The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content ...identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
Background
There is a little empirical evidence to determine which, if any, monitoring practices best achieve the goals of trial monitoring set forth in ICH E6 under the variable circumstances of ...different clinical trial settings.
Purpose
The purpose of this project was to describe current methods of monitoring clinical trials and to explore the rationale for the use of those methods.
Methods
An electronic survey of known monitoring practices was developed and sent to over 200 organizations involved in conducting clinical research. The survey collected information on institutional demographics, methods of overall study oversight, use of risk-based monitoring and factors that influence assessments of risk, and details on quality assurance and monitoring practices.
Results
Seventy-nine organizations completed the survey; our analysis included the 65 organizations that indicated they perform clinical trials. Data from the survey indicate that a wide variety of monitoring practices are currently being employed. Eighty-three percent of respondents use centrally available data to evaluate site performance, but only 12% of respondents always or frequently used centralized monitoring to replace on-site visits. Eighty-seven percent of respondents indicated that they always performed on-site visits. This varied by type of organization, with 31% of academic coordinating centers/cooperative groups/government organizations always performing on-site monitoring visits versus 84% of other organizations. The rationale for using a specific monitoring approach does not appear to be based on empirical evidence. Fifty-four percent of respondents stated that ‘usual practice’ determined the frequency with which they conducted on-site monitoring visits.
Limitations
The overall response rate to our survey was only 30%; thus, we may not have captured the full variance of current monitoring practices, and our responding sample may not be representative.
Conclusion
These findings underscore the necessity of research to provide an evidence base for monitoring practice.
Eighty planetary systems of two or more planets are known to orbit stars other than the Sun. For most, the data can be sufficiently explained by non-interacting Keplerian orbits, so the dynamical ...interactions of these systems have not been observed. Here we present 4 sets of lightcurves from the Kepler spacecraft, which each show multiple planets transiting the same star. Departure of the timing of these transits from strict periodicity indicates the planets are perturbing each other: the observed timing variations match the forcing frequency of the other planet. This confirms that these objects are in the same system. Next we limit their masses to the planetary regime by requiring the system remain stable for astronomical timescales. Finally, we report dynamical fits to the transit times, yielding possible values for the planets' masses and eccentricities. As the timespan of timing data increases, dynamical fits may allow detailed constraints on the systems' architectures, even in cases for which high-precision Doppler follow-up is impractical.
Most Sun-like stars in the Galaxy reside in gravitationally-bound pairs of stars called "binary stars". While long anticipated, the existence of a "circumbinary planet" orbiting such a pair of normal ...stars was not definitively established until the discovery of Kepler-16. Incontrovertible evidence was provided by the miniature eclipses ("transits") of the stars by the planet. However, questions remain about the prevalence of circumbinary planets and their range of orbital and physical properties. Here we present two additional transiting circumbinary planets, Kepler-34 and Kepler-35. Each is a low-density gas giant planet on an orbit closely aligned with that of its parent stars. Kepler-34 orbits two Sun-like stars every 289 days, while Kepler-35 orbits a pair of smaller stars (89% and 81% of the Sun's mass) every 131 days. Due to the orbital motion of the stars, the planets experience large multi-periodic variations in incident stellar radiation. The observed rate of circumbinary planets implies > ~1% of close binary stars have giant planets in nearly coplanar orbits, yielding a Galactic population of at least several million.
To establish expert consensus regarding the domains and topics for senior surgery residents (PGY-4) to make critical decisions and assume senior-level responsibilities, and to develop the formative ...American College of Surgeons Senior Resident Readiness Assessment (ACS SRRA) Program.
The American College of Surgeons (ACS) education leadership team conducted a focus group with surgical experts to identify the content for an assessment tool to evaluate senior residents’ readiness for their increased levels of responsibility. After the focus group, national experts were recruited to develop consensus on the topics through three rounds of surveys using Delphi methodology. The Delphi participants rated topics using Likert-type scales and their comments were incorporated into subsequent rounds. Consensus was defined as ≥ 80% agreement with internal-consistency reliability (Cronbach's alpha) ≥ 0.8. In a stepwise fashion, topics that did not achieve consensus for inclusion were removed from subsequent survey rounds.
The surveys were administered via an online questionnaire.
Twelve program directors and assistant program directors made up the focus group. The 39 Delphi participants represented seven different surgical subspecialties and were from diverse practice settings. The median length of experience in general surgery resident education was 20 years (IQR 14.3-30.0) with 64% of the experts being either current or past general surgery residency program directors.
The response rate was 100% and Cronbach's alpha was ≥ 0.9 for each round. The Delphi participants contributed a large number of comments. Of the 201 topics that were evaluated initially, 120 topics in 25 core clinical areas were included to create the final domains of ACS SRRA.
National consensus on the domain of the ACS SRRA has been achieved via the modified Delphi method among expert surgeon educators. ACS SRRA will identify clinical topics and areas in which each senior resident needs improvement and provide data to residents and residency programs to develop individualized learning plans. This would help in preparing the senior residents to assume their responsibilities and support their readiness for future fellowship training or surgical practice.
We present the discovery of the Kepler-19 planetary system, which we first identified from a 9.3-day periodic transit signal in the Kepler photometry. From high-resolution spectroscopy of the star, ...we find a stellar effective temperature Teff=5541 \pm 60 K, a metallicity Fe/H=-0.13 \pm 0.06, and a surface gravity log(g)=4.59 \pm 0.10. We combine the estimate of Teff and Fe/H with an estimate of the stellar density derived from the photometric light curve to deduce a stellar mass of M_star = 0.936 \pm 0.040 M_Sun and a stellar radius of R_star = 0.850 \pm 0.018 R_Sun. We rule out the possibility that the transits result from an astrophysical false positive by first identifying the subset of stellar blends that reproduce the precise shape of the light curve. We conclude that the planetary scenario is more than three orders of magnitude more likely than a blend. The blend scenario is independently disfavored by the achromaticity of the transit: we measure a transit depth with Spitzer at 4.5 {\mu}m of 547+113-110 ppm, consistent with the depth measured in the Kepler optical bandpass of 567\pm6 ppm. We determine a physical radius of the planet Kepler-19b of R_p = 2.209 \pm 0.048 R_Earth. From radial-velocity observations of the star, we find an upper limit on the planet mass of 20.3 M_Earth, corresponding to a maximum density of 10.4 g cm^-3. We report a significant sinusoidal deviation of the transit times from a predicted linear ephemeris, which we conclude is due to an additional perturbing body in the system. We cannot uniquely determine the orbital parameters of the perturber, as various dynamical mechanisms match the amplitude, period, and shape of the transit timing signal and satisfy the host star's radial velocity limits. However, the perturber in these mechanisms has period <160 days and mass <6 M_Jup, confirming its planetary nature as Kepler-19c. Abridged
IMPORTANCE: A standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the ...diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose. OBJECTIVE: To revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health–funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG). EVIDENCE REVIEW: Practicing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0. FINDINGS: The new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low–cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma. CONCLUSIONS AND RELEVANCE: The implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.
We report the detection of a planet whose orbit surrounds a pair of low-mass stars. Data from the Kepler spacecraft reveal transits of the planet across both stars, in addition to the mutual eclipses ...of the stars, giving precise constraints on the absolute dimensions of all three bodies. The planet is comparable to Saturn in mass and size, and is on a nearly circular 229-day orbit around its two parent stars. The eclipsing stars are 20% and 69% as massive as the sun, and have an eccentric 41-day orbit. The motions of all three bodies are confined to within 0.5 degree of a single plane, suggesting that the planet formed within a circumbinary disk.
New transiting planet candidates are identified in sixteen months (May 2009 - September 2010) of data from the Kepler spacecraft. Nearly five thousand periodic transit-like signals are vetted against ...astrophysical and instrumental false positives yielding 1,091 viable new planet candidates, bringing the total count up to over 2,300. Improved vetting metrics are employed, contributing to higher catalog reliability. Most notable is the noise-weighted robust averaging of multi-quarter photo-center offsets derived from difference image analysis which identifies likely background eclipsing binaries. Twenty-two months of photometry are used for the purpose of characterizing each of the new candidates. Ephemerides (transit epoch, T_0, and orbital period, P) are tabulated as well as the products of light curve modeling: reduced radius (Rp/R*), reduced semi-major axis (d/R*), and impact parameter (b). The largest fractional increases are seen for the smallest planet candidates (197% for candidates smaller than 2Re compared to 52% for candidates larger than 2Re) and those at longer orbital periods (123% for candidates outside of 50-day orbits versus 85% for candidates inside of 50-day orbits). The gains are larger than expected from increasing the observing window from thirteen months (Quarter 1-- Quarter 5) to sixteen months (Quarter 1 -- Quarter 6). This demonstrates the benefit of continued development of pipeline analysis software. The fraction of all host stars with multiple candidates has grown from 17% to 20%, and the paucity of short-period giant planets in multiple systems is still evident. The progression toward smaller planets at longer orbital periods with each new catalog release suggests that Earth-size planets in the Habitable Zone are forthcoming if, indeed, such planets are abundant.
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