Redefining Stewardship over Body Parts

This paper proposes one possible avenue for defining a framework to address body parts. I begin with the presumption that given the increasing use of body parts outside of our bodies, either after death or during life, society requires a framework with institutions and rules to govern our body parts. Yet there is no settled framework. Much of the controversy over differing approaches stems from whether people should be able to sell body parts. Thus, each potential framework implicitly addresses the question of monetary value. While multiple possibilities exist, the predominant models are (1) property, most often meaning ownership that permits monetary compensation; (2) stewardship, implying altruism and no monetary compensation to the donor; and (3) a compromise solution involving regulatory bodies, which could assign monetary value under certain circumstances

Mary Breckinridge Meets Healthy People 2010: A Teaching Strategy for Visioning and Building Healthy Communities

Abstract: In both midwifery and nursing education, it is essential to include innovative teaching strategies that address the health of communities. This article presents a creative learning activity for midwifery and/or nursing education that integrates Mary Breckinridge's historical example with today's national goals for building communities. The establishment of the Frontier Nursing Service in 1925 is an excellent example of the Mobilize, Assess, Plan, Implement, and Track (MAP-IT) framework for building health communities. Advanced practice nursing and midwifery students can use this historical template to implement their ideas for building healthy communities today

Identity-by-descent estimation with population- and pedigree-based imputation in admixed family data

BACKGROUND: In the past few years, imputation approaches have been mainly used in population-based designs of genome-wide association studies, although both family- and population-based imputation methods have been proposed. With the recent surge of family-based designs, family-based imputation has become more important. Imputation methods for both designs are based on identity-by-descent (IBD) information. Apart from imputation, the use of IBD information is also common for several types of genetic analysis, including pedigree-based linkage analysis. METHODS: We compared the performance of several family- and population-based imputation methods in large pedigrees provided by Genetic Analysis Workshop 19 (GAW19). We also evaluated the performance of a new IBD mapping approach that we propose, which combines IBD information from known pedigrees with information from unrelated individuals. RESULTS: Different combinations of the imputation methods have varied imputation accuracies. Moreover, we showed gains from the use of both known pedigrees and unrelated individuals with our IBD mapping approach over the use of known pedigrees only. CONCLUSIONS: Our results represent accuracies of different combinations of imputation methods that may be useful for data sets similar to the GAW19 pedigree data. Our IBD mapping approach, which uses both known pedigree and unrelated individuals, performed better than classical linkage analysis

In Vitro Data Suggest a Role for PMS2 Kozak Sequence Mutations in Lynch Syndrome Risk

This study investigates the role of 5′ UTR PMS2 Kozak sequence genetic variation in cancer risk. It accomplishes this through the development of a mid-throughput reporter assay where variants can be tested for protein translation efficiency. The results highlight the importance of continued study of the Kozak sequence related to human disease

Post-traumatic stress disorder following childbirth: an update of current issues and recommendations for future research

Objective: This paper aimed to report the current status of research in the field of post-traumatic stress disorder following childbirth (PTSD FC), and to update the findings of an earlier 2008 paper. Background: A group of international researchers, clinicians and service users met in 2006 to establish the state of clinical and academic knowledge relating to PTSD FC. A paper identified four key areas of research knowledge at that time. Methods: Fourteen clinicians and researchers met in Oxford, UK to update the previously published paper relating to PTSD FC. The first part of the meeting focused on updating the four key areas identified previously, and the second part on discussing new and emerging areas of research within the field. Results: A number of advances have been made in research within the area of PTSD FC. Prevalence is well established within mothers, several intervention studies have been published, and there is growing interest in new areas: staff and pathways; prevention and early intervention; impact on families and children; special populations; and post-traumatic growth. Conclusion: Despite progress, significant gaps remain within the PTSD FC knowledge base. Further research continues to be needed across all areas identified in 2006, and five areas were identified which can be seen as ‘new and emerging’. All of these new areas require further extensive research. Relatively little is still known about PTSD FC

Targeted Sequencing for Hereditary Breast and Ovarian Cancer in BRCA1/2-Negative Families Reveals Complex Genetic Architecture and Phenocopies

Approximately 20% of breast cancer cases are attributed to increased family risk, yet variation in BRCA1/2 can only explain 20%-25% of cases. Historically, only single gene or single variant testing were common in at-risk family members, and further sequencing studies were rarely offered after negative results. In this study, we applied an efficient and inexpensive targeted sequencing approach to provide molecular diagnoses in 245 human samples representing 134 BRCA mutation-negative (BRCAX) hereditary breast and ovarian cancer (HBOC) families recruited from 1973 to 2019 by Dr. Henry Lynch. Sequencing identified 391 variants, which were functionally annotated and ranked based on their predicted clinical impact. Known pathogenic CHEK2 breast cancer variants were identified in five BRCAX families in this study. While BRCAX was an inclusion criterion for this study, we still identified a pathogenic BRCA2 variant (p.Met192ValfsTer13) in one family. A portion of BRCAX families could be explained by other hereditary cancer syndromes that increase HBOC risk: Li-Fraumeni syndrome (gene: TP53) and Lynch syndrome (gene: MSH6). Interestingly, many families carried additional variants of undetermined significance (VOUSs) that may further modify phenotypes of syndromic family members. Ten families carried more than one potential VOUS, suggesting the presence of complex multi-variant families. Overall, nine BRCAX HBOC families in our study may be explained by known likely pathogenic/pathogenic variants, and six families carried potential VOUSs, which require further functional testing. To address this, we developed a functional assay where we successfully re-classified one family\u27s PMS2 VOUS as benign

Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations

Alzheimer disease (AD) is the most common form of senile dementia, with high incidence late in life in many populations including Caribbean Hispanic (CH) populations. Such admixed populations, descended from more than one ancestral population, can present challenges for genetic studies, including limited sample sizes and unique analytical constraints. Therefore, CH populations and other admixed populations have not been well represented in studies of AD, and much of the genetic variation contributing to AD risk in these populations remains unknown. Here, we conduct genome-wide analysis of AD in multiplex CH families from the Alzheimer Disease Sequencing Project (ADSP). We developed, validated, and applied an implementation of a logistic mixed model for admixture mapping with binary traits that leverages genetic ancestry to identify ancestry-of-origin loci contributing to AD. We identified three loci on chromosome 13q33.3 associated with reduced risk of AD, where associations were driven by Native American (NAM) ancestry. This AD admixture mapping signal spans the FAM155A, ABHD13, TNFSF13B, LIG4, and MYO16 genes and was supported by evidence for association in an independent sample from the Alzheimer's Genetics in Argentina—Alzheimer Argentina consortium (AGA-ALZAR) study with considerable NAM ancestry. We also provide evidence of NAM haplotypes and key variants within 13q33.3 that segregate with AD in the ADSP whole-genome sequencing data. Interestingly, the widely used genome-wide association study approach failed to identify associations in this region. Our findings underscore the potential of leveraging genetic ancestry diversity in recently admixed populations to improve genetic mapping, in this case for AD-relevant loci.Fil: Horimoto, Andrea R.V.R.. University of Washington; Estados UnidosFil: Boyken, Lisa A.. University of Washington; Estados UnidosFil: Blue, Elizabeth E.. University of Washington; Estados Unidos. Brotman Baty Institute for Precision Medicine; Estados UnidosFil: Grinde, Kelsey E.. University of Washington; Estados Unidos. Macalester College; Estados UnidosFil: Nafikov, Rafael A.. University of Washington; Estados UnidosFil: Sohi, Harkirat K.. University of Washington; Estados UnidosFil: Nato, Alejandro Q.. University of Washington; Estados Unidos. Marshall University; Estados UnidosFil: Bis, Joshua C.. University of Washington; Estados UnidosFil: Brusco, Luis Ignacio. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ramirez, Alfredo Jose. University Of Cologne; Alemania. Universitat Bonn; Alemania. German Center for Neurodegenerative Diseases; Alemania. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; . Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Dalmasso, Maria Carolina. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina. University Of Cologne; AlemaniaFil: Temple, Seth. University of Washington; Estados UnidosFil: Satizabal, Claudia. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; . University of Texas at San Antonio; Estados UnidosFil: Browning, Sharon R.. University of Washington; Estados UnidosFil: Seshadri, Sudha. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio; . University of Texas at San Antonio; Estados UnidosFil: Wijsman, Ellen M.. University of Washington; Estados UnidosFil: Thornton, Timothy A.. University of Washington; Estados Unido

Key Variants via the Alzheimer\u27s Disease Sequencing Project Whole Genome Sequence Data

INTRODUCTION: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer\u27s disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. METHODS: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer\u27s Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. RESULTS: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. DISCUSSION: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS

Centers For Mendelian Genomics: a Decade of Facilitating Gene Discovery

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health-supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients

Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome.

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine