Hot topics, urgent priorities, and ensuring success for racial/ethnic minority young investigators in academic pediatrics.

BackgroundThe number of racial/ethnic minority children will exceed the number of white children in the USA by 2018. Although 38% of Americans are minorities, only 12% of pediatricians, 5% of medical-school faculty, and 3% of medical-school professors are minorities. Furthermore, only 5% of all R01 applications for National Institutes of Health grants are from African-American, Latino, and American Indian investigators. Prompted by the persistent lack of diversity in the pediatric and biomedical research workforces, the Academic Pediatric Association Research in Academic Pediatrics Initiative on Diversity (RAPID) was initiated in 2012. RAPID targets applicants who are members of an underrepresented minority group (URM), disabled, or from a socially, culturally, economically, or educationally disadvantaged background. The program, which consists of both a research project and career and leadership development activities, includes an annual career-development and leadership conference which is open to any resident, fellow, or junior faculty member from an URM, disabled, or disadvantaged background who is interested in a career in academic general pediatrics.MethodsAs part of the annual RAPID conference, a Hot Topic Session is held in which the young investigators spend several hours developing a list of hot topics on the most useful faculty and career-development issues. These hot topics are then posed in the form of six "burning questions" to the RAPID National Advisory Committee (comprised of accomplished, nationally recognized senior investigators who are seasoned mentors), the RAPID Director and Co-Director, and the keynote speaker.Results/conclusionsThe six compelling questions posed by the 10 young investigators-along with the responses of the senior conference leadership-provide a unique resource and "survival guide" for ensuring the academic success and optimal career development of young investigators in academic pediatrics from diverse backgrounds. A rich conversation ensued on the topics addressed, consisting of negotiating for protected research time, career trajectories as academic institutions move away from an emphasis on tenure-track positions, how "non-academic" products fit into career development, racism and discrimination in academic medicine and how to address them, coping with isolation as a minority faculty member, and how best to mentor the next generation of academic physicians

Traumatic injury in the United States: In-patient epidemiology 2000–2011

Background Trauma is a leading cause of death and disability in the United States (US). This analysis describes trends and annual changes in in-hospital trauma morbidity and mortality; evaluates changes in age and gender specific outcomes, diagnoses, causes of injury, injury severity and surgical procedures performed; and examines the role of teaching hospitals and Level 1 trauma centres in the care of severely injured patients. Methods We conducted a retrospective descriptive and analytic epidemiologic study of an inpatient database representing 20,659,684 traumatic injury discharges from US hospitals between 2000 and 2011. The main outcomes and measures were survey-adjusted counts, proportions, means, standard errors, and 95% confidence intervals. We plotted time series of yearly data with overlying loess smoothing, created tables of proportions of common injuries and surgical procedures, and conducted survey-adjusted logistic regression analysis for the effect of year on the odds of in-hospital death with control variables for age, gender, weekday vs. weekend admission, trauma-centre status, teaching-hospital status, injury severity and Charlson index score. Results The mean age of a person discharged from a US hospital with a trauma diagnosis increased from 54.08 (s.e. = 0.71) in 2000 to 59.58 (s.e. = 0.79) in 2011. Persons age 45–64 were the only age group to experience increasing rates of hospital discharges for trauma. The proportion of trauma discharges with a Charlson Comorbidity Index score greater than or equal to 3 nearly tripled from 0.048 (s.e. = 0.0015) of all traumatic injury discharges in 2000 to 0.139 (s.e. = 0.005) in 2011. The proportion of patients with traumatic injury classified as severe increased from 22% of all trauma discharges in 2000 (95% CI 21, 24) to 28% in 2011 (95% CI 26, 30). Level 1 trauma centres accounted for approximately 3.3% of hospitals. The proportion of severely injured trauma discharges from Level 1 trauma centres was 39.4% (95% CI 36.8, 42.1). Falls, followed by motor-vehicle crashes, were the most common causes of all injuries. The total cost of trauma-related inpatient care between 2001 and 2011 in the US was $240.7 billion (95$12.0 billion (95% CI 10.5, 13.4) in 2001 to 29.1 billion (95% CI 25.2, 32.9) in 2011. Conclusions Trauma, which has traditionally been viewed as a predicament of the young, is increasingly a disease of the old. The strain of managing the progressively complex and costly care associated with this shift rests with a small number of trauma centres. Optimal care of injured patients requires a reappraisal of the resources required to effectively provide it given a mounting burden

Race and Disordered Eating: A Narrative Review of Current Literature

Research Problem: Eating disorder literature has well-established a correlation between childhood trauma and development of eating disorder symptomology. One type of trauma that is often overlooked in eating disorder research is that of racial stress faced by ethnic minorities. The literature on racism and eating disorders tends to focus on the transdiagnostic construct of disordered eating behavior rather than specific DSM-5 diagnoses. As such, the current literature review examined the findings regarding associations between racial stressors and disordered eating behavior. Methods: The current literature review between Nov 2007 and August 2020 searched 3 databases, PubMed, CINAHL, and PsycInfo for English-language publications pertaining to conflict in racial identity (e.g., racism and acculturative stress) and disordered eating (keywords provided below). As there is limited primary research examining the association between racial stress and clinical diagnoses of eating disorders, this literature review expanded the search term of “eating disorder” (and its associated subcategories) to include other types of disordered eating, a behavior that often precedes the development of clinically diagnosable eating disorders. The literature search yielded 42 results, 81% (N=34) of which were included in the review; the included articles examined the relationship between disordered eating and various racial identity conflicts, including racism, ethnic identity exploration, perceived discrimination, and acculturative stress. 32 articles were cross-sectional design, 1 article was a theoretical analysis, and 1 article was a review. Results: The included literature looked at multiple minority populations, including Asian Americans, African Americans, Hispanic Americans, and Native Americans, and overwhelmingly found that perceived racism is consistently associated with disordered eating, especially for minority women. Current research suggests that across minority groups, the mediating factor in this association is self-reported stress. Other studies (N=7) produced mixed findings (i.e., positive correlations or null results) regarding the relationship between acculturative stress and disordered eating behavior. The magnitude of the relationship often differed based on the ethnicity and gender of the population being studied. Finally, racial teasing and discrimination were associated with disordered eating, disturbed body image, and depressive symptoms primarily among females across multiple races. Conclusion: While there is a body of research examining racial stress and disordered eating behavior, samples were primarily drawn from college students, and this body of research relies almost entirely on cross-sectional methodology. Moreover, the current review did not identify any studies that examined clinically-diagnosed eating disorder populations or any studies that utilized a longitudinal design. As such, the current review indicates a need for prospective longitudinal studies examining relevant risk factors and their relationship to the development of disordered eating behaviors over time in minority populations. Additionally, it is important for physicians to assess for racial stress as a potential factor contributing to the physical and mental health outcomes of minority patients, especially among minority women

Comparison of Pattern Detection Methods in Microarray Time Series of the Segmentation Clock

While genome-wide gene expression data are generated at an increasing rate, the repertoire of approaches for pattern discovery in these data is still limited. Identifying subtle patterns of interest in large amounts of data (tens of thousands of profiles) associated with a certain level of noise remains a challenge. A microarray time series was recently generated to study the transcriptional program of the mouse segmentation clock, a biological oscillator associated with the periodic formation of the segments of the body axis. A method related to Fourier analysis, the Lomb-Scargle periodogram, was used to detect periodic profiles in the dataset, leading to the identification of a novel set of cyclic genes associated with the segmentation clock. Here, we applied to the same microarray time series dataset four distinct mathematical methods to identify significant patterns in gene expression profiles. These methods are called: Phase consistency, Address reduction, Cyclohedron test and Stable persistence, and are based on different conceptual frameworks that are either hypothesis- or data-driven. Some of the methods, unlike Fourier transforms, are not dependent on the assumption of periodicity of the pattern of interest. Remarkably, these methods identified blindly the expression profiles of known cyclic genes as the most significant patterns in the dataset. Many candidate genes predicted by more than one approach appeared to be true positive cyclic genes and will be of particular interest for future research. In addition, these methods predicted novel candidate cyclic genes that were consistent with previous biological knowledge and experimental validation in mouse embryos. Our results demonstrate the utility of these novel pattern detection strategies, notably for detection of periodic profiles, and suggest that combining several distinct mathematical approaches to analyze microarray datasets is a valuable strategy for identifying genes that exhibit novel, interesting transcriptional patterns

Streaming fragment assignment for real-time analysis of sequencing experiments

We present eXpress, a software package for efficient probabilistic assignment of ambiguously mapping sequenced fragments. eXpress uses a streaming algorithm with linear run time and constant memory use. It can determine abundances of sequenced molecules in real time and can be applied to ChIP-seq, metagenomics and other large-scale sequencing data. We demonstrate its use on RNA-seq data and show that eXpress achieves greater efficiency than other quantification methods

Capacity Building for a New Multicenter Network Within the ECHO IDeA States Pediatric Clinical Trials Network

Introduction: Research capacity building is a critical component of professional development for pediatrician scientists, yet this process has been elusive in the literature. The ECHO IDeA States Pediatric Clinical Trials Network (ISPCTN) seeks to implement pediatric trials across medically underserved and rural populations. A key component of achieving this objective is building pediatric research capacity, including enhancement of infrastructure and faculty development. This article presents findings from a site assessment inventory completed during the initial year of the ISPCTN. Methods: An assessment inventory was developed for surveying ISPCTN sites. The inventory captured site-level activities designed to increase clinical trial research capacity for pediatrician scientists and team members. The inventory findings were utilized by the ISPCTN Data Coordinating and Operations Center to construct training modules covering 3 broad domains: Faculty/coordinator development; Infrastructure; Trials/Research concept development. Results: Key lessons learned reveal substantial participation in the training modules, the importance of an inventory to guide the development of trainings, and recognizing local barriers to clinical trials research. Conclusions: Research networks that seek to implement successfully completed trials need to build capacity across and within the sites engaged. Our findings indicate that building research capacity is a multi-faceted endeavor, but likely necessary for sustainability of a unique network addressing high impact pediatric health problems. The ISPCTN emphasis on building and enhancing site capacity, including pediatrician scientists and team members, is critical to successful trial implementation/completion and the production of findings that enhance the lives of children and families

Pregnancy-induced gene expression changes in vivo among women with rheumatoid arthritis: a pilot study

Background: Little is known about gene expression changes induced by pregnancy in women with rheumatoid arthritis (RA) and healthy women because the few studies previously conducted did not have pre-pregnancy samples available as baseline. We have established a cohort of women with RA and healthy women followed prospectively from a pre-pregnancy baseline. In this study, we tested the hypothesis that pregnancy-induced changes in gene expression among women with RA who improve during pregnancy (pregDAS_(improved)) overlap substantially with changes observed among healthy women and differ from changes observed among women with RA who worsen during pregnancy (pregDAS_(worse)). Methods: Global gene expression profiles were generated by RNA sequencing (RNA-seq) from 11 women with RA and 5 healthy women before pregnancy (T0) and at the third trimester (T3). Among the women with RA, eight showed an improvement in disease activity by T3, whereas three worsened. Differential expression analysis was used to identify genes demonstrating significant changes in expression within each of the RA and healthy groups (T3 vs T0), as well as between the groups at each time point. Gene set enrichment was assessed in terms of Gene Ontology processes and protein networks. Results: A total of 1296 genes were differentially expressed between T3 and T0 among the 8 pregDAS_(improved) women, with 161 genes showing at least two-fold change (FC) in expression by T3. The majority (108 of 161 genes) were also differentially expressed among healthy women (q<0.05, FC≥2). Additionally, a small cluster of genes demonstrated contrasting changes in expression between the pregDAS_(improved) and pregDAS_(worse) groups, all of which were inducible by type I interferon (IFN). These IFN-inducible genes were over-expressed at T3 compared to the T0 baseline among the pregDAS_(improved) women. Conclusions: In our pilot RNA-seq dataset, increased pregnancy-induced expression of type I IFN-inducible genes was observed among women with RA who improved during pregnancy, but not among women who worsened. These findings warrant further investigation into expression of these genes in RA pregnancy and their potential role in modulation of disease activity. These results are nevertheless preliminary and should be interpreted with caution until replicated in a larger sample

An 11p15 Imprinting Centre Region 2 Deletion in a Family with Beckwith Wiedemann Syndrome Provides Insights into Imprinting Control at CDKN1C

We report a three generation family with Beckwith Wiedemann syndrome (BWS) in whom we have identified a 330 kb deletion within the KCNQ1 locus, encompassing the 11p15.5 Imprinting Centre II (IC2). The deletion arose on the paternal chromosome in the first generation and was only associated with BWS when transmitted maternally to subsequent generations. The deletion on the maternal chromosome was associated with a lower median level of CDKN1C expression in the peripheral blood of affected individuals when compared to a cohort of unaffected controls (p<0.05), however was not significantly different to the expression levels in BWS cases with loss of methylation (LOM) within IC2 (p<0.78). Moreover the individual with a deletion on the paternal chromosome did not show evidence of elevated CDKN1C expression or features of Russell Silver syndrome. These observations support a model invoking the deletion of enhancer elements required for CDKN1C expression lying within or close to the imprinting centre and importantly extend and validate a single observation from an earlier study. Analysis of 94 cases with IC2 loss of methylation revealed that KCNQ1 deletion is a rare cause of loss of maternal methylation, occurring in only 3% of cases, or in 1.5% of BWS overall

Anti-α-Internexin Autoantibody from Neuropsychiatric Lupus Induce Cognitive Damage via Inhibiting Axonal Elongation and Promote Neuron Apoptosis

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a major complication for lupus patients, which often leads to cognitive disturbances and memory loss and contributes to a significant patient morbidity and mortality. The presence of anti-neuronal autoantibodies (aAbs) has been identified; as examples, anti-NMDA receptors and anti-Ribsomal P aAbs have been linked to certain pathophysiological features of NPSLE.In the current study, we used a proteomic approach to identify an intermediate neurofilament alpha-internexin (INA) as a pathogenetically relevant autoantigen in NPSLE. The significance of this finding was then validated in an expanded of a cohort of NPSLE patients (n = 67) and controls (n = 270) by demonstrating that high titers of anti-INA aAb was found in both the serum and cerebrospinal fluid (CSF) of ∼50% NPSLE. Subsequently, a murine model was developed by INA immunization that resulted in pronounced cognitive dysfunction that mimicked features of NPSLE. Histopathology in affected animals displayed cortical and hippocampal neuron apoptosis. In vitro studies further demonstrated that anti-INA Ab mediated neuronal damage via inhibiting axonal elongation and eventually driving the cells to apoptosis.Taken together, this study identified a novel anti-neurofilament aAb in NPSLE, and established a hitherto undescribed mechanism of aAb-mediated neuron damage that could have relevance to the pathophysiology of NPSLE