Enhancing drug safety through active surveillance of observational healthcare data

Drug safety continues to be a major public health concern in the United States, with adverse drug reactions ranking as the 4th to 6th leading cause of death, and resulting in health care costs of $3.6 billion annually. Recent media attention and public scrutiny of high-profile drug safety issues have increased visibility and skepticism of the effectiveness of the current post-approval safety surveillance processes. Current proposals suggest establishing a national active drug safety surveillance system that leverages observational data, including administrative claims and electronic health records, to monitor and evaluate potential safety issues of medicines. However, the development and evaluation of appropriate strategies for systematic analysis of observational data have not yet been studied. This study introduces a novel exploratory analysis approach (Comparator-Adjusted Safety Surveillance or COMPASS) to identify drug-related adverse events in automated healthcare data. The aims of the study were: 1) to characterize the performance of COMPASS in identifying known safety issues associated with ACE inhibitor exposure within an administrative claims database; 2) to evaluate consistency of COMPASS estimates across a network of disparate databases; and 3) to explore differential effects across ingredients within ACE inhibitor class. COMPASS was observed to have improved accuracy to three other methods under consideration for an active surveillance system: observational screening, disproportionality analysis, and self-controlled case series. COMPASS performance was consistently strong within 5 different databases, though important differences in outcome estimates across the sources highlighted the substantial heterogeneity which makes pooling estimates challenging. The comparative safety analysis of products within the ACE inhibitor class provided evidence of similar risk profiles across an array of different outcomes, and raised questions about the product labeling differences and how observational studies should complement existing evidence as part of a broader safety assessment strategy. The results of this study should inform decisions about the appropriateness and utility of analyzing observational data as part of an active drug safety surveillance process. An improved surveillance system would enable a more comprehensive and timelier understanding of the safety of medicines. Such information supports patients and providers in therapeutic decision-making to minimize risks and improve the quality of care

Self-referenced continuous-variable quantum key distribution protocol

We introduce a new continuous-variable quantum key distribution (CV-QKD) protocol, self-referenced CV-QKD, that eliminates the need for transmission of a high-power local oscillator between the communicating parties. In this protocol, each signal pulse is accompanied by a reference pulse (or a pair of twin reference pulses), used to align Alice's and Bob's measurement bases. The method of phase estimation and compensation based on the reference pulse measurement can be viewed as a quantum analog of intradyne detection used in classical coherent communication, which extracts the phase information from the modulated signal. We present a proof-of-principle, fiber-based experimental demonstration of the protocol and quantify the expected secret key rates by expressing them in terms of experimental parameters. Our analysis of the secret key rate fully takes into account the inherent uncertainty associated with the quantum nature of the reference pulse(s) and quantifies the limit at which the theoretical key rate approaches that of the respective conventional protocol that requires local oscillator transmission. The self-referenced protocol greatly simplifies the hardware required for CV-QKD, especially for potential integrated photonics implementations of transmitters and receivers, with minimum sacrifice of performance. As such, it provides a pathway towards scalable integrated CV-QKD transceivers, a vital step towards large-scale QKD networks.Comment: 14 pages, 10 figures. Published versio

Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis

In sympathetic neurons, unlike most nonneuronal cells, growth factor withdrawal–induced apoptosis requires the development of competence in addition to cytochrome c release to activate caspases. Thus, although most nonneuronal cells die rapidly with cytosolic cytochrome c alone, sympathetic neurons are remarkably resistant unless they develop competence. We have identified endogenous X-linked inhibitor of apoptosis protein (XIAP) as the essential postcytochrome c regulator of caspase activation in these neurons. In contrast to wild-type neurons that are resistant to injection of cytochrome c, XIAP-deficient neurons died rapidly with cytosolic cytochrome c alone. Surprisingly, the release of endogenous Smac was not sufficient to overcome the XIAP resistance in sympathetic neurons. In contrast, the neuronal competence pathway permitted cytochrome c to activate caspases by inducing a marked reduction in XIAP levels in these neurons. Thus, the removal of XIAP inhibition appears both necessary and sufficient for cytochrome c to activate caspases in sympathetic neurons. These data identify a critical function of endogenous XIAP in regulating apoptosis in mammalian cells

HST Grism Observations of a Gravitationally Lensed Redshift 10 Galaxy

We present deep spectroscopic observations of a Lyman-break galaxy candidate (hereafter MACS1149-JD) at $z\sim9.5$ with the $\textit{Hubble}$ Space Telescope ($\textit{HST}$) WFC3/IR grisms. The grism observations were taken at 4 distinct position angles, totaling 34 orbits with the G141 grism, although only 19 of the orbits are relatively uncontaminated along the trace of MACS1149-JD. We fit a 3-parameter ($z$, F160W mag, and Ly$\alpha$ equivalent width) Lyman-break galaxy template to the three least contaminated grism position angles using an MCMC approach. The grism data alone are best fit with a redshift of $z_{\mathrm{grism}}=9.53^{+0.39}_{-0.60}$ ($68\%$ confidence), in good agreement with our photometric estimate of $z_{\mathrm{phot}}=9.51^{+0.06}_{-0.12}$ ($68\%$ confidence). Our analysis rules out Lyman-alpha emission from MACS1149-JD above a $3\sigma$ equivalent width of 21 \AA{}, consistent with a highly neutral IGM. We explore a scenario where the red $\textit{Spitzer}$/IRAC $[3.6] - [4.5]$ color of the galaxy previously pointed out in the literature is due to strong rest-frame optical emission lines from a very young stellar population rather than a 4000 \AA{} break. We find that while this can provide an explanation for the observed IRAC color, it requires a lower redshift ($z\lesssim9.1$), which is less preferred by the $\textit{HST}$ imaging data. The grism data are consistent with both scenarios, indicating that the red IRAC color can still be explained by a 4000 \AA{} break, characteristic of a relatively evolved stellar population. In this interpretation, the photometry indicate that a $340^{+29}_{-35}$ Myr stellar population is already present in this galaxy only $\sim500~\mathrm{Myr}$ after the Big Bang.Comment: Accepted to ApJ. This is the accepted versio

Comparison of First-Line Dual Combination Treatments in Hypertension: Real-World Evidence from Multinational Heterogeneous Cohorts.

Background and objectives: 2018 ESC/ESH Hypertension guideline recommends 2-drug combination as initial anti-hypertensive therapy. However, real-world evidence for effectiveness of recommended regimens remains limited. We aimed to compare the effectiveness of first-line anti-hypertensive treatment combining 2 out of the following classes: angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor blocker (A), calcium channel blocker (C), and thiazide-type diuretics (D).Methods: Treatment-naïve hypertensive adults without cardiovascular disease (CVD) who initiated dual anti-hypertensive medications were identified in 5 databases from US and Korea. The patients were matched for each comparison set by large-scale propensity score matching. Primary endpoint was all-cause mortality. Myocardial infarction, heart failure, stroke, and major adverse cardiac and cerebrovascular events as a composite outcome comprised the secondary measure.Results: A total of 987,983 patients met the eligibility criteria. After matching, 222,686, 32,344, and 38,513 patients were allocated to A+C vs. A+D, C+D vs. A+C, and C+D vs. A+D comparison, respectively. There was no significant difference in the mortality during total of 1,806,077 person-years: A+C vs. A+D (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.97-1.20; p=0.127), C+D vs. A+C (HR, 0.93; 95% CI, 0.87-1.01; p=0.067), and C+D vs. A+D (HR, 1.18; 95% CI, 0.95-1.47; p=0.104). A+C was associated with a slightly higher risk of heart failure (HR, 1.09; 95% CI, 1.01-1.18; p=0.040) and stroke (HR, 1.08; 95% CI, 1.01-1.17; p=0.040) than A+D.Conclusions: There was no significant difference in mortality among A+C, A+D, and C+D combination treatment in patients without previous CVD. This finding was consistent across multi-national heterogeneous cohorts in real-world practice

The Multiwavelength Survey By Yale-Chile (MUSYC) Wide K-Band Imaging, Photometric Catalogs, Clustering, And Physical Properties Of Galaxies At Z Similar To 2

We present K-band imaging of two similar to 30' x 30' fields covered by the Multiwavelength Survey by Yale-Chile (MUSYC) Wide NIR Survey. The SDSS 1030+05 and Cast 1255 fields were imaged with the Infrared Side Port Imager (ISPI) on the 4 m Blanco telescope at the Cerro Tololo Inter-American Observatory (CTIO) to a 5 sigma point-source limiting depth of K similar to 20 (Vega). Combining these data with the MUSYC optical UBVRIz imaging, we created multiband K-selected source catalogs for both fields. These catalogs, together with the MUSYC K-band catalog of the Extended Chandra Deep Field South (ECDF-S) field, were used to select K 20 BzK galaxies over an area of 0.71 deg(2). This is the largest area ever surveyed for BzK galaxies. We present number counts, redshift distributions, and stellar masses for our sample of 3261 BzK galaxies (2502 star-forming [sBzK] and 759 passively evolving [pBzK]), as well as reddening and star formation rate estimates for the star-forming BzK systems. We also present two-point angular correlation functions and spatial correlation lengths for both sBzK and pBzK galaxies and show that previous estimates of the correlation function of these galaxies were affected by cosmic variance due to the small areas surveyed. We have measured correlation lengths r(0) of 8.89 +/- 2.03 and 10.82 +/- 1.72 Mpc for sBzK and pBzK galaxies, respectively. This is the first reported measurement of the spatial correlation function of passive BzK galaxies. In the Lambda CDM scenario of galaxy formation, these correlation lengths at z similar to 2 translate into minimum masses of similar to 4 x 10(12) and similar to 9 x 10(12) M(circle dot) for the dark matter halos hosting sBzK and pBzK galaxies, respectively. The clustering properties of the galaxies in our sample are consistent with their being the descendants of bright Lyman break galaxies at z similar to 3, and the progenitors of present-day > 1L* galaxies.Astronom