Evaluating marker-guided treatment selection strategies

© 2014, The International Biometric Society.A potential venue to improve healthcare efficiency is to effectively tailor individualized treatment strategies by incorporating patient level predictor information such as environmental exposure, biological, and genetic marker measurements. Many useful statistical methods for deriving individualized treatment rules (ITR) have become available in recent years. Prior to adopting any ITR in clinical practice, it is crucial to evaluate its value in improving patient outcomes. Existing methods for quantifying such values mainly consider either a single marker or semi-parametric methods that are subject to bias under model misspecification. In this article, we consider a general setting with multiple markers and propose a two-step robust method to derive ITRs and evaluate their values. We also propose procedures for comparing different ITRs, which can be used to quantify the incremental value of new markers in improving treatment selection. While working models are used in step I to approximate optimal ITRs, we add a layer of calibration to guard against model misspecification and further assess the value of the ITR non-parametrically, which ensures the validity of the inference. To account for the sampling variability of the estimated rules and their corresponding values, we propose a resampling procedure to provide valid confidence intervals for the value functions as well as for the incremental value of new markers for treatment selection. Our proposals are examined through extensive simulation studies and illustrated with the data from a clinical trial that studies the effects of two drug combinations on HIV-1 infected patients.

NAFTA and the apparel commodity chain: Corporate strategies, interfirm networks, and industrial upgrading

The apparel industry is one of the oldest and largest export industries in the world, with global trade and production networks that connect firms and workers in countries at all levels of economic development. This chapter examines the impact of the North American Free Trade Agreement (NAFTA) as one of the most recent and significant developments to affect patterns of international trade and production in the apparel and textile industries. Tr ade policies are changing the institutional environment in which firms in this industry operate, and companies are responding to these changes with new strategies designed to increase their profitability and strengthen their control over the apparel commodity chain. Our hypothesis is that lead firms are establishing qualitatively different kinds of regional production networks in North America from those that existed prior to NAFTA, and that these networks have important consequences for industrial upgrading in the Mexican textile and apparel industries. Post-NAFTA crossborder production arrangements include full-package networks that link lead firms in the United States with apparel and textile manufacturers, contractors, and suppliers in Mexico. Full-package production is increasing the local value added provided by the apparel commodity chain in Mexico and creating new opportunities for Mexican firms and workers. The chapter is divided into four main sections. The first section uses trade and production data to analyze shifts in global apparel flows, highlighting the emergence and consolidation of a regional trade bloc in North America. The second section discusses the process of industrial upgrading in the apparel industry and introduces a distinction between assembly and full-package production networks. The third section includes case studies based on published industry sources and strategic interviews with several lead companies whose strategies are largely responsible for the shifting trade patterns and NAFTA-inspired cross-border production networks discussed in the previous section. The fourth section considers the implications of these changes for employment in the North American apparel industry. © 2009 by Temple University Press. All rights reserved.

Diversity index of mucosal resident T lymphocyte repertoire predicts clinical prognosis in gastric cancer

© 2015 Taylor & Francis Group, LLC.A characteristic immunopathology of human cancers is the induction of tumor antigen-specific T lymphocyte responses within solid tumor tissues. Current strategies for immune monitoring focus on the quantification of the density and differentiation status of tumor-infiltrating T lymphocytes; however, properties of the TCR repertoire - including antigen specificity, clonality, as well as its prognostic significance β remain elusive. In this study, we enrolled 28 gastric cancer patients and collected tumor tissues, adjacent normal mucosal tissues, and peripheral blood samples to study the landscape and compartmentalization of these patients’ TCR β repertoire by deep sequencing analyses. Our results illustrated antigen-driven expansion within the tumor compartment and the contracted size of shared clonotypes in mucosa and peripheral blood. Most importantly, the diversity of mucosal T lymphocytes could independently predict prognosis, which strongly underscores critical roles of resident mucosal T-cells in executing post-surgery immunosurveillance against tumor relapse.

Hemostatic assessment, treatment strategies, and hematology consultation in massive postpartum hemorrhage: results of a quantitative survey of obstetrician-gynecologists.

OBJECTIVE: To assess potential diagnostic and practice barriers to successful management of massive postpartum hemorrhage (PPH), emphasizing recognition and management of contributing coagulation disorders. STUDY DESIGN: A quantitative survey was conducted to assess practice patterns of US obstetrician-gynecologists in managing massive PPH, including assessment of coagulation. RESULTS: Nearly all (98%) of the 50 obstetrician-gynecologists participating in the survey reported having encountered at least one patient with "massive" PPH in the past 5 years. Approximately half (52%) reported having previously discovered an underlying bleeding disorder in a patient with PPH, with disseminated intravascular coagulation (88%, n=23/26) being identified more often than von Willebrand disease (73%, n=19/26). All reported having used methylergonovine and packed red blood cells in managing massive PPH, while 90% reported performing a hysterectomy. A drop in blood pressure and ongoing visible bleeding were the most commonly accepted indications for rechecking a "stat" complete blood count and coagulation studies, respectively, in patients with PPH; however, 4% of respondents reported that they would not routinely order coagulation studies. Forty-two percent reported having never consulted a hematologist for massive PPH. CONCLUSION: The survey findings highlight potential areas for improved practice in managing massive PPH, including earlier and more consistent assessment, monitoring of coagulation studies, and consultation with a hematologist.

CT Scan Dosimetric Parameters Routine Monitoring: First Results of Radiation Dose Optimization Strategies Promptly Provided by a Multidisciplinary Team

CONCLUSION Radiation dose reduction, while saving image quality could be easily implemented with this approach. Furthermore, the availability of a dosimetric data archive provides immediate feedbacks, related to the implemented optimization strategies. Background JCI Standards and European Legislation (EURATOM 59/2013) require the implementation of patient radiation protection programs in diagnostic radiology. Aim of this study is to demonstrate the possibility to reduce patients radiation exposure without decreasing image quality, through a multidisciplinary team (MT), which analyzes dosimetric data of diagnostic examinations. Evaluation Data from CT examinations performed with two different scanners (Siemens DefinitionTM and GE LightSpeed UltraTM) between November and December 2013 are considered. CT scanners are configured to automatically send images to DoseWatch© software, which is able to store output parameters (e.g. kVp, mAs, pitch ) and exposure data (e.g. CTDIvol, DLP, SSDE). Data are analyzed and discussed by a MT composed by Medical Physicists and Radiologists, to identify protocols which show critical dosimetric values, then suggest possible improvement actions to be implemented. Furthermore, the large amount of data available allows to monitor diagnostic protocols currently in use and to identify different statistic populations for each of them. Discussion We identified critical values of average CTDIvol for head and facial bones examinations (respectively 61.8 mGy, 151 scans; 61.6 mGy, 72 scans), performed with the GE LightSpeed CTTM. Statistic analysis allowed us to identify the presence of two different populations for head scan, one of which was only 10% of the total number of scans and corresponded to lower exposure values. The MT adopted this protocol as standard. Moreover, the constant output parameters monitoring allowed us to identify unusual values in facial bones exams, due to changes during maintenance service, which the team promptly suggested to correct. This resulted in a substantial dose saving in CTDIvol average values of approximately 15% and 50% for head and facial bones exams, respectively. Diagnostic image quality was deemed suitable for clinical use by radiologists.

Wnt Protein Signaling Reduces Nuclear Acetyl-CoA Levels to Suppress Gene Expression during Osteoblast Differentiation.

Developmental signals in metazoans play critical roles in inducing cell differentiation from multipotent progenitors. The existing paradigm posits that the signals operate directly through their downstream transcription factors to activate expression of cell type-specific genes, which are the hallmark of cell identity. We have investigated the mechanism through which Wnt signaling induces osteoblast differentiation in an osteoblast-adipocyte bipotent progenitor cell line. Unexpectedly, Wnt3a acutely suppresses the expression of a large number of genes while inducing osteoblast differentiation. The suppressed genes include Pparg and Cebpa, which encode adipocyte-specifying transcription factors and suppression of which is sufficient to induce osteoblast differentiation. The large scale gene suppression induced by Wnt3a corresponds to a global decrease in histone acetylation, an epigenetic modification that is associated with gene activation. Mechanistically, Wnt3a does not alter histone acetyltransferase or deacetylase activities but, rather, decreases the level of acetyl-CoA in the nucleus. The Wnt-induced decrease in histone acetylation is independent of β-catenin signaling but, rather, correlates with suppression of glucose metabolism in the tricarboxylic acid cycle. Functionally, preventing histone deacetylation by increasing nucleocytoplasmic acetyl-CoA levels impairs Wnt3a-induced osteoblast differentiation. Thus, Wnt signaling induces osteoblast differentiation in part through histone deacetylation and epigenetic suppression of an alternative cell fate.

Rapid immunological diagnosis of active tuberculosis, and differentiation from asymptomatic infection

info:eu-repo/semantics/nonPublished

Intracellular Cytokine Staining and Flow Cytometry: Considerations for Application in Clinical Trials of Novel Tuberculosis Vaccines.

Intracellular cytokine staining combined with flow cytometry is one of a number of assays designed to assess T-cell immune responses. It has the specific advantage of enabling the simultaneous assessment of multiple phenotypic, differentiation and functional parameters pertaining to responding T-cells, most notably, the expression of multiple effector cytokines. These attributes make the technique particularly suitable for the assessment of T-cell immune responses induced by novel tuberculosis vaccines in clinical trials. However, depending upon the particular nature of a given vaccine and trial setting, there are approaches that may be taken at different stages of the assay that are more suitable than other alternatives. In this paper, the Tuberculosis Vaccine Initiative (TBVI) TB Biomarker Working group reports on efforts to assess the conditions that will determine when particular assay approaches should be employed. We have found that choices relating to the use of fresh whole blood or peripheral blood mononuclear cells (PBMC) and frozen PBMC; use of serum-containing or serum-free medium; length of stimulation period and use of co-stimulatory antibodies can all affect the sensitivity of intracellular cytokine assays. In the case of sample material, frozen PBMC, despite some loss of sensitivity, may be more advantageous for batch analysis. We also recommend that for multi-site studies, common antibody panels, gating strategies and analysis approaches should be employed for better comparability.

Immediate early gene expression in dog thyrocytes in response to growth, proliferation, and differentiation stimuli.

In dog thyroid cells, insulin or IGF-1 induces cell growth and is required for the mitogenic action of TSH through cyclic AMP, of EGF, and of phorbol esters. HGF per se stimulates cell proliferation and is thus the only full mitogenic agent. TSH and cAMP enhance, whereas EGF phorbol esters and HGF repress differentiation expression. In this study, we have investigated for each factor and regulatory cascade of the intermediate step of immediate early gene induction, that is, c-myc, c-jun, jun D, jun B, c-fos, fos B, fra-1, fra-2, and egr1; fra-1 and fra-2 expressions were very low. TSH or forskolin increased the levels of c-myc, jun B, jun D, c-fos, and fos B while decreasing those of c-jun and egr1. Phorbol myristate ester stimulated the expression of all the genes. EGF and HGF stimulated the expression of all the genes except jun D and for EGF fos B. All these effects were obtained in the presence and in the absence of insulin, which shows that insulin is not necessary for the effects of the mitogens on immediate early gene expression. The definition of the repertoire of early immediate genes inductible by the various growth cascades provides a framework for the analysis of gene expression in tumors. (1) Insulin was able to induce all the protooncogenes investigated except fos B. This suggests that fos B could be the factor missing for insulin to induce mitogenesis. (2) No characteristic pattern of immediate early gene expression has been observed for insulin, which induces cell hypertrophy and is permissive for the action of the other growth factors. These effects are therefore not accounted for by a specific immediate early gene expression. On the other hand, insulin clearly enhances the effects of TSH, phorbol ester, and EGF on c-myc, junB, and c-fos expression. This suggests that the effect of insulin on mitogenesis might result from quantitative differences in the transcription complexes formed. (3) c-myc, c-fos, and jun B mRNA induction by all stimulating agents, whether inducing cell hypertrophy, or growth and dedifferentiation, or growth and differentiation, suggests that, although these expressions are not sufficient, they may be necessary for the various growth responses of thyroid cells. (4) The inhibition of c-jun and egr1 mRNA expression, and the marked induction of jun D mRNA appear to be specific features of the TSH cAMP pathway. They might be related to its differentiating action. (5) fos B, which is induced by TSH, forskolin, phorbol ester, and HGF but not by insulin, could be involved in the mitogenic action of the former factors.

Description of a procedure to identify strategies: The case of the tiles problem

In this paper we present a procedure to describe strategies in problems which can be solved using inductive reasoning. This procedure is based on some aspects of the analysis of the specific subject matter, concretely on the elements, the representation systems and the transformations involved. We show an example of how we used this procedure for the tiles problem. Finally we present some results and conclusions.

Converting best manual practice into generic automatable strategies for unstructured mesh parallelisation

The manual effort required to convert sequential computational mechanics programs into a useful, scalable parallel form is considerable. Tools that can assist in the conversion process are clearly required. Computer aided parallelisation tools (CAPTools) have been developed to generate efficient parallel code for real world structured grid application codes such as Computational Fluid Dynamics. Automatable single-program multi-data (SPMD) overlapping domain decomposition (DD) techniques established for structured grid codes have been adapted by the authors to manually parallelise unstructured mesh applications. Inspector loops have been used to provide generic techniques for the run-time support necessary to extend the capabilities of CAPTools to automatic implementation of SPMD DD techniques in the parallelisation of unstructured mesh codes. Copyright © 1999 John Wiley & Sons, Ltd.

Multilevel refinement strategies for the capacity vehicle routing problem

We discuss the application of the multilevel (ML) refinement technique to the Vehicle Routing Problem (VRP), and compare it to its single-level (SL) counterpart. Multilevel refinement recursively coarsens to create a hierarchy of approximations to the problem and refines at each level. A SL algorithm, which uses a combination of standard VRP heuristics, is developed first to solve instances of the VRP. A ML version, which extends the global view of these heuristics, is then created, using variants of the construction and improvement heuristics at each level. Finally some multilevel enhancements are developed. Experimentation is used to find suitable parameter settings and the final version is tested on two well-known VRP benchmark suites. Results comparing both SL and ML algorithms are presented.

Exploring strategies for promoting the use of research findings in practice

Following the integration of nurse and midwifery education into institutions of higher education in the United Kingdom, a number of studies have shown that a defined clinical framework for nursing and midwifery lecturers in practice areas is lacking. The aim of this study was to explore strategies that nurse and midwifery lecturers from one higher education institution in south east England can use to work collaboratively with nurses and midwives to promote the utilization of research findings in practice. A cross-sectional survey using a structured questionnaire was sent to a sample of 60 nurse and midwifery lecturers and 90 clinical managers. Response rates of 67% (40) and 69% (62) respectively were obtained. The main strategies suggested were to make clinical staff more aware of what research exist in their specialties; to help them to access research information from research databases; and to critically appraise this information. Other strategies were for teachers to run research workshops on site; to undertake joint research projects with clinical staff; to set up journal clubs or research interest groups; and to help formulate clinical guidelines and protocols which are explicitly research-based.

Industrial water pollution in Dhaka, Bangladesh: strategies and incentives for pollution control in small and medium enterprises

The extent and gravity of the environmental degradation of the water resources in Dhaka due to untreated industrial waste is not fully recognised in international discourse. Pollution levels affect vast numbers, but the poor and the vulnerable are the worst affected. For example, rice productivity, the mainstay of poor farmers, in the Dhaka watershed has declined by 40% over a period of ten years. The study found significant correlations between water pollution and diseases such as jaundice, diarrhoea and skin problems. It was reported that the cost of treatment of one episode of skin disease could be as high as 29% of the weekly earnings of some of the poorest households. The dominant approach to deal with pollution in the SMEs is technocratic. Given the magnitude of the problem this paper argues that to control industrial pollution by SMEs and to enhance their compliance it is necessary to move from the technocratic approach to one which can also address the wider institutional and attitudinal issues. Underlying this shift is the need to adopt the appropriate methodology. The multi-stakeholder analysis enables an understanding of the actors, their influence, their capacity to participate in, or oppose change, and the existing and embedded incentive structures which allow them to pursue interests which are generally detrimental to environmental good. This enabled core and supporting strategies to be developed around three types of actors in industrial pollution, i.e., (i) principal actors, who directly contribute to industrial pollution; (ii) stakeholders who exacerbate the situation; and (iii) potential actors in mitigation. Within a carrot-and-stick framework, the strategies aim to improve environmental governance and transparency, set up a packet to incentive for industry and increase public awareness.