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The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.
Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: ‘use as directed’, ‘moderate gene-drug interactions’, or ‘significant gene-drug interactions.’ Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).
At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).
Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.
The Taipan galaxy survey (hereafter simply ‘Taipan’) is a multi-object spectroscopic survey starting in 2017 that will cover 2π steradians over the southern sky (δ ≲ 10°, |b| ≳ 10°), and obtain optical spectra for about two million galaxies out to z < 0.4. Taipan will use the newly refurbished 1.2-m UK Schmidt Telescope at Siding Spring Observatory with the new TAIPAN instrument, which includes an innovative ‘Starbugs’ positioning system capable of rapidly and simultaneously deploying up to 150 spectroscopic fibres (and up to 300 with a proposed upgrade) over the 6° diameter focal plane, and a purpose-built spectrograph operating in the range from 370 to 870 nm with resolving power R ≳ 2000. The main scientific goals of Taipan are (i) to measure the distance scale of the Universe (primarily governed by the local expansion rate, H0) to 1% precision, and the growth rate of structure to 5%; (ii) to make the most extensive map yet constructed of the total mass distribution and motions in the local Universe, using peculiar velocities based on improved Fundamental Plane distances, which will enable sensitive tests of gravitational physics; and (iii) to deliver a legacy sample of low-redshift galaxies as a unique laboratory for studying galaxy evolution as a function of dark matter halo and stellar mass and environment. The final survey, which will be completed within 5 yrs, will consist of a complete magnitude-limited sample (i ⩽ 17) of about 1.2 × 106 galaxies supplemented by an extension to higher redshifts and fainter magnitudes (i ⩽ 18.1) of a luminous red galaxy sample of about 0.8 × 106 galaxies. Observations and data processing will be carried out remotely and in a fully automated way, using a purpose-built automated ‘virtual observer’ software and an automated data reduction pipeline. The Taipan survey is deliberately designed to maximise its legacy value by complementing and enhancing current and planned surveys of the southern sky at wavelengths from the optical to the radio; it will become the primary redshift and optical spectroscopic reference catalogue for the local extragalactic Universe in the southern sky for the coming decade.
The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse, and dependence increasing across adolescence and peaking in early adulthood. Here, we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three longitudinal community samples (N = 2,126, obs = 12,166). Consumption-repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR < 0.1) and six others met our ‘suggestive’ criterion (FDR <0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms, including neurotransmission, xenobiotic pharmacodynamics, and nuclear hormone receptors (NHR). These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies.
The structure of La2LiTaO6 has been derived from the powder X-ray powder diffraction (XRD) data. La2LiTaO6 is monoclinic with unit-cell parameters a = 5.621(1) Å, b = 5.776(1) Å, c = 7.954(2) Å, β = 90.34(2)°, space group P21/n (14), and Z = 2. The structure of La2LiTaO6 is an ordered perovskite with alternating Li and Ta octahedra. A new set of powder XRD data (d-spacing and intensity listing) has been generated to replace entry 00-039-0897 within the Powder Diffraction File. The newly elucidated structural data for La2LiTaO6 shall facilitate quantitative analysis of this impurity phase which is often observed during synthesis of the fast-ion conductor phase Li5La3Ta2O12.
In North America, terrestrial records of biodiversity and climate change that span Marine Oxygen Isotope Stage (MIS) 5 are rare. Where found, they provide insight into how the coupling of the ocean–atmosphere system is manifested in biotic and environmental records and how the biosphere responds to climate change. In 2010–2011, construction at Ziegler Reservoir near Snowmass Village, Colorado (USA) revealed a nearly continuous, lacustrine/wetland sedimentary sequence that preserved evidence of past plant communities between ~140 and 55 ka, including all of MIS 5. At an elevation of 2705 m, the Ziegler Reservoir fossil site also contained thousands of well-preserved bones of late Pleistocene megafauna, including mastodons, mammoths, ground sloths, horses, camels, deer, bison, black bear, coyotes, and bighorn sheep. In addition, the site contained more than 26,000 bones from at least 30 species of small animals including salamanders, otters, muskrats, minks, rabbits, beavers, frogs, lizards, snakes, fish, and birds. The combination of macro- and micro-vertebrates, invertebrates, terrestrial and aquatic plant macrofossils, a detailed pollen record, and a robust, directly dated stratigraphic framework shows that high-elevation ecosystems in the Rocky Mountains of Colorado are climatically sensitive and varied dramatically throughout MIS 5.
The 2013 Infection Prevention and Control (IP&C) Guideline for Cystic Fibrosis (CF) was commissioned by the CF Foundation as an update of the 2003 Infection Control Guideline for CF. During the past decade, new knowledge and new challenges provided the following rationale to develop updated IP&C strategies for this unique population:
1. The need to integrate relevant recommendations from evidence-based guidelines published since 2003 into IP&C practices for CF. These included guidelines from the Centers for Disease Control and Prevention (CDC)/Healthcare Infection Control Practices Advisory Committee (HICPAC), the World Health Organization (WHO), and key professional societies, including the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). During the past decade, new evidence has led to a renewed emphasis on source containment of potential pathogens and the role played by the contaminated healthcare environment in the transmission of infectious agents. Furthermore, an increased understanding of the importance of the application of implementation science, monitoring adherence, and feedback principles has been shown to increase the effectiveness of IP&C guideline recommendations.
2. Experience with emerging pathogens in the non-CF population has expanded our understanding of droplet transmission of respiratory pathogens and can inform IP&C strategies for CF. These pathogens include severe acute respiratory syndrome coronavirus and the 2009 influenza A H1N1. Lessons learned about preventing transmission of methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant gram-negative pathogens in non-CF patient populations also can inform IP&C strategies for CF.
The use of airborne LiDAR (Light Detection and Ranging) in western Belize, Central America, has revolutionized our understanding of the spatial dynamics of the ancient Maya. This technology has enabled researchers to successfully demonstrate the large-scale human modifications made to the ancient tropical landscape, providing insight on broader regional settlement. Before the advent of this laser-based technology, heavily forested cover prevented full coverage and documentation of Maya sites. Mayanists could not fully recover or document the extent of ancient occupation and could never be sure how representative their mapped and excavated samples were relative to ancient settlement. Employing LiDAR in tropical and subtropical environments, like that of the Maya, effectively provides ground, as well as forest cover information, leading to a much fuller documentation of the complexities involved in the ancient human-nature interface. Airborne LiDAR was first flown over a 200 km2 area of the archaeological site of Caracol, Belize, in April 2009. In April and May 2013 an additional 1,057 km2 were flown with LiDAR, permitting the contextualization of the city of Caracol within its broader region and polity. The use of this technology has transformed our understanding of regional archaeology in the Maya area.
Significant new opportunities for astrophysics and cosmology have been identified at low radio frequencies. The Murchison Widefield Array is the first telescope in the southern hemisphere designed specifically to explore the low-frequency astronomical sky between 80 and 300 MHz with arcminute angular resolution and high survey efficiency. The telescope will enable new advances along four key science themes, including searching for redshifted 21-cm emission from the EoR in the early Universe; Galactic and extragalactic all-sky southern hemisphere surveys; time-domain astrophysics; and solar, heliospheric, and ionospheric science and space weather. The Murchison Widefield Array is located in Western Australia at the site of the planned Square Kilometre Array (SKA) low-band telescope and is the only low-frequency SKA precursor facility. In this paper, we review the performance properties of the Murchison Widefield Array and describe its primary scientific objectives.
Little information exists regarding how accurately emergency physicians (EPs) predict the probability of acute coronary syndrome (ACS). Our objective was to determine if EPs can accurately predict ACS in a prospectively identified cohort of emergency department (ED) patients who met enrolment criteria for a study of coronary computed tomographic angiography (CCTA) and were admitted for a “rule out ACS” protocol.
A prospective observational pilot study in an academic medical centre was carried out. EPs caring for patients with chest pain provided whole-number estimates of the probability of ACS after clinical review. This substudy was part of the now published Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT) study, a study of CCTA and admission of patients for a rule out ACS protocol after a nondiagnostic evaluation. Predictions were grouped into probability groups based on the validated Goldman criteria. ACS was determined by an adjudication committee using American Heart Association/American College of Cardiology/European Society of Cardiology guidelines.
A total of 334 predictions were obtained for a study population with a mean age of 54 (SD 12) years, 63% of whom were male. There were 35 ACS events. EPs predicted ACS better than by chance, and increasingly higher estimates were associated with a higher incidence of ACS (p = 0.0004). The percentage of patients with ACS was 0%, 6%, 7%, and 17%, respectively, for very low, low, intermediate, and high probability groups. EPs' estimates had a sensitivity of 63% using a > 20% probability of ACS to define a positive test. Lowering this threshold to > 7% to define a test as positive increased the sensitivity of physician estimates to 89% but lowered specificity from 65% to 24%
Our data suggest that for a selected ED cohort meeting eligibility criteria for a study of CCTA, EPs predict ACS better than by chance, with an increasing proportion of patients proving to have ACS with increasing probability estimates. Lowering the estimate threshold does not result in an overall sensitivity level that is sufficient to send patients home from the ED and is associated with a poor specificity.
Scant evidence exists to guide policy-making around public health needs during mass gatherings. In 2006, the City and County of San Francisco began requiring standby ambulances at all mass gatherings with attendance of >15,500 people. The objectives were to evaluate needs for ambulances at mass gatherings, and to make evidence-based recommendations for public health policy-makers. The hypothesis was that the needs for ambulances at mass gatherings can be estimated using community baseline data.
Emergency medical services plans were reviewed for all public events with an anticipated attendance of >1,000 people in San Francisco County during the 12-month period 01 August 2006 through 31 July 2007. Ambulance transport data were confirmed by event coordinators and ambulance company records, and the rate was calculated by dividing ambulance transports by event attendance. Baseline ambulance transport rate was calculated by dividing the annual ambulance transports in the county's computer-aided dispatch system by the census population estimate. The risk ratio was calculated using the risk of transport from a mass gathering compared with the baseline risk of ambulance transport for the local community. Significance testing and confidence intervals were calculated.
Descriptive information was available for 100% of events and ambulance transport data available for 97% of events. The majority of the mass gatherings (47 unique events; 59 event days) were outdoor, weekend festivals, parades, or concerts, though a large proportion were athletic events. The ambulance transport rate from mass gatherings was 1 per 59,000 people every six hours. Baseline ambulance transport rate in San Francisco was 1 per 20,000 people every six hours. The transport rate from mass gatherings was significantly lower than the community baseline (risk ratio [RR] = 0.15, 95% CI = 0.10–0.22, p <0.001). At events reserving a standby ambulance, 46% of ambulances were unused.
San Francisco mass gatherings appear to present a lower risk of ambulance transports compared to the community baseline, suggesting that the community baseline sets an appropriate standard for requiring standby ambulances at mass gatherings. The initial ambulance requirement policy in San Francisco may have been overly conservative.
Local baseline data is a recommended starting point when setting policy for public health needs at mass gatherings.