Summary Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and ...pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging–Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β −4·0, 95% CI −5·5 to −2·6; p<0·0001; R2 0·22, p<0·0001) and with survival (–2·0, −3·2 to −0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology. Funding US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).
Abstract Background Participation in cardiac rehabilitation has been shown to decrease mortality after acute myocardial infarction, but its impact on readmissions requires examination. Methods We ...conducted a population-based surveillance study of residents discharged from the hospital after their first-ever myocardial infarction in Olmsted County, Minnesota, from January 1, 1987, to September 30, 2010. Patients were followed up through December 31, 2010. Participation in cardiac rehabilitation after myocardial infarction was determined using billing data. We used a landmark analysis approach (cardiac rehabilitation participant vs not determined by attendance in at least 1 session of cardiac rehabilitation at 90 days post-myocardial infarction discharge) to compare readmission and mortality risk between cardiac rehabilitation participants and nonparticipants accounting for propensity to participate using inverse probability treatment weighting. Results Of 2991 patients with incident myocardial infarction, 1569 (52.5%) participated in cardiac rehabilitation after hospital discharge. The cardiac rehabilitation participation rate did not change during the study period, but increased in the elderly and decreased in men and younger patients. After adjustment, cardiac rehabilitation participants had lower all-cause readmission (hazard ratio HR, 0.75; 95% confidence interval CI, 0.65-0.87; P < .001), cardiovascular readmission (HR, 0.80; 95% CI, 0.65-0.99; P = .037), noncardiovascular readmission (HR, 0.72; 95% CI, 0.61-0.85; P < .001), and mortality (HR, 0.58; 95% CI, 0.49-0.68; P < .001) risk. Conclusions Cardiac rehabilitation participation is associated with a markedly reduced risk of readmission and death after incident myocardial infarction. Improving cardiac rehabilitation participation rates may have a large impact on post-myocardial infarction healthcare resource use and outcomes.
IMPORTANCE: Polygenic risk scores comprising millions of single-nucleotide polymorphisms (SNPs) could be useful for population-wide coronary heart disease (CHD) screening. OBJECTIVE: To determine ...whether a polygenic risk score improves prediction of CHD compared with a guideline-recommended clinical risk equation. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of the predictive accuracy of a previously validated polygenic risk score was assessed among 4847 adults of white European ancestry, aged 45 through 79 years, participating in the Atherosclerosis Risk in Communities (ARIC) study and 2390 participating in the Multi-Ethnic Study of Atherosclerosis (MESA) from 1996 through December 31, 2015, the final day of follow-up. The performance of the polygenic risk score was compared with that of the 2013 American College of Cardiology and American Heart Association pooled cohort equations. EXPOSURES: Genetic risk was computed for each participant by summing the product of the weights and allele dosage across 6 630 149 SNPs. Weights were based on an international genome-wide association study. MAIN OUTCOMES AND MEASURES: Prediction of 10-year first CHD events (including myocardial infarctions, fatal coronary events, silent infarctions, revascularization procedures, or resuscitated cardiac arrest) assessed using measures of model discrimination, calibration, and net reclassification improvement (NRI). RESULTS: The study population included 4847 adults from the ARIC study (mean SD age, 62.9 5.6 years; 56.4% women) and 2390 adults from the MESA cohort (mean SD age, 61.8 9.6 years; 52.2% women). Incident CHD events occurred in 696 participants (14.4%) and 227 participants (9.5%), respectively, over median follow-up of 15.5 years (interquartile range IQR, 6.3 years) and 14.2 (IQR, 2.5 years) years. The polygenic risk score was significantly associated with 10-year CHD incidence in ARIC with hazard ratios per SD increment of 1.24 (95% CI, 1.15 to 1.34) and in MESA, 1.38 (95% CI, 1.21 to 1.58). Addition of the polygenic risk score to the pooled cohort equations did not significantly increase the C statistic in either cohort (ARIC, change in C statistic, −0.001; 95% CI, −0.009 to 0.006; MESA, 0.021; 95% CI, −0.0004 to 0.043). At the 10-year risk threshold of 7.5%, the addition of the polygenic risk score to the pooled cohort equations did not provide significant improvement in reclassification in either ARIC (NRI, 0.018, 95% CI, −0.012 to 0.036) or MESA (NRI, 0.001, 95% CI, −0.038 to 0.076). The polygenic risk score did not significantly improve calibration in either cohort. CONCLUSIONS AND RELEVANCE: In this analysis of 2 cohorts of US adults, the polygenic risk score was associated with incident coronary heart disease events but did not significantly improve discrimination, calibration, or risk reclassification compared with conventional predictors. These findings suggest that a polygenic risk score may not enhance risk prediction in a general, white middle-aged population.
Host behavior can affect host-pathogen dynamics, and sociality is predicted to increase risk of pathogen exposure. Many species minimize costs of parasitism by only aggregating seasonally, such as ...during reproductive periods, but colonial species may still be limited in their potential to evade pathogens. Bats are among the most gregarious mammals and females of many temperate species form maternity colonies in summer where they communally raise pups in both natural and anthropogenic roost structures. Social network structure may differ between natural and anthropogenic roosts in ways that affect pathogen dynamics. We used social network analysis to quantify interactions of big brown bats (Eptesicus fuscus) in a tree-roosting colony, where the colony is divided among multiple trees each day, and a building colony, where most of the colony roosts together each day. We simulated transmission of a pathogen throughout both sets of networks. We tested three hypotheses: (1) network metrics differ between pregnancy and lactation; (2) changing network structure between reproductive stages influences predicted pathogen dynamics; and (3) network metrics and predicted pathogen dynamics differ between colonies of bats in trees versus buildings. Network structure was weaker for bats roosting in trees during pregnancy and lactation compared to bats roosting in a building, and our models showed that a hypothetical pathogen would spread more rapidly for bats in the building colony. Our results are important for understanding variation in social tendencies and pathogen transmission among colonies of bats and have implications for conservation and public health. SIGNIFICANCE STATEMENT: Host behavior, particularly social behavior, can affect dynamics of wildlife pathogens. Bats are highly social mammals and females of temperate species form colonies in spring and early summer in tree or building roosts. Thermal characteristics of trees and buildings appear to differ in ways that affect roosting behavior and social interactions. We used social network analyses to quantify interactions of big brown bats in tree and building roosts and simulated consequences for pathogen dynamics. Network structure was weaker for bats roosting in trees with more frequent roost switching and relatively diffuse contacts across the network. Our models showed that a hypothetical pathogen could spread up to four times faster in a building colony compared to a colony of bats roosting in trees. Our results are important for understanding how sociality can influence pathogen dynamics in bats and have implications for conservation and public health.
Gait and balance impairments are cardinal features of Parkinson's disease (PD) that require cognitive input. However, the extent to which specific gait and balance characteristics relate to cognition ...in PD is unclear. In addition, independent models of gait and balance have not been developed from the same cohort. We aimed to i) develop models of gait and balance in a large PD cohort and ii) determine which gait and balance characteristics best related to cognition.
One hundred and ninety-eight people with PD were recruited to the Pacific Udall Center. Using six inertial sensors (APDM, Inc.), comprehensive gait measurements were collected over a 2-min continuous walk and comprehensive static balance measures were collected during a 60-second standing task. Six domains of cognition were assessed: global cognition, attention, executive function, language, memory, and visuospatial function. Correlations and hierarchical linear regression determined independent associations.
Principal components analysis identified a gait model containing four domains accounting for 80.1% of total variance: pace/turning, rhythm, variability, and trunk. The balance model contained four independent domains accounting for 84.5% of total variance: sway area/jerkiness, sway velocity, sway frequency anteroposterior, and sway frequency mediolateral. Gait domains of pace/turning and variability were strongly associated with attention and executive function. Sway area and jerkiness of balance associated with attention and visuospatial function.
Gait and balance characteristics were associated with specific types of cognition. The specific relationships between gait or balance with cognitive functions suggests shared cerebral cortical circuitry for mobility and cognitive functions.
•Separate gait and balance models consisting of different domains were identified in PD.•Pace and variability of gait were associated with attention and executive function.•Measures of static balance were associated with attention and visuospatial function.
Hepatic and biliary diseases are prevalent worldwide, but the majority of people lack access to diagnostic medical imaging for their assessment. The liver and gallbladder are readily amenable to ...sonographic examination, and ultrasound is a portable, cost-effective imaging modality suitable for use in rural and underserved areas. However, the deployment of ultrasound in these settings is limited by the lack of experienced sonographers to perform the exam. In this study, we tested an asynchronous telediagnostic system for right upper quadrant abdominal ultrasound examination operated by individuals without prior ultrasound experience to facilitate deployment of ultrasound to rural and underserved areas.
The teleultrasound system utilized in this study employs volume sweep imaging and a telemedicine app installed on a tablet which connects to an ultrasound machine. Volume sweep imaging is an ultrasound technique in which an individual scans the target region utilizing preset ultrasound sweeps demarcated by easily recognized external body landmarks. The sweeps are saved as video clips for later interpretation by an experienced radiologist. Teleultrasound scans from a Peruvian clinic obtained by individuals without prior ultrasound experience were sent to the United States for remote interpretation and quality assessment. Standard of care comparison was made to a same-day ultrasound examination performed by a radiologist.
Individuals without prior ultrasound experience scanned 144 subjects. Image quality was rated "poor" on 36.8% of exams, "acceptable" on 38.9% of exams, and "excellent" on 24.3% of exams. Among telemedicine exams of "acceptable" or "excellent" image quality (n = 91), greater than 80% of the liver and gallbladder were visualized in the majority of cases. In this group, there was 95% agreement between standard of care and teleultrasound on whether an exam was normal or abnormal, with a Cohen's kappa of 0.84 (95% CI 0.7-0.98, p <0.0001). Finally, among these teleultrasound exams of "acceptable" or "excellent" image quality, the sensitivity for cholelithiasis was 93% (95% CI 68.1%-99.8%), and the specificity was 97% (95% CI 89.5%-99.6%).
This asynchronous telediagnostic system allows individuals without prior ultrasound experience to effectively scan the liver, gallbladder, and right kidney with a high degree of agreement with standard of care ultrasound. This system can be deployed to improve access to diagnostic imaging in low-resource areas.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Forming distinct representations of multiple contexts, places, and episodes is a crucial function of the hippocampus. The dentate gyrus subregion has been suggested to fulfill this role. We have ...tested this hypothesis by generating and analyzing a mouse strain that lacks the gene encoding the essential subunit of the N-methyl-D-aspartate (NMDA) receptor NR1, specifically in dentate gyrus granule cells. The mutant mice performed normally in contextual fear conditioning, but were impaired in the ability to distinguish two similar contexts. A significant reduction in the context-specific modulation of firing rate was observed in the CA3 pyramidal cells when the mutant mice were transferred from one context to another. These results provide evidence that NMDA receptors in the granule cells of the dentate gyrus play a crucial role in the process of pattern separation.
Three key elements to precision medicine are stratification by risk, detection of pathophysiological processes as early as possible (even before clinical presentation), and alignment of mechanism of ...action of intervention(s) with an individual's molecular driver(s) of disease. Used for decades in the management of some rare diseases and now gaining broad currency in cancer care, a precision medicine approach is beginning to be adapted to cognitive impairment and dementia. This review focuses on the application of precision medicine to address the clinical and biological complexity of two common neurodegenerative causes of dementia: Alzheimer disease and Parkinson disease.
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