New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Do They Have a Choice? Surrogate Decision-Making After Severe Acute Brain Injury.

In the early phase of severe acute brain injury (SABI), surrogate decision-makers must make treatment decisions in the face of prognostic uncertainty. Evidence-based strategies to communicate uncertainty and support decision-making are lacking. Our objective was to better understand surrogate experiences and needs during the period of active decision-making in SABI, to inform interventions to support SABI patients and families and improve clinician-surrogate communication. We interviewed surrogate decision-makers during patients' acute hospitalization for SABI, as part of a larger ( n = 222) prospective longitudinal cohort study of patients with SABI and their family members. Constructivist grounded theory informed data collection and analysis. One U.S. academic medical center. We iteratively collected and analyzed semistructured interviews with 22 surrogates for 19 patients. None. Through several rounds of coding, interview notes, reflexive memos, and group discussion, we developed a thematic model describing the relationship between surrogate perspectives on decision-making and surrogate experiences of prognostic uncertainty. Patients ranged from 20 to 79 years of age (mean = 55 years) and had primary diagnoses of stroke ( n = 13; 68%), traumatic brain injury ( n = 5; 26%), and anoxic brain injury after cardiac arrest ( n = 1; 5%). Patients were predominantly male ( n = 12; 63%), whereas surrogates were predominantly female ( n = 13; 68%). Two distinct perspectives on decision-making emerged: one group of surrogates felt a clear sense of agency around decision-making, whereas the other group reported a more passive role in decision-making, such that they did not even perceive there being a decision to make. Surrogates in both groups identified prognostic uncertainty as the central challenge in SABI, but they managed it differently. Only surrogates who felt they were actively deciding described time-limited trials as helpful. In this qualitative study, not all surrogate "decision-makers" viewed themselves as making decisions. Nearly all struggled with prognostic uncertainty. Our findings underline the need for longitudinal prognostic communication strategies in SABI targeted at surrogates' current perspectives on decision-making

Fatigue and fretting fatigue of ion-nitrided 34CrNiMo6 steel

http://www.sciencedirect.com/science/article/B6V55-429XXW3-7/1/c3e534e1b97c99b0de2b599e341d09a

Increasing returns to liquidity in futures markets

A simple model, based on the binomial theorem, is employed to predict that the probability of matching buyers and sellers increases with the number of transactions. The ask-bid spread, interpreted as a measure of liquidity, is assumed to vary negatively with the probability of matching buyers and sellers. The hypothesis addressed in this paper is that the ask-bid spread varies negatively with volume. This hypothesis is investigated for six contracts traded on the Sydney Futures Exchange from 1980 to 1991. The results support the hypothesis for the majority of contracts studied. The implication of these results is that futures trading can be expected to become concentrated geographically in a few key locations, and within exchanges in a few key contracts.

Understanding cell fate acquisition in stem-cell-derived pancreatic islets using single-cell multiome-inferred regulomes

Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-β cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β cell maturation and identify sex hormones as drivers of β cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem-cell-derived islets and a framework for manipulating cell identities and maturity