Small molecule developmental screens reveal the logic and timing of vertebrate development

Much has been learned about vertebrate development by random mutagenesis followed by phenotypic screening and by targeted gene disruption followed by phenotypic analysis in model organisms. Because the timing of many developmental events is critical, it would be useful to have temporal control over modulation of gene function, a luxury frequently not possible with genetic mutants. Here, we demonstrate that small molecules capable of conditional gene product modulation can be identified through developmental screens in zebrafish. We have identified several small molecules that specifically modulate various aspects of vertebrate ontogeny, including development of the central nervous system, the cardiovascular system, the neural crest, and the ear. Several of the small molecules identified allowed us to dissect the logic of melanocyte and otolith development and to identify critical periods for these events. Small molecules identified in this way offer potential to dissect further these and other developmental processes and to identify novel genes involved in vertebrate development.

Efficient infection of a human T-cell line and of human primary peripheral blood leukocytes with a pseudotyped retrovirus vector.

Peripheral blood lymphocytes (PBLs) are an important target for gene transfer studies aimed at human gene therapy. However, no reproducibly efficient methods are currently available to transfer foreign, potentially therapeutic genes into these cells. While vectors derived from murine retroviruses have been the most widely used system, their low infection efficiency in lymphocytes has required prolonged in vitro culturing and selection after infection to obtain useful numbers of genetically modified cells. We previously reported that retroviral vectors pseudotyped with vesicular stomatitis G glycoprotein (VSV-G) envelope can infect a wide variety of cell types and can be concentrated to titers of greater than 10(9) infectious units/ml. In this present study, we examined the ability of amphotropic and pseudotyped vectors expressing a murine cell surface protein, B7-1, to infect the human T-cell line Jurkat or human blood lymphocytes. Limiting dilution analysis of transduced Jurkat cells demonstrated that the pseudotyped vector is significantly more efficient in infecting T cells than an amphotropic vector used at the same multiplicity of infection (moi). To identify the transduction efficiency on PBLs, we examined the levels of cell surface expression of the B7-1 surface marker 48 to 72 hr after infection. The transduction efficiency of PBLs with the pseudotyped vector increased linearly with increasing moi to a maximum of approximately 16-32% at an moi of 40. This relatively high efficiency of infection of a T-cell line and of blood lymphocytes with VSV-G pseudotyped virus demonstrates that such modified pseudotyped retrovirus vectors may be useful reagents for studies of gene therapy for a variety of genetic or neoplastic disorders.

Psychosocial Distress Screening in a Community Cancer Center: An Exploratory Study of Distress Screening Across the Cancer Treatment Continuum

Purpose: The primary goal of this exploratory study is to demonstrate that distress screening across the course of cancer treatment is possible and provides valuable information about patient needs over time. Distress screening is aligned with guidelines from national accrediting organizations and may lead to improved health-related quality of life, satisfaction with medical care, and possibly survival.Methods: Medical, surgical, and radiation oncology patients completed a screening instrument before their appointments during a six-month period. Patients indicated their level of distress on four domains (practical, emotional, health and social concerns). De-identified data was collected, aggregated and descriptive statistics were analyzed.Results: Approximately 3000 screens were collected and 1500 cancer patients were screened. Of patients who indicated distress, 54% demonstrated a distress level of five or greater. Distress level eight was the most frequent level of distress indicated. The Cancer Dietitian was the most commonly requested healthcare team provider. The Health Concern domain was most frequently endorsed.Conclusion: NCCN, IOM and COC guidelines recommend distress screening in all cancer treatment centers, however implementation has proven difficult. This study adds to the literature about distress in cancer patients, demonstrates the feasibility of repeated distress screening and provides a model program demonstrating the implementation of repeated distress screening at a community cancer center. Findings highlight the importance of supportive oncology services due to the prevalence of high levels of distress. Findings demonstrate the importance of the Cancer Dietitian in supportive cancer care. Additionally, the research reveals a potential perceived stigma in seeking psychosocial oncology services.

Hiring Manager Training for Strategically Selecting the Best Human Capital

The selection process is arguably the most important part of the employee life cycle in an organization, but a process often underdeveloped in many organizations. Successful selection processes can put the right people into critical positions, whereas failure to focus on selection can result in poor performance, turnover, and loss of productivity critical to the continuing success of organizations. This paper creates a model for a hiring manager training that focuses on a strategic selection process to maximize chances for successful hires. Utilizing leadership and selection models, human resources can engage hiring managers in a strategic applicant selection process as well as give tools for screening, interviewing, and selecting the best candidates for employment throughout all levels of their organization.

Determination of cyclic and linear siloxanes in wastewater samples by ultrasound-assisted dispersive liquid-liquid microextraction followed by gas chromatography-mass spectrometry

A fast, simple and environmentally friendly ultrasound-assisted dispersive liquid-liquid microextraction (USA-DLLME) procedure has been developed to preconcentrate eight cyclic and linear siloxanes from wastewater samples prior to quantification by gas chromatography-mass spectrometry (GC-MS). A two-stage multivariate optimization approach has been developed employing a Plackett-Burman design for screening and selecting the significant factors involved in the USA-DLLME procedure, which was later optimized by means of a circumscribed central composite design. The optimum conditions were: extractant solvent volume, 13 µL; solvent type, chlorobenzene; sample volume, 13 mL; centrifugation speed, 2300 rpm; centrifugation time, 5 min; and sonication time, 2 min. Under the optimized experimental conditions the method gave levels of repeatability with coefficients of variation between 10 and 24% (n=7). Limits of detection were between 0.002 and 1.4 µg L−1. Calculated calibration curves gave high levels of linearity with correlation coefficient values between 0.991 and 0.9997. Finally, the proposed method was applied for the analysis of wastewater samples. Relative recovery values ranged between 71–116% showing that the matrix had a negligible effect upon extraction. To our knowledge, this is the first time that combines LLME and GC-MS for the analysis of methylsiloxanes in wastewater samples.

Simultaneous synthesis of heat exchanger networks with pressure recovery: optimal integration between heat and work

The optimal integration between heat and work may significantly reduce the energy demand and consequently the process cost. This paper introduces a new mathematical model for the simultaneous synthesis of heat exchanger networks (HENs) in which the pressure levels of the process streams can be adjusted to enhance the heat integration. A superstructure is proposed for the HEN design with pressure recovery, developed via generalized disjunctive programming (GDP) and mixed-integer nonlinear programming (MINLP) formulation. The process conditions (stream temperature and pressure) must be optimized. Furthermore, the approach allows for coupling of the turbines and compressors and selection of the turbines and valves to minimize the total annualized cost, which consists of the operational and capital expenses. The model is tested for its applicability in three case studies, including a cryogenic application. The results indicate that the energy integration reduces the quantity of utilities required, thus decreasing the overall cost.

Using realist evaluation to assess primary healthcare teams’ responses to intimate partner violence in Spain

Objective: Few evaluations have assessed the factors triggering an adequate health care response to intimate partner violence. This article aimed to: 1) describe a realist evaluation carried out in Spain to ascertain why, how and under what circumstances primary health care teams respond to intimate partner violence, and 2) discuss the strengths and challenges of its application. Methods: We carried out a series of case studies in four steps. First, we developed an initial programme theory (PT1), based on interviews with managers. Second, we refined PT1 into PT2 by testing it in a primary healthcare team that was actively responding to violence. Third, we tested the refined PT2 by incorporating three other cases located in the same region. Qualitative and quantitative data were collected and thick descriptions were produced and analysed using a retroduction approach. Fourth, we analysed a total of 15 cases, and identified combinations of contextual factors and mechanisms that triggered an adequate response to violence by using qualitative comparative analysis. Results: There were several key mechanisms —the teams’ self-efficacy, perceived preparation, women-centred care—, and contextual factors —an enabling team environment and managerial style, the presence of motivated professionals, the use of the protocol and accumulated experience in primary health care—that should be considered to develop adequate primary health-care responses to violence. Conclusion: The full application of this realist evaluation was demanding, but also well suited to explore a complex intervention reflecting the situation in natural settings.

Biologic therapies and non-melanoma skin cancer rates in three chronic immune-mediated diseases

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Bringing South Caucasus Closer to Europe: Achievements and Challenges in ENP Implantation. Natolin Research Paper 03/March 2011

While the initial Commission Communication on Wider Europe (March 2003) did not include Armenia, Georgia and Azerbaijan in the forthcoming policy for the EU’s new neighbourhood, the Southern Caucasus region has now gained considerable attention in the framework of the ENP and beyond, not least because of security considerations. The ENP undoubtedly represents a step forward in the EU’s policy towards Armenia, Azerbaijan and Georgia, yet its implementation highlights major differences between the three countries and important weaknesses in all three of them. The Eastern Partnership addresses some of these weaknesses and it also significantly strengthens the EU’s offer to South Caucasus countries, which is now fully in line with the perspectives proposed to the Western NIS. The paper highlights five main conclusions and recommendations: • Political, economic, social and diplomatic developments in the South Caucasus in the 2000's highlight both diverging trends and the persistence of tensions between the three countries. They also have different aspirations vis-à-vis the EU and different records in ENP implementation. The EU should therefore mainly rely upon an individual approach towards each country. • While bilateral relations should form the basis of the EU's approach, most of the challenges faced by Georgia, Armenia and Azerbaijan are not confined to national borders and require regional solutions. This applies primarily, but not exclusively, to the unresolved conflicts. The EU should promote targeted regional cooperation including, inter alia, confidence-building measures to address indirectly the protracted conflicts and measures supporting drivers of change, which play a critical role in the confidence-building process; • Under the ENP, especially since the opening of negotiations for association agreements and with the perspective of DCFTA, trade-related issues, market and regulatory reform have become prominent in the EU's relations with all three Caucasus countries. At the same time, the priorities identified when the ENP was launched, i.e. good governance and the rule of law, still correspond to major challenges in the South Caucasus. The EU should more clearly prioritise good governance and the rule of law as the basis of both the ENP and successful reforms; • In all partner countries (but even more so in the South Caucasus), ENP implementation has been adversely affected by poor administrative capacities and weak institutional coordination. The EU should increasingly focus on institutional reform/capacity building in its support to partner countries and ensure that the link between the ENP and domestic reform processes is strengthened; • In the South Caucasus the EU has recently concentrated on a few assistance tools such as budget support, Twinning and TAIEX. While these instruments undoubtedly bring an added value, they should be better combined with tools allowing for greater flexibility and targeting non-governmental actors, e.g. EIDHR/NSA.

Investigation of feasibility of utilizing available heat resistant materials for hypersonic leading edge applications.

"Volumes I through VIII are unclassified while volume IX is classified secret."

Barriers and Facilitators to Treatment among Newly Diagnosed Hypertensive Patients in Nepal: a Qualitative Study

Thesis (Master's)--University of Washington, 2016-06

Longitudinal relationships among overweight, life satisfaction, and aspirations in young women

Objective: This study investigated associations of overweight status and changes in overweight status over time with life satisfaction and future aspirations among a community sample of young women. Research Methods and Procedures: A total of 7865 young women, initially 18 to 23 years of age, completed two surveys that were 4 years apart. These women provided data on their future life aspirations in the areas of further education, work/career, marital status, and children, as well as their satisfaction with achievements to date in a number of life domains. Women reported their height and weight and their sociodemographic characteristics, including current socioeconomic status (occupation). Results: Young women's aspirations were cross-sectionally related to BMI category, such that obese women were less likely to aspire to further education, although this relationship seemed explained largely by current occupation. Even after adjusting for current occupation, young women who were obese were more dissatisfied with work/career/study, family relationships, partner relationships, and social activities. Weight status was also longitudinally associated with aspirations and life satisfaction. Women who were overweight or obese at both surveys were more likely than other women to aspire to other types of employment (including self-employed and unpaid work in the home) as opposed to full-time employment. They were also less likely to be satisfied with study or partner relationships. Women who resolved their overweight/obesity status were more likely to aspire to being childless than other women. Discussion: These results suggest that being overweight/obese may have a lasting effect on young women's life satisfaction and their future life aspirations.

Colorectal cancer screening in Australia: an economic evaluation of a potential biennial screening program using faecal occult blood tests

Objective: To evaluate whether the introduction of a national, co-ordinated screening program using the faecal occult blood test represents 'value-for-money' from the perspective of the Australian Government as third-party funder. Methods: The annual equivalent costs and consequences of a biennial screening program in 'steady-state' operation were estimated for the Australian population using 1996 as the reference year. Disability-adjusted life years (DALYs) and the years of life lost (YLLs) averted, and the health service costs were modelled, based on the epidemiology and the costs of colorectal cancer in Australia together with the mortality reduction achieved in randomised controlled trials. Uncertainty in the model was examined using Monte Carlo simulation methods. Results: We estimate a minimum or 'base program' of screening those aged 55 to 69 years could avert 250 deaths per annum (95% uncertainty interval 99-400), at a gross cost of $A55 million (95% UI $A46 million to $A96 million) and a gross incremental cost-effectiveness ratio of $A17,000/DALY (95% UI $A13,000/DALY to $A52,000/DALY). Extending the program to include 70 to 74-year-olds is a more effective option (cheaper and higher health gain) than including the 50 to 54-year-olds. Conclusions: The findings of this study support the case for a national program directed at the 55 to 69-year-old age group with extension to 70 to 74-year-olds if there are sufficient resources. The pilot tests recently announced in Australia provide an important opportunity to consider the age range for screening and the sources of uncertainty, identified in the modelled evaluation, to assist decisions on implementing a full national program.

Cervical Cancer Control, Priorities and New Directions

Cervical cancer is caused by infection with a range of high risk oncogenic human papillomavirus (HPV) types, and it is now accepted that >99% of cervical cancer is initiated by HPV infection. The estimated lifetime risk of cervical cancer is nevertheless relatively low (less than I in 20 for most community based studies). Although sensitivity and specificity of the available diagnostic techniques are suboptimal, Screening for persistent HPV infection is effective in reducing the incidence of cervical cancer. Infection can be detected by molecular techniques or by cytological examination of exfoliated cervical cells. Persistent infection is the single best predictor of risk of cervical cancer.(1) The latest findings of HPV and cervical cancer research need to be widely disseminated to the scientific and medical societies that are updating screening and management protocols, public health professionals, and to women and clinicians. This report reviews current evidence, clinical implications and directions for further research in the prevention, control and management of cervical cancer. We report the conclusions of the Experts' Meeting at the EUROGIN 2003 conference. (C) 2003 Wiley-Liss, Inc.

Increased use of emergency services by older people after health screening

Background: evaluation of the 'Keep Well At Home' (KWAH) Project in West London indicated that a programme of screening persons aged 75 and over had not reduced rates of emergency attendances and admissions to hospital. However, coverage of the target population was incomplete. The present analysis addresses 'efficacy'-whether individuals who completed the screening protocol as intended did subsequently use Accident & Emergency (A&E) services less often. Methods: the target population was divided into five groups, depending on whether an individual had completed none, one or both phases of screening, and whether deviations from the protocol related to incomplete coverage or refusal to participate further. We ascertained use of emergency services before screening and for up to 3 years afterwards by linkage of records from KWAH to those of local A&E Departments. Patterns of emergency care were examined as crude races and, via proportional hazards models, after adjustment for available confounders. Results: there was an increase of 51% (95% CI 22-86%) in the crude rate of emergency admissions in the year after first-phase screening compared with the 12 months before assessment. This was most obvious in individuals deemed at high risk who also underwent the second-phase assessment (adjusted hazard ratio relative to individuals not 'at risk'= 2.33; 95% CI 1.59-3.42). Conclusions: the available data do not allow us to distinguish between several possible explanations for the paradoxical increase in use of emergency services. However, what seem to be sensible policies do not necessarily have their intended effects when implemented in practice.