Cost-Effectiveness of Magnetic Resonance Imaging with a New Contrast Agent for the Early Diagnosis of Alzheimer's Disease

Background: Used as contrast agents for brain magnetic resonance imaging (MRI), markers for beta-amyloid deposits might allow early diagnosis of Alzheimer’s disease (AD). We evaluated the cost-effectiveness of such a diagnostic test, MRI+CLP (contrastophore-linker-pharmacophore), should it become clinically available. Methodology/Principal Findings: We compared the cost-effectiveness of MRI+CLP to that of standard diagnosis using currently available cognition tests and of standard MRI, and investigated the impact of a hypothetical treatment efficient in early AD. The primary analysis was based on the current French context for 70-year-old patients with Mild Cognitive Impairment (MCI). In alternative ‘‘screen and treat’ ’ scenarios, we analyzed the consequences of systematic screenings of over-60 individuals (either population-wide or restricted to the ApoE4 genotype population). We used a Markov model of AD progression; model parameters, as well as incurred costs and quality-of-life weights in France were taken from the literature. We performed univariate and probabilistic multivariate sensitivity analyses. The base-case preferred strategy was the standard MRI diagnosis strategy. In the primary analysis however, MRI+CLP could become the preferred strategy under a wide array of scenarios involving lower cost and/or higher sensitivity or specificity. By contrast, in the ‘‘screen and treat’’ analyses, the probability of MRI+CLP becoming the preferred strategy remained lower than 5%. Conclusions/Significance: It is thought that anti-beta-amyloid compounds might halt the development of dementia i

Entrepreneurial orientation and the threat of imitation: The influence of upstream and downstream capabilities

This paper uncovers the complexity between Entrepreneurial Orientation (EO) and performance. The paper explores the effect of the threat of imitation, which is a key external factor to explain competitive dynamics, and hence highlights effectiveness of EO. Also the paper accounts for the role of upstream (technical) and downstream (marketing) capabilities as they influence effectiveness of EO. Our results show that, under threat of imitation, downstream marketing capabilities facilitate taping into opportunities derived from EO, which positively affects performance. Conversely, available upstream technical capabilities do not aim at EO when imitation threats exist in the environment. Of importance is that we question the complexity between EO and performance can be better understood using a configurational approach

Time patterns of adherence and long-term virological response to non-nucleoside reverse transcriptase inhibitor regimens in the Stratall ANRS 12110/ESTHER trial in Cameroon

Background: Although treatment adherence is a major challenge in sub-Saharan Africa, it is still unknown which longitudinal patterns of adherence are the most detrimental to long-term virological response to non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens. This analysis aimed to study the influence of different time patterns of adherence on virological failure after 24 months of treatment in Cameroon. Methods: Antiretroviral therapy (ART) adherence data were collected using face-to-face questionnaires administered at months 1, 3, 6, 12, 18 and 24. Virological failure was defined as viral load > 40 copies/ml at month 18 and/or 24. Two combined indicators of early adherence (months 1, 3 and 6) and adherence during the maintenance phase (months 12, 18 and 24) were designed to classify patients as always adherent during the early or maintenance phase, non-adherent at least once and having interrupted ART for > 2 days at least once at any visit during either of these two phases. Results: Virological failure occurred in 107 (42%) of the 254 patients included in the analysis. In the early and maintenance phases, 84% and 76%, respectively, were always adherent, 5% and 5% were non-adherent and 11% and 20% experienced >= 1 treatment interruption. Early non-adherence was independently associated with virological failure (adjusted OR 7.2 [95% CI 1.5, 34.6]), while only treatment interruptions had a significant impact on virological failure during the maintenance phase (adjusted OR 2.1 [95% CI 1.1, 4.4]). Conclusions: ART NNRTI-regimens used in sub-Saharan Africa seem to 'forgive' deviations from good adherence during the maintenance phase. Optimizing adherence in the early months of treatment remains crucial, especially in a setting of poor health care infrastructure and resources

TNFR2 blockade of regulatory T cells unleashes an antitumor immune response after hematopoietic stem-cell transplantation

Background targeting immune checkpoints that inhibit antitumor immune responses has emerged as a powerful new approach to treat cancer. We recently showed that blocking the tumor necrosis factor receptor-type 2 (tnfr2) pathway induces the complete loss of the protective function of regulatory t cells (tregs) in a model of graft-versus-host disease (gvhd) prevention that relies on treg-based cell therapy. Here, we tested the possibility of amplifying the antitumor response by targeting tnfr2 in a model of tumor relapse following hematopoietic stem-cell transplantation, a clinical situation for which the need for efficient therapeutic options is still unmet. Method we developed appropriate experimental conditions that mimic patients that relapsed from their initial hematological malignancy after hematopoietic stem-cell transplantation. This consisted of defining in allogeneic bone marrow transplantation models developed in mice, the maximum number of required tumor cells and t cells to infuse into recipient mice to develop a model of tumor relapse without inducing gvhd. We next evaluated whether anti-tnfr2 treatment could trigger alloreactivity and consequently antitumor immune response. In parallel, we also studied the differential expression of tnfr2 on t cells including treg from patients in post-transplant leukemia relapse and in patients developing gvhd. Results using experimental conditions in which neither donor t cells nor tnfr2-blocking antibody per se have any effect on tumor relapse, we observed that the coadministration of a suboptimal number of t cells and an anti-tnfr2 treatment can trigger alloreactivity and subsequently induce a significant antitumor effect. This was associated with a reduced percentage of activated cd4+ and cd8+ tregs. Importantly, human tregs over-expressed tnfr2 relative to conventional t cells in healthy donors and in patients experiencing leukemia relapse or cortico-resistant gvhd after hematopoietic stem cell transplantation. Conclusions these results highlight tnfr2 as a new target molecule for the development of immunotherapies to treat blood malignancy relapse, used either directly in grafted patients or to enhance donor lymphocyte infusion strategies. More widely, they open the door for new perspectives to amplify antitumor responses against solid cancers by directly targeting tregs through their tnfr2 expression