The Cost-Effectiveness of Monitoring Strategies for Antiretroviral Therapy of HIV Infected Patients in Resource-Limited Settings: Software Tool.

BACKGROUND The cost-effectiveness of routine viral load (VL) monitoring of HIV-infected patients on antiretroviral therapy (ART) depends on various factors that differ between settings and across time. Low-cost point-of-care (POC) tests for VL are in development and may make routine VL monitoring affordable in resource-limited settings. We developed a software tool to study the cost-effectiveness of switching to second-line ART with different monitoring strategies, and focused on POC-VL monitoring. METHODS We used a mathematical model to simulate cohorts of patients from start of ART until death. We modeled 13 strategies (no 2nd-line, clinical, CD4 (with or without targeted VL), POC-VL, and laboratory-based VL monitoring, with different frequencies). We included a scenario with identical failure rates across strategies, and one in which routine VL monitoring reduces the risk of failure. We compared lifetime costs and averted disability-adjusted life-years (DALYs). We calculated incremental cost-effectiveness ratios (ICER). We developed an Excel tool to update the results of the model for varying unit costs and cohort characteristics, and conducted several sensitivity analyses varying the input costs. RESULTS Introducing 2nd-line ART had an ICER of US$1651-1766/DALY averted. Compared with clinical monitoring, the ICER of CD4 monitoring was US$1896-US$5488/DALY averted and VL monitoring US$951-US$5813/DALY averted. We found no difference between POC- and laboratory-based VL monitoring, except for the highest measurement frequency (every 6 months), where laboratory-based testing was more effective. Targeted VL monitoring was on the cost-effectiveness frontier only if the difference between 1st- and 2nd-line costs remained large, and if we assumed that routine VL monitoring does not prevent failure. CONCLUSION Compared with the less expensive strategies, the cost-effectiveness of routine VL monitoring essentially depends on the cost of 2nd-line ART. Our Excel tool is useful for determining optimal monitoring strategies for specific settings, with specific sex-and age-distributions and unit costs.

Development of a novel driving behavior adaptations questionnaire

ABSTRACT Background: Driving a car requires adapting one's behavior to current task demands taking into account one's capacities. With increasing age, driving-relevant cognitive performance may decrease, creating a need for risk-reducing behavioral adaptations. Three different kinds of behavioral adaptations are known: selection, optimization, and compensation. These can occur on the tactical and the strategic level. Risk-reducing behavioral adaptations should be considered when evaluating older drivers' traffic-related risks. Methods: A questionnaire to assess driving-related behavioral adaptations in older drivers was created. The questionnaire was administered to 61 years older (age 65-87 years; mean age = 70.2 years; SD = 5.5 years; 30 female, 31 male) and 31 younger participants (age 22-55 years; mean age = 30.5 years; SD = 6.3 years; 16 female and 15 male) to explore age and gender differences in behavioral adaptations. Results: Two factors were extracted from the questionnaire, a risk-increasing factor and a risk-reducing factor. Group comparisons revealed significantly more risk-reducing behaviors in older participants (t(84.5) = 2.21, p = 0.013) and females (t(90) = 2.52, p = 0.014) compared, respectively, to younger participants and males. No differences for the risk-increasing factor were found (p > 0.05). Conclusions: The questionnaire seems to be a useful tool to assess driving-related behavioral adaptations aimed at decreasing the risk while driving. The possibility to assess driving-related behavioral adaptations in a systematic way enables a more resource-oriented approach in the evaluation of fitness to drive in older drivers.

Development of small molecular tools for the cellular study of adenosine receptors

The adenosine receptors are members of the G-protein coupled receptor (GPCR) family which represents the largest class of cell-surface proteins mediating cellular communication. As a result, GPCRs are formidable drug targets and it is estimated that approximately 30% of the marketed drugs act through members of this receptor class. There are four known subtypes of adenosine receptors: A1, A2A, A2B and A3. The adenosine A1 receptor, which is the subject of this presentation, mediates the physiological effects of adenosine in various tissues including the brain, heart, kidney and adipocytes. In the brain for instance, its role in epilepsy and ischemia has been the focus of many studies. Previous attempts to study the biosynthesis, trafficking and agonist-induced internalisation of the adenosine A1 receptor in neurons using fluorescent protein-receptor fusion constructs have been hampered by the sheer size of the fluorescent protein (GFP) that ultimately affected the function of the receptor. We have therefore initiated a research programme to develop small molecule fluorescent agonists that selectively activate the adenosine A1 receptor. Our probe design is based on the endogenous ligand adenosine and the known unselective adenosine receptor agonist NECA. We have synthesised a small library of non-fluorescent adenosine derivatives that have different cyclic and bicyclic moieties at the 6 position of the purine ring and have evaluated the pharmacology of these compounds using a yeast-based assay. This analysis revealed compounds with interesting behaviour, i.e. exhibiting subtype-selectivity and biased signalling, that can be potentially used as tool compounds in their own right for cellular studies of the adenosine A1 receptor. Furthermore, we have also linked fluorescent dyes to the purine ring and discovered fluorescent compounds that can activate the adenosine A1 receptor.

Simulation Games - A Creative Tool for Capacity Building: Experience from the Learning for Sustainability Approach

Games that simulate complex realities to be dealt with in teams are an effective tool for fostering interactive learning processes. they link different levels of decision-making in the household, community and societal contexts. Negotiation and harmonisation of different perceptions and interests, be it within or between different households, form the basis of a common strategy for sustainable development.

Linking Applied Ethnobotany to Social Learning: A Participatory Tool for the Promotion of Indigenous Plants Use in Matutuíne, Southern Mozambique

In its search for pathways towards a more sustainable management of natural resources, development oriented research increasingly faces the challenge to develop new concepts and tools based on transdisciplinarity. Transdisciplinarity can, in terms of an idealized goal, be defined as a research approach that identifies and solves problems not only independently of disciplinary boundaries, but also including the knowledge and perceptions of non-scientific actors in a participatory process. In Mozambique, the Centre for Development and Environment (Berne, Switzerland), in partnership with Impacto and Helvetas (Maputo, Mozambique), has elaborated a new transdisciplinary tool to identify indigenous plants with a potential for commercialization. The tool combines methods from applied ethnobotany with participatory research in a social learning process. This approach was devised to support a development project aimed at creating alternative sources of income for rural communities of Matutuíne district, Southern Mozambique, while reducing the pressure on the natural environment. The methodology, which has been applied and tested, is innovative in that it combines important data collection through participatory research with a social learning process involving both local and external actors. This mutual learning process provides a space for complementary forms of knowledge to meet, eventually leading to the adoption of an integrated approach to natural resource management with an understanding of its ecological, socio-economic and cultural aspects; local stakeholders are included in the identification of potentials for sustainable development. Sustainable development itself, as a normative concept, can only be defined through social learning and consensus building between the local and external stakeholders.

The challenge of applying Geographic Information Systems to Sustainable Mountain Development

In recent years, Geographic Information Systems (GIS) have increasingly been used in a wide array of application contexts for development cooperation in lowlands and mountain areas. When used for planning, implementation, and monitoring, GIS is a versatile and highly efficient tool, particularly in mountain areas characterized by great spatial diversity and inaccessibility. However, the establishment and application of GIS in mountain regions generally presents considerable technical challenges. Moreover, it is necessary to address specific institutional and organizational issues regarding implementation.

A Dynamical Tool to Study the Cultural Context of Conflict Escalation

The present article describes research in progress which is developing a simple, replicable methodology aimed at identifying the regularities and specificity of human behavior in conflict escalation and de-escalation prooesses. These research efforts will ultimately be used to study conflict dynamics across cultures. The experimental data collected through this methodology, together with case studies and aggregated, time-series macro data are key for identifying relevant parameters, systems' properties, and micromechanisms defining the behavior of naturally occurring conflict escalation and de-escalation dynamics. This, in turn, is critical for the development of realistic, empirically supported computational models. The article outlines the theoretical assumptions of Dynamical Systems Theory with regard to conflict dynamics, with an emphasis on the process of conflict escalation and de-escalation. Next, work on a methodology for empirical study of escalation processes from a DST perspective is outlined. Specifically, the development of a progressive scenario methodology designed to map escalation sequences, together with anexample of a preliminary study based on the proposed researcb paradigm, is presented. Implications of the approach for the study of culture are discussed.

CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis

Current therapies to treat inflammatory bowel diseases have limited efficacy, significant side effects, and often wane over time. Little is known about the cellular and molecular mechanisms operative in the process of mucosal healing from colitis. To study such events, we developed a new model of reversible colitis in which adoptive transfer of CD4(+)CD45RB(hi) T cells into Helicobacter typhlonius-colonized lymphopenic mice resulted in a rapid onset of colonic inflammation that was reversible through depletion of colitogenic T cells. Remission was associated with an improved clinical and histopathological score, reduced immune cell infiltration to the intestinal mucosa, altered intestinal gene expression profiles, regeneration of the colonic mucus layer, and the restoration of epithelial barrier integrity. Notably, colitogenic T cells were not only critical for induction of colitis but also for maintenance of disease. Depletion of colitogenic T cells resulted in a rapid drop in tumor necrosis factor α (TNFα) levels associated with reduced infiltration of inflammatory immune cells to sites of inflammation. Although neutralization of TNFα prevented the onset of colitis, anti-TNFα treatment of mice with established disease failed to resolve colonic inflammation. Collectively, this new model of reversible colitis provides an important research tool to study the dynamics of mucosal healing in chronic intestinal remitting-relapsing disorders.Mucosal Immunology advance online publication 16 September 2015; doi:10.1038/mi.2015.93.

A photopolymerized composite hydrogel and surgical implanting tool for a nucleus pulposus replacement

Nucleus pulposus replacements have been subjected to highly controversial discussions over the last 40 years. Their use has not yet resulted in a positive outcome to treat herniated disc or degenerated disc disease. The main reason is that not a single implant or tissue replacement was able to withstand the loads within an intervertebral disc. Here, we report on the development of a photo-polymerizable poly(ethylene glycol)dimethacrylate nano-fibrillated cellulose composite hydrogel which was tuned according to native tissue properties. Using a customized minimally-invasive medical device to inject and photopolymerize the hydrogel insitu, samples were implanted through an incision of 1 mm into an intervertebral disc of a bovine organ model to evaluate their long-term performance. When implanted into the bovine disc model, the composite hydrogel implant was able to significantly re-establish disc height after surgery (p < 0.0025). The height was maintained after 0.5 million loading cycles (p < 0.025). The mechanical resistance of the novel composite hydrogel material combined with the minimally invasive implantation procedure into a bovine disc resulted in a promising functional orthopedic implant for the replacement of the nucleus pulposus.

'Reform' of the British national health service after the election of a labour government: Understanding the policy development process

The policy development process leading to the Labour government's white paper of December 1997—The new NHS: Modern, Dependable—is the focus of this project and the public policy development literature is used to aid in the understanding of this process. Policy makers who had been involved in the development of the white paper were interviewed in order to acquire a thorough understanding of who was involved in this process and how they produced the white paper. A theoretical framework is used that sorts policy development models into those that focus on knowledge and experience, and those which focus on politics and influence. This framework is central to understanding the evidence gathered from the individuals and associations that participated in this policy development process. The main research question to be asked in this project is to what extent do either of these sets of policy development models aid in understanding and explicating the process by which the Labour government's policies were developed. The interview evidence, along with published evidence, show that a clear pattern of policy change emerged from this policy development process, and the Knowledge-Experience and Politics-Influence policy making models both assist in understanding this process. The early stages of the policy development process were characterized as hierarchical and iterative, yet also very collaborative among those participating, with knowledge and experience being quite prevalent. At every point in the process, however, informal networks of political influence were used and noted to be quite prevalent by all of the individuals interviewed. The later stages of the process then became increasingly noninclusive, with decisions made by a select group of internal and external policy makers. These policy making models became an important tool with which to understand the policy development process. This Knowledge-Experience and Politics-Influence dichotomy of policy development models could therefore be useful in analyzing other types of policy development. ^

Functional analysis of BMP4 signaling in mouse neural development

During early mouse neural development, bone morphogenetic protein (BMP) signaling patterns the dorsal neural tube and defines distinct neural progenitor cell domains along the dorsoventral axis. Unlike the ventral signaling molecule Sonic hedgehog, which has long-range activity by establishing a concentration gradient in the ventral neural tube, these dorsally expressed BMPs appear to have a limited domain of action. This raises questions as to how BMP activity is restricted locally and how restricted BMP signaling directs dorsal neural patterning and differentiation. I hypothesize that BMPs are restricted in the dorsal neural tube for correct dorsoventral patterning. ^ Previous studies have shown that the positively charged basic amino acids located at the N-terminus of several BMPs are essential for heparin binding and diffusion. This provides a novel tool to address these questions. Here I adapted a UAS/GAL4 bigenic mouse system to control the ectopic expression of BMP4 and a mutant form of BMP4 that lacks a subset of the N-terminal basic amino acids. The target genes, UAS-Bmp4 and UAS-mBmp4 , were introduced into the Hprt locus by gene targeting in mouse embryonic stem cells. The expression of the GAL4 transactivator was driven by a roof plate specific Wnt1 promoter. ^ The bigenic mouse embryos exhibit phenotype variations, ranging from mid/hindbrain defects, hemorrhage, and eye abnormalities to vasculture formation. Embryonic death starts around E11.5 because of severe hemorrhage. The different expression levels of the activated transgene may account for the phenotype variation. Further marker analysis reveals that mutant BMP4 induces ectopic expression of the dorsal markers MSX1/2 and PAX7 in the ventral neural tube. In addition, the expression of the ventral neural marker NKX2.2 is affected by the expanded BMP4 activity, indicating that ectopic BMP signaling can antagonize ventral signaling. Comparison of the phenotypes of the Wnt1/ Bmp4 and Wnt1/mBmp4 bigenic embryos that express transgenes at the same level, respectively, shows that mutant BMP4 causes the expansion of dorsal neural fates ventrally while wild type BMP4 does not, suggesting that mutant BMP4 acts farther than wild type BMP4. Together, these data suggest that the N-terminus basic amino acid core controls BMP4 long-range activity in neural development, and that BMP signaling patterns the dorsal neural tube through a secondary signaling pathway that involves homeodomain transcription factors MSX1/2 and PAX7. ^

Use of cognitive interviewing in the development of a Spanish language genetic knowledge instrument

Study purpose. Genetic advances are significantly impacting healthcare, yet recent studies of ethnic group participation in genetic services demonstrate low utilization rates by Latinos. Limited genetic knowledge is a major barrier. The purpose of this study was to field test items in a Spanish-language instrument that will be used to measure genetic knowledge relevant to type 2 diabetes among members of the ethnically heterogeneous U.S. Latino community. Accurate genetic knowledge measurement can provide the foundation for interventions to enhance genetic service utilization. ^ Design. Three waves of cognitive interviews were conducted in Spanish to field test 44 instrument items Thirty-six Latinos, with 12 persons representative of Mexican, Central and South American, and Cuban heritage participated, including 7 males and 29 females between 22 and 60 years of age; 17 participants had 12 years or less of education. ^ Methods. Text narratives from transcriptions of audiotaped interviews were qualitatively analyzed using a coding strategy to indicate potential sources of response error. Through an iterative process of instrument refinement, codes that emerged from the data were used to guide item revisions at the conclusion of each phase; revised items were examined in subsequent interview waves. ^ Results. Inter-cultural and cross-cultural themes associated with difficulties in interpretation and grammatical structuring of items were identified; difficulties associated with comprehension reflected variations in educational level. Of the original 44 items, 32 were retained, 89% of which were revised. Six additional items reflective of cultural knowledge were constructed, resulting in a 38-item instrument. ^ Conclusions. Use of cognitive interviewing provided a valuable tool for detecting both potential sources of response error and cultural variations in these sources. Analysis of interview data guided successive instrument revisions leading to improved item interpretability and comprehension. Although testing in a larger sample will be essential to test validity and reliability, the outcome of field testing suggests initial content validity of a Spanish-language instrument to measure genetic knowledge relative to type 2 diabetes. ^ Keywords. Latinos, genetic knowledge, instrument development, cognitive interviewing ^

The role of AKT-mediated phosphorylation in suppression of MAD1 and the development of new approach in protein complex detection

MAX dimerization protein 1 (MAD1) is a basic-helix-loop-helix transcription factors that recruits transcription repressor such as HDAC to suppress target genes transcription. It antagonizes to MYC because the promoter binding sites for MYC are usually also serve as the binding sites for MAD1 so they compete for it. However, the mechanism of the switch between MYC and MAD1 in turning on and off of genes' transcription is obscure. In this study, we demonstrated that AKT-mediated MAD1 phosphorylation inhibits MAD1 transcription repression function. The association between MAD1 and its target genes' promoter is reduced after been phosphorylated by AKT; therefore, consequently, allows MYC to occupy the binding site and activates transcription. Mutation of such phosphorylation site abrogates the inhibition from AKT. In addition, functional assays demonstrated that AKT suppressed MAD1-mediated transcription repression of its target genes hTERT and ODC. Cell cycle and cell growth were also been released from inhibition by MAD1 in the presents of AKT. Taken together, our study suggests that MAD1 is a novel substrate of AKT and AKT-mediated MAD1 phosphorylation inhibits MAD1function; therefore, activates MAD1 target genes expression. ^ Furthermore, analysis of protein-protein interaction is indispensable for current molecular biology research, but multiplex protein dynamics in cells is too complicated to be analyzed by using existing biochemical methods. To overcome the disadvantage, we have developed a single molecule level detection system with nanofluidic chip. Single molecule was analyzed based on their fluorescent profile and their profiles were plotted into 2 dimensional time co-incident photon burst diagram (2DTP). From this 2DTP, protein complexes were characterized. These results demonstrate that the nanochannel protein detection system is a promising tool for future molecular biology. ^

Can accreditation work as a tool for quality improvement in public health? A critical review

Public health departments play an important role in promoting and preserving the health of communities. The lack of a system to ensure their quality and accountability led to the development of a national voluntary accreditation program by Public Health Accreditation Board (PHAB). The concept that accreditation will lead to quality improvement in public health which will ultimately lead to healthy communities seems intuitive but lacks a robust body of evidence. A critical review of literature was conducted to explore if accreditation can lead to quality improvement in public health. The articles were selected from publically available databases using a specific set of criteria for inclusion, exclusion, and appraisal. To understand the relationship between accreditation and quality improvement, the potential strengths and limitations of accreditation process were evaluated. Recommendations for best practices are suggested so that public health accreditation can yield maximum benefits. A logic model framework to help depict the impact of accreditation on various levels of public health outcomes is also discussed in this thesis. The literature review shows that existing accreditation programs in other industries show limited but encouraging evidence that accreditation will improve quality and strengthen the delivery of public health services. While progress in introducing accreditation in public health can be informed by other accredited industries, the public health field has its own set of challenges. Providing incentives, creating financing strategies, and having a strong leadership will allow greater access to accreditation by all public health departments. The suggested recommendations include that continuous evaluation, public participation, systems approach, clear vision, and dynamic standards should become hallmarks of the accreditation process. Understanding the link between accreditation, quality improvement, and health outcomes will influence the successful adoption and implementation of the public health accreditation program. This review of literature suggests that accreditation is an important step in improving the quality of public health departments and in ultimately improving the health of communities. However, accreditation should be considered in an integrated system of tools and approaches to improve the public health practice. Hence, it is a means to an end - not an end unto itself.^

Community diagnosis: A working tool for developing culturally appropriate diarrhea intervention programs

Most studies related to diarrhea have been focused narrowly on the etiological and pathophysiological factors involved in inducing the disease. Such studies have often failed to consider other facets contributing to and possibly prolonging the problem, namely: socio-economic conditions, educational opportunities and attainments, cultural characteristics and beliefs, and the political administration and its commitment towards fulfilling its moral and ethical obligations in responding to and fostering human development.^ This study utilized the diagnostic approach of the PRECEDE model. The acronym stands for the predisposing reinforcing, and enabling constructs in educational diagnosis and evaluation. The constituents of this model were identified by utilizing participant observation field methods, traditionally applied by ethnographers to collect data describing the multiple facets of a culture, and linguistic anthropology used to capture and define characteristic semantics and viewpoints. The household study sample was randomly selected from a defined list of households known to have at least one child less than five years of age. An open-ended questionnaire format was used to interview the 115 mothers in the selected households sample.^ Kalama, the study community, is characteristically an agricultural village, situated in the Governorate of Kaliobia and located approximately 25 Km (about 15.5 miles) from the capital, Cairo, Egypt. The 1986 census indicates a population size of 13,328 people in 4,818 households. There were 65 deaths occurring among children less than five years in 1986. The causes of death were primarily related to diarrhea, followed by upper respiratory infections, congenital anomalies and birth injuries.^ This study outlines (a) practices related to the management of diarrhea, including the administration of foods and drinks during such episodes; (b) influences of governmental policies; and (c) recommended strategies for overcoming barriers and promoting effective diarrhea intervention programs. ^