with at least one AID/APOBEC mutable motif in all studied cancers.

The purpose of this study was to explore the academic, athletic, and social experiences of White college athletes at a Division I historically Black college/university (HBCU). Previous research has documented how White college athletes experience positive educational and developmental outcomes at historically White institutions (HWIs). However, there is a dearth of research on White college athletes' experiences where they are the demographic minority within collegiate institutions like HBCUs. Three focus groups and four individual interviews were conducted and the data from four White college athletes at a HBCU were examined for the current study. Using symbolic interactionism and interpretive interactionism as theoretical lenses, key findings revealed participants largely expressed satisfaction with their academic, athletic, and social experiences. Implications for policy and practice are discussed.

The purpose of this study was to examine the college experiences (academic, athletic, and social) of two groups of Black female college athletes at a Division I historically Black college and /university (HBCU). Utilizing sense of belonging theory, the current study explored how Black female college athletes navigate their experiences and manage their multiple identities (race, gender, athletic status, etc.) at a Division I HBCU. Two focus groups, seven individual interviews, and an eight-item demographic questionnaire were administered to ten participants (n = 10). Key findings highlighted participants' diverse college experiences. Implications for policy and practice are discussed.

• Fatigue is associated with impaired clinician performance and safety. • Exposure to the retrieval environment did not significantly increase the reaction times. This study aimed to assess whether undertaking retrieval was associated with fatigue independent of sleep and circadian disruption. It also aimed to assess the feasibility of routinely measuring the psychomotor vigilance test (PVT) on neonatal transport. Fatigue is associated with impaired clinician performance and safety. The association between shift work, sleep deprivation, and circadian disruption is well established. No studies have specifically assessed the independent effect of the retrieval environment on fatigue. Medical and nursing staff of the neonatal retrieval team were prospectively recruited over a 12-month period. Simple reaction times (RTs) were recorded at the start and end of a day shift using a validated 3-minute PVT. The end-of-shift RT increased (not significant) by 6.38 milliseconds (95% confidence interval [CI], −2.17 to 14.92 milliseconds; P =.149) when retrieval was undertaken. A 1-millisecond increase in RT increased the odds of being in a subjective sleepy category by 0.57% (95% CI, 0.0036-0.0078; P <.001). Consuming caffeine during the shift increased the mean RT by 16.26 milliseconds (95% CI, 4.43-28.1 milliseconds; P <.01). The RT of participants exposed to the retrieval environment was not significantly increased. Further studies are needed to consolidate these results as well as to further assess longer-range air medical retrievals. [ABSTRACT FROM AUTHOR]

This study was designed to determine if providing wheat, corn, and rice as whole (WG) or refined grains (RG) under free-living conditions will change parameters of health over a six-week intervention in healthy, habitual non-WG consumers. Measurements of body composition, fecal microbiota, fasting blood glucose, total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides were made at baseline and post intervention. Subjects were given adequate servings of either WG or RG products based on their caloric need and asked to keep records of grain consumption, bowel movements, and GI symptoms weekly. After six weeks, subjects repeated baseline testing. Significant decreases in total, LDL, and non-HDL cholesterol were seen after the WG treatments but were not observed in the RG treatment. During Week 6, bowel movement frequency increased with increased WG consumption. No significant differences in microbiota were seen between baseline and post intervention, although, abundance of order Erysipelotrichales increased in RG subjects who ate more than 50% of the RG market basket products. Increasing consumption of WGs can alter parameters of health, but more research is needed to better elucidate the relationship between the amount consumed and the health-related outcome.

The purpose of this study was to examine the perceptions and experiences of Black women college athletes at a Division I historically White institution (HWI) to understand their role negotiation processes. There is a need to explore the experiences of Black women college athletes in Olympic sports along with their same race peers in high-profile sports to ensure the professed National Collegiate Athletic Association (NCAA) mission is being fulfilled for all college athletes regardless of their race, gender, and sport and specifically related to their academic experiences and outcomes. The current study fills this gap. Data collection methods included a focus group interview with four participants, two individual interviews, and an 8-item demographic questionnaire. Priori intersectionality, psychological identity, and college student development theories were incorporated to highlight key aspects of participants' lived experiences in college. Findings revealed participants' experiences with role conflict, athletic identity foreclosure, and social isolation. Implications for policy and practice are discussed.

The purpose of this study was to examine the impact of a holistic development support program at Division I historically White institution (HWI) on Black male former college athletes' pre- and post-graduation experiences and outcomes. Previous research has documented the myriad of challenges facing Black male college athletes at Division I HWIs including exposure to exploitive athletic sub-cultures, stigmatizing campus climates, and a general lack of support for their psychosocial, personal, and professional development. In response to these disconcerting trends, culturally relevant support programs have been created to address the unique needs of this sub-group. This qualitative case study involved 14 semi-structured individual interviews with seven Black male former college athletes who participated in a culturally relevant holistic development (CRHD) support program. Using the strategic responsiveness to interest convergence (SRIC) theory and the excellence beyond athletics (EBA) framework, key findings revealed participants' involvement resulted in a range of personal and professional benefits both during and after college. Implications for policies and practices are discussed.

Purpose: Black and Latino males face challenges to college-going that may alter their decision to attend college. However, many Black and Latino males have successfully enrolled and matriculated through college. This study aims to explore the precollege factors that influenced the college enrollment and persistence for first generation Black and Latino male collegians (N = 5) at a predominantly white institution located in the Northeastern area of the USA. Two major themes (i.e., pre-college barriers and pre-college facilitators) along with several subthemes emerged from the data. The authors discuss recommendations for teachers, school counselors, and administrators in assisting Black and Latino males prepare for enrollment and persistence in college. Design/methodology/approach: A qualitative approached was used for this research study. A focus group was incorporated because it enabled participants to discuss their experiences in a single setting with other participants with similar backgrounds and thus through contrast and group dialogue vital insights related the phenomena of interest can be identified (Kitzinger, 1995). Individual interviews were conducted to engage in a more in-depth data collection process with the participants in a one-one-setting. Findings: Pre-college barriers and pre-college facilitators were the major themes of this research study. The subthemes originated from the frameworks of Community Cultural Wealth (Yosso, 2005) and Constellation Mentoring (Kelly and Dixon, 2014). Originality/value: The paper will contribute to the research literature, as the authors are exploring the experiences of Black male collegians from a Northeastern PWI. There is a dearth of literature in this area of research.

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.