Haunted Histories: Time-slip Narratives in the Antipodes

In a startling moment in Margaret Mahy’s The Tricksters, Harry draws apart from the rest of her family in her attic bedroom in the family beach house, Carnival’s Hide. She looks into a mirror and sees her image dismantle, allowing a very different, but nevertheless clearly related figure to emerge. This is a typical event in time-slip stories, with their peculiar interest in the problematic construction of subjectivity. In this case the characters who slip between times are a bizarre trio of brothers who erupt into the more or less ordinary family lives of the Hamiltons, disturbing the modern moment with ancient memories, igniting passions, provoking revelations, raising questions about identity, threatening fragmentation, but finally harnessed in the interests of the ongoing narrative in which Harry’s adult life forms

Marguerite Casey Foundation: Reflecting on 15 Years of Philanthropic Leadership Through a Summative Evaluation

This article presents the findings of a summative evaluation of the Marguerite Casey Foundation that was conducted on the occasion of its 15th anniversary. The evaluation was designed to gauge stakeholders’ perceptions of the foundation’s operations to facilitate organizational learning. In sharing these results, the authors seek to elucidate the role of evaluation as a learning practice within the field of philanthropy. The article describes the foundation’s organizational elements and evolution and discusses key themes that emerged from qualitative data collected from foundation leaders and staff, as well as findings from a survey of current grantees. The article presents a synthesis of the evaluation’s findings and recommendations for the foundation’s continued and future work, describes its initial responses to these recommendations, and concludes with thoughts regarding the foundation’s continued progress toward establishing movement building as a philanthropic strategy for the 21st century

Soziale Ungleichheit und COVID-19 in Deutschland – Wo stehen wir in der vierten Pandemiewelle?

Für eine Vielzahl von Erkrankungen und Todesursachen ist zwischen der sozioökonomischen und gesundheitlichen Lage ein enger Zusammenhang nachgewiesen. Auch die Ausbreitungsmuster von SARS-CoV-2 über verschiedene soziale Gruppen werden seit Pandemiebeginn international und in Studien des RKI bundesweit untersucht. Im Beitrag werden die zentralen Ergebnisse zum aktuellen Stand zusammengefasst und um Daten aus der dritten und vierten Pandemiewelle ergänzt. Aus den dargestellten Befunden ergeben sich Hinweise auf Möglichkeiten, die Lücken im Infektionsschutz zu schließen.Peer Reviewe

Unilateral Pelvic Lymph Node Dissection in Prostate Cancer Patients Diagnosed in the Era of Magnetic Resonance Imaging-targeted Biopsy: A Study That Challenges the Dogma

PURPOSE Bilateral extended pelvic lymph node dissection at the time of radical prostatectomy is the current standard of care if pelvic lymph node dissection is indicated; often, however, pelvic lymph node dissection is performed in pN0 disease. With the more accurate staging achieved with magnetic resonance imaging-targeted biopsies for prostate cancer diagnosis, the indication for bilateral extended pelvic lymph node dissection may be revised. We aimed to assess the feasibility of unilateral extended pelvic lymph node dissection in the era of modern prostate cancer imaging. MATERIALS AND METHODS We analyzed a multi-institutional data set of men with cN0 disease diagnosed by magnetic resonance imaging-targeted biopsy who underwent prostatectomy and bilateral extended pelvic lymph node dissection. The outcome of the study was lymph node invasion contralateral to the prostatic lobe with worse disease features, ie, dominant lobe. Logistic regression to predict lymph node invasion contralateral to the dominant lobe was generated and internally validated. RESULTS Overall, data from 2,253 patients were considered. Lymph node invasion was documented in 302 (13%) patients; 83 (4%) patients had lymph node invasion contralateral to the dominant prostatic lobe. A model including prostate-specific antigen, maximum diameter of the index lesion, seminal vesicle invasion on magnetic resonance imaging, International Society of Urological Pathology grade in the nondominant side, and percentage of positive cores in the nondominant side achieved an area under the curve of 84% after internal validation. With a cutoff of contralateral lymph node invasion of 1%, 602 (27%) contralateral pelvic lymph node dissections would be omitted with only 1 (1.2%) lymph node invasion missed. CONCLUSIONS Pelvic lymph node dissection could be omitted contralateral to the prostate lobe with worse disease features in selected patients. We propose a model that can help avoid contralateral pelvic lymph node dissection in almost one-third of cases

Geometry and subsidence history of the Dead Sea basin : a case for fluid-induced mid-crustal shear zone?

This paper is not subject to U.S. copyright. The definitive version was published in Journal of Geophysical Research 117 (2012): B01406, doi:10.1029/2011JB008711.Pull-apart basins are narrow zones of crustal extension bounded by strike-slip faults that can serve as analogs to the early stages of crustal rifting. We use seismic tomography, 2-D ray tracing, gravity modeling, and subsidence analysis to study crustal extension of the Dead Sea basin (DSB), a large and long-lived pull-apart basin along the Dead Sea transform (DST). The basin gradually shallows southward for 50 km from the only significant transverse normal fault. Stratigraphic relationships there indicate basin elongation with time. The basin is deepest (8–8.5 km) and widest (~15 km) under the Lisan about 40 km north of the transverse fault. Farther north, basin depth is ambiguous, but is 3 km deep immediately north of the lake. The underlying pre-basin sedimentary layer thickens gradually from 2 to 3 km under the southern edge of the DSB to 3–4 km under the northern end of the lake and 5–6 km farther north. Crystalline basement is ~11 km deep under the deepest part of the basin. The upper crust under the basin has lower P wave velocity than in the surrounding regions, which is interpreted to reflect elevated pore fluids there. Within data resolution, the lower crust below ~18 km and the Moho are not affected by basin development. The subsidence rate was several hundreds of m/m.y. since the development of the DST ~17 Ma, similar to other basins along the DST, but subsidence rate has accelerated by an order of magnitude during the Pleistocene, which allowed the accumulation of 4 km of sediment. We propose that the rapid subsidence and perhaps elongation of the DSB are due to the development of inter-connected mid-crustal ductile shear zones caused by alteration of feldspar to muscovite in the presence of pore fluids. This alteration resulted in a significant strength decrease and viscous creep. We propose a similar cause to the enigmatic rapid subsidence of the North Sea at the onset the North Atlantic mantle plume. Thus, we propose that aqueous fluid flux into a slowly extending continental crust can cause rapid basin subsidence that may be erroneously interpreted as an increased rate of tectonic activity.Fieldwork was funded by U.S. AID Middle Eastern Regional Cooperation Program grant M21–012, with in-kind contributions by Al-Balqa’ Applied University (Jordan), the Geophysical Institute of Israel, and the U.S. Geological Survey

Unilateral Pelvic Lymph Node Dissection in Prostate Cancer Patients Diagnosed in the Era of Magnetic Resonance Imaging-targeted Biopsy: A Study That Challenges the Dogma

PURPOSE: Bilateral extended pelvic lymph node dissection at the time of radical prostatectomy is the current standard of care if pelvic lymph node dissection is indicated; often, however, pelvic lymph node dissection is performed in pN0 disease. With the more accurate staging achieved with magnetic resonance imaging-targeted biopsies for prostate cancer diagnosis, the indication for bilateral extended pelvic lymph node dissection may be revised. We aimed to assess the feasibility of unilateral extended pelvic lymph node dissection in the era of modern prostate cancer imaging. MATERIALS AND METHODS: We analyzed a multi-institutional data set of men with cN0 disease diagnosed by magnetic resonance imaging-targeted biopsy who underwent prostatectomy and bilateral extended pelvic lymph node dissection. The outcome of the study was lymph node invasion contralateral to the prostatic lobe with worse disease features, ie, dominant lobe. Logistic regression to predict lymph node invasion contralateral to the dominant lobe was generated and internally validated. RESULTS: Overall, data from 2,253 patients were considered. Lymph node invasion was documented in 302 (13%) patients; 83 (4%) patients had lymph node invasion contralateral to the dominant prostatic lobe. A model including prostate-specific antigen, maximum diameter of the index lesion, seminal vesicle invasion on magnetic resonance imaging, International Society of Urological Pathology grade in the nondominant side, and percentage of positive cores in the nondominant side achieved an area under the curve of 84% after internal validation. With a cutoff of contralateral lymph node invasion of 1%, 602 (27%) contralateral pelvic lymph node dissections would be omitted with only 1 (1.2%) lymph node invasion missed. CONCLUSIONS: Pelvic lymph node dissection could be omitted contralateral to the prostate lobe with worse disease features in selected patients. We propose a model that can help avoid contralateral pelvic lymph node dissection in almost one-third of cases

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption

Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.Etude de cohorte sur la santé des étudiantsStopping cognitive decline and dementia by fighting covert cerebral small vessel diseaseStudy on Environmental and GenomeWide predictors of early structural brain Alterations in Young student

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