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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.
Good education requires student experiences that deliver lessons about practice as well as theory and that encourage students to work for the public good—especially in the operation of democratic institutions (Dewey 1923; Dewy 1938). We report on an evaluation of the pedagogical value of a research project involving 23 colleges and universities across the country. Faculty trained and supervised students who observed polling places in the 2016 General Election. Our findings indicate that this was a valuable learning experience in both the short and long terms. Students found their experiences to be valuable and reported learning generally and specifically related to course material. Postelection, they also felt more knowledgeable about election science topics, voting behavior, and research methods. Students reported interest in participating in similar research in the future, would recommend other students to do so, and expressed interest in more learning and research about the topics central to their experience. Our results suggest that participants appreciated the importance of elections and their study. Collectively, the participating students are engaged and efficacious—essential qualities of citizens in a democracy.
Self-criticism is a ubiquitous feature of psychopathology and can be
combatted by increasing levels of self-compassion. However, some patients
are resistant to self-compassion.
To investigate whether the effects of self-identification with virtual
bodies within immersive virtual reality could be exploited to increase
self-compassion in patients with depression.
We developed an 8-minute scenario in which 15 patients practised
delivering compassion in one virtual body and then experienced receiving
it from themselves in another virtual body.
In an open trial, three repetitions of this scenario led to significant
reductions in depression severity and self-criticism, as well as to a
significant increase in self-compassion, from baseline to 4-week
follow-up. Four patients showed clinically significant improvement.
The results indicate that interventions using immersive virtual reality
may have considerable clinical potential and that further development of
these methods preparatory to a controlled trial is now warranted.
We summarize recent results from our study of the massive young super star clusters (SSCs) in the dwarf galaxy NGC 1569, and present new high-resolution NIRSPEC spectra that permit the measurement of a cluster's intrinsic stellar velocity dispersion. Thus we derive kinematic masses for the two brightest SSCs: 2.3 × 105 Msun for SSC B, and 3.9 × 105 and 4.4 × 105 Msun for the two components of SSC A.
High quality (>2% TOC) Upper Devonian source rocks are developed in several sequence types. The commonest type, accounting for 70% of the studied examples is the transgressive sequence with a basal hiatus. Others include shallowing upward sequences (12%), lacustrine sequences in fault-controlled basins (7%), distal slope sequences (7%), and evaporite capped sequences (4%).
Starting from the synthesis of Johnson, Klapper, and Sandberg (1985) it has been possible to demonstrate correlativity of Upper Devonian transgressive episodes globally. The marked association of epeiric sea Upper Devonian source rocks with transgressions heightens interest in their causation. Could they have been produced by glacio-eustatic sea-level change as Stanley (1984; 1988) implies? Quantitative paleoclimate modeling and isotopic paleotemperatures for the Upper Devonian suggest not. Modeling using CCM1 at NCAR, including five year seasonal cycles, suggests the absence of any large southern hemisphere ice volume. Because much of the Upper Devonian land mass was either in equatorial or high latitude regions, there was little development of monsoonal climates. Midlatitude cyclonic activity was also much less than at present, meaning less polar transport of moisture and drier polar areas. Precipitation maxima largely coincided with topographic elevations. In contrast to the Late Ordovician to earliest Silurian, there was no Upper Devonian perennial snow cover even over the high latitude southern land mass. This was in spite of winter land temperatures as low as -40°. in eastern Gondwana. In that area and elsewhere, there was thin winter snow cover which melted in late spring resulting in no build-up of snow cover to produce glaciation. This was mainly the consequence of low winter precipitation in Gondwana. High latitude sea surface temperatures were certainly cold enough to displace or exclude some organisms. However, in low latitude areas where Upper Devonian extinctions also took place, modeled sea surface temperatures range between 27° and 34°. Such areas would have been refuges for any organisms displaced by cold, high latitude waters. The higher temperature values of low latitudes are convergent with the isotopic paleotemperatures determined by Brand (1989) using well preserved Upper Devonian brachiopods. Brand's determinations suggest temperatures even reaching lethal values for many plankton (37°). The extinction of reefs by the close of Frasnian time could have been partly a result of such elevated temperatures. Stacked extinctions of conodonts (Ziegler and Lane, 1987) and acritarchs may have been a further result. The loss of reefs, an important consumer of plankton, may have permitted a relative increase in plankton abundance crossing from more oceanic areas into epeiric seas, possibly contributing to high quality source rock deposition.
Testing of a water-balance equation for the Summit Lake basin in July and August 1968 indicated that, 2½ months before its fourth known draining, there existed a leak through or under the damming glacier that may have been as large as 3–5 m3/s. Lake temperatures recorded during the same period indicate water at 0.5–0.8°C near the ice dam and up to 2.6°C 4–5 km from the dam. These observations support the proposal of Liestøl (1956) and Mathews (in press) of tunnel enlargement by melting. It is calculated that lake water temperatures of 0.25, 0.9 and 0.15°C are required to account for the November 1965, September 1967 and November 1968 drainings, respectively.
The chromosphere is a complex region that acts as an intermediary between the magnetic flux emergence in the photosphere and the magnetic features seen in the corona. Large eruptions in the chromosphere of flares and filaments are often accompanied by ejections of coronal mass off the sun. Several studies have observed fast-moving progressive trains of compact bright points (called Sequential Chromospheric Brightenings or SCBs) streaming away from chromospheric flares that also produce a coronal mass ejection (CME). In this work, we review studies of SCBs and search for commonalties between them. We place these findings into a larger context with contemporary chromospheric and coronal observations. SCBs are fleeting indicators of the solar atmospheric environment as it existed before their associated eruption. Since they appear at the very outset of a flare eruption, SCBs are good early indication of a CME measured in the chromosphere.
The youngest super star clusters (SSCs) in the Antennae Galaxies (NGC 4038/39) drive supersonic mass-loaded outflows. High-resolution Keck/NIRSPEC spectroscopy reveals broad, spatially extended Brγ emission lines that are well-fit by simple wind models. Cluster mass-loss rates are up to 1.5 M⊙ yr−1 and terminal velocities are up to 205 km s−1. These emission-line clusters (ELCs) constitute at least 15% of the star formation rate in the Antennae, and their high star formation efficiencies imply that they will probably evolve into bound SSCs. The youngest ELC outflows are driven primarily by stellar winds, and they efficiently entrain ambient matter. They transfer or dissipate most of their energy and momentum in a hot or cool medium that does not emit Brγ. ELCs are the individual engines that power galactic-scale superwinds, viewed in their earliest evolutionary stage.
The youngest super star clusters (SSCs) in the merging Antennae Galaxies (NGC 4038/39) drive supersonic mass-loaded outflows from the HII regions in which they are embedded. High-resolution K-band Keck/NIRSPEC spectroscopy reveals broad, spatially extended Brγ emission in 16 targets. Simple wind models for the line profiles provide good fits and imply cluster mass-loss rates of up to 1.5 M⊙/year and terminal velocities of up to 205 km s−1. The emission-line clusters (ELCs) that drive these outflows constitute at least 15% of the star formation rate in the Antennae, and their high star formation efficiencies imply that they will probably evolve into bound SSCs. The youngest ELC outflows, which are driven primarily by stellar winds, very efficiently entrain ambient matter. The cluster winds transfer or dissipate a large fraction of their energy and momentum in a hot or cool medium that does not emit Brγ. ELCs are the individual engines that power galactic-scale superwinds, viewed in their earliest evolutionary stage.
The epidemiology of laboratory-confirmed respiratory syncytial virus (RSV) infections in young children has not recently been described in England, and is an essential step in identifying optimal target groups for future licensed RSV vaccines. We used two laboratory surveillance systems to examine the total number and number of positive RSV tests in children aged <5 years in England from 2010 to 2014. We derived odds ratios (ORs) with 95% confidence intervals (CIs) comparing children by birth month, using multivariable logistic regression models adjusted for age, season and sex. Forty-seven percent of RSV tests (29 851/63 827) and 57% (7405/13 034) of positive results in children aged <5 years were in infants aged <6 months. Moreover, 38% (4982/13 034) of positive results were in infants aged <3 months. Infants born in September, October and November had the highest odds of a positive RSV test during their first year of life compared to infants born in January (OR 2·1, 95% CI 1·7–2·7; OR 2·4, 95% CI 2·1–2·8; and OR 2·4, 95% CI 2·1–2·7, respectively). Our results highlight the importance of young age and birth month near the beginning of the RSV season to the risk of laboratory-confirmed RSV infection. Future control measures should consider protection for these groups.
Cambrian biostratigraphy of the Indian subcontinent is best documented from the Parahio Formation of the Tethyan Himalaya. Recently established trilobite biostratigraphy shows that the formation encompasses the latest part of unnamed Stage 4 and much of unnamed Stage 5. A variety of small shelly fossils have been recovered via acid digestion of carbonate beds and include tetract and pentact hexactinellid sponge spicules, chancelloriid spicules belonging to Chancelloria sp. and a new species, Archiasterella dhiraji, shells of an helcionelloid comparable to Igorella maidipingensis, a meraspid ptychopariid trilobite, the tubular Cupitheca sp., a poorly preserved hyolith, and an assortment of spinose microfossils of uncertain affinity. These newly recovered microfossils are consistent with the trilobite-based lower and middle Cambrian age determination and do not support a late Cambrian age for the top of the Parahio Formation advocated in some recent literature. The microfossils reported herein significantly expand the known diversity of such fossils from Cambrian strata in the Himalayan region, and allow for comparison of this fauna with others from Gondwanaland and elsewhere. Integration with trilobite data indicate that the stratigraphic ranges of many small shelly fossils described in this study are greater than previously recognized.
To determine the effects of dietary Fe concentration on Mn bioavailability in rats fed inorganic or organic Mn sources, fifty-four 22-d-old male rats were randomly assigned and fed a basal diet (2·63 mg Fe/kg) supplemented with 0 (low Fe (L-Fe)), 35 (adequate Fe (A-Fe)) or 175 (high Fe (H-Fe)) mg Fe/kg with 10 mg Mn/kg from MnSO4 or Mn–lysine chelate (MnLys). Tissues were harvested after 21 d of feeding. Serum Mn was greater (P<0·05) in MnLys rats than in MnSO4 rats, and in L-Fe rats than in A-Fe or H-Fe rats. Duodenal divalent metal transporter-1 (DMT1) mRNA was lower (P<0·05) in H-Fe rats than in A-Fe rats for the MnSO4 treatment; however, no significant difference was observed between them for MnLys. Liver DMT1 mRNA abundance was greater (P<0·05) in MnSO4 than in the MnLys group for H-Fe rats. The DMT1 protein in duodenum and liver and ferroportin 1 (FPN1) protein in liver was greater (P<0·05) in the MnSO4 group than in the MnLys group, and in L-Fe rats than in H-Fe rats. Duodenal FPN1 protein was greater (P<0·05) in L-Fe rats than in A-Fe rats for the MnLys treatment, but it was not different between them for the MnSO4 treatment. Results suggest that MnLys increased serum Mn concentration as compared with MnSO4 in rats irrespective of dietary Fe concentration, which was not because of the difference in DMT1 and FPN1 expression in the intestine and liver.
Ticks are vectors of pathogens which are important both with respect to human health and economically. They have a complex life cycle requiring several blood meals throughout their life. These blood meals take place on different individual hosts and potentially on different host species. Their life cycle is also dependent on environmental conditions such as the temperature and habitat type. Mathematical models have been used for the more than 30 years to help us understand how tick dynamics are dependent on these environmental factors and host availability. In this paper, we review models of tick dynamics and summarize the main results. This summary is split into two parts, one which looks at tick dynamics and one which looks at tick-borne pathogens. In general, the models of tick dynamics are used to determine when the peak in tick densities is likely to occur in the year and how that changes with environmental conditions. The models of tick-borne pathogens focus more on the conditions under which the pathogen can persist and how host population densities might be manipulated to control these pathogens. In the final section of the paper, we identify gaps in the current knowledge and future modelling approaches. These include spatial models linked to environmental information and Geographic Information System maps, and development of new modelling techniques which model tick densities per host more explicitly.
We determined prescribing rates of neuraminidase inhibitors (NIs) for influenza in UK primary care since 2009 in relation to national prescribing guidelines. All NI prescriptions issued during the influenza seasons between October 2010 and May 2013 were extracted from The Health Improvement Network (THIN), a large UK primary-care database. We calculated NI prescribing rates per 100 000 person-weeks (pw) by age group, sex, deprivation level, influenza season and presence of chronic conditions with 95% confidence intervals (CIs), and used negative binomial regression models to determine the independent association between these variables and NI prescribing. NI prescribing was rare. The prescribing rate was 1·7/100 000 pw (95% CI 1·7–1·8) during influenza-active periods, and 0·1/100 000 (95% CI 0·1–0·1) during non-active periods. Prescribing rates were highest in 25- to 44-year-olds in 2010/2011 and in persons aged ⩾85 years in 2011/2012 and 2012/2013. Individuals with chronic conditions had significantly higher prescribing rates than persons without (rate ratio 2·62, 95% CI 2·27–3·03). GPs are more likely to prescribe NIs to high-risk individuals and during influenza active periods, as per national guidelines. We could not assess the proportion of patients with influenza-like illness who were prescribed an NI.
We analyze a class of modal logics rendered insensitive to reflexivity by way of a modification to the semantic definition of the modal operator. We explore the extent to which these logics can be characterized, and prove a general completeness theorem on the basis of a translation between normal modal logics and their reflexive-insensitive counterparts. Lastly, we provide a sufficient semantic condition describing when a similarly general soundness result is also available.
Apatites are often seen as good potential candidates for the immobilization of halide-rich wastes. In particular, phosphate apatites have received much attention in recent years, however, their synthesis often produces complicated multi-phase systems, with a number of secondary phases forming [1.2]. Calcium vanadinite (Ca5(VO4)3Cl) demonstrates a much simpler phase system, with only a single Ca2V2O7 secondary phase which can easily be retarded by the addition of excess CaCl2. However, when doping with SmCl3 (as an inactive analogue for AnCl3) the Sm forms a wakefieldite (SmVO4) phase rather than being immobilized within the vanadinite, a result of having to form an energetically unfavourable Ca vacancy in order for the lattice to remain neutral overall. It has been postulated that charge-balancing the lattice via co-substitution of a monovalent cation will be less disfavoured and therefore help stabilise formation of a (Ca5-2xSmxAx)(VO4)3Cl solid solution (A = monovalent cation). This has been investigated using a combined modelling and experimental approach. Static lattice calculations performed using Li+, Na+ and K+ as charge-balancing species have shown the energy cost to be less than half that of charge-balancing via formation of a Ca vacancy. As a result, solid state synthesis of (Ca5-2xSmxLix)(VO4)3Cl, (Ca5−2xSmxNax)(VO4)3Cl and (Ca5-2xSmxKx)(VO4)3Cl solid solutions have been trialled, and analysis of the resulting products has shown a significant reduction in both the SmVO4 and Ca2V2O7 secondary phases across all dopant levels.
Sodalite (Na8[AlSiO4]6Cl2), a naturally occurring Cl-containing mineral, has long been regarded as a potential immobilization matrix for the chloride salt wastes arising from pyrochemical reprocessing operations, as it allows for the conditioning of the waste salt as a whole without the need for any pre-treatment. Here the consolidation and densification of Sm-doped sodalite (as an analogue for AnCl3) has been investigated with the aim of producing fully dense (i.e. > 95 % t.d.) ceramic monoliths via conventional cold-press-and-sinter techniques at temperatures of < 1000 °C. Microstructural analysis of pressed and sintered sodalite powders under these conditions is shown to produce poorly sintered, porous, inhomogeneous pellets. However, by the addition of a sodium aluminophosphate glass sintering aid, fully dense Sm-sodalite ceramic monoliths can successfully be produced by sintering at temperatures as low as 800 °C.
Calcium chlorosilicate (Ca3(SiO4)Cl2) is seen as a potential host phase for the immobilization of Cl-rich wastes arising from pyrochemical reprocessing, a waste stream often containing a mix of both di- and trivalent cations. Substitution of trivalent cations into the lattice requires some form of charge compensation to ensure the lattice remains charge neutral overall. Whilst previous work has only examined this through the formation of Ca vacancies, this study investigates the feasibility of charge-balancing via the substitution of a monovalent cation onto the Ca sites of the lattice. To that end, a series of static lattice calculations were performed to determine the site selectivity of monovalent cations of differing size when substituted onto the Ca sites of the calcium chlorosilicate lattice and the solution energies for the overall substitution processes compared with those for charge compensation via vacancy formation. In all cases the monovalent charge-balancing species shows a clear preference for substitution onto the Ca1 site in the calcium chlorosilicate lattice. The solution energy of the substitution process increases with the increasing ionic radii of both the mono- and trivalent species as the steric stresses associated with substitution of larger cations than the Ca2+ host increase. As such, only charge-balancing using Li+, Na+ or K+ is more favourable than via formation of a Ca vacancy.