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Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
OBJECTIVES/SPECIFIC AIMS: Negative symptoms of schizophrenia, including motivational deficits, social withdrawal, poverty of speech, decreased emotional reactivity, and psychomotor retardation, have been shown to be most predictive of functional impairment and poor outcome in patients with schizophrenia. Furthermore, these symptoms tend not to be responsive to antipsychotic medications. Inflammation could be one mechanism underlying these difficult to treat symptoms. METHODS/STUDY POPULATION: Three cohorts of patients, reflecting different phases of disease, were studied. One cohort was comprised of a sample of patients with deficit schizophrenia (characterized by primary and enduring negative symptoms; n=17), nondeficit patients (n=39), and healthy controls (n=28). ANOVA and multivariate general linear models were used to compare groups, and linear regression models were used to examine relationships between inflammatory cytokines and negative symptoms. The second cohort was comprised of 80 individuals at clinical high risk for psychosis from the North American Prodromal Longitudinal Study. Linear regression models examined the relationship between baseline inflammatory markers and subsequent negative symptoms at follow-up visits up to 2 years. The third cohort consisted of patients with treatment-resistant schizophrenia (TRS) on clozapine (n=10). Correlations were performed to examine relationships between inflammatory markers and negative symptoms. In a subgroup of patients from this third sample, resting state functional connectivity analyses were performed on fMRI data to explore relationships between inflammatory markers and connectivity in brain reward circuitry. RESULTS/ANTICIPATED RESULTS: In a sample of patients with the deficit syndrome of schizophrenia (n=17), a subtype of the disorder characterized by primary and enduring negative Symptoms, tumor necrosis factor (TNF) was significantly increased relative to nondeficit patients (n=39) and healthy controls (n=28; F2,57=3.51, p=0.036), and predicted total negative symptoms (β=0.31, p=0.012), alogia (β=0.30, p=0.024), and blunted affect (β=0.31, p=0.018) items of the Positive and Negative Symptom Scale in linear regression models while controlling for antipsychotics. In another sample of individuals at clinical-high risk for psychosis (n=80), baseline concentrations of TNF significantly predicted negative symptoms, including anhedonia, apathy, and loss of interest in linear regression models, at the 6-month (β=0.25, p=0.011) and 12-month follow-up (β=0.39, p=0.001). Interleukin (IL)-1 receptor antagonist also predicted these symptoms at the 6-month follow-up (β=0.21, p=0.037). In a third sample (n=10) of patients with TRS treated with clozapine, IL-1β was correlated with passive/apathetic social withdrawal (r=0.657, p=0.039) and disturbance of volition (r=0.686, p=0.029) items of the Positive and Negative Symptom Scale and the global avolition-apathy scores of the Scale for the Assessment of Negative Symptoms (r=0.751, p=0.012). Finally, in a small subsample (n=5) of patients from this TRS cohort for whom we collected fMRI data, we found resting-state functional connectivity from a right nucleus accumbens seed to a cluster in medial prefrontal cortex. We found relationships between higher inflammation and decreased connectivity for TNF (r=−0.64) and CRP (r=−0.89). DISCUSSION/SIGNIFICANCE OF IMPACT: Taken together, these preliminary data show the predicted relationship between inflammatory markers and negative symptoms and demonstrate the reproducibility of TNF and other monocytic-derived cytokines as reliably elevated in schizophrenia and associated with negative symptoms across samples of patients with schizophrenia and individuals at high risk for psychosis. Cytokines may exert their effects via their impact on brain reward circuitry, and could represent novel treatment targets for motivational deficits and negative symptoms of schizophrenia.
Good education requires student experiences that deliver lessons about practice as well as theory and that encourage students to work for the public good—especially in the operation of democratic institutions (Dewey 1923; Dewy 1938). We report on an evaluation of the pedagogical value of a research project involving 23 colleges and universities across the country. Faculty trained and supervised students who observed polling places in the 2016 General Election. Our findings indicate that this was a valuable learning experience in both the short and long terms. Students found their experiences to be valuable and reported learning generally and specifically related to course material. Postelection, they also felt more knowledgeable about election science topics, voting behavior, and research methods. Students reported interest in participating in similar research in the future, would recommend other students to do so, and expressed interest in more learning and research about the topics central to their experience. Our results suggest that participants appreciated the importance of elections and their study. Collectively, the participating students are engaged and efficacious—essential qualities of citizens in a democracy.
The basic theory of crevasse formation suggests that crevasses initiate at or near the surface. However, due to variations in stress with depth, it has been suggested that it is possible for crevasses to initiate at depths of 10–30m. From December 2006 to January 2007, hot-water drilling on Pine Island Glacier, West Antarctica, was found to trigger crevasses. Satellite imagery and field investigations in 2008, including ice cores, radar and GPS, revealed that these formed a new band of arcuate (curvilinear) crevasses around 70 km long and 100 m deep. This new band is located 10 km upstream from the previous limit of the arcuate crevasse zone. The crevasses were triggered on drilling through an exceptional ice layer at >20m depth. Ice layers within the firn will change both the strength and stress intensity. As the firn changes spatially and temporally (e.g. with the burial of an ice layer), it is possible for the position of crevasse initiation to change whilst the along-stream strain-rate profile remains constant. However, the main cause of an upstream migration of the arcuate crevasse zone on Pine Island Glacier is still likely to be an increase in strain rate.
We describe the design and performance of the Engineering Development Array, which is a low-frequency radio telescope comprising 256 dual-polarisation dipole antennas working as a phased array. The Engineering Development Array was conceived of, developed, and deployed in just 18 months via re-use of Square Kilometre Array precursor technology and expertise, specifically from the Murchison Widefield Array radio telescope. Using drift scans and a model for the sky brightness temperature at low frequencies, we have derived the Engineering Development Array’s receiver temperature as a function of frequency. The Engineering Development Array is shown to be sky-noise limited over most of the frequency range measured between 60 and 240 MHz. By using the Engineering Development Array in interferometric mode with the Murchison Widefield Array, we used calibrated visibilities to measure the absolute sensitivity of the array. The measured array sensitivity matches very well with a model based on the array layout and measured receiver temperature. The results demonstrate the practicality and feasibility of using Murchison Widefield Array-style precursor technology for Square Kilometre Array-scale stations. The modular architecture of the Engineering Development Array allows upgrades to the array to be rolled out in a staged approach. Future improvements to the Engineering Development Array include replacing the second stage beamformer with a fully digital system, and to transition to using RF-over-fibre for the signal output from first stage beamformers.
Although procedural sedation for cardioversion is a common event in emergency departments (EDs), there is limited evidence surrounding medication choices. We sought to evaluate geographic and temporal variation in sedative choice at multiple Canadian sites, and to estimate the risk of adverse events due to sedative choice.
This is a secondary analysis of one health records review, the Recent Onset Atrial Fibrillation or Flutter-0 (RAFF-0 [n=420, 2008]) and one prospective cohort study, the Recent Onset Atrial Fibrillation or Flutter-1 (RAFF-1 [n=565, 2010 – 2012]) at eight and six Canadian EDs, respectively. Sedative choices within and among EDs were quantified, and the risk of adverse events was examined with adjusted and unadjusted comparisons of sedative regimes.
In RAFF-0 and RAFF-1, the combination of propofol and fentanyl was most popular (63.8% and 52.7%) followed by propofol alone (27.9% and 37.3%). There were substantially more adverse events in the RAFF-0 data set (13.5%) versus RAFF-1 (3.3%). In both data sets, the combination of propofol/fentanyl was not associated with increased adverse event risk compared to propofol alone.
There is marked variability in procedural sedation medication choice for a direct current cardioversion in Canadian EDs, with increased use of propofol alone as a sedation agent over time. The risk of adverse events from procedural sedation during cardioversion is low but not insignificant. We did not identify an increased risk of adverse events with the addition of fentanyl as an adjunctive analgesic to propofol.
Gurga Chiya and Tepe Marani are small, adjacent mounds located close to the town of Halabja in the southern part of the Shahrizor Plain, one of the most fertile regions of Iraqi Kurdistan. Survey and excavation at these previously unexplored sites is beginning to produce evidence for human settlement spanning the sixth to the fourth millennia, c. 5600–3300 cal. b.c. In Mesopotamian chronology this corresponds to the Late Neolithic through to Chalcolithic periods; the Halaf, Ubaid, and Uruk phases of conventional culture history. In Iraqi Kurdistan, documentation of these periods—which witnessed many important transformations in prehistoric village life—is currently very thin. Here we offer a preliminary report on the emerging results from the Shahrizor Plain, with a particular focus on the description of material culture (ceramic and lithic assemblages), in order to establish a benchmark for further research. We also provide a detailed report on botanical remains and accompanying radiocarbon dates, which allow us to place this new evidence in a wider comparative framework. A further, brief account is given of Late Bronze Age material culture from the upper layers at Gurga Chiya. We conclude with observations on the significance of the Shahrizor Plain for wider research into the later prehistory of the Middle East, and the importance of preserving and investigating its archaeological record.
Updated information on the epidemiology of dementia due to Alzheimer’s disease (AD) is needed to ensure that adequate resources are available to meet current and future healthcare needs. We conducted a systematic review and meta-analysis of the incidence and prevalence of AD.
The MEDLINE and EMBASE databases were searched from 1985 to 2012, as well as the reference lists of selected articles. Included articles had to provide an original population-based estimate for the incidence and/or prevalence of AD. Two individuals independently performed abstract and full-text reviews, data extraction and quality assessments. Random-effects models were employed to generate pooled estimates stratified by age, sex, diagnostic criteria, location (i.e., continent) and time (i.e., when the study was done).
Of 16,066 abstracts screened, 707 articles were selected for full-text review. A total of 119 studies met the inclusion criteria. In community settings, the overall point prevalence of dementia due to AD among individuals 60+ was 40.2 per 1000 persons (CI95%: 29.1-55.6), and pooled annual period prevalence was 30.4 per 1000 persons (CI95%: 15.6-59.1). In community settings, the overall pooled annual incidence proportion of dementia due to AD among individuals 60+ was 34.1 per 1000 persons (CI95%: 16.4-70.9), and the incidence rate was 15.8 per 1000 person-years (CI95%: 12.9-19.4). Estimates varied significantly with age, diagnostic criteria used and location (i.e., continent).
The burden of AD dementia is substantial. Significant gaps in our understanding of its epidemiology were identified, even in a high-income country such as Canada. Future studies should assess the impact of using such newer clinical diagnostic criteria for AD dementia such as those of the National Institute on Aging–Alzheimer’s Association and/or incorporate validated biomarkers to confirm the presence of Alzheimer pathology to produce more precise estimates of the global burden of AD.
Population-based prevalence and incidence studies are essential for understanding the burden of frontotemporal dementia (FTD).
The MEDLINE and EMBASE databases were searched to identify population-based publications from 1985 to 2012, addressing the incidence and/or prevalence of FTD. References of included articles and prior systematic reviews were searched for additional studies. Two reviewers screened all abstracts and full-text reviews, abstracted data and performed quality assessments.
Twenty-six studies were included. Methodological limitations led to wide ranges in the estimates for prevalence (point prevalence 0.01-4.6 per 1000 persons; period prevalence 0.16-31.04 per 1000 persons) and incidence (0.0-0.3 per 1000 person-years). FTD accounted for an average of 2.7% (range 0-9.1%) of all dementia cases among prevalence studies that included subjects 65 and older compared to 10.2% (range 2.8-15.7%) in studies restricted to those aged less than 65. The cumulative numbers of male (373 [52.5%]) and female (338 [47.5%]) cases from studies reporting this information were nearly equal (p=0.18). The behavioural variant FTD (bvFTD) was almost four times as common as the primary progressive aphasias.
Population-based estimates for the epidemiology of FTD varied widely in the included studies. Refinements in the diagnostic process, possibly by the use of validated biomarkers or limiting case ascertainment to specialty services, are needed to obtain more precise estimates of the prevalence and incidence of FTD.
Dementia is a common neurological condition affecting many older individuals that leads to a loss of independence, diminished quality of life, premature mortality, caregiver burden and high levels of healthcare utilization and cost. This is an updated systematic review and meta-analysis of the worldwide prevalence and incidence of dementia.
The MEDLINE and EMBASE databases were searched for relevant studies published between 2000 (1985 for Canadian papers) and July of 2012. Papers selected for full-text review were included in the systematic review if they provided an original population-based estimate for the incidence and/or prevalence of dementia. The reference lists of included articles were also searched for additional studies. Two individuals independently performed abstract and full-text review, data extraction, and quality assessment of the papers. Random-effects models and/or meta-regression were used to generate pooled estimates by age, sex, setting (i.e., community, institution, both), diagnostic criteria utilized, location (i.e., continent) and year of data collection.
Of 16,066 abstracts screened, 707 articles were selected for full-text review. A total of 160 studies met the inclusion criteria. Among individuals 60 and over residing in the community, the pooled point and annual period prevalence estimates of dementia were 48.62 (CI95%: 41.98-56.32) and 69.07 (CI95%: 52.36-91.11) per 1000 persons, respectively. The respective pooled incidence rate (same age and setting) was 17.18 (CI95%: 13.90-21.23) per 1000 person-years, while the annual incidence proportion was 52.85 (CI95%: 33.08-84.42) per 1,000 persons. Increasing participant age was associated with a higher dementia prevalence and incidence. Annual period prevalence was higher in North America than in South America, Europe and Asia (in order of decreasing period prevalence) and higher in institutional compared to community and combined settings. Sex, diagnostic criteria (except for incidence proportion) and year of data collection were not associated with statistically significant different estimates of prevalence or incidence, though estimates were consistently higher for females than males.
Dementia is a common neurological condition in older individuals. Significant gaps in knowledge about its epidemiology were identified, particularly with regard to the incidence of dementia in low- and middle-income countries. Accurate estimates of prevalence and incidence of dementia are needed to plan for the health and social services that will be required to deal with an aging population.
Understanding the origin of modern communities is a fundamental goal of ecology, but reconstructing communities with durations of 103–106 years requires data from the fossil record. Early Pliocene to latest Pleistocene faunas and sediments in the Meade Basin and modern soils and rodents from the same area are used to examine the role of environmental change in the emergence of the modern community. Paleoenvironmental proxies measured on modern surface soils and paleosols are described, and faunal dynamics of fossil rodents are discussed. Mean annual precipitation (MAP) was estimated from elemental concentrations and magnetic properties, and warm-season temperature and δ18O of soil water was estimated using carbonate isotope paleothermometry on pedogenic nodules. MAP and temperature estimates from paleosols exhibit no short-term variability, no long-term trends, and generally bracket modern values. Estimated soil water δ18O values increased through time, suggesting aridification played a role in the evolution of the regional grassland ecosystem. Carbon isotope analyses of biomarkers are used to examine the abundance of C4 grasses, which suggest more C4 biomass and more variability in C4 biomass than carbonate proxies. Rodent species richness remained constant due to balanced rates of extinction and immigration, both of which show episodic spikes consistent with a balance between forcing mechanisms that result in equilibrium on long time scales. Overall, these results suggest that different mechanisms of faunal change may be acting at different time scales, although the stratigraphic resolution of paleoenvironmental proxies needs to be increased, and body size and dietary distributions of rodents need to be determined before which processes of change are most important can be decided.
Recent studies suggest that sand can serve as a vehicle for exposure of humans to pathogens at beach sites, resulting in increased health risks. Sampling for microorganisms in sand should therefore be considered for inclusion in regulatory programmes aimed at protecting recreational beach users from infectious disease. Here, we review the literature on pathogen levels in beach sand, and their potential for affecting human health. In an effort to provide specific recommendations for sand sampling programmes, we outline published guidelines for beach monitoring programmes, which are currently focused exclusively on measuring microbial levels in water. We also provide background on spatial distribution and temporal characteristics of microbes in sand, as these factors influence sampling programmes. First steps toward establishing a sand sampling programme include identifying appropriate beach sites and use of initial sanitary assessments to refine site selection. A tiered approach is recommended for monitoring. This approach would include the analysis of samples from many sites for faecal indicator organisms and other conventional analytes, while testing for specific pathogens and unconventional indicators is reserved for high-risk sites. Given the diversity of microbes found in sand, studies are urgently needed to identify the most significant aetiological agent of disease and to relate microbial measurements in sand to human health risk.
This report summarises the aims and methods of the Fezzan Project, a new interdisciplinary investigation of human settlement in the Saharan environment of southern Libya. The work follows up earlier British work by Charles Daniels on the Garamantes and focuses on the Wadi el-Agial in the vicinity of Germa (ancient Garama). The time frame of the project is the last 12,000 years. A variety of methodologies has been employed, including topographic survey, standing building recording, excavation, field walking, palaeobotanical and faunal sampling, geophysics and human bone analysis.