Identifying the molecular systems that influence cognitive resilience to Alzheimer\u27s disease in genetically diverse mice.

Individual differences in cognitive decline during normal aging and Alzheimer\u27s disease (AD) are common, but the molecular mechanisms underlying these distinct outcomes are not fully understood. We utilized a combination of genetic, molecular, and behavioral data from a mouse population designed to model human variation in cognitive outcomes to search for the molecular mechanisms behind this population-wide variation. Specifically, we used a systems genetics approach to relate gene expression to cognitive outcomes during AD and normal aging. Statistical causal-inference Bayesian modeling was used to model systematic genetic perturbations matched with cognitive data that identified astrocyte and microglia molecular networks as drivers of cognitive resilience to AD. Using genetic mapping, we identifie

Development and Pilot Feasibility Study of a Health Information Technology Tool to Calculate Mortality Risk for Patients with Asymptomatic Carotid Stenosis: The Carotid Risk Assessment Tool (CARAT)

Patients with no history of stroke but with stenosis of the carotid arteries can reduce the risk of future stroke with surgery or stenting. At present, a physicians’ ability to recommend optimal treatments based on an individual’s risk profile requires estimating the likelihood that a patient will have a poor peri-operative outcomes and the likelihood that the patient will survive long enough to gain benefit from the procedure. We describe the development of the CArotid Risk Assessment Tool (CARAT) into a 2-year mortality risk calculator within the electronic medical record, integrating the tool into the clinical workflow, training the clinical team to use the tool, and assessing the feasibility and acceptability of the tool in one clinic setting

Identifying Mechanisms of Normal Cognitive Aging Using a Novel Mouse Genetic Reference Panel.

Developing strategies to maintain cognitive health is critical to quality of life during aging. The basis of healthy cognitive aging is poorly understood; thus, it is difficult to predict who will have normal cognition later in life. Individuals may have higher baseline functioning (cognitive reserve) and others may maintain or even improve with age (cognitive resilience). Understanding the mechanisms underlying cognitive reserve and resilience may hold the key to new therapeutic strategies for maintaining cognitive health. However, reserve and resilience have been inconsistently defined in human studies. Additionally, our understanding of the molecular and cellular bases of these phenomena is poor, compounded by a lack of longitudinal molecular and cognitive data that fully capture the dynamic trajectories of cognitive aging. Here, we used a genetically diverse mouse population (B6-BXDs) to characterize individual differences in cognitive abilities in adulthood and investigate evidence of cognitive reserve and/or resilience in middle-aged mice. We tested cognitive function at two ages (6 months and 14 months) using y-maze and contextual fear conditioning. We observed heritable variation in performance on these traits

The Interrelationships of Placental Mammals and the Limits of Phylogenetic Inference

Placental mammals comprise three principal clades: Afrotheria (e.g., elephants and tenrecs), Xenarthra (e.g., armadillos and sloths), and Boreoeutheria (all other placental mammals), the relationships among which are the subject of controversy and a touchstone for debate on the limits of phylogenetic inference. Previous analyses have found support for all three hypotheses, leading some to conclude that this phylogenetic problem might be impossible to resolve due to the compounded effects of incomplete lineage sorting (ILS) and a rapid radiation. Here we show, using a genome scale nucleotide data set, microRNAs, and the reanalysis of the three largest previously published amino acid data sets, that the root of Placentalia lies between Atlantogenata and Boreoeutheria. Although we found evidence for ILS in early placental evolution, we are able to reject previous conclusions that the placental root is a hard polytomy that cannot be resolved. Reanalyses of previous data sets recover Atlantogenata + Boreoeutheria and show that contradictory results are a consequence of poorly fitting evolutionary models; instead, when the evolutionary process is better-modeled, all data sets converge on Atlantogenata. Our Bayesian molecular clock analysis estimates that marsupials diverged from placentals 157-170 Ma, crown Placentalia diverged 86-100 Ma, and crown Atlantogenata diverged 84-97 Ma. Our results are compatible with placental diversification being driven by dispersal rather than vicariance mechanisms, postdating early phases in the protracted opening of the Atlantic Ocean

Variables Associated with Intravenous Rehydration and Hospitalization in Children with Acute Gastroenteritis: A Secondary Analysis of 2 Randomized Clinical Trials

Importance: Despite guidelines endorsing oral rehydration therapy, intravenous fluids are commonly administered to children with acute gastroenteritis in high-income countries. Objective: To identify factors associated with intravenous fluid administration and hospitalization in children with acute gastroenteritis. Design, Setting, and Participants: This study is a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) probiotic trials. Participants include children aged 3 to 48 months with 3 or more watery stools in 24 hours between November 5, 2013, and April 7, 2017, for the PERC study and July 8, 2014, and June 23, 2017, for the PECARN Study. Children were from 16 pediatric emergency departments throughout Canada (6) and the US (10). Data were analyzed from November 2, 2018, to March 16, 2021. Exposures: Sex, age, preceding health care visit, distance between home and hospital, country (US vs Canada), frequency and duration of vomiting and diarrhea, presence of fever, Clinical Dehydration Scale score, oral ondansetron followed by oral rehydration therapy, and infectious agent. Main Outcomes and Measures: Intravenous fluid administration and hospitalization. Results: This secondary analysis of 2 randomized clinical trials included 1846 children (mean [SD] age, 19.1 [11.4] months; 1007 boys [54.6%]), of whom 534 of 1846 (28.9%) received oral ondansetron, 240 of 1846 (13.0%) received intravenous rehydration, and 67 of 1846 (3.6%) were hospitalized. The following were independently associated with intravenous rehydration: higher Clinical Dehydration Scale score (mild to moderate vs none, odds ratio [OR], 8.73; 95% CI, 5.81-13.13; and severe vs none, OR, 34.15; 95% CI, 13.45-86.73); country (US vs Canada, OR, 6.76; 95% CI, 3.15-14.49); prior health care visit with intravenous fluids (OR, 4.55; 95% CI, 1.32-15.72); and frequency of vomiting (per 5 episodes, OR, 1.66; 95% CI, 1.39-1.99). The following were independently associated with hospitalization: higher Clinical Dehydration Scale score (mild to moderate vs none, OR, 11.10; 95% CI, 5.05-24.38; and severe vs none, OR, 23.55; 95% CI, 7.09-78.25) and country (US vs Canada, OR, 3.37; 95% CI, 1.36-8.40). Oral ondansetron was associated with reduced odds of intravenous rehydration (OR, 0.21; 95% CI, 0.13-0.32) and hospitalization (OR, 0.44; 95% CI, 0.21-0.89). Conclusions and Relevance: Intravenous rehydration and hospitalization were associated with clinical evidence of dehydration and lack of an oral ondansetron-supported oral rehydration period. Strategies focusing on oral ondansetron administration followed by oral rehydration therapy in children with dehydration may reduce the reliance on intravenous rehydration and hospitalization. Trial Registration: ClinicalTrials.gov Identifiers: NCT01853124 (PERC) and NCT01773967 (PECARN)

Women returning to employment, education and training in Ireland: an analysis of transitions

Recent improvements in the Irish labour market have led to a substantial increase in the labour force participation rate of women in Ireland. Part of this increase has been fuelled by women moving from the home into paid employment. Much of the existing research on labour market activity among Irish women has focused on cross-sectional analyses of the stock of labour market participants. In this paper we aim to address some of the gaps in the literature by investigating the transition from home to work, and from home to education, training and employment schemes among women in Ireland during the period 1994 to 1999. We adopt a dynamic approach by drawing on the nationally representative longitudinal data in the Living in Ireland Survey. This allows us to provide, for the first time, a representative profile of returners, and to formally model the transition process in terms of supply and demand factors. The analysis also investigates the factors associated with the return to part-versus full-time work. Our analysis reveals that about one-quarter of those engaged full-time in home duties in 1994 had made a transition to paid work within the six-year period 1994-1999. The study identifies a number of key factors that influence the transition from home to work or education, training and employment schemes, including, on the supply side, age, education, previous work experience, time out of the labour force, and the presence of young children in the household, and on the demand side, macro-economic conditions and urban versus rural residence

Is there a wage premium for returning Irish migrants?

Higher rates of economic growth in recent years have led Ireland from being a country characterised by emigration to one where population inflows have become an important issue. This paper contains an analysis of one element of the current inflow. Drawing on data collected in 1998 on over 800 Irish individuals who had graduated from Irish colleges in 1992, we compare the wages of returned migrants with the wages of those who stayed in Ireland. In a recent paper, it has been argued that returned migrants accumulate skills and competencies while away that are rewarded on return to the home country. We find support for this argument for men. On average, returning males earn 10 per cent more than men who stayed in Ireland, controlling for a range of factors. However, men who say that they originally migrated for labour-related reasons earn 15 per cent more. No wage premium is found for female returning migrants relative to female stayers