Incidence of and Risk Factors for Sick Sinus Syndrome in the General Population

AbstractBackgroundLittle is known about the incidence of and risk factors for sick sinus syndrome (SSS), a common indication for pacemaker implantation.ObjectivesThis study sought to describe the epidemiology of SSS.MethodsThis analysis included 20,572 participants (mean baseline age 59 years, 43% male) in the ARIC (Atherosclerosis Risk In Communities) study and the CHS (Cardiovascular Health Study), who at baseline were free of prevalent atrial fibrillation and pacemaker therapy, had a heart rate of ≥50 beats/min unless using beta blockers, and were identified as of white or black race. Incident SSS cases were identified by hospital discharge International Classification of Disease-revision 9-Clinical Modification code 427.81 and validated by medical record review.ResultsDuring an average 17 years of follow-up, 291 incident SSS cases were identified (unadjusted rate 0.8 per 1,000 person-years). Incidence increased with age (hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 1.47 to 2.05 per 5-year increment), and blacks had a 41% lower risk of SSS than whites (HR: 0.59; 95% CI: 0.37 to 0.98). Incident SSS was associated with greater baseline body mass index, height, N-terminal pro–B-type natriuretic peptide, and cystatin C, with longer QRS interval, with lower heart rate, and with prevalent hypertension, right bundle branch block, and cardiovascular disease. We project that the annual number of new SSS cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060.ConclusionsBlacks have a lower risk of SSS than whites, and several cardiovascular risk factors were associated with incident SSS. With the aging of the population, the number of Americans with SSS will increase dramatically over the next 50 years

Breakdown of the Central Synapses in C9orf72-Linked ALS/FTD

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease that leads to the death of motor and cortical neurons. The clinical manifestations of ALS are heterogenous, and efficacious treatments to significantly slow the progression of the disease are lacking. Cortical hyper-excitability is observed pre-symptomatically across disease-causative genetic variants, as well as in the early stages of sporadic ALS, and typically precedes motor neuron involvement and overt neurodegeneration. The causes of cortical hyper-excitability are not yet fully understood but is mainly agreed to be an early event. The identification of the nucleotide repeat expansion (GGGGCC)n in the C9ORF72 gene has provided evidence that ALS and another neurodegenerative disease, frontotemporal dementia (FTD), are part of a disease spectrum with common genetic origins. ALS and FTD are diseases in which synaptic dysfunction is reported throughout disease onset and stages of progression. It has become apparent that ALS/FTD-causative genes, such as C9ORF72, may have roles in maintaining the normal physiology of the synapse, as mutations in these genes often manifest in synaptic dysfunction. Here we review the dysfunctions of the central nervous system synapses associated with the nucleotide repeat expansion in C9ORF72 observed in patients, organismal, and cellular models of ALS and FTD

Intentional research design in implementation science: implications for the use of nomothetic and idiographic assessment

The advancement of implementation science is dependent on identifying assessment strategies that can address implementation and clinical outcome variables in ways that are valid, relevant to stakeholders, and scalable. This paper presents a measurement agenda for implementation science that integrates the previously disparate assessment traditions of idiographic and nomothetic approaches. Although idiographic and nomothetic approaches are both used in implementation science, a review of the literature on this topic suggests that their selection can be indiscriminate, driven by convenience, and not explicitly tied to research study design. As a result, they are not typically combined deliberately or effectively. Thoughtful integration may simultaneously enhance both the rigor and relevance of assessments across multiple levels within health service systems. Background on nomothetic and idiographic assessment is provided as well as their potential to support research in implementation science. Drawing from an existing framework, seven structures (of various sequencing and weighting options) and five functions (Convergence, Complementarity, Expansion, Development, Sampling) for integrating conceptually distinct research methods are articulated as they apply to the deliberate, design-driven integration of nomothetic and idiographic assessment approaches. Specific examples and practical guidance are provided to inform research consistent with this framework. Selection and integration of idiographic and nomothetic assessments for implementation science research designs can be improved. The current paper argues for the deliberate application of a clear framework to improve the rigor and relevance of contemporary assessment strategies

Assigning chemoreceptors to chemosensory pathways in Pseudomonas aeruginosa

In contrast to Escherichia coli, a model organism for chemotaxis that has 5 chemoreceptors and a single chemosensory pathway, Pseudomonas aeruginosa PAO1 has a much more complex chemosensory network, which consists of 26 chemoreceptors feeding into four chemosensory pathways. While several chemoreceptors were rigorously linked to specific pathways in a series of experimental studies, for most of them this information is not available. Thus, we addressed the problem computationally. Protein–protein interaction network prediction, coexpression data mining, and phylogenetic profiling all produced incomplete and uncertain assignments of chemoreceptors to pathways. However, comparative sequence analysis specifically targeting chemoreceptor regions involved in pathway interactions revealed conserved sequence patterns that enabled us to unambiguously link all 26 chemoreceptors to four pathways. Placing computational evidence in the context of experimental data allowed us to conclude that three chemosensory pathways in P. aeruginosa utilize one chemoreceptor per pathway, whereas the fourth pathway, which is the main system controlling chemotaxis, utilizes the other 23 chemoreceptors. Our results show that while only a very few amino acid positions in receptors, kinases, and adaptors determine their pathway specificity, assigning receptors to pathways computationally is possible. This requires substantial knowledge about interacting partners on a molecular level and focusing comparative sequence analysis on the pathway-specific regions. This general principle should be applicable to resolving many other receptor–pathway interactions

Ultrasensitive force and displacement detection using trapped ions

The ability to detect extremely small forces is vital for a variety of disciplines including precision spin-resonance imaging, microscopy, and tests of fundamental physical phenomena. Current force-detection sensitivity limits have surpassed 1 $aN/\sqrt{Hz}$ (atto $=10^{-18}$) through coupling of micro or nanofabricated mechanical resonators to a variety of physical systems including single-electron transistors, superconducting microwave cavities, and individual spins. These experiments have allowed for probing studies of a variety of phenomena, but sensitivity requirements are ever-increasing as new regimes of physical interactions are considered. Here we show that trapped atomic ions are exquisitely sensitive force detectors, with a measured sensitivity more than three orders of magnitude better than existing reports. We demonstrate detection of forces as small as 174 $yN$ (yocto $=10^{-24}$), with a sensitivity 390$\pm150$ $yN/\sqrt{Hz}$ using crystals of $n=60$ $^{9}$Be$^{+}$ ions in a Penning trap. Our technique is based on the excitation of normal motional modes in an ion trap by externally applied electric fields, detection via and phase-coherent Doppler velocimetry, which allows for the discrimination of ion motion with amplitudes on the scale of nanometers. These experimental results and extracted force-detection sensitivities in the single-ion limit validate proposals suggesting that trapped atomic ions are capable of detecting of forces with sensitivity approaching 1 $yN/\sqrt{Hz}$. We anticipate that this demonstration will be strongly motivational for the development of a new class of deployable trapped-ion-based sensors, and will permit scientists to access new regimes in materials science.Comment: Expanded introduction and analysis. Methods section added. Subject to press embarg

Tracing PAHs and Warm Dust Emission in the Seyfert Galaxy NGC 1068

We present a study of the nearby Seyfert galaxy NGC 1068 using mid- and far- infrared data acquired with the IRAC, IRS, and MIPS instruments aboard the Spitzer Space Telescope. The images show extensive 8 um and 24 um emission coinciding with star formation in the inner spiral approximately 15" (1 kpc) from the nucleus, and a bright complex of star formation 47" (3 kpc) SW of the nucleus. The brightest 8 um PAH emission regions coincide remarkably well with knots observed in an Halpha image. Strong PAH features at 6.2, 7.7, 8.6, and 11.3 um are detected in IRS spectra measured at numerous locations inside, within, and outside the inner spiral. The IRAC colors and IRS spectra of these regions rule out dust heated by the AGN as the primary emission source; the SEDs are dominated by starlight and PAH emission. The equivalent widths and flux ratios of the PAH features in the inner spiral are generally consistent with conditions in a typical spiral galaxy ISM. Interior to the inner spiral, the influence of the AGN on the ISM is evident via PAH flux ratios indicative of a higher ionization parameter and a significantly smaller mean equivalent width than observed in the inner spiral. The brightest 8 and 24 um emission peaks in the disk of the galaxy, even at distances beyond the inner spiral, are located within the ionization cones traced by [O III]/Hbeta, and they are also remarkably well aligned with the axis of the radio jets. Although it is possible that radiation from the AGN may directly enhance PAH excitation or trigger the formation of OB stars that subsequently excite PAH emission at these locations in the inner spiral, the orientation of collimated radiation from the AGN and star formation knots in the inner spiral could be coincidental. (abridged)Comment: 20 pages, 11 figures; AJ, accepted; full resolution version available at http://spider.ipac.caltech.edu/staff/jhhowell/astro/howelln1068.pd

Chiral unitary approach to S-wave meson baryon scattering in the strangeness S=0 sector

We study the S-wave interaction of mesons with baryons in the strangeness S=0 sector in a coupled channel unitary approach. The basic dynamics is drawn from the lowest order meson baryon chiral Lagrangians. Small modifications inspired by models with explicit vector meson exchange in the t-channel are also considered. In addition the pi pi N channel is included and shown to have an important repercussion in the results, particularly in the isospin 3/2 sector.Comment: 23 pages, LaTeX, 21 figure

A mouse model with widespread expression of the C9orf72-linked glycine-arginine dipeptide displays non-lethal ALS/FTD-like phenotypes

Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single DPR to disease pathogenesis. We show here that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is also reported in vivo in our novel knock-in mouse model characterized by widespread central nervous system (CNS) expression of the short-length poly-GR. We observe sex-specific chronic ALS/FTD-like phenotypes in these mice, including mild motor neuron loss, but no TDP-43 mis-localization, as well as motor and cognitive impairments. We suggest that this model can serve as the foundation for phenotypic exacerbation through second-hit forms of stress