Search

Abstract Background Cancer is the second most common cause of death in Germany, and treatment in certified cancer networks is recommended to ensure high-quality care. This study sought to (1) determine the percentage of all primary tumors that might potentially have been treated in certified cancer networks and (2) assess the development and current state of quality-assured cancer care for all cancer patients from a locally defined region in Upper Franconia, Germany. Methods This study was a population-centered retrospective cohort analysis based on data from the Bavarian Cancer Registry (2017–2023). First, we determined all potentially available cancer network certifications and calculated the percentage of cancer care that could potentially have been conducted in certified cancer networks. Second, we considered the certification status of the involved healthcare providers and analyzed whether or not cancer care was actually carried out in certified cancer networks. Results Overall, 90.1% (62,119/68,973) of all primary tumors, from a total of 63,372 patients, might potentially have been treated in certified cancer networks. The percentage of patients actually receiving care in certified cancer center networks was 40.7% for initial diagnosis, 59.0% for surgery, 53.2% for chemotherapy, and 50.7% for radiotherapy; the weighted mean was 50.3%. The results thus ranged between 46.9% (2023) and 52.8% (2022). The highest proportions of patients who received quality-assured treatment in certified cancer center networks were determined for breast cancer (79.5%), colon cancer (73.1%), and lymphoma (60.1%); in contrast, the lowest results were shown for lung cancer (2.7%), anal cancer (0.0%), and mesothelioma (0.0%). Female patients as well as younger patients were significantly more likely to receive care in certified care networks compared with their counterparts. In addition, we did not find a clear trend whether patients in different tumor stages were more or less likely to receive care in certified care networks. Conclusions We found meaningful differences in the proportion of patients who received quality-assured treatment in certified cancer center networks. Following this, patients should receive comprehensive information about receiving care in certified cancer center networks and consider longer travel distances, especially for those cancer types without locally available certified cancer networks.

This issue of the Weizenbaum Journal of the Digital Society brings together contributions that deal with the transformation of the public sphere in times of digitalization from an interdisciplinary perspective. Authors are Pu Yan and Ralph Schroeder, Paddy Leerssen, Damian Trilling, and Sercan Kiyak, Stefan Mertens, David De Coninck, and Leen d’Haenens.

Conceptualizations of scaling sustainable practices tend to focus on the uptake of new technologies and practices, whereas the scaling or maintaining of convival practices with a long history has received less attention. In this article, we explore mainstreaming of cycling along three contemporary paths: the spread of e-bikes, bike sharing, and bike kitchens. We develop an analytical framework for assessing mainstreaming of sustainable practices and its impacts on conviviality – exploring which new groups are reached and new forms of usage opened up, as well as the impacts on accessibility, adaptability, and socio-ecological relations. Our analysis shows that the spread of e-bikes and bike sharing are associated with a certain loss of conviviality, while bike kitchens explicitly aim to maintain conviviality. The mainstreaming paths also widen and deepen the practice and notion of cycling. We conclude by reflecting on policy implications and how strategies for more convivial mainstreaming can be organized.

Summary: Quantifying the number of proteins that interact with mRNAs, in particular with poly(A) tails of mRNAs, is crucial for understanding gene regulation. Biochemical assays offer significant advantages for this purpose. Here, we present a protocol for synthesizing mRNAs with accurate, length-specific poly(A) tails through a PCR-based approach. We also describe steps for an in vitro (i.e., cell-free) approach for visualizing the sequential binding of Cytoplasmic Poly(A)-Binding Proteins (PABPCs) to these poly(A) tails. We detail quality control steps throughout the procedure.For complete details on the use and execution of this protocol, please refer to Grandi et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.

Computational biologists are frequently engaged in collaborative data analysis with wet lab researchers. These interdisciplinary projects, as necessary as they are to the scientific endeavor, can be surprisingly challenging due to cultural differences in operations and values. In this Ten Simple Rules guide, we aim to help dry lab researchers identify sources of friction and provide actionable tools to facilitate respectful, open, transparent, and rewarding collaborations.

Tristetraprolin (TTP) is an RNA binding protein that destabilizes mRNAs of factors involved in proliferation, invasiveness, and inflammation. Disruption of the gene that codes for TTP (Zfp36) led to severe arthritis, autoimmunity, cachexia and dermatitis in mice. It has been shown that these phenotypes were mostly due to excessive TNFα levels in the affected tissues. We have previously reported that TTP expression is required for lactation maintenance. Our results indicated that conditional MG TTP-KO female mice displayed early involution due to the untimely induction of pro-inflammatory pathways led mostly by TNFα overexpression. Here we show that reducing TTP levels not only affects the fully differentiated mammary gland, but also harms morphogenesis of this tissue by impairing the progenitor cell population. We found that Zfp36 expression is linked to mammary stemness in human and mice. In addition, diminishing TTP expression and activity induced apoptosis of stem-like mouse mammary cells, reduced its ability to form mammospheres in culture and to develop into complete glands when implanted into cleared mammary fat pads in vivo. Our results show that survival of the stem-like cells is compromised by increased levels of inflammatory cytokines and stimulation of signaling cascades involving NFκB, STAT3 and MAPK-p38 activation. Moreover, TNFα overexpression and the consequent p38 phosphorylation would be the leading cause of progenitor cell death upon TTP expression restriction. Taken together, our results reveal the relevance of TTP for the maintenance of the mammary progenitor cell compartment by maintaining local TNFα levels at bay.

A new martensitic stainless steel with high nitrogen and carbon content at low pressures was designed using the CALPHAD method. The chemical composition of the steel was checked by optical emission spectrometry, obtaining 0.17 wt%-N and 1.33 wt%-C. Scanning electron microscopy (SEM) analyses were carried out for microstructural characterization. The properties of the steel were assessed by Rockwell hardness and potentiodynamic polarization tests in 0.6M NaCl. The steel showed maximum hardness values of 60 HRC, regarded as a hard material. However, the passive film formation was prevented by the high carbon content promoting excessive Cr-rich carbides.

The five papers in this issue of the Weizenbaum Journal of the Digital Society examine processes of digitalization from a perspective that encompasses political economy, political science, psychology, and communication science. In turn, the contributors explore the relationship between digitalization and capitalism, the role of civic tech initiatives, the regulation of political micro-targeting on social media, the use of fictive accounts of historical figures on social media, and concepts for the participatory development of research agendas.

Introduction : Kalanchoe crenata est une espèce utilisée traditionnellement au Cameroun pour le traitement des plaies et la bave d’escargot (Achatina fulica) est reconnue comme efficace pour le renouvellement des cellules de la peau. La présente étude avait pour objectif de formuler une crème cicatrisante du mélange de Kalanchoe crenata et Achatina fulica pour la prise en charge des brȗlures de deuxième degré sur les rats de souche Wistar. Méthodologie : Une étude expérimentale a été menée de décembre 2021 à juin 2022. L’induction des brûlures a été faite sur des rats femelles de souches Wistar selon le modèle de Rozaini et al modifié. Le screening phytochimique a été réalisé selon les principes de Harbone, Sofowora et Evans. Les tests au DPPH, FRAP et TAC ont permis d’évaluer l’activité antioxydante. La propriété cicatrisante quant à elle, a été évaluée selon le modèle de Kamdemir et al. Concernant la fabrication de la crème, la phase hydrophile était constituée de glycérol, de mucus d’Achatina fulica, d’eau purifiée, d’eextrait aqueux de Kalanchoe crenata, et de Tween 20, et portée à 70°C au bain-marie ; parallèlement, la phase lipophile était composée de vaseline, d’huile de coco, d’huile de noisette, de laurylsulfate de sodium, et également portée à 70°C. La phase hydrophile a été additionnée à la phase lipophile sous agitation pendant 20 minutes à 60°C. Le mélange a été laissé à refroidir sous agitation plus lente jusqu'à la température ambiante. Les caractères organoleptiques, le pH, le sens de l’émulsion, l’homogénéité et la stabilité ont été évalués. Résultats : Les composés phénoliques, terpénoïdes et les alcaloïdes ont été révélés dans l’extrait de Kalanchoe crenata et le mucus d’Achatina fulica. Les tests antioxydants ont mis en évidence une activité antiradicalaire (SC50 = 1,25 mg/ml), une activité chélatrice (20 µg EAA/g MS), et un TAC à 11µg EAA/g MS. Les plaies traitées par les produits naturels, le jus de Kalanchoe crenata (98,72% à J10), le mucus d’Achatina fulica (99,40% à J10) et leur mélange (99,76% à J10) présentent une évolution de cicatrisation très proche du produit de référence (100% à J10). La crème élaborée à 8,4 %, dénommée KALANC’AF, était une crème H/L, d’odeur d’huile d’olive, couleur verte olive, consistance molle, aspect lisse et brillant, Ph 4,36, présentant des particules visibles, stable à l’étuve et à la centrifugation. Conclusion : A l’issue de l’étude, une crème stable aux propriétés cicatrisantes à partir du jus de Kalanchoe crenata et du mucus d’Achatina fulica a été formulée.

Joseph Weizenbaum would have been 100 years old on January 8, 2023. This anniversary was a welcome occasion to remember the life, work, and impact of the great computer scientist and public intellectual at the Weizenbaum Institute. This special issue compiles a series of articles directly or indirectly related to his work. Contributions center on Weizenbaum as an individual and his public role as a progressive intellectual, encompassing contemporary viewpoints on ethics in digital technology.

Las áreas de reproducción del chorlo nevado (Charadrius nivosus) conocidas en México, se localizan en zonas costeras y en algunos humedales del centro del país. El 7 de mayo de 2022, observamos por primera vez, nueve C. nivosus, con plumaje reproductivo, en la Laguna de Santiaguillo, Durango. En subsecuentes visitas durante el mes de mayo y hasta 18 de junio del 2022, registramos hasta un total de 45 chorlos, incluyendo la presencia de hasta 21 pollos. Esto representa el primer reporte de actividad reproductiva de C. nivosus en la región norte de México, en un humedal del estado de Durango. La reproducción de C. nivosus en este sitio RAMSAR amplía la importancia biológica y avifaunística del área, así como también brinda la oportunidad de incrementar su protección e implementar acciones de manejo e investigación para su conservación.

Introducción: La incontinencia es un problema de salud frecuente que afecta la calidad de vida de las personas, limitando la autonomía y reduciendo la autoestima. Entre el 36-54% de las personas con incontinencia severa pueden presentar deterioro moderado a extremo en su cotidianidad y confianza. Objetivo: Evaluar la percepción de pacientes adultos con incontinencia urinaria y/o incontinencia fecal severa frente al uso de los pañales desechables. Metodología: Estudio observacional de cohorte, en pacientes afiliados a programas de atención domiciliaria usuarios de tres marcas comerciales de pañales. La percepción se evaluó con el instrumento ICIQ-PadPROM®. Resultados: Participaron I79 pacientes, 68% mujeres con edad promedio 7I,9 años. El dominio de diseño de pañal y efecto físico fue el que presentó mejor calificación, siendo el pañal Content Medical® el mejor calificado, con diferencias significativas principalmente frente al grupo de Rely®; en el ítem de filtraciones del dominio carga del pañal, Content Medical® presenta mejor percepción comparado contra los otros grupos (p

In response to housing shortages in densely inhabited urban areas, there is a search for structural engineering solutions for serial and modular construction. Prefabricated concrete columns can make an important difference. Using industrial manufacturing processes, it is possible to produce highly loadable, durable and true-to-size columns that enable accelerated construction progress and dismantling or reuse of the components at the end of the structure’s economic life. However, there are challenges in designing the detachable connection between highly loaded columns due to an undesired reduction of the load-bearing capacity on the one hand and a high sensitivity to geometrical deviations on the other hand. To investigate the load-bearing and deformation behaviour of butt-jointed columns, large-scale component tests as well as three-dimensional numerical analyses using the finite element method were carried out. The analyses show that measures to increase the stiffness of the joint, such as thicker steel plates, lower mortar thickness, etc., lead to an increase of the ultimate load. It could also be demonstrated that butt-jointed columns are very sensitive to unevenness of the end faces. Finally, the investigations allow first conclusions on the design and detailing of detachable compression connections between prefabricated concrete columns.

Background: The RNA-binding protein IGF2BP2/IMP2/VICKZ2/p62 is an oncofetal protein that is overexpressed in several cancer entities. Employing IMP2 knockout colorectal cancer cells, we could show the important role of IMP2 in several hallmarks of cancer. This study aimed to functionally characterize IMP2 in lung (A549, LLC1) and hepatocellular carcinoma (HepG2, Huh7) cell lines to assess its role as a potential target for these cancer entities. Methods: IMP2 knockouts were generated by CRISPR/Cas9 and its variant approach prime editing; the editing efficiency of two single guide RNAs (sgRNAs) was verified via next-generation sequencing. We studied the effect of IMP2 knockout on cell proliferation, colony formation, and migration and employed small-molecule inhibitors of IMP2. Results: Despite multiple attempts, it was not possible to generate IMP2 biallelic knockouts in A549 and Huh7 cells. Both sgRNAs showed good editing efficiency. However, edited cells lost their ability to proliferate. The attempt to generate an IMP2 biallelic knockout in LLC1 cells using CRISPR/Cas9 was successful. Monoallelic knockout cell lines of IMP2 showed a reduction in 2D cell proliferation and reduced migration. In 3D cultures, a change in morphology from compact spheroids to loose aggregates and a distinct reduction in the colony formation ability of the IMP2 knockouts was observed, an effect that was mimicked by previously identified IMP2 inhibitor compounds that also showed an inhibitory effect on colony formation. Conclusions: Our in vitro target validation supports that IMP2 is essential for tumor cell proliferation, migration, and colony formation in several cancer entities.

This second issue of the Weizenbaum Journal of the Digital Society brings together four contributions that examine the role of actors and regulation in processes of digitalization from the perspective of different disciplines. The topics include the role of the Silicon Valley discourse on entrepreneurship in legitimizing a specific model of work in the IT industry, the particularities of the European platform regulation approach, the development and enforcement problems of copyright liability regulation in Germany, and the development and regulation of automation processes in the workplace.

La distribución de los recursos utilizados por las aves direcciona procesos ecológicos como la selección del hábitat. El objetivo del presente estudio fue comparar durante dos inviernos consecutivos, la selección del hábitat de gorriones de pastizal y evaluar la influencia de la precipitación anual y la biomasa de semillas disponible en el suelo. Durante dos inviernos colectamos semillas del suelo en 45 sitios usados por el gorrión de Baird (Centronyx bairdii) y el gorrión chapulín (Ammodramus savannarum) y en lugares aleatorios (n= 45) sin aves registradas. Determinamos los sitios de uso mediante la captura de aves a las que les colocamos un transmisor y dimos seguimiento mediante telemetría. Los sitios utilizados por los gorriones tuvieron una biomasa de semillas significativamente mayor que los sitios aleatorios, y fue similar entre especies. Por lo que el recurso alimenticio juega un papel importante en la selección del hábitat invernal de los gorriones. Además, encontramos una correlación positiva entre la precipitación anual y la biomasa de semillas lo que resulta importante ante un escenario de cambio climático, por la influencia que encontramos en las aves para seleccionar sitios de invernada con mayor biomasa de semillas en años de menor cantidad de lluvia. Nuestros resultados amplían la información disponible sobre la selección del hábitat invernal de C. bairdii y A. savannarum en México

In recent debates on offensive language in participatory online spaces, the term ‘hate speech’ has become especially prominent. Originating from a legal context, the term usually refers to violent threats or expressions of prejudice against particular groups on the basis of race, religion, or sexual orientation. However, due to its explicit reference to the emotion of hate, it is also used more colloquially as a general label for any kind of negative expression. This ambiguity leads to misunderstandings in discussions about hate speech and challenges its identification. To meet this challenge, this article provides a modularized framework to differentiate various forms of hate speech and offensive language. On the basis of this framework, we present a text annotation study of 5,031 user comments on the topic of immigration and refuge posted in March 2019 on three German news sites, four Facebook pages, 13 YouTube channels, and one right-wing blog. An in-depth analysis of these comments identifies various types of hate speech and offensive language targeting immigrants and refugees. By exploring typical combinations of labeled attributes, we empirically map the variety of offensive language in the subject area ranging from insults to calls for hate crimes, going beyond the common ‘hate/no-hate’ dichotomy found in similar studies. The results are discussed with a focus on the grey area between hate speech and offensive language.

The Weizenbaum Journal of the Digital Society is an open access journal and could not function any other way, because we see digitalization as a process that changes traditional forms of communication and cooperation, which raises the questions of control of data, information and knowledge anew. We look forward to contributions about the conditions, forms and consequences of the digitalization of society and its sub-sectors such as politics, business, science, labor, the public, civil society, law and culture. The digitalization of society has many facets: the disruptive transformation of the world of work, radical changes in the economic and innovation systems, new forms of learning and the restructuring of educational systems, the transformation of public space through digital media and platforms, changes in the way democracies function, massive challenges for the legal system and the planning and design of technical infrastructures. In light of these developments, the question arises as to how social actors can shape the digital transformation while safeguarding the foundations for individual and societal self-determination.

Context: The lack of dissolved oxygen (DO) in water bodies has become a serious problem for several ecosystems due to drastic changes in their climatic, biological, and physical conditions. The presence of microorganisms, organic matter, and clays, which are carried by landslides and rainwater, affect the process of restoration and transfer of DO in water, thus making it necessary to study how these factors affect the process of DO transfer in water bodies. Method: This work is focused on studying the influence of clays during the DO transfer process in water bodies. To this effect, samples of clays from the region of Paipa, Boyacá, were added in 1, 3 and 5% by weight into the samples of clean water. The aeration process was performed using a constant flow diffusion system. The tests were carried out until the saturation of dissolved oxygen in each of the water samples was obtained. Results: The results show that the presence of clays during the transfer of DO have little influence on bodies of water. However, variations were observed in time intervals of

The importance of citizenship norms—shared understandings of how citizens ought to participate in society—has been discussed at length in the past two decades, particularly in conversations around changing notions of citizenship in the digital age. Yet, most studies have gravitated between the two poles of dutiful and self-actualizing citizenship. In this study, we explore which citizenship norms people express related to their political participation in social media environments and which affordances and experiences in social media environments shape these norms. Through interviews and focus group discussions, we found that citizenship norms emerge in response to positive and negative experiences in social media environments. We found three groups of norms that are distinctive to the networked environments of social media: individual information care, discourse care , and considered contribution . These can serve as conceptual frames for understanding the normative underpinnings of discursive participation in social media environments from the perspective of ordinary citizens.

Uno de los factores claves que inciden en la calidad de la educación básica y media es la formación profesional y de alto nivel de los docentes, aspecto sobre el cual no se ha evidenciado el desarrollo de estudios basados en análisis espacial de los datos. En este artículo se presenta como aporte la aplicación del análisis espacial de los datos en la caracterización de la formación profesional de los docentes de educación básica y media de la ciudad de Bogotá. El estudio propuesto en este artículo fue desarrollado sobre el dataset provisto por el portal de datos abiertos de Bogotá para el año 2019, haciendo uso de la herramienta de software libre GeoDa, la cual permite realizar un análisis espacial de cuantiles y correlación lineal, así como aplicar de modelos de clustering mediante el uso del algoritmo K-Means. El estudio desarrollado, pretende servir de apoyo en cuanto a la toma de decisiones por parte de las autoridades pertinentes con respecto a la cobertura y la inversión en formación de los docentes en las diferentes localidades de la ciudad de Bogotá. Del mismo modo, este estudio pretende servir de referencia para ser extrapolado tanto a nivel de diferentes departamentos, como a nivel nacional, de cara a la caracterización y evaluación de la calidad de la educación en Colombia.

El mundo actual exige nuevas estrategias de formación profesional, que mejoren las prácticas de enseñanza-aprendizaje, teniendo en cuenta las características de las nuevas generaciones. El objetivo de este trabajo es proponer una estrategia didáctica para cursos de ingeniería de software, fundamentada en la ingeniería inversa y el aprendizaje basado en problemas (ABP). Se aplicó la metodología de investigación-acción, con la participación de 86 estudiantes y 3 docentes, usando observación participante, entrevistas y repositorios de trabajos de los estudiantes. La estrategia didáctica propuesta se estructura en un conjunto de principios, lineamientos, actividades de clase y recomendaciones. Los resultados del estudio permitieron concluir que la estrategia didáctica propuesta ayudó a estimular la motivación de los estudiantes y contribuyó al logro de los resultados de aprendizaje, porque desarrollaron habilidades técnicas, cognitivas y conductuales.

La pandemia originada por el COVID-19 ha obligado a las instituciones de educación superior a adaptar sus diferentes procesos académicos (clases, reuniones, eventos académicos) a las dinámicas y desafíos de la virtualidad. En este sentido además de la brecha digital, entre los desafíos suscitados por esta pandemia en el contexto académico se encuentran: la formación de los profesores en el uso de las TIC y en la apropiación de metodologías para la virtualidad, así como el desarrollo de competencias en cursos prácticos en presencialidad remota. Este artículo presenta como contribución la aplicación de la metodología de aprendizaje colaborativo en el desarrollo de actividades prácticas dentro del curso de Interacción Humano Computador del Programa de Ingeniería de Sistemas de la Universidad de Cartagena. De manera específica, se adaptó a la presencialidad remota, la metodología de las sesiones prácticas desarrolladas dentro de la temática de inspecciones de usabilidad, teniendo en cuenta herramientas de teleconferencia y de trabajo colaborativo. Mediante las sesiones colaborativas diseñadas, se pudieron desarrollar en el curso diferentes ejercicios de inspección sobre aplicaciones de propósito general, aplicativos web y videojuegos. La propuesta presentada pretende extrapolarse para el desarrollo de actividades prácticas remotas en otros cursos del área de la Ingeniería.

Con el incremento actual en el número de aplicaciones y recursos que son publicados en diferentes repositorios y tiendas de apps, la usabilidad se ha convertido en un atributo fundamental para garantizar tanto la productividad del usuario final, como la competitividad de las empresas de desarrollo de software en el mercado. En el caso de los recursos educativos en línea es importante no sólo centrarse en el diseño pedagógico de los contenidos, sino también en proporcionar una interacción adecuada, a partir de una interfaz sencilla e intuitiva, la cual se oriente a un mayor número de usuarios. A partir de lo anterior, en este artículo se propone como contribución, la definición de un conjunto de criterios de usabilidad pedagógica para guiar el proceso de diseño y evaluación de recursos educativos en línea, los cuales fueron clasificados en tres dimensiones: navegación, diseño y contenido. Partiendo de los criterios propuestos, se desarrolló una herramienta de apoyo que puede ser usada para verificar la usabilidad pedagógica de los recursos educativos, de cara a identificar aspectos a mejorar en la interacción y en los contenidos. Estos criterios pretenden servir de apoyo a los profesores y diseñadores de contenido, en cuanto al mejoramiento de los recursos creados en entornos de E-Learning.

During the breeding season the Grasshopper Sparrow (Ammodramus savannarum) is widely distributed over the plains of North America. Consisting of four subspecies its populations are classified as resident, migratory and partially migratory. In Mexico and Central America, distribution of the taxon is poorly known, especially those populations that are breeding. There is only one breeding record for the grasslands of northern Mexico in the State of Zacatecas back to the mid-1950’s. During the summer breeding season of 2017, we documented the presence of six Grasshopper Sparrows in the grassland of northern Durango. With the aid of song playback two birds actively responded to the broadcasted song. The birds performed territorial displays which facilitated our locating a nest with four nestlings. This is the first summer record for the State of Durango at Cuchillas de la Zarca, 80 km south of Parral, Chihuahua City, a Grasslands Priority Conservation Area of North America.

The paper presents a method to establish a performance-based fibre design of high-strength micro steel fibres for ultra-high-performance concrete (UHPC). The performance-based fibre design considers effects of fibre layout, fibre orientation, and type of loading (quasi-static and cyclic) and expands the current approach using experiences and suitability testing results. The performance-based fibre design is based on a so-called utilization rate, which is determined via pullout tests of high-strength micro steel fibres in UHPC under quasi-static as well as high cyclic loading with varying orientations and embedment depths. The utilization rate for a straight fibre pullout is 0.27 on average considering the measured tensile strength of the fibre and 0.50 considering the manufacturers specifications. For inclined fibres, additional bending stresses occur at the exit point of the fibre channels, leading to a significant increase in local tensile stress. Therefore, the utilization rate of inclined fibres under quasi-static loading is approximately 60–70% higher than in the case of straight embedded fibres (comparing it to the measured tensile strength). Comparing the utilization rate to the manufacturer’s specification, it increases to approximately 1.00. Under cyclic loading, the additional bending stresses in inclined fibres result in a local increase of the load amplitude, leading to a reduced fatigue resistance and premature fibre rupture, underlining the feasibility of a performance-based fibre design.

BackgroundFeedback from patients is an essential element of a patient-oriented health care system. Physician rating websites (PRWs) are a key way patients can provide feedback online. This study analyzes an entire decade of online ratings for all medical specialties on a German PRW. ObjectiveThe aim of this study was to examine how ratings posted on a German PRW have developed over the past decade. In particular, it aimed to explore (1) the distribution of ratings according to time-related aspects (year, month, day of the week, and hour of the day) between 2010 and 2019, (2) the number of physicians with ratings, (3) the average number of ratings per physician, (4) the average rating, (5) whether differences exist between medical specialties, and (6) the characteristics of the patients rating physicians. MethodsAll scaled-survey online ratings that were posted on the German PRW jameda between 2010 and 2019 were obtained. ResultsIn total, 1,906,146 ratings were posted on jameda between 2010 and 2019 for 127,921 physicians. The number of rated physicians increased constantly from 19,305 in 2010 to 82,511 in 2018. The average number of ratings per rated physicians increased from 1.65 (SD 1.56) in 2010 to 3.19 (SD 4.69) in 2019. Overall, 75.2% (1,432,624/1,906,146) of all ratings were in the best rating category of “very good,” and 5.7% (107,912/1,906,146) of the ratings were in the lowest category of “insufficient.” However, the mean of all ratings was 1.76 (SD 1.53) on the German school grade 6-point rating scale (1 being the best) with a relatively constant distribution over time. General practitioners, internists, and gynecologists received the highest number of ratings (343,242, 266,899, and 232,914, respectively). Male patients, those of higher age, and those covered by private health insurance gave significantly (P100 ratings received the best ratings (mean 1.34, SD 0.47). ConclusionsThis study is one of the most comprehensive analyses of PRW ratings to date. More than half of all German physicians have been rated on jameda each year since 2016, and the overall average number of ratings per rated physicians nearly doubled over the decade. Nevertheless, we could also observe a decline in the number of ratings over the last 2 years. Future studies should investigate the most recent development in the number of ratings on both other German and international PRWs as well as reasons for the heterogeneity in online ratings by medical specialty.

Abstract Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry‐driven hit‐to‐lead optimization and in‐depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter‐gene with IC50 values as low as 200 and 11 × 10−9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI‐tobramycin (Tob) combination against PA biofilms using a tailor‐made squalene‐derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32‐fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker‐mediated therapy against PA infections opening up avenues for preclinical development.

Introducción: el ejercicio de la docencia universitaria por parte de estudiantes de Medicina ofrecería múltiples beneficios. Sin embargo, no hay evidencia de que mejore el desempeño en los exámenes estandarizados en el posgrado. El objetivo de este estudio fue describir la diferencia de los puntajes en el examen de residencias médicas municipales entre ayudantes y no ayudantes, y evaluar la autopercepción del efecto de ser ayudante sobre el desempeño en dicho examen y sobre las habilidades académicas. Métodos: estudio observacional, descriptivo, de corte transversal, con un muestreo por conveniencia de médicos participantes del examen de residencias médicas municipales de la Ciudad Autónoma de Buenos Aires (CABA) de 2018, a partir del listado oficial. Se excluyeron aquellos a quienes fue imposible contactar, que se negaran a participar o cuya identidad discrepara con la de la persona seleccionada para incluir en el estudio. Resultados: de los 3579 médicos que concursaron en el examen de residencias médicas básicas municipales de CABA 2018, se tomó una muestra aleatoria de 300 sujetos, de los cuales se contactó a 87. De ellos, 20 sujetos cumplían con criterios de exclusión; por lo tanto fueron 67 sujetos los que finalmente participaron del estudio. La proporción de respuestas con respecto a los sujetos que pudieron ser contactados mediante redes sociales fue 77%. El puntaje de examen entre los ayudantes fue de 32,3 ± 5,7 puntos mientras que entre los no ayudantes fue 29,5 ± 6,1 puntos. Entre los ayudantes, el 68% informó percibir que el hecho de haber realizado una ayudantía en el pregrado tuvo un efecto de levemente a muy positivo sobre su desempeño en el examen, un 76% refirió la profundización de conocimientos específicos, el 73% informó una mejoría en sus habilidades comunicacionales y el 59% una mayor capacidad para jerarquizar contenidos. Conclusión: el desarrollo de una actividad docente en el pregrado sería percibida por quienes la desarrollan como una actividad promotora de habilidades comunicacionales y de jerarquización de contenidos y, ulteriormente, como una influencia positiva en el desempeño académico en el examen de residencias médicas municipales. Estas conclusiones deben confirmarse con estudios futuros.

Understanding the influence of physical drivers and their scale-dependent interactions on ecosystem structure and function is becoming increasingly relevant as ecologists are challenged to quantify and predict the biological implications of anthropogenic activities and climate changes. Here, we aim to quantify the impact of multiple physical drivers (ice scour, wave exposure, and air temperature) and their interactions with small scale modifying factors (tidal level, substrate rugosity, and canopy forming macroalgae) on rocky intertidal community structure. We did this by quantifying intertidal biomass, cover and species richness at three tidal levels (high, mid, and low) at four sites in a sub-arctic Greenland fjord. We found a well-developed intertidal community, with a total of 16 macroalgae and 20 invertebrate species. At one locality, the total biomass was dominated by canopy forming algae exceeding 16 kg wet weight per m–2. Physical stress from ice scour, waves, and air exposure had negative effects on all three community metrics but important interactions and modifying processes were identified. The effect of tidal level differed between sites ranging from an absence of organisms at both high- and mid-intertidal level at the most ice- and wave exposed site to extensive cover across all three tidal levels at the wave and ice sheltered site. Canopy forming macroalgae and substrate rugosity both modified the impacts of physical stress. In the absence of ice scour, canopy forming algae formed extensive cover that modified extreme air temperatures, and the abundance of dominant invertebrate species were all positively related to the biomass of macroalgae. Rugosity provided refuge from ice scour, facilitating increased species richness and cover at exposed sites. Moreover, we detected no negative effects of fast ice, and ice scour impacts were primarily found where presence of glacial ice was combined with wave exposure. Our results provide an example of how large-scale physical factors pass through a filter of several modifying smaller scale processes before their impact on plot scale community structure is manifested.

Both knapped and polished lithic industries have traditionally been given great regard within the archaeological studies of northwestern Iberian Peninsula, mostly focusing on their typologies and the materials used. However, this has not been the case with other stone objects, such as rolling stones, that tend to appear in certain prehistoric contexts - especially when they do not show signs of intentional knapping. We propose the study of a set of pieces of this type coming from an Iron Age context with the objective of categorizing its use, multifunctionality, and importance within the domestic sphere. For this, we will elaborate on the given article in three parts: firstly, carrying out a morpho-typological study based on the existing bibliography, secondly, trying to establish the corresponding ethnoarchaeological equivalents, and, finally, experimenting with the use of utensils of the type proposed in various domestic applications.

The study described in this contribution contains a fundamental strategy to select geometries for dry joint profiles in 3D-printed concrete constructions. A database, here called the ‘joint catalogue’, contains a variety of joint types adapted from timber, steel, and bionic connections. Weighting factors and different criteria evaluate and score the various joint profiles (e.g., manufacturability, duration of manufacturing, and mechanical behaviour). Therefore, an algorithm sums up the scores leading to the preselection of better suitable profiles. The preselected joint profiles were afterwards analysed by the finite element method, determining the load capacity of the joint in a unit specimen. According to the joint catalogue, a smooth, triangular, truncated cone and arc joint profile appeared to be the optimal combination for dry joints in additive manufacturing of construction (AMC).

The Gram-negative opportunistic pathogen Pseudomonas aeruginosa causes severe nosocomial infections. It uses quorum sensing (QS) to regulate and coordinate population-wide group behaviours in the infection process like concerted secretion of virulence factors. One very important signalling network is the Pseudomonas quinolone signal (PQS) QS. With the aim to devise novel and innovative anti-infectives, inhibitors have been designed to address the various potential drug targets present within pqs QS. These range from enzymes within the biosynthesis cascade of the signal molecules PqsABCDE to the receptor of these autoinducers PqsR (MvfR). This review shortly introduces P. aeruginosa and its pathogenicity traits regulated by the pqs system and highlights the published drug discovery efforts providing insights into the compound binding modes if available. Furthermore, suitability of the individual targets for pathoblocker design is discussed.

Abstract Background Little is known about the usefulness of online ratings when searching for a hospital. We therefore assess the association between quantitative and qualitative online ratings for US hospitals and clinical quality of care measures. Methods First, we collected a stratified random sample of 1000 quantitative and qualitative online ratings for hospitals from the website RateMDs. We used an integrated iterative approach to develop a categorization scheme to capture both the topics and sentiment in the narrative comments. Next, we matched the online ratings with hospital-level quality measures published by the Centers for Medicare and Medicaid Services. Regarding nominally scaled measures, we checked for differences in the distribution among the online rating categories. For metrically scaled measures, we applied the Spearman rank coefficient of correlation. Results Thirteen of the twenty-nine quality of care measures were significantly associated with the quantitative online ratings (Spearman p = ±0.143, p

Ultra-high-performance fibre-reinforced concrete (UHPFRC) can preferably be used for lean and thin-walled structures due to its very high compressive strength. Based on the adverse relation between the increased load bearing capacities and the condensed dead weight of UHPFRC-structures, the impact of live loads in the design gets bigger and, in case of traffic loads, the effects of a cyclic loading have to be considered in more detail. In this context, this study investigated the material behaviour of UHPFRC, especially the tensile fatigue behaviour of high-strength micro steel fibres and the bond behaviour between those fibres and plain UHPC. The test programme included once tensile tests of high-strength micro steel fibres under monotonic and cyclic loading. Based on the test results, an S/N-curve was set up with the characteristic values. Furthermore, the test programme included pullout tests of fibre groups with different embedded lengths and orientations under monotonic and cyclic loading. It was observed that some fibres rupture under certain test configurations like the angle of orientation and the load amplitude.

Abstract Objective To evaluate the impact of different dissemination channels on the awareness and usage of hospital performance reports among referring physicians, as well as the usefulness of such reports from the referring physicians’ perspective. Data sources/Study setting Primary data collected from a survey with 277 referring physicians (response rate = 26.2%) in Nuremberg, Germany (03–06/2016). Study design Cluster-randomised controlled trial at the practice level. Physician practices were randomly assigned to one of two conditions: (1) physicians in the control arm could become aware of the performance reports via mass media channels (Mass Media, n MM pr $$ {n}_{MM}^{pr} $$ =132, n MM ph $$ {n}_{MM}^{ph} $$ =147); (2) physicians in the intervention arm also received a printed version of the report via mail (Mass and Special Media, n MSM pr $$ {n}_{MSM}^{pr} $$ =117; n MSM ph $$ {n}_{MSM}^{ph} $$ =130). Principal findings Overall, 68% of respondents recalled hospital performance reports and 21% used them for referral decisions. Physicians from the Mass and Special Media group were more likely to be aware of the performance reports (OR 4.16; 95% CI 2.16–8.00, p .05). On a 1 (very good) to 6 (insufficient) scale, the usefulness of the performance reports was rated 3.67 (±1.40). Aggregated presentation formats were rated more helpful than detailed hospital quality information. Conclusions Hospital quality reports have limited impact on referral practices. To increase the latter, concerns raised by referring physicians must be given more weight. Those principally refer to the underlying data, the design of the reports, and the lack of important information.

Abstract Background To identify, characterize and compare existing pay-for-performance approaches and their impact on the quality of care and efficiency in ophthalmology. Methods A systematic evidence-based review was conducted. English, French and German written literature published between 2000 and 2015 were searched in the following databases: Medline (via PubMed), NCBI web site, Scopus, Web of Knowledge, Econlit and the Cochrane Library. Empirical as well as descriptive articles were included. Controlled clinical trials, meta-analyses, randomized controlled studies as well as observational studies were included as empirical articles. Systematic characterization of identified pay-for-performance approaches (P4P approaches) was conducted according to the “Model for Implementing and Monitoring Incentives for Quality” (MIMIQ). Methodological quality of empirical articles was assessed according to the Critical Appraisal Skills Programme (CASP) checklists. Results Overall, 13 relevant articles were included. Eleven articles were descriptive and two articles included empirical analyses. Based on these articles, four different pay-for-performance approaches implemented in the United States were identified. With regard to quality and incentive elements, systematic comparison showed numerous differences between P4P approaches. Empirical studies showed isolated cost or quality effects, while a simultaneous examination of these effects was missing. Conclusion Research results show that experiences with pay-for-performance approaches in ophthalmology are limited. Identified approaches differ with regard to quality and incentive elements restricting comparability. Two empirical studies are insufficient to draw strong conclusions about the effectiveness and efficiency of these approaches.

Huntington disease (HD) is a devastating monogenic autosomal dominant disorder. HD is caused by a CAG expansion in exon 1 of the gene coding for huntingtin, placed in the short arm of chromosome 4. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract.Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unraveling mechanisms are still unknown. This practical and brief review summarizes some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis.

Las obras La condición humana (Hannah Arendt) y De la idea de universidad a la universidad de ideas (Boaventura de Sousa Santos), constituyen el fundamento teórico y conceptual del presente artículo cuyo objetivo central es mostrar que la función de la educación universitaria, además de “instruir” para el “trabajo”, consiste en “educar” para la “acción”. En este sentido se desarrollan las siguientes cuestiones: 1) el ethos humanístico de la educación universitaria –investigación, cultura, formación- se encuentra en “lo seco”, 2) los procesos de acreditación de alta calidad contienen unos elementos “totalitarios” –innovación, productividad, competitividad- que condicionan la educación universitaria y amenazan con la desaparición curricular definitiva de su ethos humanístico. A modo de conclusión se plantea la urgencia de reivindicar el ethos humanístico de la educación universitaria a través de una específica estructura de saber: filosofía, pedagogía, política. A nivel metodológico, este artículo se vale de la hermenéutica propia de la reflexión filosófica en la cual se dialoga con las teorías existentes con el fin de producir una nueva interpretación del problema que se plantea.

This paper reports on the construction of masculinities in the narratives of 11 motorcyclists in Valledupar – Colombia. The aim was to establish the ways masculinities are expressed and recreated by motorcycle riders and the importance of motorcycles in these expressions. To do this, semistructured interviews were conducted to search for the evolution of their personal stories as men and on their relationship with motorcycles. We found that their masculinities are currently “in transit”: they vary from hegemonic manifestations to peripheral masculine ways of expression. Evidence of these transits can be grouped around four emerging categories: risk behavior, amusement settings, sexual expression and roles in public and private settings. Results show that, in some of these categories, the hegemonic patriarchal masculine logic prevails, especially through risky behaviors and motorcycle riding. However, other disruptive ways of expressing masculinities were found, motivated by the social transformations in equality policies, changes in interpersonal relationships and the participants’ own experiences. Supporting the transition process of masculinities is a large responsibility in social interventions seeking for a more equitable and fair society.

The crack widths in reinforced concrete structures are affected by various influencing parameters, such as the tensile strength of the concrete, which is a highly variable parameter. While safe predictions of crack widths are possible with the existing models supplied in the code provisions accompanied by suitable safety factors, there are large discrepancies between the experimentally measured crack widths and the calculated values. Even within a uniaxial tensile test on reinforced concrete components, several crack parameters (spacings and widths) are usually measured. To further investigate the effects of scattering input parameters on the distribution of crack parameters, a crack propagation model (CPM) is developed, which is a powerful tool that can be used to observe sequential cracking of uniaxially loaded reinforced concrete components. In the present paper, the background of the scattering of the concrete tensile strength will be explained and the procedure for the simulation in the CPM, including the investigation of different bond–slip relationships, will be introduced. Finally, the CPM will be used to calculate experimental crack parameters and the distribution of the calculated crack parameters will be discussed.

INTRODUCTION:South Africa is among countries with the highest burden of drug resistant tuberculosis (DR-TB). The Eastern Cape Province reported the highest MDR-TB mortality rates in South Africa for the 2010 treatment cohorts. This study aimed to determine risk factors for mortality among adult patients registered for DR-TB treatment in the province. METHODS:We conducted a retrospective cohort study of adult patients treated for laboratory confirmed DR-TB between January 2011 and December 2013. Demographic and clinical characteristics of the patients were obtained from a web-based electronic database of patients treated for DR-TB. We applied modified Poisson regression with robust standard errors to identify risk factors for DR-TB mortality. We also stratified the analyses into multi-drug resistant TB (MDR-TB) and extensively drug resistant (XDR-TB). RESULTS:Among 3,729 patients that met the inclusion criteria, 39% (n = 1,445) died. Of the patients that died, 53% (n = 766) were male, 68% (n = 982) had MDR-TB, 72% (n = 1,038) were HIV co-infected, and median age was 37 years (Interquartile Range [IQR] 30-46). Patients were at higher risk of mortality during DR-TB treatment if they were HIV co-infected not on antiretroviral treatment (ART) (adjusted incidence risk ratio [aIRR] 3.3, 95% confidence interval [CI] 2.9-3.8), were 60 years or older (aIRR 1.7, 95%CI 1.5-2.0), had a diagnosis of XDR-TB (aIRR 1.6, 95%CI 1.5-1.7), or had been hospitalised at treatment start (aIRR 1.7, 95%CI 1.5-1.8). Among MDR-TB patients, risk of mortality was higher if patients were HIV co-infected not on ART (aIRR 3.9, 95%CI 3.3-4.6), were 60 years or older (aIRR 1.9, 95%CI 1.6-2.3), or had been hospitalised at start of MDR-TB treatment (aIRR 1.7, 95%CI 1.5-1.9). Among XDR-TB patients, risk of mortality was higher in patients who were HIV co-infected not on ART (aIRR 1.8, 95%CI 1.5-2.2), or had been hospitalised at the start of XDR-TB treatment (aIRR 1.5, 95%CI 1.3-1.8). CONCLUSION:HIV co-infected not on ART, older age, XDR-TB and hospital admission for DR-TB treatment were independent risk factors for DR-TB mortality. Integration of TB and HIV services, with focus on voluntary HIV testing and counselling of DR-TB patients with unknown HIV status, and provision of ART for all co-infected patients may reduce DR-TB mortality in the Eastern Cape.

Background: Despite ACC/AHA guidelines indicating implantable cardioverter defibrillator (ICD) as class I therapy for primary prevention of sudden cardiac death in patients with EF≤35%, ICD utilization rates in real world practice have been low. Objective: To determine the rate of ICD implantation at a tertiary care academic center and to assess the reasons for under-utilization of the same. Methods: Review of a prospectively collected database which included all patients diagnosed with an EF≤35% was performed to assess the rate of ICD implantation and mortality. Reasons for non-implantation of ICD were then assessed from detailed chart review. Results: A total of 707 patients (age 69.4 ± 14.1 years) with mean EF of 26±7% were analyzed. Only 28% (200/707) of patients had ICDs implanted. Mortality was lower in the group with ICD (25% vs 37%, p=0.004). When patients who either died or were lost to follow-up prior to 2005 were excluded, ICD utilization rate was still low at 37.6%. The most common reason for non-implantation of ICD was physicians not discussing this option with their patients. Patient refusal was the second most common reason. Conclusions: ICD Implantation rates for primary prevention of SCD in patients with EF≤35% is low. Physician and patient education should be addressed to improve the utilization rates.

The record of the aberrations in the plumage coloration in birds is important because allow to know the frequency and conditions with which they occur in the wild populations, which improves the knowledge in the subject. We report two specimens of white-fronted goose (Anser albifrons) with partial leucism in Los Alamos, a wetland in Durango municipality, Mexico, 25 km northeast of Durango City. No isolation was observed in the observed individuals, being part of a flock of specimens of the same species with normal coloration, which was an interesting condition of this report. This is the first record of leucism for this species in Mexico.

Pseudomonas aeruginosa is a Gram-negative bacterium, which causes opportunistic infections in immuno-compromised individuals. Due to its multiple resistances toward antibiotics, the development of new drugs is required. Interfering with Quorum Sensing (QS), a cell-to-cell communication system, has shown to be highly efficient in reducing P. aeruginosa pathogenicity. One of its QS systems employs Pseudomonas Quinolone Signal (PQS) and 4-hydroxy-2-heptylquinoline (HHQ) as signal molecules. Both activate the transcriptional regulator MvfR (Multiple Virulence Factor Regulator), also called PqsR, driving the production of QS molecules as well as toxins and biofilm formation. The aim of this work was to elucidate the effects of QS inhibitors (QSIs), such as MvfR antagonists and PqsBC inhibitors, on the biosynthesis of the MvfR-regulated small molecules 2′-aminoacetophenone (2-AA), dihydroxyquinoline (DHQ), HHQ, PQS, and 4-hydroxy-2-heptylquinoline-N-oxide (HQNO). The employed synthetic MvfR antagonist fully inhibited pqs small molecule formation showing expected sigmoidal dose-response curves for 2-AA, HQNO, HHQ and PQS. Surprisingly, DHQ levels were enhanced at lower antagonist concentrations followed by a full suppression at higher QSI amounts. This particular bi-phasic profile hinted at the accumulation of a biosynthetic intermediate resulting in the observed overproduction of the shunt product DHQ. Additionally, investigations on PqsBC inhibitors showed a reduction of MvfR natural ligands, while increased 2-AA, DHQ and HQNO levels compared to the untreated cells were detected. Moreover, PqsBC inhibitors did not show any significant effect in PA14 pqsC mutant demonstrating their target selectivity. As 2-AA is important for antibacterial tolerance, the QSIs were evaluated in their capability to attenuate persistence. Indeed, persister cells were reduced along with 2-AA inhibition resulting from MvfR antagonism, but not from PqsBC inhibition. In conclusion, antagonizing MvfR using a dosage capable of fully suppressing this QS system will lead to a favorable therapeutic outcome as DHQ overproduction is avoided and bacterial persistence is reduced.