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Background: Our aim was to develop a National Quality Indicators Set for the Care of Adults Hospitalized for Neurological Problems, to serve as a foundation to build regional or national quality initiatives in Canadian neurology centres. Methods: We used a national eDelphi process to develop a suite of quality indicators and a parallel process of surveys and patient focus groups to identify patient priorities. Canadian content and methodology experts were invited to participate. To be included, >70% of participants had to rate items as critical and <15% had to rate it as not important. Two rounds of surveys and consensus meetings were used identify and rank indicators, followed by national consultation with members of the Canadian Neurological Society. Results: 38 neurologists and methodologists and 56 patients/caregivers participated in this project. An initial list of 91 possible quality indicators was narrowed to 40 indicators across multiple categories of neurological conditions. 21 patient priorities were identified. Conclusions: This quality indicators suite can be used regionally or nationally to drive improvement initiatives for inpatient neurology care. In addition, we identified multiple opportunities for further research where evidence was lacking or patient and provider priorities did not align.
OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.
Trace fossils record foraging behaviors, the search for resources in patchy environments, of animals in the rock record. Quantification of the strength, density, and nature of foraging behaviors enables the investigation of how these may have changed through time. Here, we present a novel approach to explore such patterns using spatial point process analyses to quantify the scale and strength of ichnofossil spatial distributions on horizontal bedding planes. To demonstrate the utility of this approach, we use two samples from the terminal Ediacaran Shibantan Member in South China (between 551 and 543 Ma) and the early Cambrian Nagaur Sandstone in northwestern India (between 539 and 509 Ma). We find that ichnotaxa on both surfaces exhibited significant nonhomogeneous lateral patterns, with distinct levels of heterogeneity exhibited by different types of trace fossils. In the Shibantan, two ichnotaxa show evidence for mutual positive aggregation over a shared resource, suggesting the ability to focus on optimal resource areas. Trace fossils from the Nagaur Sandstone exhibit more sophisticated foraging behavior, with greater niche differentiation. Critically, mark correlation functions highlight significant spatial autocorrelation of trace fossil orientations, demonstrating the greater ability of these Cambrian tracemakers to focus on optimal patches. Despite potential limitations, these analyses hint at changes in the development and optimization of foraging at the Ediacaran/Cambrian transition and highlight the potential of spatial point process analysis to tease apart subtle differences in behavior in the trace fossil record.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
ABSTRACT IMPACT: Understanding dietary patterns and nutrient intakes of the aging population may help address concerns and dietary guidelines regarding their nutritional needs. OBJECTIVES/GOALS: The objective of this study is to test the hypothesis that a healthy dietary pattern in the oldest old (aged 80 years and older) is related to greater compliance with dietary recommendations and better nutrient intake profiles. METHODS/STUDY POPULATION: We conducted a cross-sectional study of 122 participants aged 82 to 97 years old from the Geisinger Rural Aging Study (GRAS) cohort in rural Pennsylvania (n = 56 men and 66 women). The main outcome measures of the investigation were the daily nutrient intakes and food group intakes evaluated from the average of three 24-hour dietary recalls. The dietary patterns were determined by cluster analysis from 28 food groups. Diet quality and adherence to the Dietary Guidelines for Americans was assessed by the Healthy Eating Index (HEI)-2015 and the Dietary Screening Tool (DST). Recommended intakes were determined by the Recommended Dietary Allowances (RDAs) or Adequate Intakes (AIs). RESULTS/ANTICIPATED RESULTS: Less than 50% of participants met the dietary recommended intakes for vitamins D, E, K, B6, dietary fiber, zinc, potassium, and calcium. The more-nutrient-dense cluster was characterized by higher intakes of fruits and vegetables. The less-nutrient-dense cluster was characterized by higher intakes of foods including desserts and sweets. After adjusting for age, sex, and energy intake, participants in the more-nutrient-dense dietary pattern had a higher intake of vitamins A, D, K, C, fiber, and potassium (p < 0.05 for all). After adjusting for age and sex, participants in the more-nutrient-dense pattern had better diet quality assessed by the (HEI)-2015 (p < 0.001) and DST (p = 0.006). DISCUSSION/SIGNIFICANCE OF FINDINGS: Among the oldest old, many participants were found to have nutrient intakes lower than the recommended levels for fundamental nutrients suggesting that dietary guidance in addition to a dietary pattern more aligned with dietary guidelines may be beneficial for supporting healthy aging.
In this article the erratic coupling that can occur in screeching supersonic twin jets is characterised. Non-stationary acoustic analysis is used to investigate the temporal behaviour of the coupling phenomena. The results show that where the phase between the jets is time varying, the screech tone experiences interruptions. The interruptions are either correlated and experienced by both jets or are anti-correlated and only by one. During the anti-correlated interruption, the uninterrupted jet screeches as an isolated jet. The instantaneous velocity field shows that for the majority of snapshots during an acoustic interruption, the jets do not exhibit a coupled oscillation. When the jets are uninterrupted, they are oscillating in either a coupled symmetric or anti-symmetric mode. This behaviour manifests at a condition between two operating points characterised by different coupling modes. It suggests the interruptions arise due to a competition between two global modes of the flow. Despite the existence of multiple acoustic tones in the region where these modes are competing, analysis of the individual jets reveals energetic structures with only a single wavelength. It is found that jets whose own oscillation is characterised by a single wavelength can, through coupling either symmetrically or anti-symmetrically about their symmetry plane, produce different acoustic tones. These findings are consistent across three experimental facilities. The observed modes are a function of the jet spacing and nozzle pressure, therefore future studies investigating other spacings must recharacterise the encountered coupled modes. This article provides the signatures to characterise the behaviour for future studies.
This paper discusses the evidence for periodic human activity in the Cairngorm Mountains of Scotland from the late 9th millennium to the early 4th millennium cal bc. While contemporary paradigms for Mesolithic Europe acknowledge the significance of upland environments, the archaeological record for these areas is not yet as robust as that for the lowland zone. Results of excavation at Chest of Dee, along the headwaters of the River Dee, are set into a wider context with previously published excavations in the area. A variety of site types evidences a sophisticated relationship between people and a dynamic landscape through a period of changing climate. Archaeological benefits of the project include the ability to examine novel aspects of the archaeology leading to a more comprehensive understanding of Mesolithic lifeways. It also offers important lessons in site survival, archaeological investigation, and the management of the upland zone.
Bipolar disorder (BD) is a familial psychiatric disorder associated with frontotemporal and subcortical brain abnormalities. It is unclear whether such abnormalities are present in relatives without BD, and little is known about structural brain trajectories in those at risk.
Neuroimaging was conducted at baseline and at 2-year follow-up interval in 90 high-risk individuals with a first-degree BD relative (HR), and 56 participants with no family history of mental illness who could have non-BD diagnoses. All 146 subjects were aged 12–30 years at baseline. We examined longitudinal change in gray and white matter volume, cortical thickness, and surface area in the frontotemporal cortex and subcortical regions.
Compared to controls, HR participants showed accelerated cortical thinning and volume reduction in right lateralised frontal regions, including the inferior frontal gyrus, lateral orbitofrontal cortex, frontal pole and rostral middle frontal gyrus. Independent of time, the HR group had greater cortical thickness in the left caudal anterior cingulate cortex, larger volume in the right medial orbitofrontal cortex and greater area of right accumbens, compared to controls. This pattern was evident even in those without the new onset of psychopathology during the inter-scan interval.
This study suggests that differences previously observed in BD are developing prior to the onset of the disorder. The pattern of pathological acceleration of cortical thinning is likely consistent with a disturbance of molecular mechanisms responsible for normal cortical thinning. We also demonstrate that neuroanatomical differences in HR individuals may be progressive in some regions and stable in others.
We apply two methods to estimate the 21-cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly spaced triangles of antenna tiles, as well as an estimate based on data gridded to the uv-plane. The direct and gridded bispectrum estimators are applied to 21 h of high-band (167–197 MHz; z = 6.2–7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point-source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 h, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21-cm bispectrum may be accessible in less time than the 21-cm power spectrum for some wave modes, with detections in hundreds of hours.
The late Miocene is a time of strong environmental change in SW Asia. Himalayan foreland stable isotope data show a shift in the dominant vegetation of the flood plains away from trees and shrubs towards more C4 grasslands at a time when oceanic upwelling increased along the Oman margin. We present integrated geochemical and colour spectral records from International Ocean Discovery Program Site U1456 in the eastern Arabian Sea to reconstruct changing chemical weathering and erosion, as well as relative humidity during this climatic transition. Increasing hematite/goethite ratios derived from spectral data are consistent with long-term drying after c. 7.7 Ma. Times of dry conditions are largely associated with weaker chemical alteration measured by K/Rb and reduced coarse clastic flux, constrained by Si/Al and Zr/Al. A temporary phase of increased humidity from 6.3 to 5.95 Ma shows a reversal to stronger weathering and erosion. Wetter conditions can result in both more and less alteration due to the nonlinear relationship between weathering rates, precipitation and sediment transport times. Trends in relative aridity do not follow existing palaeoceanographic records and are not apparently linked to changes in Tibetan or Himalayan elevation, but more closely correlate with global cooling. An apparent opposing trend in the humidity evolution in the Indus compared to southern China, as tracked by spectrally estimated hematite/goethite, likely reflects differences in the topography in the Indus compared to the Pearl River drainage basins, as well as the generally wetter climate in southern China.
The K/Ar characteristics of 53 clay assemblages (Triassic–Cretaceous), representing the detrital, volcanogenic and arid-facies clay mineral associations, are interpreted in relation to their mineralogy, chronostratic age and geological origins. The K-bearing mineral components of the 1–2 μm, 0.2–1 μm and <0.2 μm fractions of each clay assemblage together display one of two characteristic patterns of K2O and 40Ar values (the K/Ar signature of the assemblage) on a 40Ar/K2O correlation diagram. Interpretation of the K/Ar signatures indicates that: (1) all of these clay assemblages are apparently unaffected by burial diagenetic illitization; (2) the Jurassic and Cretaceous detrital clay assemblages are derived from the reworking of weathered Caledonian metasediments (420 500 Ma) and weathered kaolin-bearing sediments of Upper Devonian/ Carboniferous age; and (3) the role played by palaeoclimate in developing the pattern of clay minerals in the Mesozoic sediments of England is much less significant than previously believed.
The mineralogy, petrology and trace element geochemistry of volcanogenic glauconites and smectite-rich clays are described and related to clay assemblages in Lower and Upper Cretaceous sediments of southern England and Northern Ireland. Volcanogenic glauconite grains represent argillized lava particles of predominantly mafic composition and may have been derived from submarine basaltic magmatism; they occur in all the sediments examined (Aptian-Senonian), and are particularly abundant in the Cenomanian-Campanian Hibernian Greensand of Antrim. The smectite-rich clays in southern England have developed by the argillization of predominantly acid or alkaline ash during early diagenesis. Three types of volcanogenic deposit are recognized. Primary bentonites are thin ash-falls deposited in quiet, brackish and marine waters (Speeton Clay, Ryazanian; Weald Clay, Barremian). Secondary bentonites are local accumulations of ash transported into the Cretaceous seas by rivers draining ash-blanketed, local land areas (London Platform, Portsdown Axis). These deposits are well-developed in the Sandgate Beds, Folkestone Beds and their contiguous deposits, and the lower part of the Gault (Upper Aptian-Middle Albian). The ash originated from penecontemporaneous, subaerial vulcanism located in the southern part of the North Sea. The most conspicuous phase of activity occurred during late Aptian times and has been dated by 40Ar/39Ar isotope analysis at 112 m.y. Bentonitic clays and marls are widespread accumulations of argillized ash that occur as a fine-grained fringing facies to glauconitic quartz sand facies. They make up the upper part of the Atherfleld Clay (Aptian) and the upper part of the Gault (Upper Albian), and they are associated respectively with the Hythe Beds (Aptian) and the Upper Greensand (Upper Albian). They may also occur in the lower part of the Lower Chalk (Cenomanian). The distribution pattern of these smectite-rich clays in southern England is related to the changing palaeogeography of the area in Cretaceous times, and the general coincidence of extensive glaueonite deposits and smectite-rich clays in the Middle and Upper Cretaceous of western Europe and along the eastern seaboard of North America is briefly discussed.
A small 33 ± 0.8 Ma lamproite pluton is exposed in the midst of a 23–26 Ma basalt-rhyolite province in Middle Park, NW Colorado. It contains abundant phlogopite phenocrysts in a fine-grained groundmass of analcime pseudomorphs after leucite, biotite, potassic richterite, apatite, ilmenite and accessory diopside. The phlogopite phenocryst cores contain ∼4 wt.% TiO2, 1% Cr2O3 and 0.2% BaO. The smallest groundmass biotites have normal pleochroism but compositions unlike any previously reported, with ∼2% Al2O3, ∼8% TiO2 and F <1.5%. Apart from those elements affected by leucite alteration, both the elemental and isotopic composition of this lamproite are close to those of the Leucite Hills, Wyoming. Its Nd-isotopic model age (TDM = 1.6 Ga) is outside the Leucite Hills range but within that of other Tertiary strongly potassic magmatism in the region underlain by the Wyoming craton. Evidence from both teleseismic tomography and the mantle xenoliths within other western USA mafic ultrapotassic igneous suites shows that the total lithospheric thickness beneath NW Colorado was probably ∼150–200 km at 33 Ma, when the Middle Park lamproite was emplaced. This is an important constraint on tectonomagmatic models for the Cenozoic evolution of this northernmost part of the Rio Grande rift system.
Introduction: The ECG diagnosis of acute coronary occlusion (ACO) in the setting of ventricular paced rhythm (VPR) is purported to be impossible. However, VPR has a similar ECG morphology to LBBB. The validated Smith-modified Sgarbossa criteria (MSC) have high sensitivity (Sens) and specificity (Spec) for ACO in LBBB. MSC consist of 1 of the following in 1 lead: concordant ST Elevation (STE) 1 mm, concordant ST depression 1 mm in V1-V3, or ST/S ratio <−0.25 (in leads with 1 mm STE). We hypothesized that the MSC will have higher Sens for diagnosis of ACO in VPR when compared to the original Sgarbossa criteria. We report preliminary findings of the Paced Electrocardiogram Requiring Fast Emergency Coronary Therapy (PERFECT) study Methods: The PERFECT study is a retrospective, multicenter, international investigation of ED patients from 1/2008 - 12/2016 with VPR on the ECG and symptoms suggestive of acute coronary syndrome (e.g. chest pain or shortness of breath). Data from four sites are presented. Acute myocardial infarction (AMI) was defined by the Third Universal Definition of AMI. A blinded cardiologist adjudicated ACO, defined as thrombolysis in myocardial infarction score 0 or 1 on coronary angiography; a pre-defined subgroup of ACO patients with peak cardiac troponin (cTn) >100 times the 99% upper reference limit (URL) of the cTn assay was also analyzed. Another blinded physician measured all ECGs. Statistics were by Mann Whitney U, Chi-square, and McNemars test. Results: The ACO and No-AMI groups consisted of 15 and 79 encounters, respectively. For the ACO and No-AMI groups, median age was 78 [IQR 72-82] vs. 70 [61-75] and 13 (86%) vs. 48 (61%) patients were male. The median peak cTn ratio (cTn/URL) was 260 [33-663] and 0.5 [0-1.3] for ACO vs. no-AMI. The Sens and Spec for the MSC and the original Sgarbossa criteria were 67% (95%CI 39-87) vs. 46% (22-72; p=0.25) and 99% (92-100) vs. 99% (92-100; p=0.5). In pre-defined subgroup analysis of ACO patients with peak cTn >100 times the URL (n=10), the Sens was 90% (54-100) for the MSC vs. 60% (27- 86) for original Sgarbossa criteria (p=0.25). Conclusion: ACO in VPR is an uncommon condition. The MSC showed good Sens for diagnosis of ACO in the presence of VPR, especially among patients with high peak cTn, and Spec was excellent. These methods and results are consistent with studies that have used the MSC to diagnose ACO in LBBB.
We present techniques developed to calibrate and correct Murchison Widefield Array low-frequency (72–300 MHz) radio observations for polarimetry. The extremely wide field-of-view, excellent instantaneous (u, v)-coverage and sensitivity to degree-scale structure that the Murchison Widefield Array provides enable instrumental calibration, removal of instrumental artefacts, and correction for ionospheric Faraday rotation through imaging techniques. With the demonstrated polarimetric capabilities of the Murchison Widefield Array, we discuss future directions for polarimetric science at low frequencies to answer outstanding questions relating to polarised source counts, source depolarisation, pulsar science, low-mass stars, exoplanets, the nature of the interstellar and intergalactic media, and the solar environment.
Despite the known heightened risk and burden of various somatic diseases in people with depression, very little is known about physical health multimorbidity (i.e. two or more physical health co-morbidities) in individuals with depression. This study explored physical health multimorbidity in people with clinical depression, subsyndromal depression and brief depressive episode across 43 low- and middle-income countries (LMICs).
Cross-sectional, community-based data on 190 593 individuals from 43 LMICs recruited via the World Health Survey were analysed. Multivariable logistic regression analysis was done to assess the association between depression and physical multimorbidity.
Overall, two, three and four or more physical health conditions were present in 7.4, 2.4 and 0.9% of non-depressive individuals compared with 17.7, 9.1 and 4.9% among people with any depressive episode, respectively. Compared with those with no depression, subsyndromal depression, brief depressive episode and depressive episode were significantly associated with 2.62, 2.14 and 3.44 times higher odds for multimorbidity, respectively. A significant positive association between multimorbidity and any depression was observed across 42 of the 43 countries, with particularly high odds ratios (ORs) in China (OR 8.84), Laos (OR 5.08), Ethiopia (OR 4.99), the Philippines (OR 4.81) and Malaysia (OR 4.58). The pooled OR for multimorbidity and depression estimated by meta-analysis across 43 countries was 3.26 (95% confident interval 2.98–3.57).
Our large multinational study demonstrates that physical health multimorbidity is increased across the depression spectrum. Public health interventions are required to address this global health problem.
There is a need for clinical tools to identify cultural issues in diagnostic assessment.
To assess the feasibility, acceptability and clinical utility of the DSM-5 Cultural Formulation Interview (CFI) in routine clinical practice.
Mixed-methods evaluation of field trial data from six countries. The CFI was administered to diagnostically diverse psychiatric out-patients during a diagnostic interview. In post-evaluation sessions, patients and clinicians completed debriefing qualitative interviews and Likert-scale questionnaires. The duration of CFI administration and the full diagnostic session were monitored.
Mixed-methods data from 318 patients and 75 clinicians found the CFI feasible, acceptable and useful. Clinician feasibility ratings were significantly lower than patient ratings and other clinician-assessed outcomes. After administering one CFI, however, clinician feasibility ratings improved significantly and subsequent interviews required less time.
The CFI was included in DSM-5 as a feasible, acceptable and useful cultural assessment tool.