Factors associated with mortality in patients with tuberculosis

<p>Abstract</p> <p>Background</p> <p>Known risk factors for death following a diagnosis of tuberculosis may not be applicable to current U.S. cases. We evaluated the factors associated with all-cause mortality in patients with tuberculosis in Washington State.</p> <p>Methods</p> <p>Using data from the Tuberculosis Information Management System of Washington State, we conducted a cohort study of all residents diagnosed with tuberculosis from 1993 through 2005. Death from any cause was ascertained through the Washington State Death Certificate Data Files. Proportional hazards models were used to estimate the independent effect on all-cause mortality of demographic, clinical, and behavioral characteristics.</p> <p>Results</p> <p>During a median follow-up of 6 years in 3451 patients treated for tuberculosis, there were 417 deaths. Mortality was independently associated with increasing age, male gender, HIV-coinfection, and U.S. birth. Within 1 year of tuberculosis diagnosis, treatment by a private provider and the use of directly observed therapy were also independently associated with increased mortality. In addition, an interaction term of private provider times directly observed therapy was also significantly associated with mortality.</p> <p>Conclusions</p> <p>We identified factors independently associated with increased all-cause mortality following a diagnosis of tuberculosis. The associations between mortality and provider type should be evaluated with more thorough adjustment for severity of illness, but suggest important directions for future research.</p

Associations of sperm telomere length with semen parameters, clinical outcomes and lifestyle factors in human normozoospermic samples

Background Many studies have demonstrated that lifestyle factors can affect sperm quality and fertility. Sperm telomere length (STL) has been reported as potential biomarker or sperm quality. However, no studies have investigated how lifestyle factors can affect STL and associated clinical outcomes. Objectives The purpose of this manuscript is to investigate any association between STL with lifestyle factors, semen parameters and clinical outcomes. Materials and methods Sperm telomere length was measured using real‐time PCR in normozoospermic male partners (n = 66) of couples undergoing ART treatment. Each participant also completed a detailed questionnaire about general lifestyle. Linear regression univariate analysis and ANCOVA were performed to respectively determine correlations between STL and study parameters or identify statistically significant differences in STL while controlling for age, BMI and other factors. Results Using a linear regression model, STL is positively correlated with in vitro fertilization success (n = 65, r = 0.37, P = .004) but not with embryo cleavage rates and post‐implantation clinical outcomes including gestational age‐adjusted birth weight. No associations were observed between STL and sperm count, concentration or progressive motility. We further found that STL did not associate age, BMI, health or lifestyle factors. Discussion In somatic cells, the rate of telomere shortening is influenced by a number of lifestyle factors such as smoking, diet and occupation. However, little is known about how lifestyle factors affect STL and subsequently reproductive outcome. Out data suggest that STL might have an important role mechanistically for fertilization rate regardless of sperm parameters and lifestyle factors. Conclusion The results of this study demonstrate that STL is associated with in vitro fertilization rates, but not with semen parameters nor lifestyle factors. Further investigations are warranted to identify the potential variation of STL overtime to clarify its significance as a potential biomarker in ART

The Sloan Digital Sky Survey Reverberation Mapping Project: No Evidence for Evolution in the M-sigma Relation to z~1

We present host stellar velocity dispersion measurements for a sample of 88 broad-line quasars at 0.10.6) from the Sloan Digital Sky Survey Reverberation Mapping (SDSS-RM) project. High signal-to-noise ratio coadded spectra (average S/N~30 per 69 km/s pixel) from SDSS-RM allowed decomposition of the host and quasar spectra, and measurement of the host stellar velocity dispersions and black hole (BH) masses using the single-epoch (SE) virial method. The large sample size and dynamic range in luminosity (L5100=10^(43.2-44.7) erg/s) lead to the first clear detection of a correlation between SE virial BH mass and host stellar velocity dispersion far beyond the local universe. However, the observed correlation is significantly flatter than the local relation, suggesting that there are selection biases in high-z luminosity-threshold quasar samples for such studies. Our uniform sample and analysis enable an investigation of the redshift evolution of the M-sigma relation free of caveats by comparing different samples/analyses at disjoint redshifts. We do not observe evolution of the M-sigma relation in our sample, up to z~1, but there is an indication that the relation flattens towards higher redshifts. Coupled with the increasing threshold luminosity with redshift in our sample, this again suggests certain selection biases are at work, and simple simulations demonstrate that a constant M-sigma relation is favored to z~1. Our results highlight the scientific potential of deep coadded spectroscopy from quasar monitoring programs, and offer a new path to probe the co-evolution of BHs and galaxies at earlier times.Comment: replaced with the accepted version (minor changes and updated references); ApJ in press; changed title to highlight the main resul

Site-Selective Aliphatic C–H Chlorination Using N -Chloroamides Enables a Synthesis of Chlorolissoclimide

Methods for the practical, intermolecular functionalization of aliphatic C-H bonds remain a paramount goal of organic synthesis. Free radical alkane chlorination is an important industrial process for the production of small molecule chloroalkanes from simple hydrocarbons, yet applications to fine chemical synthesis are rare. Herein, we report a site-selective chlorination of aliphatic C-H bonds using readily available N-chloroamides and apply this transformation to a synthesis of chlorolissoclimide, a potently cytotoxic labdane diterpenoid. These reactions deliver alkyl chlorides in useful chemical yields with substrate as the limiting reagent. Notably, this approach tolerates substrate unsaturation that normally poses major challenges in chemoselective, aliphatic C-H functionalization. The sterically and electronically dictated site selectivities of the C-H chlorination are among the most selective alkane functionalizations known, providing a unique tool for chemical synthesis. The short synthesis of chlorolissoclimide features a high yielding, gram-scale radical C-H chlorination of sclareolide and a three-step/two-pot process for the introduction of the β-hydroxysuccinimide that is salient to all the lissoclimides and haterumaimides. Preliminary assays indicate that chlorolissoclimide and analogues are moderately active against aggressive melanoma and prostate cancer cell lines

Deployable Optical Receiver Array Cubesat

Small satellites and cubesats often have low data transmission rates due to the use of low-gain radio links in UHF and S bands. These links typically provide up to only 1 Mbps for communication between the ground and LEO, limiting the applications and mission operations of small satellites. Optical communication technology can enable much higher data rates and is rapidly gaining hold for larger satellites, including for crosslinks within SpaceX’s Starlink constellation and upcoming NASA deep space missions. However, it has been difficult to implement on small satellites and cubesats due to the need for precision pointing on the order of arcseconds to align the narrow optical laser beam between terminals--a laser transmitter in LEO may yield a footprint less than 100 meters wide at its receiving ground station. We report the development of a 3U cubesat to demonstrate new optical communication technology that eliminates precision pointing accuracy requirements on the host spacecraft. The deployable optical receiver aperture (DORA) aims to demonstrate 1 Gbps data rates over distances of thousands of kilometers. DORA requires an easily accommodated host pointing accuracy of only 10 degrees with minimal stability, allowing the primary mission to continue without reorienting to communicate and/or enabling small satellite missions using low-cost off-the-shelf ADCS systems. To achieve this performance, DORA replaces the traditional receiving telescope on the spacecraft with a collection of wide-angle photodiodes that can identify the angle of arrival for incoming communication lasers and steer the onboard transmitting laser in the corresponding direction. This work is motivated by NASA’s plans for a lunar communications and navigation network and supported by NASA’s Space Technology Program (STP). It is ideally suited for crosslink communications among small spacecraft, especially for those forming a swarm and/or a constellation, and for surface to orbit communications. We will implement the deployable optical receiver aperture and miniature transmission telescope as a 1U payload in the 3U cubesat and conduct the demonstration flight in LEO. Future implementations of the DORA technology are expected to further enable omnidirectional receiving of multiple optical communications simultaneously and accommodate multiple transmitting modules on a single cubesat

Granulovirus PK-1 kinase activity relies on a side-to-side dimerization mode centered on the regulatory αC helix

The life cycle of Baculoviridae family insect viruses depends on the viral protein kinase, PK-1, to phosphorylate the regulatory protein, p6.9, to induce baculoviral genome release. Here, we report the crystal structure of Cydia pomenella granulovirus PK-1, which, owing to its likely ancestral origin among host cell AGC kinases, exhibits a eukaryotic protein kinase fold. PK-1 occurs as a rigid dimer, where an antiparallel arrangement of the αC helices at the dimer core stabilizes PK-1 in a closed, active conformation. Dimerization is facilitated by C-lobe:C-lobe and N-lobe:N-lobe interactions between protomers, including the domain-swapping of an N-terminal helix that crowns a contiguous β-sheet formed by the two N-lobes. PK-1 retains a dimeric conformation in solution, which is crucial for catalytic activity. Our studies raise the prospect that parallel, side-to-side dimeric arrangements that lock kinase domains in a catalytically-active conformation could function more broadly as a regulatory mechanism among eukaryotic protein kinases

CaMKK2 as an emerging treatment target for bipolar disorder

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder

The Sloan Digital Sky Survey Reverberation Mapping Project: Technical Overview

The Sloan Digital Sky Survey Reverberation Mapping project (SDSS-RM) is a dedicated multi-object RM experiment that has spectroscopically monitored a sample of 849 broad-line quasars in a single 7 deg$^2$ field with the SDSS-III BOSS spectrograph. The RM quasar sample is flux-limited to i_psf=21.7 mag, and covers a redshift range of 0.1<z<4.5. Optical spectroscopy was performed during 2014 Jan-Jul dark/grey time, with an average cadence of ~4 days, totaling more than 30 epochs. Supporting photometric monitoring in the g and i bands was conducted at multiple facilities including the CFHT and the Steward Observatory Bok telescopes in 2014, with a cadence of ~2 days and covering all lunar phases. The RM field (RA, DEC=14:14:49.00, +53:05:00.0) lies within the CFHT-LS W3 field, and coincides with the Pan-STARRS 1 (PS1) Medium Deep Field MD07, with three prior years of multi-band PS1 light curves. The SDSS-RM 6-month baseline program aims to detect time lags between the quasar continuum and broad line region (BLR) variability on timescales of up to several months (in the observed frame) for ~10% of the sample, and to anchor the time baseline for continued monitoring in the future to detect lags on longer timescales and at higher redshift. SDSS-RM is the first major program to systematically explore the potential of RM for broad-line quasars at z>0.3, and will investigate the prospects of RM with all major broad lines covered in optical spectroscopy. SDSS-RM will provide guidance on future multi-object RM campaigns on larger scales, and is aiming to deliver more than tens of BLR lag detections for a homogeneous sample of quasars. We describe the motivation, design and implementation of this program, and outline the science impact expected from the resulting data for RM and general quasar science.Comment: 25 pages, submitted to ApJS; project website at http://www.sdssrm.or

Discovery and characterization of WASP-6b, an inflated sub-Jupiter mass planet transiting a solar-type star

We report the discovery of WASP-6b, an inflated sub-Jupiter mass planet transiting every 3.3610060^{\rm + 0.0000022 }_ days a mildly metal-poor solar-type star of magnitude V = 11.9. A combined analysis of the WASP photometry, high-precision followup transit photometry and radial velocities yield a planetary mass M_{\rm p} = 0.503^_ $M_{\rm J}$ and radius R_{\rm p} = 1.224^_ $R_{\rm J}$, resulting in a density $\rho_{\rm p} = 0.27 \pm 0.05$ $\rho_{\rm J}$. The mass and radius for the host star are M_\ast = 0.88^_ $M_\odot$ and R_\ast = 0.870^_ $R_\odot$. The non-zero orbital eccentricity e = 0.054^{\rm +0.018}_ that we measure suggests that the planet underwent a massive tidal heating ~1 Gyr ago that could have contributed to its inflated radius. High-precision radial velocities obtained during a transit allow us to measure a sky-projected angle between the stellar spin and orbital axis \beta = 11^_ deg. In addition to similar published measurements, this result favors a dominant migration mechanism based on tidal interactions with a protoplanetary disk