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Objective: Examine the concordance of perceived operative autonomy between attendings and resident trainees., Design: Faculty and trainees rated trainee operative autonomy using the 4-level Zwisch scale over a variety of cases and training years. The respective ratings were then compared to explore the effects of experience, gender, case complexity, trainee, trainer, and other covariates to perceived autonomy., Setting: This study was conducted over 14 general surgery programs in the United States, members of the Procedural Learning and Safety Collaborative., Participants: Participants included faculty and categorical trainees from 14 general surgery programs., Results: A total of 8681 observations was obtained. The sample included 619 unique residents and 457 different attendings. A total of 598 distinct procedures was performed. In 60% of the cases, the autonomy ratings between trainees and attendings were concordant, with only 3.5% of cases discrepant by more than 1 level. An autonomy perception gap was modeled based on the discrepancy between the trainee and attending Zwisch ratings for the same case. The mean Zwisch score expected for a trainee was lower than the attending across all scenarios. Trainees were more likely to perceive relatively more autonomy in the second half of the year. The autonomy perception gap decreased with increasing case complexity. As trainees gained experience, the perception gap increased with trainees underestimating autonomy., Conclusions: Trainees and attendings generally demonstrated concordance on autonomy perception scores. However, in 40% of cases, a perception gap exists between trainee and attending with the trainee generally underestimating autonomy. The gap worsens as the trainee progresses through residency. This perception gap suggests that attendings and trainees could be better aligned on teaching goals and expectations., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To assess whether the fixation method and vitamin D supplementation affect the risk of patient-important outcomes within 12 months of injury in nongeriatric femoral neck fracture patients., Design: A pilot factorial randomized controlled trial., Setting: Fifteen North American clinical sites., Participants: Ninety-one adults 18-60 years of age with a femoral neck fracture requiring surgical fixation., Intervention: Participants were randomized to a surgical intervention (sliding hip screw or cancellous screws) and a vitamin D intervention (vitamin D3 4000 IU daily vs. placebo for 6 months)., Main Outcome Measurements: The primary clinical outcome was a composite of patient-important complications (reoperation, femoral head osteonecrosis, severe femoral neck malunion, and nonunion). Secondary outcomes included fracture-healing complications and radiographic fracture healing., Results: Eighty-six participants with a mean age of 41 years were included. We found no statistically significant difference in the risk of patient-important outcomes between the surgical treatment arms (hazard ratio 0.90, 95% confidence interval 0.40-2.02, P = 0.80) and vitamin D supplementation treatment arms (hazard ratio 0.96, 95% confidence interval 0.42-2.18, P = 0.92)., Conclusions: These pilot trial results continue to describe the results of current fixation implants, inform the challenges of improving outcomes in this fracture population, and may guide future vitamin D trials to improve healing outcomes in young fracture populations. Although the pilot trial was not adequately powered to detect treatment effects, publishing these results may facilitate future meta-analyses on this topic., Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Statement: Rapid-cycle deliberate practice (RCDP) is a learner-centered simulation instructional strategy that identifies performance gaps and targets feedback to improve individual or team deficiencies. Learners have multiple opportunities to practice observational, deductive, decision-making, psychomotor, and crisis resource management skills. As its implementation grows, simulationists need to have a shared mental model of RCDP to build high-quality RCDP-based initiatives. To compare and make general inferences from RCDP data, each training needs to follow a similar structure. This article seeks to describe the fundamentals of RCDP, including essential components and potential variants. We also summarize the current published evidence regarding RCDP's effectiveness. This article serves to create a shared understanding of RCDP, provide clear definitions and classifications for RCDP research, and provide options for future RCDP investigation.

Purpose Gradual and sudden perturbations of vocal fundamental frequency ( f o ), also known as adaptive and reflexive f o perturbations, are techniques to study the influence of auditory feedback on voice f o control mechanisms. Previous vocal f o perturbations have incorporated varied setup-specific feedback delays and amplifications. Here, we investigated the effects of feedback delays (10-100 ms) and amplifications on both adaptive and reflexive f o perturbation paradigms, encapsulating the variability in equipment-specific delays (3-45 ms) and amplifications utilized in previous experiments. Method Responses to adaptive and reflexive f o perturbations were recorded in 24 typical speakers for four delay conditions (10, 40, 70, and 100 ms) or three amplification conditions (-10, +5, and +10 dB relative to microphone) in a counterbalanced order. Repeated-measures analyses of variance were carried out on the magnitude of f o responses to determine the effect of feedback condition. Results There was a statistically significant effect of the level of auditory feedback amplification on the response magnitude during adaptive f o perturbations, driven by the difference between +10- and -10-dB amplification conditions (hold phase difference: M = 38.3 cents, SD = 51.2 cents; after-effect phase: M = 66.1 cents, SD = 84.6 cents). No other statistically significant effects of condition were found for either paradigm. Conclusions Experimental equipment delays below 100 ms in behavioral paradigms do not affect the results of f o perturbation paradigms. As there is no statistically significant difference between the response magnitudes elicited by +5- and +10-dB auditory amplification conditions, this study is a confirmation that an auditory feedback amplification of +5 dB relative to microphone is sufficient to elicit robust compensatory responses for f o perturbation paradigms.

A growing number of studies make claims about canine sociability in both applied and basic contexts. Yet, there is currently no standard for measuring sociability in dogs. The purpose of this two-part study was to determine whether procedural differences among canine sociability tests would affect dogs' behavior. In Experiment 1, we used a mixed-subjects design to assess whether experimenter position (standing, sitting, or kneeling) and presence of affection (petting and praise or none) affected leashed dogs' social behavior. Mixed-effect logistic regression modeling showed statistically significant main effects and interactions between posture and social contact. On average, dogs were more social when the experimenter knelt and provided social contact. However, there were individual differences in how dogs were affected by changes in procedure. In Experiment 2, we examined correspondence between leashed and unleashed dogs' social behaviors including time in proximity, following patterns, eye gaze, body orientation, jumping, and touching. Individual differences were examined by calculating a binomial mixed-effect logistic regression with condition (leashed, off-leash, following) and subject ID as fixed effects. Interactions were statistically significant for all behaviors, indicating that individual differences were present. The results have implications for the validity of sociability tests., Competing Interests: Declaration of Competing Interest The authors declare no competing interests, financial or otherwise., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To characterize hemodynamic alterations occurring during diabetic ketoacidosis (DKA) in a large cohort of children and to identify clinical and biochemical factors associated with hypertension., Study Design: This was a planned secondary analysis of data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in DKA Study, a randomized clinical trial of fluid resuscitation protocols for children in DKA. Hemodynamic data (heart rate, blood pressure) from children with DKA were assessed in comparison with normal values for age and sex. Multivariable statistical modeling was used to explore clinical and laboratory predictors of hypertension., Results: Among 1258 DKA episodes, hypertension was documented at presentation in 154 (12.2%) and developed during DKA treatment in an additional 196 (15.6%), resulting in a total of 350 DKA episodes (27.8%) in which hypertension occurred at some time. Factors associated with hypertension at presentation included more severe acidosis, (lower pH and lower pCO 2 ), and stage 2 or 3 acute kidney injury. More severe acidosis and lower Glasgow Coma Scale scores were associated with hypertension occurring at any time during DKA treatment., Conclusions: Despite dehydration, hypertension occurs in a substantial number of children with DKA. Factors associated with hypertension include greater severity of acidosis, lower pCO 2, and lower Glasgow Coma Scale scores during DKA treatment, suggesting that hypertension might be centrally mediated., (Copyright © 2020 Elsevier Inc. All rights reserved.)

To test the hypothesis that multiple integrated root phenotypes would co-optimize drought tolerance, we phenotyped the root anatomy and architecture of 400 mature maize ( Zea mays ) genotypes under well-watered and water-stressed conditions in the field. We found substantial variation in all 23 root phenes measured. A phenotypic bulked segregant analysis revealed that bulks representing the best and worst performers in the field displayed distinct root phenotypes. In contrast to the worst bulk, the root phenotype of the best bulk under drought consisted of greater cortical aerenchyma formation, more numerous and narrower metaxylem vessels, and thicker nodal roots. Partition-against-medians clustering revealed several clusters of unique root phenotypes related to plant performance under water stress. Clusters associated with improved drought tolerance consisted of phene states that likely enable greater soil exploration by reallocating internal resources to greater root construction (increased aerenchyma content, larger cortical cells, fewer cortical cell files), restrict uptake of water to conserve soil moisture (reduced hydraulic conductance, narrow metaxylem vessels), and improve penetrability of hard, dry soils (thick roots with a larger proportion of stele, and smaller distal cortical cells). We propose that the most drought-tolerant-integrated phenotypes merit consideration as breeding ideotypes., (© 2020 American Society of Plant Biologists. All Rights Reserved.)

Simulation has been utilized widely in nurse practitioner programs for competency development and training. With the growing number of online educational programs, innovative solutions need to be developed to assess student competency for a variety of clinical situations and scenarios. An innovative method is the implementation of telepresence robots for multiple patient scenarios in a simulated environment. This article demonstrates the use of multiple patient scenarios using telepresence robots in an online post master's acute care pediatric nurse practitioner program.

Background: Exposure to adverse social factors has been associated with an altered inflammatory profile, a risk factor for several acute and chronic diseases. Differential gene expression may be a biological mediator in the relationship. In this study, associations between a range of social factors and expression of inflammation-related genes were investigated., Methods: Social factor and gene expression data were collected from 1,264 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA). Inflammation-related genes were identified from the Gene Ontology database. The associations between social factors and gene expression were first assessed using the Global Analysis of Covariance (Global ANCOVA) gene set enrichment test. When the global test was significant, linear regression and elastic net penalized regression were employed to identify the individual gene transcripts within each gene set associated with the social factor., Results: Loneliness (p = 0.003), chronic burden (p = 0.002), and major or lifetime discrimination (p = 0.045) were significantly associated with global expression of the chronic inflammatory gene set. Of the 20 transcripts that comprise this gene set, elastic net selected 12 transcripts for loneliness, 8 for chronic burden, and 3 for major or lifetime discrimination. Major or lifetime discrimination was also associated with the inflammatory response (p = 0.029), regulation of the inflammatory response (p = 0.041), and immune response (p = 0.025) gene sets in global analyses, and 53, 136, and 26 transcripts were selected via elastic net for these gene sets respectively. There were no significant associations in linear regression analyses after adjustment for multiple testing., Conclusions: This study highlights gene expression as a biological mechanism through which social factors may affect inflammation., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020. Published by Elsevier Ltd.)

Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.

Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAF V600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.

Root phenotypes regulate soil resource acquisition; however, their genetic control and phenotypic plasticity are poorly understood. We hypothesized that the responses of root architectural phenes to water deficit (stress plasticity) and different environments (environmental plasticity) are under genetic control and that these loci are distinct. Root architectural phenes were phenotyped in the field using a large maize association panel with and without water deficit stress for three seasons in Arizona and without water deficit stress for four seasons in South Africa. All root phenes were plastic and varied in their plastic response. We identified candidate genes associated with stress and environmental plasticity and candidate genes associated with phenes in well-watered conditions in South Africa and in well-watered and water-stress conditions in Arizona. Few candidate genes for plasticity overlapped with those for phenes expressed under each condition. Our results suggest that phenotypic plasticity is highly quantitative, and plasticity loci are distinct from loci that control phene expression in stress and non-stress, which poses a challenge for breeding programs. To make these loci more accessible to the wider research community, we developed a public online resource that will allow for further experimental validation towards understanding the genetic control underlying phenotypic plasticity., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Purpose: Visits to pediatric emergency departments (EDs) are increasing, leading to overcrowding, prolonged patient wait times, and negative patient experiences. In our system, these prolonged wait times and negative experiences notably impact mid-acuity patients. As such, we sought to decrease their time-to-first-provider from 92 to 60 minutes., Methods: After identifying inefficiencies in patient arrival, triage, and assessment, we redesigned our physical space and implemented a new triage process. Further, we deployed a new multidisciplinary front-end team consisting of a physician, nurses, and ED tech specialists to create and implement an initial management plan. Time-to-first-provider for mid-acuity patients was the main outcome measure. We examined ED length of stay (LOS) as a balancing measure. Post hoc, we measured time-to-first-nursing assessment and the proportion of high-acuity patients seen within 20 minutes as additional measures of the impact of these interventions on our system. All analyses were measured using statistical process control charts., Results: During high patient volumes, we decreased the time-to-first-provider to 70 minutes, but exceeded our goal during low patient volumes (41 minutes). We observed a 5% decrease in LOS during both high and low patient volumes (5% and 8%, respectively). There was a 60% increase in the time-to-first-nursing assessment., Conclusions: A new front-end process resulted in improved time-to-first-provider and LOS. The new process was associated with longer times for nursing assessments but did not negatively impact the rapid physician assessment of higher acuity patients., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: To conduct a pilot trial for the Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2) protocol to assess feasibility of a definitive trial., Design: Pilot trial., Setting: Twenty-five clinical sites across North America and Australia were initiated, but enrolment occurred in only 15 North American sites., Patients/participants: Ninety-one randomized adults aged 18 to 60 years with a femoral neck fracture requiring surgical fixation., Intervention: Eligible patients were randomized to receive surgical treatment (sliding hip screw or cancellous screws) AND nutritional supplementation (4000 IU of vitamin D or placebo) for 6 months postfracture., Main Outcome Measurements: Feasibility outcomes included: clinical site initiation, participant enrolment rate, proportion of participants with complete 12-month follow-up, level of data quality, and rate of protocol adherence (number of randomization errors, crossovers between treatment groups, and daily supplementation adherence)., Results: Eighty-six of 91 participants randomized into the pilot trial from 15 North American hospitals were deemed eligible. Four of five primary feasibility criteria were not achieved as we were unable to initiate clinical sites outside of North America and Australia due to feasibility constraints, slow participant enrolment (60 participants recruited over 36 mo), low adherence with daily nutritional supplementation at the 6-week (72.1%), 3-month (60.5%), and 6-month (54.7%) follow-up visits, and a high loss to follow-up rate of 22.1% at 12 months., Conclusions: Despite not meeting key feasibility criteria, we increased our knowledge on the logistics and anticipated barriers when conducting vitamin D supplementation trials in this trauma population, which can be used to inform the design and conduct of future trials on this topic., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type-specific genes extracted from genome-wide methylation arrays. Unsupervised clustering identified three immune methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss-of-function events for melanomas unresponsive to immunotherapies (immune-low). To understand whether melanoma tumors resemble other solid tumors in terms of immune methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low-dimensional projection based on immune cell type-specific methylation revealed grouping of the solid tumors in line with melanoma immune methylation clusters rather than tumor types. Association of survival outcome with immune cell type-specific methylation differed across tumor and cell types. However, in melanomas immune cell type-specific methylation was associated with inferior patient survival. Exploration of the immune methylation patterns in a pan-cancer context suggested that specific immune microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

The original version of this article unfortunately contained a mistake. Supplementary Tables 3 and 4 are not available with the rest of the supplementary material available online.

Phenomenon: Given the growing number of medical science educators, an examination of institutions' promotion criteria related to educational excellence and scholarship is timely. This study investigates the extent to which medical schools' promotion criteria align with published standards for documenting and evaluating educational activities. Approach: This document analysis systematically analyzed promotion and tenure (P&T) guidelines from U.S. medical schools. Criteria and promotion expectations (related to context, quantity, quality, and engagement) were explored across five educational domains including: (i) teaching, (ii) curriculum/program development, (iii) mentoring/advising, (iv) educational leadership/administration, and (v) educational measurement and evaluation, in addition to research/scholarship and service. After independent review and data extraction, paired researchers compared findings and reached consensus on all discrepancies prior to final data submission. Descriptive statistics assessed the frequency of referenced promotion criteria. Findings: Promotion-related documents were retrieved from 120 (of 185) allopathic and osteopathic U.S. medical schools. Less than half of schools (43%; 52 of 120) documented a well-defined education-related pathway for advancement in academic rank. Across five education-specific domains, only 24% (12 of 50) of the investigated criteria were referenced by at least half of the schools. The least represented domain within P&T documents was "Educational Measurement and Evaluation." P&T documents for 47% of schools were rated as "below average" or "very vague" in their clarity/specificity. Insights: Less than 10% of U.S. medical schools have thoroughly embraced published recommendations for documenting and evaluating educational excellence. This raises concern for medical educators who may be evaluated for promotion based on vague or incomplete promotion criteria. With greater awareness of how educational excellence is currently documented and how promotion criteria can be improved, education-focused faculty can better recognize gaps in their own documentation practices, and more schools may be encouraged to embrace change and align with published recommendations.

Objective: To describe the relationship between statewide pediatric facility recognition (PFR) programs and pediatric readiness in emergency departments (EDs) in the US., Study Design: Data were extracted from the 2013 National Pediatric Readiness Project assessment (4083 EDs). Pediatric readiness was assessed using the weighted pediatric readiness score (WPRS) based on a 100-point scale. Descriptive statistics were used to compare WPRS between recognized and nonrecognized EDs and between states with or without a PFR program. A linear mixed model with WPRS was used to evaluate state PFR programs on pediatric readiness., Results: Eight states were identified with a PFR program. EDs in states with a PFR program had a higher WPRS compared with states without a PFR program (overall a 9.1-point higher median WPRS; P < .001); EDs recognized in a PFR program had a 21.7-point higher median WPRS compared with nonrecognized EDs (P < .001); and between states with a statewide PFR program, there was high variability of participation within the states. We found state-level PFR programs predicted a higher WPRS compared with states without a PFR program (β = 5.49; 95% CI 2.76-8.23)., Conclusions: Statewide PFR programs are based on national guidelines and identify those EDs that adhere to a standard level of readiness for children. These statewide PFR initiatives are associated with higher pediatric readiness. As scalable strategies are needed to improve emergency care for children, our study suggests that statewide PFR programs may be one way to improve pediatric readiness and underscores the need for further implementation and evaluation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Pediatric patients who develop acute kidney injury (AKI) while hospitalized have longer hospital stays, increased morbidity and mortality, and are at an increased risk for developing chronic kidney disease. Early recognition of AKI is becoming a major clinical focus. There is little research focusing on nursing interventions that may affect a pediatric patient's risk for developing AKI. The purpose of this review is to summarize reported predictors of AKI to improve its early recognition and treatment among hospitalized pediatric patients., Methods: A review of research was conducted to further identify risk factors of AKI among noncritically ill hospitalized pediatric patients., Results: The current literature demonstrated inconsistent findings in early recognition of AKI among hospitalized pediatric patients., Discussion: Interventions for early recognition and treatment of AKI should consider other variables, such as previous history of AKI and fluid status as risk factors, warranting additional research., (Copyright © 2019 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 × 10 -06 ) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 × 10 -04 ) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.

Animal shelters must incorporate empirically validated programs to increase life-saving measures; however, altering existing protocols is often a challenge. The current study assessed the feasibility of nine animal shelters within the United States to replicate a validated procedure for introducing an adoptable dog with a potential adopter (i.e., "meet-and-greet") following an educational session. Each of the shelters were first entered into the "baseline" condition, where introduction between adoptable dogs and potential adopters were as usual. After a varying number of months, each shelter entered into the "experimental" phase, where staff and volunteers were taught best practices for a meet-and-greet using lecture, demonstration, and role-play. Data on the likelihood of adoption following a meet-and-greet were collected with automated equipment installed in meet-and-greet areas. Data on feasibility and treatment integrity were collected with questionnaires administered to volunteers and staff followed by a focus group. We found that a single educational session was insufficient to alter the meet-and-greet protocol; challenges included not remembering the procedure, opposing opinions of volunteers and staff, lack of resources, and a procedural drift effect in which the protocol was significantly altered across time. In turn, no animal shelters increased their dog adoptions in the "experimental" phase. New research is needed to develop effective educational programs to encourage animal shelters to incorporate empirical findings into their protocols.

Micronemes are specialized secretory organelles present in all motile forms of apicomplexan parasites. Microneme vesicles hold adhesins and other proteins that are secreted to facilitate parasite attachment, invasion of host cells, and egress following replication-all processes indispensable for cell-to-cell transmission of these obligate intracellular parasites. Defining the signaling pathways that lead to microneme secretion is an important part of understanding the infectious cycle of apicomplexan parasites. However, the classical method of measuring microneme secretion by immunoblotting for microneme proteins in parasite excreted/secreted antigen (ESA) preparations is low-throughput and only semiquantitative. We recently reported a new luciferase-based method for measuring microneme secretion in a 96-well format with high sensitivity in the model apicomplexan Toxoplasma gondii. Here, we aim to elaborate on this detection method and review current practices for stimulating microneme secretion in vitro.

Background and Purpose: Nurse practitioners (NPs) perform diagnostic and clinical procedure skills in the acute, specialty, urgent, and primary care settings. Nurse practitioners surveyed on readiness for practice report a lack of confidence and education preparation for performing selected advanced diagnostic and skills. As NPs gain independent, full practice scope, it is imperative advanced diagnostic and procedure skills used in practice are taught in nurse practitioner curriculum. The purpose of this review is to document a systematic review of the literature, answering the following question: Among primary care NPs, does current program curriculum align with current procedures and skills in theclinical setting?, Methods: PubMed, Cochrane, Scopus, CINAHL, and Embase were searched between inception and 2018 using the search terms "advanced practice nursing, clinical competence, diagnostic techniques or procedures, and primary health care." Following the preferred reporting items for systematic reviews and meta-analysis guidelines, nine articles were included in the synthesis., Conclusion: There is scant research regarding NP educational preparation of skills and procedures. Study findings indicate that programs are not teaching all the procedures deemed important. Education should promote improved congruence between the skills and procedures taught in program curricula and those used in clinical practice., Implications for Practice: It is critical to complete an education practice survey measuring skill and procedure preparation and competency at graduation. Survey results will determine whether skill and procedure guidelines are indicated for NP education. A recommendation may include minimal skills and procedure for all nurse practitioner curricula.

Root anatomical phenotypes vary among maize (Zea mays) cultivars and may have adaptive value by modifying the metabolic cost of soil exploration. However, the microbial trade-offs of these phenotypes are unknown. We hypothesized that nodal roots of maize with contrasting cortical anatomy have different patterns of mutualistic and pathogenic fungal colonization. Arbuscular mycorrhizal colonization in the field and mesocosms, root rots in the field, and Fusarium verticillioides colonization in mesocosms were evaluated in maize genotypes with contrasting root cortical anatomy. Increased aerenchyma and decreased living cortical area were associated with decreased mycorrhizal colonization in mesocosm and field experiments with inbred genotypes. In contrast, mycorrhizal colonization of hybrids increased with larger aerenchyma lacunae; this increase coincided with larger root diameters of hybrid roots. F. verticillioides colonization was inversely correlated with living cortical area in mesocosm-grown inbreds, and no relation was found between root rots and living cortical area or aerenchyma in field-grown hybrids. Root rots were positively correlated with cortical cell file number and inversely correlated with cortical cell size. Mycorrhizae and root rots were inversely correlated in field-grown hybrids. We conclude that root anatomy is associated with differential effects on pathogens and mycorrhizal colonization of nodal roots in maize., (© 2019 John Wiley & Sons Ltd.)

For most general dentists, direct resin composite restorations are mainstay procedures performed on a daily basis in their practice. As patients become more cognizant of the conservative nature of composites, they are increasingly demanding these types of minimally invasive restorations, especially in the anterior segment when chipped incisal edges, interproximal decay, or space discrepancies are involved. Over the past several decades dental manufacturers have developed a broad spectrum of composite materials to meet these demands, all of which feature varying characteristics. A new composite resin utilizes a single shade capable of matching any tooth, thus dramatically impacting the manner in which clinicians may approach direct composite restorations regarding time, costs, and ease of use.

Objective: The aim of this study was to determine the psychometric properties of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) 2-question alcohol screen within 16 Pediatric Emergency Care Applied Research Network pediatric emergency departments. This article describes the study methodology, sample characteristics, and baseline outcomes of the NIAAA 2-question screen., Methods: Participants included 12- to 17-year-olds treated in one of the participating pediatric emergency departments across the United States. After enrollment, a criterion assessment battery including the NIAAA 2-question screen and other measures of alcohol, drug use, and risk behavior was self-administered by participants on a tablet computer. Two subsamples were derived from the sample. The first subsample was readministered the NIAAA 2-question screen 1 week after their initial visit to assess test-retest reliability. The second subsample is being reassessed at 12 and 24 months to examine predictive validity of the NIAAA 2-question screen., Results: There were 4834 participants enrolled into the study who completed baseline assessments. Participants were equally distributed across sex and age. Forty-six percent of the participants identified as white, and 26% identified as black. Approximately one quarter identified as Hispanic. Using the NIAAA 2-question screen algorithm, approximately 8% were classified as low risk, 12% were classified as moderate risk, and 4% were classified as highest risk. Alcohol use was less likely to be reported by black participants, non-Hispanic participants, and those younger than 16 years., Discussion: This study successfully recruited a large, demographically diverse sample to establish rates of the NIAAA screen risk categories across age, sex, ethnicity, and race within pediatric emergency departments.

Children's repair of conflict with parents may be particularly challenging in maltreating families, and early, stressful parent-child interactions may contribute to children's altered neurobiological regulatory systems. To explore neurobiological signatures of repair processes, we examined whether mother and child individual and dyadic respiratory sinus arrhythmia (RSA) covaried with interactive repair differently in maltreating versus nonmaltreating mother-preschooler dyads ( N = 101), accounting for whether repair was mother or child initiated. Mother-initiated repair was equally frequent and protective across groups, associated with no change in mother or child RSA at higher levels of repair. But lower levels of mother repair were associated with child RSA withdrawal in nonmaltreating dyads versus child RSA augmentation in maltreating dyads. In maltreating dyads only, higher child-initiated repair was associated with higher mean mother RSA, whereas lower child repair was associated with mother RSA withdrawal. Findings suggest that interactive repair may have a buffering effect on neurobiological regulation but also that maltreating mothers and children show atypical neurobiological response to interpersonal challenges including differences related to children conducting the work of interactive repair that maltreating parents are less able to provide. We conclude by considering the role of maladaptive parent-child relationship processes in the biological embedding of early adversity.

Individual variability is evident in behavior and physiology of animals. Determining whether behavior at intake may predict subsequent illness in the animal shelter may influence the management of dogs housed at animal shelters and reduce overall disease. While normally associated with mild disease and low mortality rates, respiratory disease nevertheless poses significant challenges to the management of dogs in the stressful environment of animal shelters due to its highly infectious nature. Therefore, the aim of the study was to explore whether behavior at intake can predict subsequent occurrence and progression of upper respiratory disease in dogs at animal shelters. In a correlational study, 84 dogs were assessed throughout their stay at a city animal shelter. The dogs were subjected to a behavioral assessment, 1 min in-kennel behavioral observations across two observation periods, and the collection of urinary cortisol:creatinine (C:C) ratio. The occurrence and progression of upper respiratory disease was monitored through repeated clinical exams (rectal temperature and the occurrence of nasal and ocular discharge, and presence of coughing and sneezing). A basic PLS Path regression model revealed that time in the shelter (estimate = .53, p < .001), and sociability (estimate = .24, p < .001) and curiosity scores (estimate = .09, p = .026) were associated with increased illness. Activity and anxiety scores, however, were not associated with illness. Urinary C:C, taken on the first full day, did not predict subsequent illness when accounting for time. Limitations included attrition of dogs, a small percentage receiving vaccinations, and continuous and non-systematic rotation of dogs in the kennels. Understanding if behavior can predict subsequent illness may improve shelter management practices, and in turn, result in improved live-release outcomes., Competing Interests: The authors have declared that no competing interests exist.

BRAF fusions are detected in numerous neoplasms, but their clinical management remains unresolved. We identified six melanoma lines harboring BRAF fusions representative of the clinical cases reported in the literature. Their unexpected heterogeneous responses to RAF and MEK inhibitors could be categorized upon specific features of the fusion kinases. Higher expression level correlated with resistance, and fusion partners containing a dimerization domain promoted paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, next-generation αC-IN/DFG-OUT RAF inhibitors blunted paradoxical activation across all lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors, opening perspectives in the clinical management of tumors harboring BRAF fusions., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Root phenotypes that improve nitrogen acquisition are avenues for crop improvement. Root anatomy affects resource capture, metabolic cost, hydraulic conductance, anchorage, and soil penetration. Cereal root phenotyping has centered on primary, seminal, and early nodal roots, yet critical nitrogen uptake occurs when the nodal root system is well developed. This study examined root anatomy across nodes in field-grown maize (Zea mays L.) hybrid and inbred lines under high and low nitrogen regimes. Genotypes with high nitrogen use efficiency (NUE) had larger root diameter and less cortical aerenchyma across nodes under stress than genotypes with lower NUE. Anatomical phenes displayed slightly hyperallometric relationships to shoot biomass. Anatomical plasticity varied across genotypes; most genotypes decreased root diameter under stress when averaged across nodes. Cortex, stele, total metaxylem vessel areas, and cortical cell file and metaxylem vessel numbers scaled strongly with root diameter across nodes. Within nodes, metaxylem vessel size and cortical cell size were correlated, and root anatomical phenotypes in the first and second nodes were not representative of subsequent nodes. Node, genotype, and nitrogen treatment affect root anatomy. Understanding nodal variation in root phenes will enable the development of plants that are adapted to low nitrogen conditions., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (OR male ) = 0.83 [95% CI = 0.78-0.89], P male  = 1.71 × 10 -8 compared with female odds ratio (OR female ) = 0.98 [95% CI = 0.90-1.07], P female  = 0.68) and 12q23.3 (intergenic, OR male  = 0.75 [95% CI = 0.68-0.83], P male  = 1.59 × 10 -8 compared with OR female  = 0.93 [95% CI = 0.82-1.06], P female  = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

The Fitzpatrick Skin Phototypes (FSP) were developed to classify skin color and response to ultraviolet radiation. FSP are used clinically to assess risk for sunburn and skin cancer. Our aim was to determine the criterion-related validity of self-reported FSP when compared with skin color and sunburn history, controlling for age, race/ethnicity, and seasonality/geography. We performed a secondary analysis of data (N=466) from an observational study. The racial/ethnic composition of the sample was 45% White/White Hispanic (WWH), 40% Black/Black Hispanic (BBH), and 15% Other Identities. Outcome measures were self-reported FSP and sunburn history, as well as physiological measures of skin color (L* lightness/darkness, a* redness/greenness, b* yellowness/blueness). Correlation between FSP and L* was -.77 (95% CI -.81, -.73; P<.001). Although 60% of the variance in FSP was accounted for by L* values for the entire sample, only 5% of the variance was accounted for among BBH participants ( r =-.23), and up to 30% for WWH/Other Identity participants ( r =-.48 and -.52). Multiple regression analysis indicated L* and b* values, sunburn history, and race/ethnicity, but not geography/seasonality or a* values significantly and collectively accounted for 72% of the variance in FSP. While the criterion validity of FSP was established by the strong relationship between L* values and FSP for the entire sample, when examined at the level of individual racial/ethnic subgroups, criterion validity of FSP was not demonstrated. When self-reported FSP are used for clinical skin assessment and sun cancer screening, they provide a restricted range of options for people with darker skin that does not capture variations in their skin color. Inaccuracy of clinical data may lead to unequal treatment or inadequate cancer risk assessment., Competing Interests: Competing Interests: None declared.

Background: Association studies in recently admixed populations are extremely useful to identify the genetic architecture of pigmentation, due to their high genotypic and phenotypic variation. However, to date only four Genome-Wide Association Studies (GWAS) have been carried out in these populations., Results: We present a GWAS of skin pigmentation in an admixed sample from Cuba (N = 762). Additionally, we conducted a meta-analysis including the Cuban sample, and admixed samples from Cape Verde, Puerto Rico and African-Americans from San Francisco. This meta-analysis is one of the largest efforts so far to characterize the genetic basis of skin pigmentation in admixed populations (N = 2,104). We identified five genome-wide significant regions in the meta-analysis, and explored if the markers observed in these regions are associated with the expression of relevant pigmentary genes in human melanocyte cultures. In three of the regions identified in the meta-analysis (SLC24A5, SLC45A2, and GRM5/TYR), the association seems to be driven by non-synonymous variants (rs1426654, rs16891982, and rs1042602, respectively). The rs16891982 polymorphism is strongly associated with the expression of the SLC45A2 gene. In the GRM5/TYR region, in addition to the rs1042602 non-synonymous SNP located on the TYR gene, variants located in the nearby GRM5 gene have an independent effect on pigmentation, possibly through regulation of gene expression of the TYR gene. We also replicated an association recently described near the MFSD12 gene on chromosome 19 (lead variant rs112332856). Additionally, our analyses support the presence of multiple signals in the OCA2/HERC2/APBA2 region on chromosome 15. A clear causal candidate is the HERC2 intronic variant rs12913832, which has a profound influence on OCA2 expression. This variant has pleiotropic effects on eye, hair, and skin pigmentation. However, conditional and haplotype-based analyses indicate the presence of other variants with independent effects on melanin levels in OCA2 and APBA2. Finally, a follow-up of genome-wide signals identified in a recent GWAS for tanning response indicates that there is a substantial overlap in the genetic factors influencing skin pigmentation and tanning response., Conclusions: Our meta-analysis of skin pigmentation GWAS in recently admixed populations provides new insights about the genetic architecture of this complex trait.

Black men suffer inequalities in health and health-care outcomes relative to other racial/ethnic groups, requiring well-informed efforts for health promotion. Fewer Black men have a usual source of health care, which may be a contributor to these disparities. Increasing access to and the likelihood of a usual source of care among Black men are important to address health and health-care disparities. In this focus group study, we sought to better understand how Black men think about primary care and usual sources of care. A total of six focus groups were conducted with N = 25 men. Groups were a mix of men with and without a usual source of care. Several themes were identified through analysis of the data regarding factors that contribute to Black men going to the doctor. Themes identified in the data analysis included Lack of Health Insurance as a Barrier to Establishing Usual Source of Care; Family Promoting Health Care Use; Relationship With Doctor, Trust, and Empowerment; Age and Maturity in Health Promotion; and Positive Tone of Messaging. Future research should explore if similar findings are obtained among men in different regions of the United States or between Black men of different backgrounds. Taking a step beyond this research, specifically, future research can also examine the impact of particular health messages/messaging on Black men's health-care-seeking behaviors.

Background: Gene expression may be an important biological mediator in associations between social factors and health. However, previous studies were limited by small sample sizes and use of differing cell types with heterogeneous expression patterns. We use a large population-based cohort with gene expression measured solely in monocytes to investigate associations between seven social factors and expression of genes previously found to be sensitive to social factors., Methods: We employ three methodological approaches: 1) omnibus test for the entire gene set (Global ANCOVA), 2) assessment of each association individually (linear regression), and 3) machine learning method that performs variable selection with correlated predictors (elastic net)., Results: In global analyses, significant associations with the a priori defined socially sensitive gene set were detected for major or lifetime discrimination and chronic burden (p = 0.019 and p = 0.047, respectively). Marginally significant associations were detected for loneliness and adult socioeconomic status (p = 0.066, p = 0.093, respectively). No associations were significant in linear regression analyses after accounting for multiple testing. However, a small percentage of gene expressions (up to 11%) were associated with at least one social factor using elastic net., Conclusion: The Global ANCOVA and elastic net findings suggest that a small percentage of genes may be "socially sensitive," (i.e. demonstrate differential expression by social factor), yet single gene approaches such as linear regression may be ill powered to capture this relationship. Future research should further investigate the biological mechanisms through which social factors act to influence gene expression and how systemic changes in gene expression affect overall health., Competing Interests: The authors have declared that no competing interests exist.

Background: There are concerns that non-anatomical resection (NAR) worsens perioperative and oncological outcomes compared with those following anatomical resection (AR) for colorectal liver metastases (CRLM). Most previous studies have been biased by the effect of tumour size. The aim of this study was to compare oncological outcomes after NAR versus AR., Methods: This was a retrospective study of consecutive patients who underwent CRLM resection with curative intent from 1999 to 2016. Data were retrieved from a prospectively developed database. Survival and perioperative outcomes for NAR and AR were compared using propensity score analyses., Results: Some 358 patients were included in the study. Median follow-up was 34 (i.q.r. 16-68) months. NAR was associated with significantly less morbidity compared with AR (31·1 versus 44·4 per cent respectively; P  = 0·037). Larger (hazard ratio (HR) for lesions 5 cm or greater 1·81, 95 per cent c.i. 1·13 to 2·90; P  = 0·035) or multiple (HR 1·48, 1·03 to 2·12; P  = 0·035) metastases were associated with poor overall survival (OS). Synchronous (HR 1·33, 1·01 to 1·77; P  = 0·045) and multiple (HR 1·51, 1·14 to 2·00; P  = 0·004) liver metastases, major complications after liver resection (HR 1·49, 1·05 to 2·11; P  = 0·026) or complications after resection of the primary colorectal tumour (HR 1·51, 1·01 to 2·26; P  = 0·045) were associated with poor disease-free survival (DFS). AR was prognostic for poor OS only in tumours smaller than 30 mm, and R1 margin status was not prognostic for either OS or DFS. NAR was associated with a higher rate of salvage resection than AR following intrahepatic recurrence., Conclusions: NAR has at least equivalent oncological outcomes to AR while proving to be safer. NAR should therefore be the primary surgical approach to CRLM, especially for lesions smaller than 30 mm.

Polyunsaturated fatty acids (PUFAs) are essential dietary components. They are not only used for energy, but also act as signaling molecules. The delta-6 desaturase (D6D) enzyme, encoded by the FADS2 gene, is one of two rate limiting enzymes that convert the PUFA precursors - α-linolenic (n-3) and linoleic acid (n-6) to their respective metabolites. Alterations in the D6D enzyme activity alters fatty acid profiles and are associated with metabolic and inflammatory diseases including cardiovascular disease and type 2 diabetes. Omega-3 PUFAs, specifically its constituent fatty acids DHA and EPA, are known for their anti-inflammatory ability and are also beneficial in the prevention of skeletal muscle wasting, however the mechanism for muscle preservation is not well understood. Moreover, little is known of the effects of altering the n-6/n-3 ratio in the context of a high-fat diet, which is known to downregulate protein synthesis. Twenty C57BL6 male mice were fed a high-fat lard (HFL, 45% fat (mostly lard), 35% carbohydrate and 20% protein, n-6:n-3 PUFA, 13:1) diet for 6 weeks. Mice were then divided into 4 groups (n = 5 per group): HFL- , high-fat oil- (HFO, 45% fat (mostly Menhaden oil), 35% carbohydrate and 20% protein, n-6:n-3 PUFA, 1:3), HFL+ (HFL diet plus an orally administered FADS2 inhibitor, 100 mg/kg/day), and HFO+ (HFO diet plus an orally administered FADS2 inhibitor, 100 mg/kg/day). After 2 weeks on their respective diets and treatments, animals were sacrificed and gastrocnemius muscle harvested. Protein turnover signaling were analyzed via Western Blot. 4-EBP1 and ribosomal protein S6 expression were measured. A two-way ANOVA revealed no significant change in the phosphorylation of both 4EBP-1 and ribosomal protein S6 with diet or inhibitor. There was a significant reduction in STAT3 phosphorylation with the inhibition of FADS2 (p = 0.03). Additionally, we measured markers of protein degradation through levels of FOXO phosphorylation, ubiquitin, and LC3B expression; there was a trend towards increased phosphorylation of FOXO (p = 0.08) and ubiquitinated proteins (p = 0.05) with FADS2 inhibition. LC3B expression, a marker of autophagy, was significantly higher in the HFL plus FADS2 inhibition group from all other comparisons. Lastly, we analyzed activation of mitochondrial biogenesis which is closely linked with protein synthesis through PGC1-α and Cytochrome-C expression, however no significant differences were associated with either marker across all groups. Collectively, these data suggest that the protective effects of muscle mass by omega-3 fatty acids are from inhibition of protein degradation. Our aim was to determine the role of PUFA metabolites, DHA and EPA, in skeletal muscle protein turnover and assess the effects of n-3s independently. We observed that by inhibiting the FADS2 enzyme, the protective effect of n-3s on protein synthesis and proliferation was lost; concomitantly, protein degradation was increased with FADS2 inhibition regardless of diet.

Background: Image-guided microwave ablation (MWA) is a technically demanding procedure, involving advanced visual-spatial perception skills. This study sought to create and evaluate a low-cost model and training curriculum for open ultrasound-guided liver tumor MWA., Methods: Simulated tumors were created, implanted into bovine livers, and visualized by ultrasound. A high-fidelity abdominal model was constructed, with a total cost of $30. Experienced physicians in MWA performed simulated ablations and evaluated the model. Expert performance metrics were established and served as targets for our training curriculum. These included time, number of passes, number of repositionings, and percentage of tumor ablated. Next, 8 novice trainees completed our deliberate practice curriculum. Participants' performances were recorded throughout., Results: Physicians completed a structured feedback questionnaire rating the model's realism and training utility at 8/10 and 10/10, respectively. Tumors appeared hyperechoic and were clearly visualized on ultrasound. Trainees performed a total of 32 ablations. Our trainees' performance improved significantly in all outcomes of interest in the postcurriculum ablations compared to precurriculum ablations., Conclusion: We have created a cost-effective, high-fidelity model of MWA, with a deliberate practice curriculum. Trainees can practice to proficiency with clear target metrics prior to participating in clinical cas., (Copyright © 2018 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The National Institute on Alcohol Abuse and Alcoholism (NIAAA) 2-question screen is a valid adolescent alcohol screening tool. No studies have examined if this tool predicts future alcohol problems. We conducted a study at 16 pediatric emergency departments to determine the tool's predictive validity for alcohol misuse and alcohol use disorders (AUDs)., Methods: Participants ( N = 4834) completed a baseline assessment battery. A subsample of participants completed the battery at 1, 2, and 3 years follow up., Results: Of the 2209 participants assigned to follow-up, 1611 (73%) completed a 1-year follow-up, 1591 (72%) completed a 2-year follow-up, and 1377 (62%) completed a 3-year follow-up. The differences in AUDs between baseline NIAAA screen nondrinkers and lower-risk drinkers were statistically significant at 1 year ( P = .0002), 2 years ( P <.0001), and 3 years ( P = .0005), as were the differences between moderate- and highest-risk drinkers at 1 and 2 years ( P < .0001 and P = .0088, respectively) but not at 3 years ( P = .0758). The best combined score for sensitivity (86.2% at 1 year, 75.6% at 2 years, and 60.0% at 3 years) and specificity (78.1% at 1 year, 79.2% at 2 years, and 80.0% at 3 years) was achieved by using "lower risk" and higher as a cutoff for the prediction of a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis., Conclusions: The NIAAA 2-question screen can accurately characterize adolescent risk for future AUDs. Future studies are needed to determine optimaluse of the screen., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Microneme (MIC) proteins play important roles in the recognition, adhesion, and invasion of host cells by Toxoplasma gondii Previous studies have shown that MIC proteins are highly immunogenic in the mouse and recognized by human serum antibodies. Here we report that T. gondii antigens MIC1, MIC3, MIC4, and MIC6 were capable of inducing memory responses leading to production of gamma interferon (IFN-γ) by T cells from T. gondii -infected mice. Production of IFN-γ was demonstrated using enzyme-linked immunosorbent spot (ELISPOT) assay and also intracellular cytokine staining. All four MIC antigens displayed very high sensitivity (100%) and specificity (86 to 100%) for detecting chronic infection. Interestingly, IFN-γ was produced by both CD4 + and CD8 + T cells in BALB/c mice but primarily by CD4 + T cells in C57BL/6 mice. Phenotypic characterization of IFN-γ-producing CD4 + and CD8 + T cells in BALB/c mice and CD4 + T cells in C57BL/6 mice revealed effector memory T cells (CD44 hi CD62L lo ) as the predominant cells that contributed to IFN-γ production in response to MIC antigens. Effector memory responses were seen in mice of different major histocompatibility complex class II (MHC-II) haplotypes, suggesting that MIC antigens contain epitopes that are broadly recognized. IMPORTANCE Current diagnosis of toxoplasmosis relies almost exclusively on antibody detection, and while detection of IgG provides a useful estimate of prior infection, it does not alone indicate immune status. In contrast, detection of IFN-γ responses to T. gondii antigens has been used to monitor immune responsiveness in HIV-infected patients, thus providing valuable predictions about the potential for disease reactivation. However, specific T. gondii antigens that can be used in assays to detect cellular immunity remain largely undefined. In this study, we examined the diagnostic potential of microneme antigens of T. gondii using IFN-γ detection assays. Our findings demonstrate that MIC antigens (MIC1, MIC3, MIC4, and MIC6) elicit IFN-γ responses from memory T cells in chronically infected mice. Monitoring IFN-γ production by T cells stimulated with MIC antigens provided high sensitivity and specificity for detection of T. gondii infection in mice. Taken together, these studies suggest that microneme antigens might be useful as an adjunct to serological testing to monitor immune status during infection., (Copyright © 2019 Saraav et al.)

We developed algorithms to identify pregnant women with suicidal behavior using information extracted from clinical notes by natural language processing (NLP) in electronic medical records. Using both codified data and NLP applied to unstructured clinical notes, we first screened pregnant women in Partners HealthCare for suicidal behavior. Psychiatrists manually reviewed clinical charts to identify relevant features for suicidal behavior and to obtain gold-standard labels. Using the adaptive elastic net, we developed algorithms to classify suicidal behavior. We then validated algorithms in an independent validation dataset. From 275,843 women with codes related to pregnancy or delivery, 9331 women screened positive for suicidal behavior by either codified data (N = 196) or NLP (N = 9,145). Using expert-curated features, our algorithm achieved an area under the curve of 0.83. By setting a positive predictive value comparable to that of diagnostic codes related to suicidal behavior (0.71), we obtained a sensitivity of 0.34, specificity of 0.96, and negative predictive value of 0.83. The algorithm identified 1423 pregnant women with suicidal behavior among 9331 women screened positive. Mining unstructured clinical notes using NLP resulted in a 11-fold increase in the number of pregnant women identified with suicidal behavior, as compared to solely reliance on diagnostic codes.

Efforts from the past decade in genomic analyses improved our understanding of genetic susceptibility to epithelial ovarian cancer (EOC). While genome-wide association studies (GWAS) have successfully identified approximately 40 genomic loci contributing to risk, a functional understanding of the molecular mechanisms underlying all but a few of these loci is lacking. The work by Buckley and colleagues has comprehensively characterized an EOC locus on chromosome band 9p22.2, identifying cis -regulatory functional sequence variants underlying multiple independent GWAS signals at 9p22.2 both within enhancer elements, as well as within a nuclear scaffold/matrix attachment region. Their findings further provide evidence implicating the basonuclin 2 ( BNC2 ) gene in EOC risk and broaden the understanding of ovarian cancer biology. See related article by Buckley et al., p. 467 ., (©2019 American Association for Cancer Research.)

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation., Methods and Findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose., Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: TE declared employment, research support, and stock in AstraZeneca and research support from Bayer and Pfizer. PCH is a population health fellow of Cancer Research UK. GDS is a member of the Editorial Board of PLOS Medicine.

Background: Exposure to psychosocial stress and employment of high effort coping strategies have been identified as risk factors that may partially explain the high prevalence of hypertension among African Americans. One biological mechanism through which stress and coping may affect risk of hypertension is via epigenetic modifications (e.g. DNA methylation) in blood pressure-related genes, however this area remains understudied in African Americans., Methods: We used data from the ongoing Intergenerational Blood Pressure Study (InterGEN), a longitudinal study designed to investigate factors that contribute to hypertension risk in African American women (n=120) and their young children, to investigate the association between stress overload, problem solving coping, avoidance coping, and social support coping with DNA methylation (DNAm) in 25 candidate genes related to blood pressure. Multivariable linear regression and multilevel modeling were used to conduct methylation site level and gene level analyses respectively., Results: In site level analyses, stress overload, problem solving coping, social support coping, and avoidance coping were associated with 47, 63, 66, and 61 sites respectively at p<0.05. However, no associations were statistically significant after multiple testing correction. There were also no significant associations in gene level analyses., Conclusions: As human social epigenomics is an emerging, evolving area of research there is much to be learned from studies with statistically significant findings as well as studies with null findings. Factors such as characteristics of the social stressor, source of DNA, and synchronization of exposure and outcome are likely important considerations as we move the field forward., Competing Interests: Declaration of conflicting interests The authors declare that there is no conflict of interest.

While prior meta-analyses in anatomy education have explored the effects of laboratory pedagogies and histology media on learner performance, the effects of student-centered learning (SCL) and computer-aided instruction (CAI) have not been broadly evaluated. This research sought to answer the question, "How effective are student-centered pedagogies and CAI at increasing student knowledge gains in anatomy compared to traditional didactic approaches?" Relevant studies published within the past 51 years were searched using five databases. Predetermined eligibility criteria were applied to the screening of titles and abstracts to discern their appropriateness for study inclusion. A summary effect size was estimated to determine the effects of SCL and CAI on anatomy performance outcomes. A moderator analysis of study features was also performed. Of the 3,035 records screened, 327 underwent full-text review. Seven studies, which comprised 1,564 participants, were included in the SCL analysis. An additional 19 studies analyzed the effects of CAI in the context of 2,570 participants. Upon comparing SCL to traditional instruction, a small positive effect on learner performance was detected (standardized mean difference (SMD = 0.24; [CI = 0.07, 0.42]; P = 0.006). Likewise, students with CAI exposure moderately outscored those with limited or no access to CAI (SMD = 0.59; [CI = 0.20, 0.98]; P = 0.003). Further analysis of CAI studies identified effects (P ≤ 0.001) for learner population, publication period, interventional approach, and intervention frequency. Overall, learners exposed to SCL and supplemental CAI outperformed their more classically-trained peers as evidenced by increases in short-term knowledge gains. Anat Sci Educ. © 2018 American Association of Anatomists., (© 2018 American Association of Anatomists.)

Purpose: Magnetic resonance imaging guided (MRI-g) radiation therapy provides visualization of the target and organs at risk (OARs), allowing for daily online adaptive radiation therapy (OART). We hypothesized that MRI-g OART would improve OAR sparing and target coverage in patients with pancreatic cancer treated with stereotactic body radiation therapy (SBRT)., Methods and Materials: Ten patients received pancreas SBRT to a dose of 33 to 40 Gy in 5 fractions. The dose was prescribed to 90% coverage of the planning target volume at 100% isodose (PTV100). After each fraction's setup magnetic resonance imaging scan, the target position was aligned by 3-dimensional shifts, the normal anatomy was recontoured, and the original radiation therapy plan was recalculated to create a nonadaptive plan. A reoptimized (adaptive) plan was then generated for each fraction and renormalized to 90% coverage of PTV100. Target and OAR doses between nonadaptive and adaptive plans were compared to assess the dosimetric impact of daily adaptation., Results: The PTV100 mean for adaptive and nonadaptive techniques was 90% and 80.4% (range, 46%-97%), respectively (P = .0008). Point maximum (Dmax) 38 Gy duodenum objectives were met in 43 adaptive fractions compared with 32 nonadaptive fractions (P = .022). Both PTV100 ≥90% and all OAR objectives were achieved in 28 adaptive fractions compared with only 3 nonadaptive fractions. For nonadaptive plans, interfraction increases in stomach volume correlated with higher stomach V33 (P = .004), stomach Dmax (P = .009), duodenum V33 (P = .021), and duodenum Dmax (P = .105). No correlation was observed between stomach volume and OAR doses for adaptive plans. OART plans with Dmax violations of the spinal cord (20 Gy) in 4 fractions and large bowel (38 Gy) in 5 fractions were identified (although not delivered)., Conclusions: MRI-g OART improves target coverage and OAR sparing for pancreas SBRT. This benefit partially results from mitigation of interfraction variability in stomach volume. Caution must be exercised to evaluate all OARs near the treatment area., (Copyright © 2018 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: The pediatric emergency department (PED) represents an opportune time for alcohol and drug screening. The National Institute of Alcohol Abuse and Alcoholism (NIAAA) recommends a two-question alcohol screen for adolescents as a predictor of alcohol and drug misuse., Objective: A multi-site PED study was conducted to determine the association between the NIAAA two-question alcohol screen and adolescent cannabis use disorders (CUD), cigarette smoking, and lifetime use of other drugs., Methods: Participants included 12-17-year olds (n = 4834) treated in one of 16 participating PEDs. An assessment battery, including the NIAAA two-question screen and other measures of alcohol, tobacco and drug use, was self-administered on a tablet computer., Results: A diagnosis of CUD, lifetime tobacco use or lifetime drug use was predicted by any self-reported alcohol use in the past year, which indicates a classification of moderate risk for middle school ages and low risk for high school ages on the NIAAA two-question screen. Drinking was most strongly predictive of a CUD, somewhat weaker for lifetime tobacco use, and weakest for lifetime drug use. This same pattern held for high school and middle school students and was stronger for high school students over middle school students for all three categories. This association was also found across gender, ethnicity and race. The association was strongest for CUD for high school students, sensitivity 81.7% (95% CI, 77.0, 86.5) and specificity 70.4% (95% CI, 68.6, 72.1). Conclusions/Importance: A single question about past year alcohol use can provide valuable information about other substance use, particularly marijuana.