BACKGROUND:The frequency of cardiac rhythm abnormalities and their risk factors in community-dwelling adults are not well characterized.
METHODS:We determined the frequency of rhythm abnormalities in ...the UK Biobank, a national prospective cohort. We tested associations between risk factors and incident rhythm abnormalities using multivariable proportional hazards regression.
RESULTS:Of 502 627 adults (median age, 58 years interquartile range, 13; 54.4% women), 2.35% had a baseline rhythm abnormality. The prevalence increased with age with 4.84% of individuals aged 65 to 73 years affected. During 3 368 332 person-years of follow-up, 15 906 new rhythm abnormalities were detected (4.72 per 1000 person-years; 95% confidence interval CI4.65–4.80). Atrial fibrillation (3.11 per 1000 person-years; 95% CI3.05–3.17), bradyarrhythmias (0.89 per 1000 person-years; 95% CI0.86–0.92), and conduction system diseases (1.06 per 1000 person-years; 95% CI1.02–1.09) were more common than supraventricular (0.51 per 1000 person-years; 95% CI0.48–0.53) and ventricular arrhythmias (0.57 per 1000 person-years; 95% CI0.55–0.60). Older age (hazard ratio HR2.35 per 10-year increase; 95% CI2.29–2.41; P<0.01), male sex (HR1.83; 95% CI1.76–1.89; P<0.01), hypertension (HR1.49; 95% CI1.44–1.54; P<0.01), chronic kidney disease (HR1.95; 95% CI1.67–2.27; P<0.01), and heart failure (HR1.99; 95% CI1.76–2.26; P<0.01) were associated with new rhythm abnormalities.
CONCLUSIONS:The frequency of rhythm abnormalities in middle-aged to older community-dwelling adults is substantial. Atrial fibrillation, bradyarrhythmias, and conduction system diseases account for most rhythm conditions.
The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability
. Yet, recent studies have ...demonstrated that brain ageing is sensitive to circulatory proteins
. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The human brain vasculature is of great medical importance: its dysfunction causes disability and death
, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of ...nearly all brain disorders
. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This database study assesses the misclassification of death reports for 2 medical devices within the US Food and Drug Administration’s Manufacturer and User Facility Device Experience database.
Despite growing evidence of cardiovascular complications associated with coronavirus disease 2019 (COVID-19), there are few data regarding the performance of transthoracic echocardiography (TTE) and ...the spectrum of echocardiographic findings in this disease.
A retrospective analysis was performed among adult patients admitted to a quaternary care center in New York City between March 1 and April 3, 2020. Patients were included if they underwent TTE during the hospitalization after a known positive diagnosis for COVID-19. Demographic and clinical data were obtained using chart abstraction from the electronic medical record.
Of 749 patients, 72 (9.6%) underwent TTE following positive results on severe acute respiratory syndrome coronavirus-2 polymerase chain reaction testing. The most common clinical indications for TTE were concern for a major acute cardiovascular event (45.8%) and hemodynamic instability (29.2%). Although most patients had preserved biventricular function, 34.7% were found to have left ventricular ejection fractions ≤ 50%, and 13.9% had at least moderately reduced right ventricular function. Four patients had wall motion abnormalities suggestive of stress-induced cardiomyopathy. Using Spearman rank correlation, there was an inverse relationship between high-sensitivity troponin T and left ventricular ejection fraction (ρ = -0.34, P = .006). Among 20 patients with prior echocardiograms, only two (10%) had new reductions in LVEF of >10%. Clinical management was changed in eight individuals (24.2%) in whom TTE was ordered for concern for acute major cardiovascular events and three (14.3%) in whom TTE was ordered for hemodynamic evaluation.
This study describes the clinical indications for use and diagnostic performance of TTE, as well as findings seen on TTE, in hospitalized patients with COVID-19. In appropriately selected patients, TTE can be an invaluable tool for guiding COVID-19 clinical management.
•URO17 demonstrated an overall sensitivity of 90% and a specificity of 88%.•No controls demonstrated a positive URO17 result, and URO17 superseded urine cytology detection of low-grade and high-grade ...Ta.•False positive results were associated with inflamed tissue or urothelial atypia on histology.•The combined interpretation of cytomorphology (high specificity of cytology) and URO17 (improves sensitivity) will yield a comprehensive result for patient management.
: The gold standard for detecting bladder cancer is cystoscopy with biopsy or transurethral resection confirming histologic diagnosis. URO17® employs a chromogenically labeled monoclonal antibody to keratin 17 (k17), an intermediate filament cytoskeleton molecule associated with bladder, pancreatic, and cervical cancers. Preliminary studies evaluating k17 demonstrated a high sensitivity and specificity for the detection of bladder cancer, supporting the need for further study.
To evaluate the sensitivity and specificity of URO17.
This is a cross-sectional study of participants undergoing urologic procedures between July 6, 2018 and July 17, 2019 at a single institution. Patients undergoing cystectomy, endoscopic bladder and/or upper tract procedure for probable urothelial carcinoma comprised cases; patients undergoing urologic procedures for other reasons comprised the control group (i.e. prostatectomy, nephrectomy, etc.). Voided urine samples were at the time of procedure; a minority of participants underwent multiple resections in the study period, thus, as many as three urine samples were taken from any given participant. Samples were distributed for blinded testing with URO17. Sensitivity and specificity were calculated.
In 152 participants and 167 samples, URO17 demonstrated an overall sensitivity of 90% and 92% and a specificity of 88% and 87%, respectively. In 76 participants and 91 samples from patients with suspected urothelial carcinoma, the sensitivity was 90% and 92%, and the specificity was 50% and 54%, respectively. No controls demonstrated a positive URO17 result, and URO17 superseded urine cytology detection of low-grade and high-grade Ta. False positive results were associated with inflamed tissue or urothelial atypia on histology; the large majority had a history of intravesical therapy.
Limitations include cross-sectional design and convenience sampling. URO17 may improve sensitivity of urine cytology in the detection of urothelial cancer, though further study is required to refine the application of this biomarker in clinical practice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There are multiple levels of processing relevant to reading that vary in their visual, sublexical, and lexical orthographic processing demands. Segregating distinct cortical sources for each of these ...levels has been challenging in EEG studies of early readers. To address this challenge, we applied recent advances in analyzing high‐density EEG using Steady‐State Visual Evoked Potentials (SSVEPs) via data‐driven Reliable Components Analysis (RCA) in a group of early readers spanning from kindergarten to second grade. Three controlled stimulus contrasts—familiar words versus unfamiliar pseudofonts, familiar words versus pseudowords, and pseudowords versus nonwords—were used to isolate coarse print tuning, lexical processing, and sublexical orthography‐related processing, respectively. First, three overlapping yet distinct neural sources—left vOT, dorsal parietal, and primary visual cortex were revealed underlying coarse print tuning. Second, we segregated distinct cortical sources for the other two levels of processing: lexical fine tuning over occipito‐temporal/parietal regions; sublexical orthographic fine tuning over left occipital regions. Finally, exploratory group analyses based on children's reading fluency suggested that coarse print tuning emerges early even in children with limited reading knowledge, while sublexical and higher‐level lexical processing emerge only in children with sufficient reading knowledge.
Research Highlights
Cognitive processes underlying coarse print tuning, sublexical, and lexical fine tuning were examined in beginning readers.
Three overlapping yet distinct neural sources—left ventral occipito‐temporal (vOT), left temporo‐parietal, and primary visual cortex—were revealed underlying coarse print tuning.
Responses to sublexical orthographic fine tuning were found over left occipital regions, while responses to higher‐level linguistic fine tuning were found over occipito‐temporal/parietal regions.
Exploratory group analyses suggested that coarse print tuning emerges in children with limited reading knowledge, while sublexical and higher‐level linguistic fine tuning effects emerge in children with sufficient reading knowledge.
First, three overlapping yet distinct neural sources—left vOT, dorsal parietal, and primary visual cortex were revealed underlying coarse print tuning. Second, we segregated distinct cortical sources for the other two levels of processing: lexical fine tuning over occipitotempopral/parietal regions; sublexical orthographic fine tuning over left occipital regions.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Abstract Although the prevalence of coronary heart disease (CHD) in the United States has increased during the past 25 years, cardiovascular mortality has declined due to advances in CHD therapy and ...prevention. We sought to determine the proportion of patients with CHD who die of cardiovascular versus non-cardiovascular causes and the causes and predictors of death, in a cohort of patients with CHD. The Heart and Soul Study enrolled 1024 participants with stable CHD between 2000-02 and followed them for 10 years. Causes of mortality were assigned based on detailed review of medical records, death certificates and coroner reports by blinded adjudicators. During 7680 person years of follow up, 401 participants died. Of these deaths, 42.4% were cardiovascular and 54.4% were non-cardiovascular. Myocardial infarction, stroke, and sudden death accounted for 72% of cardiovascular deaths. Cancer, pneumonia, and sepsis accounted for 67% of non-cardiovascular deaths. Independent predictors of cardiac mortality were older age, inducible ischemia on stress echocardiography, higher resting heart rate, smoking, lower hemoglobin, and higher N-terminal pro-brain natriuretic peptide (all p values <0.05); independent predictors of non-cardiac mortality included older age, inducible ischemia, higher heart rate, lower exercise capacity, and non-use of statins (all p values <0.05). In conclusion, mortality in this cohort was more frequently due to non-cardiovascular causes, and predictors of non-cardiovascular mortality included factors traditionally associated with cardiovascular mortality.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Stem cells in many tissues sustain themselves by entering a quiescent state to avoid genomic insults and to prevent exhaustion caused by excessive proliferation. In the mammary gland, the identity ...and characteristics of quiescent epithelial stem cells are not clear. Here, we identify a quiescent mammary epithelial cell population expressing high levels of Bcl11b and located at the interface between luminal and basal cells. Bcl11bhigh cells are enriched for cells that can regenerate mammary glands in secondary transplants. Loss of Bcl11b leads to a Cdkn2a-dependent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. Gain- and loss-of-function studies show that Bcl11b induces cells to enter the G0 phase of the cell cycle and become quiescent. Taken together, these results suggest that Bcl11b acts as a central intrinsic regulator of mammary epithelial stem cell quiescence and exhaustion and is necessary for long-term maintenance of the mammary gland.
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•A subset of mammary basal epithelial cells express high levels of Bcl11b•Loss of Bcl11b impairs mammary gland development and regenerative capacity•Bcl11bhigh cells are quiescent but have potent regenerative activity in transplants
Bcl11b interacts with cell-cycle regulators to induce a quiescent state. Cai et al. describe a quiescent mammary stem cell population labeled by Bcl11b and located at the luminal-basal interface that supports mammary gland regeneration. Bcl11b sustains this population by inducing cell-cycle regulators that promote the dormant state.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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