Approaches to Carrier Testing and Results Disclosure in Translational Genomics Research

Background: Clinical genome and exome sequencing (CGES) is primarily used to address specific clinical concerns by detecting risk of future disease, clarifying diagnosis, or directing treatment. Additionally, CGES makes possible the disclosure of autosomal recessive and X-linked carrier results as additional secondary findings, and research about the impact of carrier results disclosure in this context is needed. Methods: Representatives from 11 projects in the clinical sequencing exploratory research (CSER) consortium collected data from their projects using a structured survey. The survey focused on project characteristics, which variants were offered and/or disclosed to participants as carrier results, methods for carrier results disclosure, and project?specific outcomes. We recorded quantitative responses and report descriptive statistics with the aim of describing the variability in approaches to disclosing carrier results in translational genomics research projects. Results: The proportion of participants with carrier results was related to the number of genes included, ranging from 3% (three genes) to 92% (4,600 genes). Between one and seven results were disclosed to those participants who received any positive result. Most projects offered participants choices about whether to receive some or all of the carrier results. There were a range of approaches to communicate results, and many projects used separate approaches for disclosing positive and negative results. Conclusion: Future translational genomics research projects will need to make decisions regarding whether and how to disclose carrier results. The CSER consortium experience identifies approaches that balance potential participant interest while limiting impact on project resources

Importance of decision support implementation in emergency department vancomycin dosing

INTRODUCTION: The emergency department (ED) plays a critical role in the management of life-threatening infection. Prior data suggest that ED vancomycin dosing is frequently inappropriate. The objective is to assess the impact of an electronic medical record (EMR) intervention designed to improve vancomycin dosing accuracy, on vancomycin dosing and clinical outcomes in critically ill ED patients. METHODS: Retrospective before-after cohort study of all patients (n=278) treated with vancomycin in a 60,000-visit Midwestern academic ED (March 2008 and April 2011) and admitted to an intensive care unit. The primary outcome was the proportion of vancomycin doses defined as “appropriate” based on recorded actual body weight. We also evaluated secondary outcomes of mortality and length of stay. RESULTS: The EMR dose calculation tool was associated with an increase in mean vancomycin dose ([14.1±5.0] vs. [16.5±5.7] mg/kg, p<0.001) and a 10.3% absolute improvement in first-dose appropriateness (34.3% vs. 24.0%, p=0.07). After controlling for age, gender, methicillin-resistant staphylococcus aureus infection, and Acute Physiology and Chronic Health Evaluation II score, 28-day in-hospital mortality (odds ratio OR 1.72; 95% CI [0.76–3.88], p=0.12) was not affected. CONCLUSION: A computerized decision-support tool is associated with an increase in mean vancomycin dose in critically ill ED patients, but not with a statistically significant increase in therapeutic vancomycin doses. The impact of decision-support tools should be further explored to optimize compliance with accepted antibiotic guidelines and to potentially affect clinical outcome

Third-Party Effects in Stakeholder Interviews

This paper examines the effect of having a third-party scientific expert present in stakeholder interviews. The study was conducted as part of a larger project on stakeholder engagement for natural resource management in the Verde Valley region of Arizona. We employed an experimental design, conducting stakeholder interviews both with and without an identified scientific expert present. Our sample consisted of 12 pairs of interviewees (24 total participants) who we matched based on their occupation, sex, and spatial proximity. For each pair, the scientific expert was present as a third party in one interview and absent in the other. We used a word-based coding strategy to code all interview responses for three known areas of sensitivity among the study population (risk, gatekeeping, and competence). We then performed both quantitative and qualitative analyses to compare responses across the two interview groups. We found that the presence of a scientific expert did not have a statistically significant effect on the mention of sensitive topics among stakeholders. However, our qualitative results show that the presence of a scientific expert had subtle influences on the ways that stakeholders discussed sensitive topics, particularly in placing emphasis on their own credibility and knowledge. Our findings indicate that researchers may be able to pursue collaborative, interdisciplinary research designs with multiple researchers present during interviews without concerns of strongly influencing data elicitation on sensitive topics. However, researchers should be cognizant of the subtle ways in which the presence of a third-party expert may influence the credibility claims and knowledge assertions made by respondents when a third-party expert is present during stakeholder interviews

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease.

BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.MethodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.ResultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.ConclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses

Geoarchaeology and Heritage Management:Identifying and Quantifying Multi-Scalar Erosional Processes at Kisese II Rockshelter, Tanzania

Natural and anthropogenically induced soil erosion can cause serious loss of the archaeological record. Our work shows the value of multi-scalar geoarchaeological study when excavating and re-excavating rockshelters in a highly dynamic sedimentary environment where erosion is prominent. Here we present our work on Kisese II rockshelter, Tanzania, originally excavated in the 1950s and largely unpublished, that preserves an important Pleistocene-Holocene archaeological record integral to understanding the deep history of the Kondoa Rock-Art World Heritage Center. Unlike rockshelters in quiescent tectonic settings, like much of central Europe or South Africa, Kisese II exists in highly dynamic sedimentary environments associated with the active tectonics of the Great Rift Valley system exacerbated by human-induced environmental and climate change. We report on our 2017 and 2019 exploratory research that includes integrated regional-, landscape-, and site-scale geoarchaeological analyses of past and present sedimentary regimes and micromorphological analyses of the archaeological sediments. Historical records and aerial photographs document extensive changes in vegetation cover and erosional regimes since the 1920s, with drastic changes quantified between 1960 and 2019. Field survey points to an increased erosion rate between 2017 and 2019. To serve future archaeologists, heritage specialists, and local populations we combine our data in a geoarchaeological catena that includes soil, vegetation, fauna, and anthropogenic features on the landscape. At the site, micromorphological coupled with chronological analyses demonstrate the preservation of in situ Pleistocene deposits. Comparison of photographs from the 1956 and 2019 excavations show a maximum sediment loss of 68 cm in 63 years or >10% of >6-m-thick sedimentary deposit. In the studied area of the rockshelter we estimate ∼1 cm/yr of erosion, suggesting the ongoing removal of much of the higher archaeological sediments which, based on the coarse stratigraphic controls and chronology of the original Inskeep excavations, would suggest the loss of much of the archaeological record of the last ∼4000 years. These multi-scalar data are essential for the construction of appropriate mitigation strategies and further study of the remaining stratigraph

Validation of the Persistent Complex Bereavement Disorder (PCBD) Checklist: A Developmentally Informed Assessment Tool for Bereaved Youth

The inclusion of Persistent Complex Bereavement Disorder (PCBD) in the DSMâ 5 appendix signifies a call for research regarding the distinguishing features and clinical utility of proposed PCBD criteria. Rigorously constructed tools for assessing PCBD are lacking, especially for youth. This study evaluated the validity and clinical utility of the PCBD Checklist, a 39â item measure designed to assess PCBD criteria in youth aged 8 to18 years. Test construction procedures involved: (a) reviewing the literature regarding developmental manifestations of proposed criteria, (b) creating a developmentally informed item pool, (c) surveying an expert panel to evaluate the clarity and developmental appropriateness of candidate items, (d) conducting focus groups to evaluate the comprehensibility and acceptability of items, and (e) evaluating psychometric properties in 367 bereaved youth (Mage = 13.49, 55.0% female). The panel, clinicians, and youth provided favorable content validity and comprehensibility ratings for candidate items. As hypothesized, youth who met full PCBD criteria, Criterion B (e.g., preoccupation with the deceased and/or circumstances of the death), or Criterion C (e.g., reactive distress and/or social/identity disruption) reported higher posttraumatic stress and depressive symptoms than youth who did not meet these criteria, ηp2 = .07â .16. Youth who met Criterion C reported greater functional impairment than youth who did not, ηp2 = .08â .12. Youth who qualified for the â traumatic bereavement specifierâ reported more frequent posttraumatic stress symptoms than youth who did not, ηp2 = .04. Findings support the convergent, discriminant, and discriminantâ groups validity, developmental appropriateness, and clinical utility of the PCBD Checklist.ResumenValidación de Lista de verificación del Trastorno por Duelo Complejo Persistente (TDCP): Un informe del desarrollo de herramientas de medición para duelo en jóvenesLISTA DE CHEQUEO DE TRASTORNO DE DUELO COMPLEJO PERSISTENTELa inclusión del trastorno de duelo complejo persistente (TDCP en su sigla en español; PCBD en sus siglas en inglés) en el apéndice del DSMâ 5 significa un llamado para investigar en relación a las características distintivas y la utilidad clínica de los criterios propuestos para el TDCP. Se carece de herramientas rigurosamente construidas para evaluar TDCP, especialmente para jóvenes. Este estudio evalúa la validez y utilidad clínica de la lista de verificación de TPCP, una medida con 39 ítems diseñada para medir el criterio de TDCP en jóvenes de edades entre 8 a 18 años. El procedimiento de construcción del test involucró: (a) revisión de la literatura relacionada con manifestaciones desarrolladas del criterio propuesto; (b) creación de un pool de ítems informados para el desarrollo; (c) encuesta a un panel experto para evaluar la claridad y desarrollo apropiado de los ítems; (d) conducir grupos focales para evaluar la compresibilidad y aceptabilidad de los ítems; y (e) evaluación de propiedades psicométricas en 367 jóvenes en proceso de duelo (M edad = 13.49, 55.0% femenino). El panel, los clínicos y los jóvenes en proceso de duelo proveyeron una validez de contenido favorable y rangos de comprensibilidad para los ítems candidatos. Como se hipotetizó, los jóvenes que cumplieron el criterio completo de TDCP, criterio B (ej., preocupación por el fallecido y/o las circunstancias de la muerte) o el criterio C (ej., estrés reactivo y/o perturbación social/identidad) reportaron alto estrés postraumático y síntomas depresivos que los jóvenes que no cumplen este criterio, ηp2 = .07 a .16. Los jóvenes que no cumplieron el criterio C reportaron mayor deterioro funcional que los jóvenes que no lo cumplieron ηp2 = .08 a .12. Los jóvenes que calificaron para el â duelo traumático especificoâ reportaron mayor frecuencia de síntomas de estrés postraumático que jóvenes que no calificaron ηp2 = .04. Los resultados apoyan la validez convergente, discriminante y de grupos discriminante; y el apropiado desarrollo y utilidad clínica de la lista de verificación de TDCP para jóvenes con duelo.æ ½è±¡Validation of the Persistent Complex Bereavement Disorder (PCBD) Checklist: A Developmentallyâ Informed Assessment Tool for Bereaved YouthTraditional Chineseæ¨ é¡ : é© è­ ã æ çº æ §è¤ é å æ é ç¤ ç (PCBD)æª¢æ ¥è¡¨ã :ä¸ å é å° å æ é å° å¹´ã å ·ç ¼å± é ©å æ §ç è© ä¼°å·¥å ·æ ®è¦ : DSMâ 5å ¨é é 裡å å «äº æ çº æ §è¤ é å æ é ç¤ ç (PCBD), å æ  æ å æ é è¦ ç  ç©¶å ¶æ å ºç PCBDæ¨ æº ç ¨ç ¹ç ç ¹å¾µå è ¨åº æ ç ¨ã ç ¹å ¥æ ¯é å° é å° å¹´ç PCBD, æ å ç ®å ä» æ¬ ç¼ºå ´æ ¼è¨­è¨ ç è© ä¼°å·¥å ·ã æ ¬ç  ç©¶æª¢è¦ ã PCBDæª¢æ ¥è¡¨ã ç æ 度å è ¨åº æ ç ¨ã å® å ·å 39å 測é é  ç ®, ç ¨ä»¥è© ä¼°å¹´é½¡ä» ä¹ 8è ³18æ­²ç é å° å¹´ç PCBDã ç·¨å ¶è© ä¼°ç é ç¨ å æ ¬: (ä¸ ) å¯©è¦ æ æ å ºç æ¨ æº å ¨é å¾ ç  ç©¶ç ç ¼å± æ ¸æ ; (äº ) å  æ ç ¼å± æ ¸æ å»ºç« ä¸ å é  ç ®åº«; (ä¸ ) 訪å ä¸ ç¾¤å° æ¥­äººå£«, æª¢è¦ æ å å»ºç« ç è© ä¼°é  ç ®ç æ¸ æ¥ æ §å ç ¼å± é ©å æ §; (å ) ä»¥ç ¦é» å° çµ ç å½¢å¼ , æª¢è¦ è© ä¼°é  ç ®ç å ¯ç è§£æ §å å ¯æ ¥å 度; (äº ) æª¢è¦ 367å å æ é å° å¹´ (Mage = 13.49, 55.0% ç ºå¥³æ §)ç å¿ ç 測é ç ¹è³ªã å° æ¥­å é ã è ¨åº æ²»ç 師å å æª¢è¦ ç å æ é å° å¹´, é ½å° è© ä¼°é  ç ®ç å §å®¹æ 度å å ¯ç è§£æ §ä½ å ºè ¯å¥½è© å ã ä¸ å¦ å 設, å® å ¨ç¬¦å PCBDæ¨ æº , æ 符å æ¨ æº B (å¦ å° æ­»è å /æ å ¶æ­»äº¡æ æ³ é ·æ æ æ ) ã æ æ¨ æº C (å¦ å æ æ §æ ²ç å /æ 社交/èº«ä»½èª å å æ ¾) ç é å° å¹´, æ¯ ä¸ ç¬¦ç é å° å¹´æ è¼ é« æ°´å¹³ç å µå ·å¾ å£ å å æ 鬱ç ç (ηp2 = .07 è ³ .16)ã 符å æ¨ æº Cç é å° å¹´æ¯ ä¸ ç¬¦ç é å° å¹´æ è¼ é« æ°´å¹³ç å è ½å æ (ηp2 = .08 è ³ .12)ã 符å æ ã å µå ·æ §å æ ç ¹å¾µã ç é å° å¹´, æ¯ ä¸ ç¬¦ç é å° å¹´æ è¼ é »ç¹ ç å µå ·å¾ å£ å ç ç (ηp2 = .04)ã çµ æ è­ æ ç ¨ä»¥è© ä¼°å æ é å° å¹´ç ã PCBDæª¢æ ¥è¡¨ã æ å ¯è æ 度ã å ¤å ¥æ 度ã çµ å ¥å ¤å ¥æ 度, 亦æ ç ¼å± é ©å æ §å è ¨åº æ ç ¨ã Simplified Chineseæ  é¢ : éª è¯ ã æ ç»­æ §å¤ æ å æ ¸é ç¢ ç (PCBD)æ£ æ ¥è¡¨ã :ä¸ ä¸ªé 对å æ ¸é å° å¹´ã å ·å å± é å æ §ç è¯ ä¼°å·¥å ·æ ®è¦ : DSMâ 5å ¨é å½ é å å «äº æ ç»­æ §å¤ æ å æ ¸é ç¢ ç (PCBD), å æ  æ 们æ é è¦ ç  ç©¶å ¶æ å ºç PCBDæ  å ç ¬ç ¹ç ç ¹å¾ å ä¸´åº æ ç ¨ã ç ¹å «æ ¯é 对é å° å¹´ç PCBD, æ ä»¬ç ®å ä» æ¬ ç¼ºä¸¥æ ¼è®¾è®¡ç è¯ ä¼°å·¥å ·ã æ ¬ç  ç©¶æ£ è§ ã PCBDæ£ æ ¥è¡¨ã ç æ 度å ä¸´åº æ ç ¨ã å® å ·å¤ 39ä¸ªæµ é é¡¹ç ®, ç ¨ä»¥è¯ ä¼°å¹´é¾ ä» ä¹ 8è ³18å² ç é å° å¹´ç PCBDã ç¼ å ¶è¯ ä¼°ç è¿ ç¨ å æ ¬: (ä¸ ) å®¡è§ æ æ å ºç æ  å å ¨è¿ å¾ ç  ç©¶ç å å± æ °æ ®; (äº ) å  åº å å± æ °æ ®å»ºç« ä¸ ä¸ªé¡¹ç ®åº ; (ä¸ ) è®¿é ®ä¸ ç¾¤ä¸ ä¸ äººå£«, æ£ è§ æ ä»¬å»ºç« ç è¯ ä¼°é¡¹ç ®ç æ¸ æ¥ æ §å å å± é å æ §; (å ) ä»¥ç ¦ç ¹å° ç» ç å½¢å¼ , æ£ è§ è¯ ä¼°é¡¹ç ®ç å ¯ç è§£æ §å å ¯æ ¥å 度; (äº ) æ£ è§ 367å å æ ¸é å° å¹´ (Mage = 13.49, 55.0% ä¸ºå¥³æ §)ç å¿ ç æµ é ç ¹è´¨ã ä¸ ä¸ å ¢é ã ä¸´åº æ²»ç å¸ å å æ£ è§ ç å æ ¸é å° å¹´, é ½å¯¹è¯ ä¼°é¡¹ç ®ç å 容æ 度å å ¯ç è§£æ §ä½ å ºè ¯å¥½è¯ å ã ä¸ å¦ å 设, å® å ¨ç¬¦å PCBDæ  å , æ 符å æ  å B (å¦ å¯¹æ­»è å /æ å ¶æ­»äº¡æ å µé ¿æ æ 忧) ã æ æ  å C (å¦ å åº æ §æ ²ç å /æ 社交/身份认å å æ °) ç é å° å¹´, æ¯ ä¸ ç¬¦ç é å° å¹´æ è¾ é« æ°´å¹³ç å 伤å å å å æ é ç ç ¶(ηp2 = .07 è ³ .16)ã 符å æ  å Cç é å° å¹´æ¯ ä¸ ç¬¦ç é å° å¹´æ è¾ é« æ°´å¹³ç å è ½å æ (ηp2 = .08 è ³ .12)ã 符å æ ã å ä¼¤æ §å æ ¸ç ¹å¾ ã ç é å° å¹´, æ¯ ä¸ ç¬¦ç é å° å¹´æ è¾ é¢ ç¹ ç å 伤å å å ç ç ¶(ηp2 = .04)ã ç» æ è¯ æ ç ¨ä»¥è¯ ä¼°å æ ¸é å° å¹´ç ã PCBDæ£ æ ¥è¡¨ã æ æ± è æ 度ã å ¤å «æ 度ã ç» å «å ¤å «æ 度, 亦æ å å± é å æ §å ä¸´åº æ ç ¨ãPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143677/1/jts22277.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143677/2/jts22277_am.pd

Development of the NIH PROMIS® Sexual Function and Satisfaction Measures in Patients with Cancer

We describe the development and validation of the PROMIS Sexual Function and Satisfaction (PROMIS SexFS) measures version 1.0 for cancer populations

Human Pathogen Shown to Cause Disease in the Threatened Eklhorn Coral Acropora palmata

Coral reefs are in severe decline. Infections by the human pathogen Serratia marcescens have contributed to precipitous losses in the common Caribbean elkhorn coral, Acropora palmata, culminating in its listing under the United States Endangered Species Act. During a 2003 outbreak of this coral disease, called acroporid serratiosis (APS), a unique strain of the pathogen, Serratia marcescens strain PDR60, was identified from diseased A. palmata, human wastewater, the non-host coral Siderastrea siderea and the corallivorous snail Coralliophila abbreviata. In order to examine humans as a source and other marine invertebrates as vectors and/or reservoirs of the APS pathogen, challenge experiments were conducted with A. palmata maintained in closed aquaria to determine infectivity of strain PDR60 from reef and wastewater sources. Strain PDR60 from wastewater and diseased A. palmata caused disease signs in elkhorn coral in as little as four and five days, respectively, demonstrating that wastewater is a definitive source of APS and identifying human strain PDR60 as a coral pathogen through fulfillment of Koch's postulates. A. palmata inoculated with strain PDR60 from C. abbreviata showed limited virulence, with one of three inoculated fragments developing APS signs within 13 days. Strain PDR60 from non-host coral S. siderea showed a delayed pathogenic effect, with disease signs developing within an average of 20 days. These results suggest that C. abbreviata and non-host corals may function as reservoirs or vectors of the APS pathogen. Our results provide the first example of a marine “reverse zoonosis” involving the transmission of a human pathogen (S. marcescens) to a marine invertebrate (A. palmata). These findings underscore the interaction between public health practices and environmental health indices such as coral reef survival