A Proposal for Integrated Efficacy-to-Effectiveness (E2E) Clinical Trials

We propose an “efficacy-to-effectiveness” (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes.National Center for Research Resources (U.S.) (Grant UL1 RR025752)National Center for Advancing Translational Sciences (U.S.) (Grant UL1 TR000073

Fibroblast cell-based therapy prevents induction of alopecia areata in an experimental model

YesAlopecia areata (AA) is an autoimmune hair loss disease with infiltration of proinflammatory cells into hair follicles. Current therapeutic regimens are unsatisfactory mainly because of the potential for side effects and/or limited efficacy. Here we report that cultured, transduced fibroblasts, which express the immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO), can be applied to prevent hair loss in an experimental AA model. A single intraperitoneal (IP) injection of IDO-expressing primary dermal fibroblasts was given to C3H/HeJ mice at the time of AA induction. While 60–70% of mice that received either control fibroblasts or vehicle injections developed extensive AA, none of the IDO-expressing fibroblast-treated mice showed new hair loss up to 20 weeks post injection. IDO cell therapy significantly reduced infiltration of CD4+ and CD8+ T cells into hair follicles and resulted in decreased expression of TNF-α, IFN-γ and IL-17 in the skin. Skin draining lymph nodes of IDO fibroblast-treated mice were significantly smaller, with more CD4+ CD25+ FoxP3+ regulatory T cells and fewer Th17 cells than those of control fibroblast and vehicle-injected mice. These findings indicate that IP injected IDO-expressing dermal fibroblasts can control inflammation and thereby prevent AA hair loss.Canadian Institutes of Health Researches (Funding Reference Number: 134214 and 136945)

Payments for ecosystem services in the tropics: a closer look at effectiveness and equity

We undertake a review of academic literature that examines the effectiveness and equity-related performance of PES initiatives targeting biodiversity conservation in tropical and sub-tropical countries. We investigate the key features of such analyses as regards their analytical and methodological approach and we identify emerging lessons from PES practice, leading to a new suggested research agenda. Our results indicate that analyses of PES effectiveness have to date focused on either ecosystem service provision or habitat proxies, with only half of them making explicit assessment of additionality and most describing that payments have been beneficial for land cover and biodiversity. Studies evaluating the impact of PES on livelihoods suggest more negative outcomes, with an uneven treatment of the procedural and distributive considerations of scheme design and payment distribution, and a large heterogeneity of evaluative frameworks. We propose an agenda for future PES research based on the emerging interest in assessing environmental outcomes more rigorously and documenting social impacts in a more comparative and contextually situated form

Molecular Time-Course and the Metabolic Basis of Entry into Dauer in Caenorhabditis elegans

When Caenorhabditis elegans senses dauer pheromone (daumone), signaling inadequate growth conditions, it enters the dauer state, which is capable of long-term survival. However, the molecular pathway of dauer entry in C. elegans has remained elusive. To systematically monitor changes in gene expression in dauer paths, we used a DNA microarray containing 22,625 gene probes corresponding to 22,150 unique genes from C. elegans. We employed two different paths: direct exposure to daumone (Path 1) and normal growth media plus liquid culture (Path 2). Our data reveal that entry into dauer is accomplished through the multi-step process, which appears to be compartmentalized in time and according to metabolic flux. That is, a time-course of dauer entry in Path 1 shows that dauer larvae formation begins at post-embryonic stage S4 (48 h) and is complete at S6 (72 h). Our results also suggest the presence of a unique adaptive metabolic control mechanism that requires both stage-specific expression of specific genes and tight regulation of different modes of fuel metabolite utilization to sustain the energy balance in the context of prolonged survival under adverse growth conditions. It is apparent that worms entering dauer stage may rely heavily on carbohydrate-based energy reserves, whereas dauer larvae utilize fat or glyoxylate cycle-based energy sources. We created a comprehensive web-based dauer metabolic database for C. elegans (www.DauerDB.org) that makes it possible to search any gene and compare its relative expression at a specific stage, or evaluate overall patterns of gene expression in both paths. This database can be accessed by the research community and could be widely applicable to other related nematodes as a molecular atlas

Assessing Natural Resource Use by Forest-Reliant Communities in Madagascar Using Functional Diversity and Functional Redundancy Metrics

Biodiversity plays an integral role in the livelihoods of subsistence-based forest-dwelling communities and as a consequence it is increasingly important to develop quantitative approaches that capture not only changes in taxonomic diversity, but also variation in natural resources and provisioning services. We apply a functional diversity metric originally developed for addressing questions in community ecology to assess utilitarian diversity of 56 forest plots in Madagascar. The use categories for utilitarian plants were determined using expert knowledge and household questionnaires. We used a null model approach to examine the utilitarian (functional) diversity and utilitarian redundancy present within ecological communities. Additionally, variables that might influence fluctuations in utilitarian diversity and redundancy—specifically number of felled trees, number of trails, basal area, canopy height, elevation, distance from village—were analyzed using Generalized Linear Models (GLMs). Eighteen of the 56 plots showed utilitarian diversity values significantly higher than expected. This result indicates that these habitats exhibited a low degree of utilitarian redundancy and were therefore comprised of plants with relatively distinct utilitarian properties. One implication of this finding is that minor losses in species richness may result in reductions in utilitarian diversity and redundancy, which may limit local residents' ability to switch between alternative choices. The GLM analysis showed that the most predictive model included basal area, canopy height and distance from village, which suggests that variation in utilitarian redundancy may be a result of local residents harvesting resources from the protected area. Our approach permits an assessment of the diversity of provisioning services available to local communities, offering unique insights that would not be possible using traditional taxonomic diversity measures. These analyses introduce another tool available to conservation biologists for assessing how future losses in biodiversity will lead to a reduction in natural resources and provisioning services from forests

Bishops who live like princes: Bishop Tebartz-van Elst and the challenge of defining corruption

This article contributes to the debate on defining corruption. Rather than attempting to provide a definitive definition, it uses the case of Franz-Peter Tebartz-van Elst, a German bishop from the diocese of Limburg who stepped down in 2014, to illustrate that the disciplines of law, political science, economics, and anthropology all make important contributions to understanding what corruption is and how it should be conceptualized. Seen through these different lenses, the article argues, the case of “Bishop Bling” can be understood in strikingly different ways. This has ramifications not just for the case itself but also for how analysts understand corruption more broadly. Adopting an overtly interdisciplinary approach does not represent a way to “solve” the definitional dilemma, but it can help analysts understand more about corruption’s multiplicity

Design and performance of the ENUBET monitored neutrino beam

The ENUBET project is aimed at designing and experimentally demonstrating the concept of monitored neutrino beams. These novel beams are enhanced by an instrumented decay tunnel, whose detectors reconstruct large-angle charged leptons produced in the tunnel and give a direct estimate of the neutrino flux at the source. These facilities are thus the ideal tool for high-precision neutrino cross-section measurements at the GeV scale because they offer superior control of beam systematics with respect to existing facilities. In this paper, we present the first end-to-end design of a monitored neutrino beam capable of monitoring lepton production at the single particle level. This goal is achieved by a new focusing system without magnetic horns, a 20 m normal-conducting transfer line for charge and momentum selection, and a 40 m tunnel instrumented with cost-effective particle detectors. Employing such a design, we show that percent precision in cross-section measurements can be achieved at the CERN SPS complex with existing neutrino detectors

A Conserved PHD Finger Protein and Endogenous RNAi Modulate Insulin Signaling in Caenorhabditis elegans

Insulin signaling has a profound effect on longevity and the oxidative stress resistance of animals. Inhibition of insulin signaling results in the activation of DAF-16/FOXO and SKN-1/Nrf transcription factors and increased animal fitness. By studying the biological functions of the endogenous RNA interference factor RDE-4 and conserved PHD zinc finger protein ZFP-1 (AF10), which regulate overlapping sets of genes in Caenorhabditis elegans, we identified an important role for these factors in the negative modulation of transcription of the insulin/PI3 signaling-dependent kinase PDK-1. Consistently, increased expression of pdk-1 in zfp-1 and rde-4 mutants contributed to their reduced lifespan and sensitivity to oxidative stress and pathogens due to the reduction in the expression of DAF-16 and SKN-1 targets. We found that the function of ZFP-1 in modulating pdk-1 transcription was important for the extended lifespan of the age-1(hx546) reduction-of-function PI3 kinase mutant, since the lifespan of the age-1; zfp-1 double mutant strain was significantly shorter compared to age-1(hx546). We further demonstrate that overexpression of ZFP-1 caused an increased resistance to oxidative stress in a DAF-16–dependent manner. Our findings suggest that epigenetic regulation of key upstream signaling components in signal transduction pathways through chromatin and RNAi may have a large impact on the outcome of signaling and expression of numerous downstream genes.Leukemia & Lymphoma Society of America (3260-07 Special Fellow Award)Arnold and Mabel Beckman Foundation (Young Investigator Award)United States. National Institutes of Health (Director's New Innovator Award (1 DP2 OD006412-01))United States. National Institutes of Health (grant GM66269)modENCODE (grant U01 HG004270)United States. National Institutes of Health (training grant 5T32 GM07088-34