Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Review of \u3ci\u3eRudolfo A. Anaya: A Critical Companion\u3c/i\u3e By Margarite Fernandez Olmos

Rudolfo Anaya is one of today\u27s leading Chicano writers. Since the release of Bless Me, Ultima, his groundbreaking first novel in 1972, Anaya has published eight additional novels, a collection of short stories, a travel journal, an epic poem, and several plays. Over the years his work has received widespread praise throughout the Latino literary community, earning him such laudatory epithets as Godfather and guru of Chicano literature, the most acclaimed and universal Chicano writer, and our poet of the llano and the barrio. Margarite Fernandez Olmos discusses how Anaya garnered this standing-and more-in Rudolfo A. Anaya: A Critical Companion. Focusing primarily on Anaya\u27s first seven novels, this excellent overview also includes helpful commentary on his lengthy career and some of his lesser-known works. Olmos argues that Anaya\u27s fiction has not only secured his place in Chicano literature but helped establish his reputation among mainstream contemporary American writers. Like other texts in the Critical Companions series, the book is divided into three sections: a biographical sketch tracing Anaya\u27s early days as a novelist and professor at the University of New Mexico to his more recent career as a writer of detective fiction; a chapter outlining Anaya\u27s place in the larger context of Chicano literature; and an extensive analysis of Anaya\u27s main fiction, beginning with Ultima, a coming-of-age story about a young boy finding strength and wisdom in a curandera, or healer, and concluding with Jalamanta: A Message from the Desert (1996), which Olmos maintains reflects the quest for truth that pervades all of Anaya\u27s writings. As with most studies of Anaya\u27s work, Bless Me, Ultima receives the most critical praise. One of very few Chicano \u27best-sellers,\u27 the novel celebrates most of the themes that identify Anaya\u27s best fiction-an appreciation for the land, especially New Mexico, for which Anaya feels a spiritual bond ; indigenous myths, legends, and symbols that preserve Latino and Native American culture; bilingualism; and the constant search for knowledge. While his next two novels, Heart of Aztlan (1976) and Tortuga (1979), fail to measure up to Ultima, they express Anaya\u27s ongoing concerns with spiritualism, cultural diversity, and community. Alburquerque, one of Anaya\u27s more accessible novels, published in 1992, introduces a minor character named Sonny Baca, who figures prominently in Zia Summer (1995), Rio Grande Fall (1996), and Shaman Winter (1999), Anaya\u27s detective novels, which represent a dramatic shift in subject matter and style, but reflect many of the ideas in Anaya\u27s other fiction, including respect for the environment and traditional cultures. Olmos\u27s Critical Companion is a welcome addition to Anaya scholarship. It should appeal not only to the beginning student of Latino literature but to the scholar interested in Anaya\u27s ongoing and important role in contemporary American letters

Moving on: Transition experiences of young adults with chronic pain

Purpose: The purpose of this study was to explore the transition experience of young adults with chronic pain in Canada from the pediatric health care setting to the adult health care setting. Materials and Methods: A qualitative descriptive approach using semistructured interviews was used to capture the transition experiences of young people with chronic pain who have recently transferred from the pediatric setting to the adult health care setting. Participants were recruited from west, central, and the east coast of Canada to situate the findings within the context of Canada. Interviews were transcribed and analyzed using qualitative inductive content analysis. Results: Nine participants were interviewed, three from each part of Canada (west, central, and east). Five common categories were determined to describe the transition experience of young adults with chronic pain which include (1) independence (I can do it, maybe?), (2) pain trajectory (stress and pain along for the ride), (3) social support networks (need a shoulder to lean on), (4) parental support (obviously they are there), and (5) collaborative systems (the bridge). Conclusion: Young people with chronic pain experience unique challenges when faced with transitioning to the adult health care setting. Supporting the young person and his or her family in preparation and readiness and collaboration between the pediatric and adult health care settings are essential to ensure a smooth transition and avoid negative transition outcomes. Further research is needed to determine the best ways to prepare young people for transition and the care activities required in both pediatric and adult health care settings to improve pain-related outcomes posttransition

Experiences of Pediatric Pain Professionals Providing Care during the COVID-19 Pandemic: A Qualitative Study

Chronic pain affects 1 in 5 youth, many of whom manage their pain using a biopsychosocial approach. The COVID-19 pandemic has impacted the way that healthcare is delivered. As part of a larger program of research, this study aimed to understand the impact of the pandemic on pediatric chronic pain care delivery including impact on patients’ outcomes, from the perspective of pediatric healthcare providers. A qualitative descriptive study design was used and 21 healthcare providers from various professional roles, clinical settings, and geographic locations across Canada were interviewed. Using a reflexive thematic analysis approach 3 themes were developed: (1) duality of pandemic impact on youth with chronic pain (i.e., how the pandemic influenced self-management while also exacerbating existing socioeconomic inequalities); (2) changes to the healthcare system and clinical practices (i.e., triaging and access to care); (3) shift to virtual care (i.e., role of institutions and hybrid models of care). These findings outline provider perspectives on the positive and negative impacts of the pandemic on youth with chronic pain and highlight the role of socioeconomic status and access to care in relation to chronic pain management during the pandemic in a high-income country with a publicly funded healthcare system

Marking out the pitch: a historiography and taxonomy of football fiction

Football, or soccer as it is more commonly referred to in Australia and the US, is arguably the world’s most popular sport. It generates a proportionate volume of related writing. Within this landscape, works of novel-length fiction are seemingly rare. This paper establishes and maps a substantial body of football fiction works, explores elements and qualities exhibited individually and collectively. In bringing together current, limited surveys of the field, it presents the first rigorous definition of football fiction and captures the first historiography of the corpus. Drawing on distant reading methods developed in conjunction with closer textual analyses, the historiography and subsequent taxonomy represent the first articulation of relationships across the body of work, identify growth areas and establish a number of movements and trends. In advancing the understanding of football fiction as a collective body, the paper lays foundations for further research and consideration of the works in generic terms