Subtle heterogeneity of high-affinity choline transporter expression and localization in limbic projections of the cholinergic brainstem tegmentum

The high-affinity choline transporter (CHT) supplies the substrate, choline, for the synthesis of acetylcholine (ACh) within cholinergic neurons. Choline uptake mediated by this protein has been studied for over 30 years and many of the regulatory mechanisms governing its function are well characterized. Early studies, as well as more recent investigations, focused on specific populations of cholinergic axons in the brain, namely the cholinergic innervations of cortical, striatal, and hippocampal regions. Details of the expression and subcellular localization of the high-affinity choline transporter within the projections of the pedunculopontine (PPT) and laterodorsal (LDT) tegmental cholinergic neurons have not been examined. The studies described herein compare the cholinergic axons within two limbic regions that are innervated by the ascending projections from these brainstem nuclei. These experiments were designed to characterize: 1) the relative amount and pattern of subcellular localization of the high-affinity choline transporter protein in the axon varicosities of this projection system; 2) the co-expression of the high-affinity choline transporter and the vesicular acetylcholine transporter in these two populations of axon varicosities; and 3) the organization and possible collateralized projections of the cholinergic neurons that provide cholinergic innervation to these regions. The results of these studies indicate that the expression and localization of the high-affinity choline transporter differs only subtly across brain regions innervated by the brainstem tegmental cholinergic neurons, and suggest that these differences may be accounted for by a pattern of specific innervation arising from distinct subsets of pedunculopontine and laterodorsal tegmental cholinergic neurons

Elimination of the BKCa Channel's High-Affinity Ca2+ Sensitivity

We report here a combination of site-directed mutations that eliminate the high-affinity Ca2+ response of the large-conductance Ca2+-activated K+ channel (BKCa), leaving only a low-affinity response blocked by high concentrations of Mg2+. Mutations at two sites are required, the “Ca2+ bowl,” which has been implicated previously in Ca2+ binding, and M513, at the end of the channel's seventh hydrophobic segment. Energetic analyses of mutations at these positions, alone and in combination, argue that the BKCa channel contains three types of Ca2+ binding sites, one of low affinity that is Mg2+ sensitive (as has been suggested previously) and two of higher affinity that have similar binding characteristics and contribute approximately equally to the power of Ca2+ to influence channel opening. Estimates of the binding characteristics of the BKCa channel's high-affinity Ca2+-binding sites are provided

Digital hypertension management: clinical and cost outcomes of a pilot implementation of the OMRON hypertension management platform

ImportanceHome monitoring of blood pressure (BP) in hypertensive patients can improve outcomes, but challenges to both patient compliance and the effective transmission of home BP readings to physicians can limit the extent to which physicians can use this information to improve care. The OMRON Hypertension Management Platform (OMRON HMP) pairs a home BP cuff with a digital product that tracks data, provides reminders to improve patient compliance, and provides a streamlined source of information to physicians.ObjectiveThe primary objective of the quality improvement (QI) project was to test the hypothesis that use of the OMRON HMP could reduce the number and cost of hypertension related claims, relative to a retrospectively matched cohort of insured members. A secondary objective was to demonstrate improvement in control of BP among patients.DesignEligible members were recruited to the QI project between December 1, 2018 and December 30, 2020 and data collected for six months following recruitment. All members received the OMRON HMP intervention.SettingEnrollment and data collection were coordinated on-site at selected PCP partner providers in Western Pennsylvania. Eligible members were identified from insurance claims data as those receiving care for primary hypertension from participating primary care physicians and/or cardiologists.ParticipantsEligible members were between the ages of 35 and 85, with a diagnosis of primary hypertension. The retrospective cohort was selected from electronic medical records of Highmark-insured patients with hypertension who received care at Allegheny Health Network (AHN), a subsidiary of Highmark Health. Members were matched on baseline BP and lipid measures, age, smoking status, diabetes status, race and sex.InterventionDaily home BP readings were recorded by the OMRON HMP app. Patient data was reviewed by clinical staff on a weekly basis and treatment plans could be adjusted in response to this data.ResultsOMRON HMP users showed a significant increase in the number and cost of hypertension-related claims, contrary to the hypothesis, but did display improvements in control of BP.Conclusions and RelevanceThe use of a digital platform to facilitate at-home BP monitoring appeared to improve BP control but led to increased hypertension-related costs in the short-term

Source apportionment of circum-Arctic atmospheric black carbon from isotopes and modeling

Black carbon (BC) contributes to Arctic climate warming, yet source attributions are inaccurate due to lacking observational constraints and uncertainties in emission inventories. Year-round, isotope-constrained observations reveal strong seasonal variations in BC sources with a consistent and synchronous pattern at all Arctic sites. These sources were dominated by emissions from fossil fuel combustion in the winter and by biomass burning in the summer. The annual mean source of BC to the circum-Arctic was 39 ± 10% from biomass burning. Comparison of transport-model predictions with the observations showed good agreement for BC concentrations, with larger discrepancies for (fossil/biomass burning) sources. The accuracy of simulated BC concentration, but not of origin, points to misallocations of emissions in the emission inventories. The consistency in seasonal source contributions of BC throughout the Arctic provides strong justification for targeted emission reductions to limit the impact of BC on climate warming in the Arctic and beyond

Identifying Unique Neighborhood Characteristics to Guide Health Planning for Stroke and Heart Attack: Fuzzy Cluster and Discriminant Analyses Approaches

Socioeconomic, demographic, and geographic factors are known determinants of stroke and myocardial infarction (MI) risk. Clustering of these factors in neighborhoods needs to be taken into consideration during planning, prioritization and implementation of health programs intended to reduce disparities. Given the complex and multidimensional nature of these factors, multivariate methods are needed to identify neighborhood clusters of these determinants so as to better understand the unique neighborhood profiles. This information is critical for evidence-based health planning and service provision. Therefore, this study used a robust multivariate approach to classify neighborhoods and identify their socio-demographic characteristics so as to provide information for evidence-based neighborhood health planning for stroke and MI.The study was performed in East Tennessee Appalachia, an area with one of the highest stroke and MI risks in USA. Robust principal component analysis was performed on neighborhood (census tract) socioeconomic and demographic characteristics, obtained from the US Census, to reduce the dimensionality and influence of outliers in the data. Fuzzy cluster analysis was used to classify neighborhoods into Peer Neighborhoods (PNs) based on their socioeconomic and demographic characteristics. Nearest neighbor discriminant analysis and decision trees were used to validate PNs and determine the characteristics important for discrimination. Stroke and MI mortality risks were compared across PNs. Four distinct PNs were identified and their unique characteristics and potential health needs described. The highest risk of stroke and MI mortality tended to occur in less affluent PNs located in urban areas, while the suburban most affluent PNs had the lowest risk.Implementation of this multivariate strategy provides health planners useful information to better understand and effectively plan for the unique neighborhood health needs and is important in guiding resource allocation, service provision, and policy decisions to address neighborhood health disparities and improve population health

Neighborhood disparities in stroke and myocardial infarction mortality: a GIS and spatial scan statistics approach

<p>Abstract</p> <p>Background</p> <p>Stroke and myocardial infarction (MI) are serious public health burdens in the US. These burdens vary by geographic location with the highest mortality risks reported in the southeastern US. While these disparities have been investigated at state and county levels, little is known regarding disparities in risk at lower levels of geography, such as neighborhoods. Therefore, the objective of this study was to investigate spatial patterns of stroke and MI mortality risks in the East Tennessee Appalachian Region so as to identify neighborhoods with the highest risks.</p> <p>Methods</p> <p>Stroke and MI mortality data for the period 1999-2007, obtained free of charge upon request from the Tennessee Department of Health, were aggregated to the census tract (neighborhood) level. Mortality risks were age-standardized by the direct method. To adjust for spatial autocorrelation, population heterogeneity, and variance instability, standardized risks were smoothed using Spatial Empirical Bayesian technique. Spatial clusters of high risks were identified using spatial scan statistics, with a discrete Poisson model adjusted for age and using a 5% scanning window. Significance testing was performed using 999 Monte Carlo permutations. Logistic models were used to investigate neighborhood level socioeconomic and demographic predictors of the identified spatial clusters.</p> <p>Results</p> <p>There were 3,824 stroke deaths and 5,018 MI deaths. Neighborhoods with significantly high mortality risks were identified. Annual stroke mortality risks ranged from 0 to 182 per 100,000 population (median: 55.6), while annual MI mortality risks ranged from 0 to 243 per 100,000 population (median: 65.5). Stroke and MI mortality risks exceeded the state risks of 67.5 and 85.5 in 28% and 32% of the neighborhoods, respectively. Six and ten significant (p < 0.001) spatial clusters of high risk of stroke and MI mortality were identified, respectively. Neighborhoods belonging to high risk clusters of stroke and MI mortality tended to have high proportions of the population with low education attainment.</p> <p>Conclusions</p> <p>These methods for identifying disparities in mortality risks across neighborhoods are useful for identifying high risk communities and for guiding population health programs aimed at addressing health disparities and improving population health.</p

Research that Facilitates Praxis and Praxis Development

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Construct development: The Suicide Trigger Scale (STS-2), a measure of a hypothesized suicide trigger state

This study aims to develop the construct of a 'suicide trigger state' by exploring data gathered with a novel psychometric self-report instrument, the STS-2. The STS-2, was administered to 141 adult psychiatric patients with suicidal ideation. Multiple statistical methods were used to explore construct validity and structure. Cronbach's alpha (0.949) demonstrated excellent internal consistency. Factor analyses yielded two-component solutions with good agreement. The first component described near-psychotic somatization and ruminative flooding, while the second described frantic hopelessness. ROC analysis determined an optimal cut score for a history of suicide attempt, with significance of p < 0.03. Logistic regression analysis found items sensitive to history of suicide attempt described ruminative flooding, doom, hopelessness, entrapment and dread. The STS-2 appears to measure a distinct and novel clinical entity, which we speculatively term the 'suicide trigger state.' High scores on the STS-2 associate with reported history of past suicide attempt