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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.
Attendance at overnight school camp is an integral component of the Australian educational landscape. However, some students are reluctant to attend camp, while others refuse to attend at all. School psychologists play an important part in supporting these students and their families, and teachers. While much is published about general school refusal, there is surprisingly little attention given to the specific management of school camp refusal and reluctance. This article summarises the contribution of the related theoretical areas of childhood anxiety, school refusal, and homesickness. It then outlines, through a case study example, a management approach for school psychologists, from presentation of the problem to assessment, through to informed intervention, including a suite of strategies to support the student, parents and teachers, who have duty of care during camps.
Objectives: The aim of this study was to demonstrate the utility of an evidence-based assessment (EBA) model to establish a multimodal set of tools for identifying students at risk for perceived post-injury academic problems. Methods: Participants included 142 students diagnosed with concussion (age: M=14.95; SD=1.80; 59% male), evaluated within 4 weeks of injury (median=16 days). Demographics, pre-injury history, self- and parent-report measures assessing symptom severity and executive functions, and cognitive test performance were examined as predictors of self-reported post-injury academic problems. Results: Latent class analysis categorized participants into “high” (44%) and “low” (56%) levels of self-reported academic problems. Receiver operating characteristic analyses revealed significant discriminative validity for self- and parent-reported symptom severity and executive dysfunction and self-reported exertional response for identifying students reporting low versus high academic problems. Parent-reported symptom ratings [area under the receiver operating characteristic curve (AUC)=.79] and executive dysfunction (AUC=.74), and self-reported ratings of executive dysfunction (AUC=.84), symptoms (AUC=.80), and exertional response (AUC=.70) each classified students significantly better than chance (ps<.001). Hierarchical logistic regression indicated that, of the above, self-reported symptoms and executive dysfunction accounted for the most variance in the prediction of self-reported academic problems. Conclusions: Post-concussion symptom severity and executive dysfunction significantly predict perceived post-injury academic problems. EBA modeling identified the strongest set of predictors of academic challenges, offering an important perspective in the management of concussion by applying traditional strengths of neuropsychological assessment to clinical decision making. (JINS, 2016, 22, 1038–1049)
In the United States alone, ∼14,000 children are hospitalised annually with acute heart failure. The science and art of caring for these patients continues to evolve. The International Pediatric Heart Failure Summit of Johns Hopkins All Children’s Heart Institute was held on February 4 and 5, 2015. The 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children’s Heart Institute was funded through the Andrews/Daicoff Cardiovascular Program Endowment, a philanthropic collaboration between All Children’s Hospital and the Morsani College of Medicine at the University of South Florida (USF). Sponsored by All Children’s Hospital Andrews/Daicoff Cardiovascular Program, the International Pediatric Heart Failure Summit assembled leaders in clinical and scientific disciplines related to paediatric heart failure and created a multi-disciplinary “think-tank”. The purpose of this manuscript is to summarise the lessons from the 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children’s Heart Institute, to describe the “state of the art” of the treatment of paediatric cardiac failure, and to discuss future directions for research in the domain of paediatric cardiac failure.
The electronic structure of delta plutonium (δ-Pu) and plutonium compounds is investigated using photoelectron spectroscopy (PES). Results for δ-Pu show a small component of the valence electronic structure which might reasonably be associated with a 5f6 configuration. PES results for PuTe are used as an indication for the 5f6 configuration due to the presence of atomic multiplet structure. Temperature dependent PES data on δ-Pu indicate a narrow peak centered 20 meV below the Fermi energy and 100 meV wide. The first PES data for PuCoIn5 indicate a 5f electronic structure more localized than the 5fs in the closely related PuCoGa5. There is support from the PES data for a description of Pu materials with an electronic configuration of 5f5 with some admixture of 5f6 as well as a localized/delocalized 5f5 description.
Many metallic actinide systems host partially filled 5f electrons in the low-energy spectrum. Consequently, they exhibit diverse quantum mechanical phenomena such as magnetism, superconductivity, a mysterious hidden-order phase, or heavy-fermion behavior. Here we present results of a unified theoretical method based on the self-consistent GW formalism for the electronic many-body self-energy. We calculate the dynamic electronic correlation spectra starting from materials specific first-principles electronic band-structure. In particular, we present results for four isostructural intermetallic actinides PuCoIn5, PuCoGa5, PuRhGa5, and UCoGa5. A common underlying property of these materials is a strong spin–orbit coupling split band structure that enables substantial spin fluctuations. In a feedback effect on the electronic structure they create electronic ‘hot spots’, where the single-particle spectral weight is maximum, resulting in a universal peak-dip-hump feature. These results are in good agreement with experiments, suggesting that actinides are adequately described by the intermediate Coulomb interaction regime, where both itinerant (peak) and localized (hump) features coexist.
This paper describes a semi-automated conductive ink process used for packaging MEMS devices. The method is applied to packaging of MEMS sensors for wind tunnel testing. The primary advantage of the method is a reduction in surface topology between the package and the integrated MEMS sensors. In this paper we explore the relationship between trace dimensions, resistivity, and deposition parameters such as feed rate, tip-substrate separation and tip diameter. Using this procedure it is possible to generate interconnects between a PC board and MEMS sensor chip with a topology of less than 25 micrometers.
The electronic structure of Pu materials is examined using photoelectron spectroscopy. For delta-phase Pu metal as well as PuCoGa5 and PuIn3, the 5f electrons appear to be at the threshold between localized and itinerant character. A mixed level model computational scheme is used which results in non-magnetic solutions for the electronic structure and agrees well with the photoemission measurements. Several other computational schemes are assessed against photoemission results for delta Pu. Additional insight is provided by O2 and H2 dosing of the delta Pu samples and consideration of surface effects. The experimental and computational results are consistent with the 5f electrons in Pu materials exhibiting a dual nature with some fraction of the 5f levels localized and not participating in the bonding while the other fraction of 5f character is involved in bonding and hybridization with the conduction electrons.
The purpose of this paper is to provide an introduction for non-experts to first-principles electronic structure methods that are widely used in the field of condensed-matter physics, including applications to actinide materials. The methods I describe are based on density functional theory (DFT) within the local density approximation (LDA) and the generalized gradient approximation (GGA). In addition to explaining the meaning of this terminology I also describe the underlying theory itself in some detail in order to enable a better understanding of the relative strengths and weaknesses of the methods. I briefly mention some particular numerical implementations of DFT, including the linear muffin-tin orbital (LMTO), linear augmented plane wave (LAPW), and pseudopotential methods, as well as general methodologies that go beyond DFT and specifically address some of the weaknesses of the theory. The last third of the paper is devoted to a few selected applications that illustrate the ideas discussed in the first two-thirds. In particular, I conclude by addressing the current controversy regarding magnetic DFT calculations for actinide materials. Throughout this paper particular emphasis is placed on providing the appropriate background to enable the non-expert to gain a better appreciation of the application of first-principles electronic structure methods to the study of actinide and other materials.
The 5f electronic states in elemental Pu and Pu compounds exhibit elements of both itinerant and localized behavior. Several first-principles calculations have been presented to describe this balance, differing in the manner in which electron correlation is included in the calculation. This paper describes a calculations performed with the Mixed Level Model (MLM), presenting calculated results for the two Pu compounds, PuRhGa5 and PuCoGa5. The MLM results are compared with other calculations and the differences discussed.
Lawton R. Burns, Professor of Health Care Systems and Managements University of Pennsylvania,
Sean Nicholson, Assistant Professor Department of Policy Analysis and Management Cornell University,
Preceding chapters have dealt with a common set of topics: horizontal consolidation, mergers and acquisitions, the advantages of size, economies of scale and scope, diversification, and industry concentration. These topics all inter-relate around the fundamental issue in industrial organization: how best to organize firms and markets in order to achieve optimal economic performance? For example, mergers and acquisitions lead to greater firm size and industry concentration, are often undertaken to achieve scale and scope economies, and can involve horizontal integration of similar firms, vertical integration of firms in adjacent stages in the chain of production, or diversification into related and unrelated industries. What is important for our purposes is that these topics all have implications for firm innovation and performance.
In this chapter we analyze the impact of these combinations on innovation and financial performance among pharmaceutical firms. Researchers are still unsure whether innovation leads to improved firm performance, or whether past performance fosters future innovation, or both. Thus, we examine the impact of industrial organization on both sets of measures. We specifically focus on mergers and acquisitions (M&As) due to the rich research literature here as well as the successive waves of M&As in the pharmaceutical sector during the past fifteen years.
Our analysis addresses several related questions. What is the value of size, scale, and M&As for pharmaceutical firms? Do such strategies help firms to develop new products? What are the challenges and opportunities created by M&As?
Previous chapters in this book have addressed particular challenges that firms face as they globalize, such as governance or branding or supply chain management. Or they have addressed themes in globalization such as the cross-border funding of entrepreneurial ventures or government responses to globalization issues. This chapter addresses the many faces of globalization as they play out in the management decisions within a particular sector of national economies – healthcare. The authors examine the complex forces driving and impeding globalization, and the opportunities they create for different players in different places in the world.
Rolf Schmidt, the CEO of a major global pharmaceutical company, looks out of his office at the twinkling lights of a major European city that has been its home for more than a century. The current conglomerate that occupies these offices bears little relationship to the sleepy little chemical company that was founded in the historic offices where the chief executive now paces late into the night. The company now operates across a global patchwork of complex regulations governing its pricing, advertising, and drug development and approval. Its research and development organization is stretched across diverse centers in the United States, Europe, and Asia. Its marketing initiatives are a combination of resource-intensive global brands and increasingly tightly tailored local brands. Its global supply chains and financing create new risks and make the company susceptible to unexpected shocks as it gears up for the rapid production of new drugs that have an ever-narrower window of opportunity.
Concentrations of large numbers of endemic species have been singled out in prioritization exercises as significant areas for global biodiversity conservation. This paper describes bird and mammal endemicity in Indo-Pacific ecoregions. An ecoregion is a relatively large unit of land or water that contains a distinct assemblage of natural communities. We prioritize 133 ecoregions according to their levels of endemicity, and explain how variables such as biome type, whether the ecoregion is on an island or continental mass, montane or non-montane, correlate with the proportion of the total species assemblage that are endemic. Following an exploratory principal components analysis we classify all ecoregions according to the relationship between numbers of endemics and overall species richness. Endemicity is negatively correlated with species richness. We show that plotting the logit transformation of the endemicity of birds and mammals against log of species richness is a more effective and useful way of identifying important ecoregions than simply ordering ecoregions by the proportion of endemic species, or any other single measure. The plot, divided into 16 regions corresponding to the quartiles of the two variables, was used to identify ecoregions of high conservation value. These are the ecoregions with the highest endemicity and lowest species richness. Further analysis shows that island and montane ecoregions, regardless of their biome type, are by far the most important for endemic species.
Twins of like sex and concordant for William's syndrome are presented. The first twin presented late with aortic arch atresia and has subsequently developed hypertension associated with renal arterial stenosis. The second twin died with myocardial ischemia late after surgery for supravalvar aortic and pulmonary stenosis.