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OBJECTIVES/SPECIFIC AIMS: Women with pulmonary arterial hypertension (PAH) exhibit superior right ventricular (RV) function and survival compared with men, a phenomenon attributed to poorly understood cardioprotective effects of 17β-estradiol (E2). We hypothesize that E2, through ERα, attenuates PH-induced RV dysfunction by upregulating the pro-contractile and pro-angiogenic peptide apelin. This ERα-mediated increase in apelin is mediated by the myocardial remodeling effector bone morphogenetic protein receptor 2 (BMPR2). METHODS/STUDY POPULATION: ERα, BMPR2, and apelin were measured (western blot) in RVs from patients with PAH-induced RV failure and in RV homogenates from male or female Sprague-Dawley rats with sugen/hypoxia (SuHx) or monocrotaline (MCT)-induced PH. H9c2 rat cardiomyoblasts and cardiac endothelial cells were stressed with TNF-α (10 ng/mL) or staurosporine (50 nM)±E2 (100 nM; 24 h). ERα-, BMPR2-, and apelin-dependence were evaluated by siRNA (5 pM). Downstream apelin target and pro-survival factor ERK1/2 expression was measured (western blot). p<0.05 by ANOVA was considered significant. RESULTS/ANTICIPATED RESULTS: ERα correlated positively with BMPR2 and apelin expression in SuHx-RVs and human RVs. Treatment of SuHx-PH rats with E2 or ERα agonist increased RV BMPR2 and apelin, whereas RV apelin was decreased in E2-treated hypoxic ERα knockout mice (p<0.05), but not in ERβ knockout mice. In H9c2 cells, E2 or ERα agonist attenuated TNF-α- or staurosporine-induced decreases in BMPR2, apelin, and phospho-ERK1/2 (p<0.05 for all endpoints). E2 protection was lost in presence of siRNA directed against ERα, BMPR2, or apelin (p<0.05). ERα was necessary for E2-mediated increases in BMPR2, apelin, and ERK1/2, and BMPR2 was required for the E2-mediated increase in apelin (p<0.05 for siRNA vs. scramble). ERα, BMPR2, and apelin protein was increased in decompensated human RVs but downstream phospho-ERK signaling was disrupted. DISCUSSION/SIGNIFICANCE OF IMPACT: E2, via ERα, increases BMPR2 and apelin in the failing RV and in stressed rat cardiomyoblasts. The E2-mediated increase in apelin is BMPR2-dependent and likely occurs through direct binding of ERα to the BMPR2 promoter. Harnessing this E2-ERα-BMPR2-apelin axis during RV compensation may lead to novel, RV-targeted therapies for PAH patients of either sex.
Objectives: The evaluation of public health interventions poses some challenges. As a consequence, health technology assessment (HTA) methods for public health interventions (PHI) have to be adapted. This study aimed to summarize the available guidance on methods for HTA of PHI.
Methods: We systematically searched for methodological guidance on HTA of PHIs. Our focus was on research synthesis methods to evaluate effectiveness. Relevant information was synthesized narratively in a standardized way.
Results: Only four guidance documents were identified specifically for HTAs of PHI. The approaches used for HTAs of PHIs are broader and more flexible than those for medical interventions. For this reason, there is a tendency to identify the intervention components and context factors that influence the effectiveness and transferability of an intervention rather than to assess its effectiveness in general. The details in the guidance vary without justification. Unjustified heterogeneity between the different guidance approaches is most pronounced for quality assessment, assessment of applicability, and methods to integrate qualitative and quantitative evidence. Descriptions for the assessment of integrity, heterogeneity, sustainability, context factors, and applicability are often vague.
Conclusions: The heterogeneity in approaches indicates that there is currently no consensus on methods to deal with the challenges of the PHI evaluations. A possible explanation for this may be that the methods are not sufficiently developed, and advantages and disadvantages of a certain method in relation to the research question (e.g., broad/focused) have not yet been sufficiently evaluated.
The mean rate-of-change of the surface elevation on lower Lambert Glacier is measured with satellite-radar altimetry from the Geosat Exact Repeat Mission (ERM) (1987 89) and Seasat (1978), using orbit cross-over analysis. The measurement region extends 190km in the along-flow direction from 72.1° to 70.4° S, an area that includes the grounding zone of Lambert Glacier. The Geosat ERM and Seasat altimetry are referenced to GEM T2 orbits. The random-noise levels in the data are reduced by low-pass filtering. The orbit bias between the two satellites is estimated from cross-over differences over sea ice seaward of the calving front of the Amery Ice Shelf. The results show a mean rate of increase of the surface height on lower Lambert Glacier of 31±10 mm year-1 during the decade from 1978 to 1987–89. The computation is also carried out independently using data not low-pass filtered but with orbit bias minimized by adjusting the Seasat and Geosat ERM orbits into a common ocean surface. The latter analysis shows a mean rate of increase of the surface height of 83 ± 9 mm year-1 during the same time period. Cross-over analyses carried out using altimetry not low-pass filtered and with orbits not adjusted into a common ocean surface yield intermediate results. Taken together, the cross-over analyses show that the surface height on lower Lambert Glacier increased at a mean rate within the range 20–90 mm year-1 during the decade 1978 to 1987–89.
This article offers a discursive analysis of UK Parliamentary debate on the proscription of terrorist organisations between 2002 and 2014. It argues that these debates play an important constitutive role in the (re)production of national Self and terrorist Other that remains largely overlooked in existing work on this counter-terrorism mechanism. The article begins with an overview of this literature, arguing it is overwhelmingly oriented around questions of efficacy and ethics. While important, this focus has concentrated academic attention on the causal question of what proscription does, rather than the constitutive question of what is made possible by proscription. The article’s second section situates our analysis within discursive work in International Relations, upon which we investigate three pervasive themes in Parliamentary debate: (i) Constructions of terrorism and its threat; (ii) Constructions of specific groups being proscribed; and, (iii) Constructions of the UK Self. We argue that these debates (re)produce an antagonistic relationship between a liberal, open, and responsible UK mindful of cultural and religious difference, on the one hand. And, on the other, its illiberal, irrational terrorist Others conducting immoral violences on behalf of particularistic identity claims. This analysis, we conclude, has significance for contemporary debate on security politics, as well as for studies of counter-terrorism and international politics more generally.
The present study aimed to identify themes emerging from an inclusive therapeutic recreational camp experience for children with disabilities who attended a 10-day summer camp. Concept mapping was used to analyse the experience of 42 participants. Results emerged with seven themes: Personal Growth; Nurturing Relationships; Non-judgmental Environment and Attitude; Traditional/Classic Camp Fun; Beneficial and Unique Opportunities; Learning/Thinking with Structures and Rules; and Independence and Recognition. Results suggested that children with disabilities experienced positive personal growth and learned new skills from an integrated, therapeutic camp. These children benefited from the social and psychological aspects of the camp experience, as well as the learned skillset and behaviours. Clinical implications and future research directions are also discussed.
The safe operating area (SOA) of InGaP/GaAs heterojunction bipolar transistors has been studied using two-dimensional Technology Computer-Aided Design (TCAD) tool. Comprehensive physical models, including hydrodynamic transport-based impact ionization and self-heating models were implemented. The simulations for two DC modes (constant Ib and Vb modes) captured all the SOA features observed in measurements and some failure mechanisms were revealed for the first time by TCAD simulations. The simulated results are also in agreement with analytical modeling. The simulation not only gives us insight to the detailed failure mechanisms, but also provides guidance for the design of devices with better ruggedness and improved SOA performances.
Objectives: The objective of this systematic review was to evaluate the cost-effectiveness of interventions aiming to increase the adherence to highly active antiretroviral therapy (HAART) in HIV-infected patients in developed countries (WHO stratum A).
Methods: A systematic search for comparative health economic studies was conducted in the following databases: EMBASE, MEDLINE, NHS Economic Evaluation Database, CINAHL, HEED, and EconLit. The identified publications were selected by two reviewers independently according to predefined inclusion and exclusion criteria. Furthermore, these were evaluated according to a standardized checklist and finally extracted, analyzed, and summarized.
Results: After reviewing the abstracts and full texts four relevant studies were identified. Different educational programs were compared as well as the Directly Observed Therapy (DOT). A critical aspect to be considered in particular was the poor transparency of the cost data. In three cost-utility analyses the costs per quality-adjusted life-year (QALY) in the baseline scenario were each under USD 15,000. The sensitivity analyses with a presumed maximum threshold of USD 50,000/QALY showed a predominantly cost-effective result. In one study that examined DOT the costs add up to over USD 150,000/QALY.
Conclusions: It seems that adherence interventions for HAART in HIV-infected patients can be cost-effective. Nevertheless, the quality of the included studies is deficient and only a few of the possible adherence interventions are taken into consideration. A final assessment of the cost-effectiveness of adherence interventions in general is, therefore, not possible.
The residual-stress-gradient distribution just below the surface of a material is an important factor to consider during the engineering and design of a component. With the availability of an intense energy-tunable synchrotron x-ray source, it becomes easier to analyze the stress gradient below the surface, using a multi-energy x-ray diffraction method. A program was developed to efficiently determine possible experimental parameters using a sample with a known stress gradient distribution. In addition, this program can also calculate the stress gradient distribution below the surface taking into account experimental results. It also includes a subroutine for calculating the x-ray absorption coefficients of all of the elements, generalizing it for use with any material. As an example, in the present study, the relationship between x-ray energy and the residual stress gradient is discussed according to the calculated result for a silicon nitride composition.
Electro-optic polymers are of great interest for inserting photonic elements into electronic systems. Recently Much progress has been made in both materials and processing. These polymers must have low optical loss, high mechanical integrity, low processing cost, and high temperature stability. In the first part of our talk, we present our work to produce etched single mode buried channel waveguides in an all polymide system. We have chosen polyimide because of its high temperature stability. Optical losses and waveguide characteristics are described as a function of waveguide width and index ofrefraction difference between core and cladding.
Mach Zehnder Modulators fabricated using a DCM-polymide core are also described The waveguide cores are etched and fully embedded in a polyimide cladding. The active arms of the modulator are poled using parallel plate poling. The electro-optic properties of the Mach Zehnder are described operating at 830nm. Photobleached DCM waveguides are also describe. A new high temperature chromophore is presented.
We present a new method of increasing the effective electrode surface for improved neural recording. To optimize the electrode, the impedance can be decreased by introducing surface roughness or nanostructures on the electrode. High aspect ratio pillar-like polysilicon nanostructures are created in a reactive ion etch. Nanostructure robustness in cell culture is examined.
The commonest cause of lymphoedema worldwide is filariasis
In the Western world the commonest cause is malignancy and its treatment
Oedema is initially pitting, but becomes non-pitting due to fibrosis of subcutaneous tissues
Diagnosis is confirmed by isotope lymphangioscintigraphy
Satisfactory treatment can usually be achieved by conservative measures that include manual drainage, compression hosiery, complex decongestive therapy and prevention of infection
There are various conditions that cause chronic lower limb swelling (Table 17.1). The two most common are chronic venous insufficiency and lymphoedema. Lymphoedema is a debilitating condition that has no cure. Several million people are affected worldwide.
Lymphoedema can be defined as the accumulation of fluid rich in protein in the skin and subcutaneous tissues due to a defect in the lymphatic system resulting in swelling of the limb.
Lymphoedema can be primary or secondary.
Primary lymphoedema can be classified based on the age of onset (Table 17.2). Women are more likely to be affected than men. The lower limbs are more frequently affected than the upper limbs.
Congenital lymphoedema is present at birth and can be autosomally inherited (Milroy's disease). Oedema is present at birth and two-thirds of affected patients have bilateral lymphoedema. It accounts for 25% of all cases.
Lymphoedema praecox presents up to the age of 35 years, usually during adolescence. It is the commonest form of congenital lymphoedema. Most patients have unilateral limb involvement.
Lymphoedema tarda presents after the age of 35 years. This is the least common form and accounts for about 10% of cases.