Simulating and reporting frequentist operating characteristics of clinical trials that borrow external information: Towards a fair comparison in case of one‐arm and hybrid control two‐arm trials

Borrowing information from historical or external data to inform inference in a current trial is an expanding field in the era of precision medicine, where trials are often performed in small patient cohorts for practical or ethical reasons. Even though methods proposed for borrowing from external data are mainly based on Bayesian approaches that incorporate external information into the prior for the current analysis, frequentist operating characteristics of the analysis strategy are often of interest. In particular, type I error rate and power at a prespecified point alternative are the focus. We propose a procedure to investigate and report the frequentist operating characteristics in this context. The approach evaluates type I error rate of the test with borrowing from external data and calibrates the test without borrowing to this type I error rate. On this basis, a fair comparison of power between the test with and without borrowing is achieved. We show that no power gains are possible in one‐sided one‐arm and two‐arm hybrid control trials with normal endpoint, a finding proven in general before. We prove that in one‐arm fixed‐borrowing situations, unconditional power (i.e., when external data is random) is reduced. The Empirical Bayes power prior approach that dynamically borrows information according to the similarity of current and external data avoids the exorbitant type I error inflation occurring with fixed borrowing. In the hybrid control two‐arm trial we observe power reductions as compared to the test calibrated to borrowing that increase when considering unconditional power

Stretchable inkjet-printed electronics on mechanically compliant island-bridge architectures covalently bonded to elastomeric substrates

Herein, we present an approach that allows versatile combination of inkjet-printed electronics and stretchable substrates. For this, we created a hybrid platform made out of stretchable Ecoflex covalently bonded via silane monolayers to flexible polyethylene terephthalate islands interconnected by bridges. The islands served as platforms where conductive lines, capacitive sensors and electrochromic devices (ECDs) were fabricated by inkjet printing. The robustness of the approach is highlighted by the minor influence of strain on the conductivity of printed Ag electrodes, which changed the resistance only by 1.3% at an applied strain of 50%. Furthermore, we demonstrated capacitor sensors capable of responding to strain changing their capacitance from 0.2 to 1.6 pF. To further show the applicability of the approach for multilayer/multimaterial optoelectronic elements, we processed ECDs capable of displaying information on the stretchable platform. Thus, we demonstrate how this digital and additive concept can be applied for the scalable integration of printed optoelectronic devices onto stretchable systems without relying on lithographic processes

Biodegradable inkjet-printed electrochromic display for sustainable short-lifecycle electronics

The fabrication of electronics on the basis of biofriendly materials aims to counterbalance the negative trends conveyed by the short life-cycle of electronics. Furthermore, these materials open the possibility to develop optoelectronic technologies which will be in contact with the human body. In this work, we present an electrochromic display fabricated by resource- and energy-efficient digital printing techniques. The biodegradation of the device is certified under the ISO 14855 standard. The display comprises of a poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) electrochromic layer, a gelatin-based electrolyte and Au electrodes deposited on a cellulose di-acetate substrate. We investigate the impact of various naturally sourced ionic species on the ionic conductivity of the electrolyte and the figures of merit of the display. The printed devices show an electrochromic contrast of 32 ± 4% and switching times of 3.0 ± 1.4 s, comparable to the spincoated reference devices. The utilization of inkjet printing enables the fabrication of different device designs with individually addressable pixels. The display can be worn innocuously on the skin without loss of performance thanks to the self-adhesion properties of the gelatin hydrogel. The present work highlights the use of industrial relevant technology for the fabrication of truly ecofriendly optoelectronic systems

Mejoramiento del desempeño térmico de sistemas de construcción no convencional en el NEA: evaluación y propuesta de atenuación de puntes térmicos

El buen comportamiento higrotérmico de las envolventes perimetrales de edificios construidos en el Nordeste Argentino (NEA) resulta de primordial importancia, dado el clima la región registra. No obstante, este se ve desmejorado debido a la gran cantidad de heterogeneidades (puentes térmicos) que la naturaleza estructural de los sistemas de construcción no convencional genera; esto posibilita un mayor flujo de calor a través de las secciones transversales. Teniendo en cuenta que únicamente el 20 % de este tipo de soluciones constructivas resulta apto ante este punto crítico intrínseco, el presente trabajo propone su evaluación y atenuación mediante pautas de diseño

Building envelopes in non-conventional building construction in northeast argentina and the problem of thermal bridges.

This research analyzed the thermal performance of building envelopes in Northeast Argentina (NEA), whose construction systems use mass-produced, prefabricated materials and specialized workers. Particular attention was paid to the impact of thermal bridges. The objective was to diagnose and develop criteria to optimize the energy performance of these envelopes. To this end, the types and subtypes of non-conventional buildings were studied and samples of those most used in NEA were selected. These were evaluated using the calculation procedures established by the 11,600 series of the IRAM standards, as well as by simulations performed with THERM software. The values that were obtained with both procedures presented average discrepancies of 2.6%. With the software it is possible to obtain a weighted coefficient of transmittance that incorporates opaque walls and thermal bridges and, by graphing the heat flow through the element, easily recognize the most critical points, to thus concentrate optimization actionsEste trabajo analizó el comportamiento térmico de las envolventes de edificios en el Nordeste Argentino (NEA), cuyos sistemas constructivos emplean materiales prefabricados elaborados en serie y mano de obra especializada, atendiendo particularmente al impacto de los puentes térmicos. El objetivo fue diagnosticar y desarrollar criterios de optimización del desempeño energético de estas envolventes. Se estudiaron, para ello, los tipos y subtipos de construcciones no convencionales y se seleccionaron muestras de aquellos más empleados en el NEA. Éstas fueron evaluadas con los procedimientos de cálculo establecidos por las normas IRAM, de la serie 11.600, así como también mediante simulaciones realizadas con el software THERM. Los valores que pudieron obtenerse con ambos procedimientos presentaron discrepancias promedio del 2,6%. Con el software es posible obtener un coeficiente ponderado de transmitancia que incorpora muro opaco y puente térmico y, con la graficación del flujo de calor a través del cerramiento, reconocer fácilmente los puntos más críticos, para concentrar las acciones de optimización en ellos.  Documeto ejecutado bajo en proyecto "Rehabilitación higrotérmico-energética de edificios en el NEA: evaluación, diagnóstico, desarrollo de soluciones técnico constructivas y valoración costo-beneficio. Calificación energética de la edificación". Acreditado por la Secretaría General de Ciencia y Técnica de la Universidad Nacional del Nordeste - SGCyT-UNNE, Corrientes, Argentina. Resolución Nº 0155/2015-CS-UNNE 2015. Código del Proyecto: C001/2014

Lipocalin-2 as an Infection-Related Biomarker to Predict Clinical Outcome in Ischemic Stroke

Objectives From previous data in animal models of cerebral ischemia, lipocalin-2 (LCN2), a protein related to neutrophil function and cellular iron homeostasis, is supposed to have a value as a biomarker in ischemic stroke patients. Therefore, we examined LCN2 expression in the ischemic brain in an animal model and measured plasma levels of LCN2 in ischemic stroke patients. Methods In the mouse model of transient middle cerebral artery occlusion (tMCAO), LCN2 expression in the brain was analyzed by immunohistochemistry and correlated to cellular nonheme iron deposition up to 42 days after tMCAO. In human stroke patients, plasma levels of LCN2 were determined one week after ischemic stroke. In addition to established predictive parameters such as age, National Institutes of Health Stroke Scale and thrombolytic therapy, LCN2 was included into linear logistic regression modeling to predict clinical outcome at 90 days after stroke. Results Immunohistochemistry revealed expression of LCN2 in the mouse brain already at one day following tMCAO, and the amount of LCN2 subsequently increased with a maximum at 2 weeks after tMCAO. Accumulation of cellular nonheme iron was detectable one week post tMCAO and continued to increase. In ischemic stroke patients, higher plasma levels of LCN2 were associated with a worse clinical outcome at 90 days and with the occurrence of post-stroke infections. Conclusions LCN2 is expressed in the ischemic brain after temporary experimental ischemia and paralleled by the accumulation of cellular nonheme iron. Plasma levels of LCN2 measured in patients one week after ischemic stroke contribute to the prediction of clinical outcome at 90 days and reflect the systemic response to post-stroke infections

A Community in Life and Death: The Late Neolithic Megalithic Tomb at Alto de Reinoso (Burgos, Spain)

The analysis of the human remains from the megalithic tomb at Alto de Reinoso represents the widest integrative study of a Neolithic collective burial in Spain. Combining archaeology, osteology, molecular genetics and stable isotope analysis (87Sr/86Sr, δ15N, δ13C) it provides a wealth of information on the minimum number of individuals, age, sex, body height, pathologies, mitochondrial DNA profiles, kinship relations, mobility, and diet. The grave was in use for approximately one hundred years around 3700 cal BC, thus dating from the Late Neolithic of the Iberian chronology. At the bottom of the collective tomb, six complete and six partial skeletons lay in anatomically correct positions. Above them, further bodies represented a subsequent and different use of the tomb, with almost all of the skeletons exhibiting signs of manipulation such as missing skeletal parts, especially skulls. The megalithic monument comprised at least 47 individuals, including males, females, and subadults, although children aged 0–6 years were underrepresented. The skeletal remains exhibited a moderate number of pathologies, such as degenerative joint diseases, healed fractures, cranial trauma, and a low intensity of caries. The mitochondrial DNA profiles revealed a pattern pointing to a closely related local community with matrilineal kinship patterns. In some cases adjacent individuals in the bottom layer showed familial relationships. According to their strontium isotope ratios, only a few individuals were likely to have spent their early childhood in a different geological environment, whilst the majority of individuals grew up locally. Carbon and nitrogen isotope analysis, which was undertaken to reconstruct the dietary habits, indicated that this was a homogeneous group with egalitarian access to food. Cereals and small ruminants were the principal sources of nutrition. These data fit in well with a lifestyle typical of sedentary farming populations in the Spanish Meseta during this period of the Neolithi

Resistencia a antimicrobianos en E. coli y Salmonella spp. de terneros del sur de Chile

Objective: Description of antimicrobial resistance in E. coli and Salmonella spp. isolates from calves <30 days of age from southern Chile. Material and methods: Necropsy and microbiology reports of 107 calves <30 days of age received at the Animal Pathology Institute between 2002 and 2015 were considered. Additionally, an antimicrobial resistance score was generated to allow comparisons among isolates with different antimicrobial susceptibility profiles. Results: There was no clear trend in antimicrobial resistance during the study period, with similar levels of resistance for E. coli, β-hemolytic E. coli and Salmonella spp. Approximately 50% of isolates were sensitive to antimicrobials, and between 19 and 36% of samples showed possible extended- or pan- drug resistance. Multiple different antimicrobial resistance patterns were found, including 32 for E. coli, 17 for β-hemolytic E. coli and 10 for Salmonella spp. Conclusions: Overall, E. coli samples were most sensitive to ceftriaxone; β-hemolytic E. coli to florfenicol; and Salmonella spp. to gentamicin. In contrast, these agents were resistant to amoxicillin, ampicillin and oxytetracycline respectively. This study is unique in its approach and provides useful information for veterinarians and producers on the antibiotic resistance patterns of bacteria posing a serious threat to calves. These results can help field veterinarians to control and treat bacterial diarrhea in calves.Objetivo: Describir los hallazgos de resistencia a antimicrobianos en aislados de Salmonella spp. y E. coli obtenidos de terneros de menos de 30 días de edad en el sur de Chile. Materiales y métodos: Se obtuvieron reportes de necropsia y microbiología de 107 terneros en el período comprendido entre 2002 y 2015. Adicionalmente se generó un Score de Resistencia a antimicrobianos para permitir la comparación entre aislados que fueron evaluados contra un set de distintos antimicrobianos. Resultados: No se observa una clara tendencia en la resistencia en el período en estudio, con similares niveles de resistencia observados para E. coli, E. coli β-hemolítica y Salmonella spp. Aproximadamente 50% de los aislados mostraron amplia sensibilidad a antimicrobianos, y entre 19 y 36% de los aislados demostraron potencial de resistencia extendida y pan resistencia respectivamente. Se encontraron múltiples patrones de resistencia, incluyendo 32 para E. coli, 17 para E. coli β-hemolítica y 10 para Salmonella spp. Conclusiones: En general, E. coli se mostró más sensible a ceftriaxona, E. coli β-hemolítica a Florfenicol y Salmonella spp. a gentamicina. En contraste, estos agentes fueron resistentes a amoxicilina, ampicilina y oxitetraciclina respectivamente. Este estudio es único en su aproximación y provee de información útil para médicos veterinarios y productores sobre los patrones de resistencia que amenazan la salud de los terneros. Estos resultados pueden ayudar a médicos veterinarios de campo a enfrentar y controlar efectivamente las diarreas en terneros.

A justification of whistleblowing

Penultimate version accepted for publicationWhistleblowing is the act of disclosing information from a public or private organization in order to reveal cases of corruption that are of immediate or potential danger to the public. Blowing the whistle involves personal risk, especially when legal protection is absent, and charges of betrayal, which often come in the form of legal prosecution under treason laws. In this article we argue that whistleblowing is justified when disclosures are made with the proper intent and fulfill specific communicative constraints in addressing issues of public interest. Three communicative constraints of informativeness, truthfulness and evidence are discussed in this regard. We develop a ‘harm test’ to assess the intent for disclosures, concluding that it is not sufficient for justification. Along with the proper intent, a successful act of whistleblowing should provide information that serves the public interest. Taking cognizance of the varied conceptions of public interest, we present an account of public interest that fits the framework of whistleblowing disclosures. In particular, we argue that whistleblowing is justified inter alia when the information it conveys is of a presumptive interest for a public insofar as it reveals an instance of injustice or violation of a civil or political right done against and unbeknown to some members of a polity.Project: ‘Change of Direction. Fostering Whistleblowing in the Fight against Corruption’ co-funded by the Internal Security Fund of the European Union (Grant Agreement Number: HOME/2014/ISFP/AG/EFCE/7233); SFRH/BPD/108669/2015info:eu-repo/semantics/publishedVersio