Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation.

BackgroundPrevious studies of drug trials submitted to regulatory authorities have documented selective reporting of both entire trials and favorable results. The objective of this study is to determine the publication rate of efficacy trials submitted to the Food and Drug Administration (FDA) in approved New Drug Applications (NDAs) and to compare the trial characteristics as reported by the FDA with those reported in publications.Methods and findingsThis is an observational study of all efficacy trials found in approved NDAs for New Molecular Entities (NMEs) from 2001 to 2002 inclusive and all published clinical trials corresponding to the trials within the NDAs. For each trial included in the NDA, we assessed its publication status, primary outcome(s) reported and their statistical significance, and conclusions. Seventy-eight percent (128/164) of efficacy trials contained in FDA reviews of NDAs were published. In a multivariate model, trials with favorable primary outcomes (OR = 4.7, 95% confidence interval [CI] 1.33-17.1, p = 0.018) and active controls (OR = 3.4, 95% CI 1.02-11.2, p = 0.047) were more likely to be published. Forty-one primary outcomes from the NDAs were omitted from the papers. Papers included 155 outcomes that were in the NDAs, 15 additional outcomes that favored the test drug, and two other neutral or unknown additional outcomes. Excluding outcomes with unknown significance, there were 43 outcomes in the NDAs that did not favor the NDA drug. Of these, 20 (47%) were not included in the papers. The statistical significance of five of the remaining 23 outcomes (22%) changed between the NDA and the paper, with four changing to favor the test drug in the paper (p = 0.38). Excluding unknowns, 99 conclusions were provided in both NDAs and papers, nine conclusions (9%) changed from the FDA review of the NDA to the paper, and all nine did so to favor the test drug (100%, 95% CI 72%-100%, p = 0.0039).ConclusionsMany trials were still not published 5 y after FDA approval. Discrepancies between the trial information reviewed by the FDA and information found in published trials tended to lead to more favorable presentations of the NDA drugs in the publications. Thus, the information that is readily available in the scientific literature to health care professionals is incomplete and potentially biased

Towards sustainable energy for All. Designing Sustainable Product-Service System applied to Distributed Renewable Energy.

Nowadays, is a consolidated understanding that “Sustainable development is not possible without Sustainable Energy for All” (UN, 2011). In this framework, the Distributed Renewable Energy (DRE) concept, is recognized as a promising one to achieve this aim, bringing Sustainable Energy to All. This research, fits within this framework, as it aims to validate and characterize the promising model of Sustainable Product-Service System applied to Distributed Renewable Energy (S.PSS applied to DRE) as a win-win solution to diffuse sustainable energy access to All, in low and middle-income (all) contexts. Moreover, this research aims to equip the designers with a knowledge-base and know-how to deal with such model and towards Sustainable Energy for All. This chapter presents the results achieved by this research and especially the contribution given in terms of know-how for the designers in the practice. A design activity conducted by the researcher in Africa with energy professionals, using the developed design approach and tools, is introduced. Finally, future opportunities based on the research are presented

A design approach with method and tools to support SMEs in designing and implementing Distributed Renewable Energy (DRE) solutions based on Sustainable Product-Service System (S.PSS).

Nowadays, around 1.2 billion people lack access to electricity. This condition hampers the provision of basic services such as health care and education. In this challenging scenario, Distributed Renewable Energy (DRE), meaning locally-based and small-scale energy systems based on renewable resources (e.g. sunlight and wind), is perceived as a possible solution towards sustainable energy access for All. ‬‬ ‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬ Some authors agree that the diffusion and implementation of DRE solutions can be facilitated if Sustainable Product-Service Systems (S.PSSs) are applied to them, as S.PSSs offer models able to move the focus from product ownership (e.g. solar panel) to the satisfaction of a specific demand (e.g. energy access). In fact, “S.PSSs applied to DRE are able to cut/reduce both the initial investment (e.g. solar panel purchase) and life-cycle costs (e.g. maintenance, repair of solar panel) democratizing the access to energy and energy-related services.” (LeNSes project – EU funded, Edulink II program, 2013-2016). ‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬ ‬‬‬‬ However, designing and implementing S.PSS-applied-to-DRE solutions is still a complex process. ‬‬‬The paper describes the design approach, method and tools used to support local SMEs (as well as NGOs, students, designers, researchers) in the design and implementation of S.PSS-applied-to-DRE solutions, the design process itself and the results achieved. The current generation of local entrepreneurs and designers worldwide need a broad knowledge base and know-how, as well as effective design approaches, methods and tools, in order to play an active role in promoting, designing and implementing S.PSS-applied-to-DRE solutions, and thus foster sustainable energy access for All

Benefits and costs of additive manufacturing applications: an evaluation guideline

With an ever growing diffusion of additive manufacturing (AM) system in industrial and consumer level, as well as the direct and indirect dynamics which are being introduced resulting from its inclusion as a viable production system on companies’ portfolio, the need to reconfigure production system and adapt the production line becomes even more relevant than before. There are several studies which have emphasized on the importance of a paradigm shift in order to exploit advantages of AM, not only considering design and functionality of the product but also with regards to its impact on the entire value chain reconfiguration. Thus, it is of crucial importance to take into consideration that for this shift to be feasible and manageable, it needs to include both technical and managerial aspects of manufacturing. This work proposes a new perspective to provide a guideline for the proper evaluation of AM implementation from a holistic viewpoint. Starting from a priori analysis, the authors provide a three-steps evaluation guideline, thanks to which companies interested in additive manufacturing could verify both technical and economical feasibility of its implementation, comparing it to the conventional subtractive techniques. The proposed guideline is tested in real case study, which the main results are shown in section 5

Quantifying Isoniazid Levels in Small Hair Samples: A Novel Method for Assessing Adherence during the Treatment of Latent and Active Tuberculosis.

BackgroundTuberculosis (TB) is the leading cause of death from an infectious pathogen worldwide and the most prevalent opportunistic infection in people living with HIV. Isoniazid preventive therapy (IPT) reduces the incidence of active TB and reduces morbidity and mortality in HIV-infected patients independently of antiretroviral therapy. However, treatment of latent or active TB is lengthy and inter-patient variability in pharmacokinetics and adherence common. Current methods of assessing adherence to TB treatment using drug levels in plasma or urine assess short-term exposure and pose logistical challenges. Drug concentrations in hair assess long-term exposure and have demonstrated pharmacodynamic relevance in HIV.MethodsA large hair sample from a patient with active TB was obtained for assay development. Methods to pulverize hair and extract isoniazid were optimized and then the drug detected by liquid chromatography/ tandem mass spectrometry (LC/MS-MS). The method was validated for specificity, accuracy, precision, recovery, linearity and stability to establish the assay's suitability for therapeutic drug monitoring (TDM). Hair samples from patients on directly-observe isoniazid-based latent or active TB therapy from the San Francisco Department of Public Health TB clinic were then tested.ResultsOur LC/MS-MS-based assay detected isoniazid in quantities as low as 0.02ng/mg using 10-25 strands hair. Concentrations in spiked samples demonstrated linearity from 0.05-50ng/mg. Assay precision and accuracy for spiked quality-control samples were high, with an overall recovery rate of 79.5%. In 18 patients with latent or active TB on treatment, isoniazid was detected across a wide linear dynamic range.ConclusionsAn LC-MS/MS-based assay to quantify isoniazid levels in hair with performance characteristics suitable for TDM was developed and validated. Hair concentrations of isoniazid assess long-term exposure and may be useful for monitoring adherence to latent or active TB treatment in the setting of HIV

Cortisol patterns are associated with T cell activation in HIV.

ObjectiveThe level of T cell activation in untreated HIV disease is strongly and independently associated with risk of immunologic and clinical progression. The factors that influence the level of activation, however, are not fully defined. Since endogenous glucocorticoids are important in regulating inflammation, we sought to determine whether less optimal diurnal cortisol patterns are associated with greater T cell activation.MethodsWe studied 128 HIV-infected adults who were not on treatment and had a CD4(+) T cell count above 250 cells/µl. We assessed T cell activation by CD38 expression using flow cytometry, and diurnal cortisol was assessed with salivary measurements.ResultsLower waking cortisol levels correlated with greater T cell immune activation, measured by CD38 mean fluorescent intensity, on CD4(+) T cells (r = -0.26, p = 0.006). Participants with lower waking cortisol also showed a trend toward greater activation on CD8(+) T cells (r = -0.17, p = 0.08). A greater diurnal decline in cortisol, usually considered a healthy pattern, correlated with less CD4(+) (r = 0.24, p = 0.018) and CD8(+) (r = 0.24, p = 0.017) activation.ConclusionsThese data suggest that the hypothalamic-pituitary-adrenal (HPA) axis contributes to the regulation of T cell activation in HIV. This may represent an important pathway through which psychological states and the HPA axis influence progression of HIV

One-of-a-Kind Production (OKP) planning and control: An empirical framework for the special purpose machines industry

In this paper, we focus on the One-of-a-Kind Production (OKP) industry, where each product is designed and manufactured based on specific customer requirements to a large extent, according to an Engineer To Order (ETO) approach. This research has been carried out among the "SIGI-X" project, funded by the Italian Ministry of Economic Development (MISE). The paper illustrates an empirical study on the state-of-the-art of information systems supporting the leading processes in OKP companies. Through a set of 21 case studies in Italian companies producing special machines, we aim to: identify and investigate strengths and weaknesses of the main OKP business processes; analyze the ICT support and its level of integration among the different ICT solutions; identify levers for improvement, concerning organizational, methodological and informatics aspects; build a practical framework that could define and link the main processes in order to obtain a sort of guideline useful for reengineering the processes, and laying the foundation for a new integrated ICT business template for OKP companies. The lack of support of three fundamental tasks such as project management, planning and cost control underlines that there is substantial room for improvement under the ICT support perspective. Finally, the development of an integrated IT environment to support (in particular) project management and planning activities, specifically addressed to OKP context, would help these companies to improve their performance and competitiveness