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Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.
1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.
At week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.
Combinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.
Funding Acknowledgements: This study was supported by Assurex Health, Inc.
Six snow-pit records recovered from Siple Dome, West Antarctica, during 1994 are used to study seasonal variations in chemical (major ion and H202), isotopic (deuterium) and physical stratigraphic properties during the 1988-94 period. Comparison of δD measurements and satellite-derived brightness temperature for the Siple Dome area suggests that most seasonal SD maxima occur within ±4 weeks of each 1 January. Several other chemical species (H2O2, non-sea-salt (nss) SO42-, methanesulfonic acid and NO3-) show coeval peaks with SD, together providing an accurate method for identifying summer accumulation. Sea-salt-derived species generally peak during winter/spring, but episodic input is noted throughout some years. No reliable seasonal signal is identified in species with continental sources (nssCa2+ nss Mg2+), NH4+ or nssCl-. Visible strata such as large depth-hoar layers (>5 cm) are associated with summer accumulation and its metamorphosis, but smaller hoar layers and crusts are more difficult to interpret. A multi-parameter approach is found to provide the most accurate dating of these snow-pit records, and is used to determine annual layer thicknesses at each site Significant spatial accumulation variability exists on an annual basis, but mean accumulation in the sampled 10 km2 grid for the 1988-94 period is fairly uniform.
We have used ground-based radio-echo sounding (RES) profiles to reveal the spatial distribution of basal and internal ice properties across Siple Dome, West Antarctica, and under the dormant ice streams on its flanks. The RES-detected bed-reflection power, corrected for the effects of instrumentation and ice-thickness variation, is nearly constant across Siple Dome at a value suggesting spatially homogeneous basal properties of ice frozen to bedrock. Till, if present under the dome, must be thin (<0.1 m). The high basal reflectivity measured under now dormant “Siple Ice Stream” (SIS) and Ice Stream C suggests that they are underlain by either a thin (<0.05 m) water layer or a thick (>1 m) thawed or frozen till layer. The evidence that the dormant SIS is not frozen directly to underlying bedrock (but is separated by a water or till layer) is a further indication that it was once an active ice stream, and suggests that streaming motion may have ceased before the basal layer was frozen. The absence of a thick till layer beneath Siple Dome is consistent with its apparent stability as an inter-ice-stream ridge in the past and may suggest that it will remain as a stable limitation of ice-stream width in the future.
It has been suggested that offspring of parents with bipolar disorder are at increased risk for disruptive mood dysregulation disorder (DMDD), but the specificity of this association has not been established.
We examined the specificity of DMDD to family history by comparing offspring of parents with (a) bipolar disorder, (b) major depressive disorder and (c) a control group with no mood disorders.
We established lifetime diagnosis of DMDD using the Schedule for Affective Disorders and Schizophrenia for School Aged Children for DSM-5 in 180 youth aged 6–18 years, including 58 offspring of parents with bipolar disorder, 82 offspring of parents with major depressive disorder and 40 control offspring.
Diagnostic criteria for DMDD were met in none of the offspring of parents with bipolar disorder, 6 of the offspring of parents with major depressive disorder and none of the control offspring. DMDD diagnosis was significantly associated with family history of major depressive disorder.
Our results suggest that DMDD is not specifically associated with a family history of bipolar disorder and may be associated with parental depression.
We present near-IR spectroscopy of a sample of 30 IRAS sources recently identified as late AGB stars, post-AGB stars or early PNe. The spectra obtained are centred at various wavelengths covering the molecular hydrogen v=1→0 S(1) 2.122 μm and v=2→1 S(1) 2.248 μm emission lines, the recombination lines of hydrogen Brγ 2.166 μm, Pfγ 3.741 μm and Brα 4.052 μm, and the CO[v=2→0] first overtone bandhead at 2.294 μm. As a result of these observations we have increased from 4 to 13 the total number of proto-PNe detected in H2 and we have confirmed that the onset of H2 emission takes place in the post-AGB phase. When the molecular hydrogen is fluorescence-excited the detection rate is found to be directly correlated with the evolutionary stage of the central star, rather than with the nebular morphology. In contrast, shocked-excited H2 is detected only in strongly bipolar proto-PNe, sometimes even at an early stage in the post-AGB phase. The strong correlation of shocked-excited H2 emission with bipolarity found confirms the result previously reported by Kastner et al. (1996) in evolved PNe. However, our results show that this correlation does not exist in the case of fluorescence-excited molecular hydrogen. (to be published in A&A).
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.
Native to temperate South America, deeproot sedge has naturalized throughout the southeastern United States. Often forming dense, homogenous stands, deeproot sedge has become widespread, invasive, and potentially harmful ecologically throughout the coastal prairie ecoregion of Texas. Possessing characteristics (rapid growth, generalized habitat requirements) of other weedy congeners (purple nutsedge and yellow nutsedge), its relatively recent expansion highlights the critical need to develop effective control techniques and strategies for this species throughout this endangered ecoregion. Research was performed to delineate total nonstructural carbohydrate (TNC) trends in deeproot sedge rhizomes for development of a phenologically based schedule for herbicide applications and mechanical treatments. Overall, TNC levels were greatest in May to August and lowest from October to January, regardless of study area. Apparently, deeproot sedge exerts little energy into seed production because TNC levels were continually replenished throughout the growing season. As such, foliar-herbicide application throughout the growing season should achieve total plant kill. Conversely, deeproot sedge rhizome TNC levels never fell below 30%, even during winter, which indicates that winter mechanical treatments or winter prescribed fires will not be effective because substantial rhizome reserves are present to support resprouting during the next growing season. Beyond a priori prevention, sequential herbicide applications combined with integrated, sequential, prescribed fire and herbicide treatments will be needed for long-term deeproot sedge control throughout its geographic range.
Insurance accounting has for many years proved a challenging topic for standard setters, preparers and users, often described as a “black box”. Will recent developments, in particular the July 2010 Insurance Contracts Exposure Draft, herald a new era?
This paper reviews these developments, setting out key issues and implications. It concentrates on issues relevant to life insurers, although much of the content is also relevant to non-life insurers.
The paper compares certain IFRS and Solvency II developments, recognising that UK insurers face challenges in implementing new financial and regulatory reporting requirements in similar timeframes. The paper considers resulting external disclosure requirements and a possible future role for supplementary information.
The field emission properties of hydrogenated amorphous carbon containing up to 29at% nitrogen (a-C:N:H), grown in an integrated distributed electron cyclotron resonance (IDECR) reactor were studied using a sphere-plane geometry. All films were smooth in character and required a high field (20-70V/νm) activation process before emission, which created micron- sized craters in the emission region. Further analysis suggested that the emission originates from activation-created geometrically enhanced areas around the crater region. Upon low-level nitrogen incorporation (N/N+C≤0.2), the field required for activation decreased from 54V/νm to a minimum value of 20V/νm. The turn-on field required for 1νA of current also decreased, reaching a minimum of 11.3V/νm. The decrease in activation and turn-on field was related to the increase in conductivity observed with increasing nitrogen content. At higher nitrogen concentrations, the increase in activation energy and turn on field for emission may be due to changes in overall material structure, as indicated by the decreasing optical gap
Chemical profiles of interfacial (transition) regions in InP-based heterostructures, fabricated by (1) vapor levitation epitaxy (VLE), (2) liquid phase epitaxy (LPE), and (3) molecular beam epitaxy (MBE), have been measured with a high degree of resolution on inclined surfaces by Auger electron microscopy (AES). This particular technique involves production of a chamfered wedge, characterized by a surface inclined by angle ø(≈ 0.02°) with respect to the interface, by controlled chemical etching and subsequent scanning across the trace of the interface on the (inclined) surface by AES, thereby allowing enhanced magnification of the interface by a factor of cot ø (≈ 2,000X) without deleterious effects associated with mechanical polishing and/or ion milling. Results indicate that corresponding transition widths δ between adjacent layers vary according to δLPE < δMBE < δVLE and may be explained by a combination of inherent surface roughness and interdiffusion of various chemical species across the original interface during and subsequent to the deposition process. It is concluded that the chamfered wedge technique provides a reliable and sensitive method to determine chemical profiles across a wide variety of heterojunctions, provided that a suitable chemical etch is available.
Surface passivation of device-grade radiation detector materials was investigated using x-ray photoelectron spectroscopy in combination with transport property measurements before and after various chemical treatments. Specifically Br-MeOH (2% Br), KOH with NH4F/H2O2 and NH4OH solutions were used to etch, reduce and oxidize the surface of Cd(1-x)ZnxTe semiconductor crystals. Scanning electron microscopy was used to evaluate the resultant microscopic surface morphology. Angle-resolved high-resolution photoemission measurements on the valence band electronic structure and core lines were used to evaluate the surface chemistry of the chemically treated surfaces. Metal overlayers were then deposited on these chemically treated surfaces and the I-V characteristics measured. The measurements were correlated to understand the effect of interface chemistry on the electronic structure at these interfaces with the goal of optimizing the Schottky barrier height for improved radiation detector devices.