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We explore the impact of geographically bounded, intrafirm linkages (internal agglomerations) and geographically bounded, interfirm linkages (external agglomerations) on firms’ location strategies. Using data from the Census Bureau’s Longitudinal Business Database, we analyze the locations of new establishments of biopharmaceutical firms in the United States from 1993 to 2005. We consider all activities in the value chain and allow location choices to vary by research and development, manufacturing, and sales. Our findings suggest that internal agglomerations have a positive impact on location. The effects of internal agglomerations vary by activity, and they arise both within an activity (e.g., among plants) and across activities (e.g., between sales and manufacturing). Our results also suggest that previous estimates of the effect of external agglomerations may be overestimated because the existing literature abstracted from internal agglomerations. This paper was accepted by Bruno Cassiman, business strategy .

Background Detection of epidermal growth factor receptor ( EGFR) mutations in exons 18–21 is recommended in all patients with advanced Non-small-cell lung carcinoma due to the demonstrated efficiency of the standard therapy with tyrosine kinase inhibitors in EGFR -mutated patients. Therefore, choosing a suitable technique to test EGFR mutational status is crucial to warrant a valid result in a short turnaround time using the lowest possible amount of tissue material. The Idylla™ EGFR Mutation Test is a simple, fast and reliable method designed for the detection of EGFR mutations from formalin-fixed paraffin-embedded samples. The aim of this study was the Clinical Performace Evaluation of the Idylla™ EGFR Mutation Test on the Idylla™ System. Methods EGFR mutational status was determined on 132 archived formalin-fixed paraffin-embedded tissue sections with Idylla™ technology. Results were compared with the results previously obtained by routine method in the reference lab (Therascreen® EGFR RGQ PCR v2, Qiagen in Molecular Pathology lab, Hospital Universitario Virgen del Rocío de Sevilla). Results The overall agreement between results obtained with the Idylla™ EGFR Mutation Test and the Comparator test method was 95.38% (with 1-sided 95% lower limit of 91.7%) showing Positive Diagnostic Agreement of 93.22% and Negative Diagnostic Agreement of 97.18%, with a Limit Of Detection ≤5%. Conclusions The Idylla™ EGFR Mutation Test passed its clinical validity performance characteristics for accuracy.

This paper investigates how the implementation of intellectual property rights in developing countries under the 1995 TRIPS agreement affected trade in knowledge-intensive goods. We compare trade in knowledge-intensive goods with trade in other types of goods for 158 members and observers of the World Trade Organization from 1993—2009. Trade in knowledge-intensive goods increased relative to a control group after TRIPS implementation. The increase in imports by developing countries was driven by exchange with high-income countries and was concentrated in the information and communications technology sector. Our findings suggest that the effect of TRIPS on promoting knowledge diffusion from high-income to developing countries varies by sector.

Background Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential. Methods We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on 18 F-fluoro-deoxyglucose ( 18 FDG) uptake by positron emission tomography (PET). Results Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18 FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro . Conclusions In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

Although the failure of antibiotic treatment is normally attributed to resistance, tolerance and persistence display a significant role in the lack of response to antibiotics. Due to the fact that several nosocomial pathogens show a high level of tolerance and/or resistance to chlorhexidine, in this study we analyzed the molecular mechanisms associated with chlorhexidine adaptation in two clinical strains of Klebsiella pneumoniae by phenotypic and transcriptomic studies. These two strains belong to ST258-KPC3 (high-risk clone carrying β-lactamase KPC3) and ST846-OXA48 (low-risk clone carrying β-lactamase OXA48). Our results showed that the K. pneumoniae ST258-KPC3CA and ST846-OXA48CA strains exhibited a different behavior under chlorhexidine (CHLX) pressure, adapting to this biocide through resistance and tolerance mechanisms, respectively. Furthermore, the appearance of cross-resistance to colistin was observed in the ST846-OXA48CA strain (tolerant to CHLX), using the broth microdilution method. Interestingly, this ST846-OXA48CA isolate contained a plasmid that encodes a novel type II toxin/antitoxin (TA) system, PemI/PemK. We characterized this PemI/PemK TA system by cloning both genes into the IPTG-inducible pCA24N plasmid, and found their role in persistence and biofilm formation. Accordingly, the ST846-OXA48CA strain showed a persistence biphasic curve in the presence of a chlorhexidine-imipenem combination, and these results were confirmed by the enzymatic assay (WST-1).

Junto al desarrollo de las ciudades inteligentes, están emergiendo mecanismos colaborativos de innovación que facilitan la cocreación de valor público. Siendo los ecosistemas de innovación un elemento dinamizador de tales mecanismos, se hace necesario sistematizar las esencias conceptuales de su influencia en el desarrollo actual de las ciudades inteligentes. Este artículo se centra en dicho propósito, para lo cual se realiza una revisión basada en una estrategia de búsqueda en la base de datos de Google Académico para el periodo 2015-2021. La sistematización conceptual sigue una metodología que consta de tres etapas: i) conceptualización, que permite distinguir las definiciones de ciudad inteligente con énfasis en los ecosistemas de innovación; ii) desarrollo, que profundiza en los modelos teóricos que destacan cómo tiene lugar la cocreación de valor público en los entornos urbanos actuales, y iii) aprendizaje, donde se hace hincapié en los hallazgos del estudio para proponer guías para la acción. Como resultado, se presentan regularidades conceptuales que ponen al descubierto la importancia de analizar las ciudades inteligentes desde una perspectiva innovadora, colaborativa y centrada en las personas. El principal aporte de este artículo radica en la obtención de un modelo conceptual general para la cocreación de valor público en ciudades inteligentes, con base en los hallazgos conceptuales obtenidos, de los cuales también se derivan recomendaciones, con el fin de fomentar su exitosa implementación. Collaborative innovation mechanisms that facilitate the co-creation of public value are emerging along with the development of smart cities. Since innovation ecosystems are a dynamic element of such mechanisms, it becomes necessary to systematize the conceptual foundations of their influence over the current development of smart cities. This article focuses on this purpose through a literature review study in Google Scholar database for the period 2015-2021. The conceptual systematization of this issue follows a methodology consisting of three stages: i) conceptualization, which distinguishes “smart city” definitions with an emphasis on innovation ecosystems; ii) development, which delves into the theoretical models that explain how public value co-creation takes place in current urban environments; and iii) learning, where research findings serve as the basis to propose guidelines for action. As a result, conceptual regularities that expose the importance of analyzing smart cities from an innovative, collaborative and people-centered perspective are presented. The main contribution of this article is offering a general conceptual model for the co-creation of public value in smart cities based on the conceptual findings obtained, from which recommendations for its successful implementation are also introduced. junto ao desenvolvimento das cidades inteligentes, estão emergindo mecanismos colaborativos de inovação que facilitam a cocriação de valor público. Sendo os ecossistemas de inovação um elemento dinamizador desses mecanismos, é necessário sistematizar as essências conceituais de sua influência no desenvolvimento atual das cidades inteligentes. Este artigo está focado nesse propósito, para o qual é realizada uma revisão baseada numa estratégia de busca na base de dados do Google Acadêmico para o período de 2015-2021. A sistematização conceitual continua uma metodologia que consta de três etapas: 1) conceitualização, que permite diferenciar as definições de cidade inteligente com ênfase nos ecossistemas de inovação; 2) desenvolvimento, que aprofunda nos modelos teóricos que destacam como tem lugar a cocriação de valor público nos entornos urbanos atuais e 3) aprendizagem, em que se faz relação com os achados do estudo para propor guias para a ação. Como resultado, são apresentadas regularidades conceituais que evidenciam a importância de analisar as cidades inteligentes sob uma perspectiva inovadora, colaborativa e centralizada nas pessoas. A principal contribuição deste artigo se encontra na obtenção de um modelo conceitual geral para a cocriação de valor público em cidades inteligentes, com base nos achados conceituais obtidos, dos quais também são derivadas recomendações a fim de fomentar sua bem-sucedida implementação. Parallèlement au développement des villes intelligentes, on assiste à l'émergence de mécanismes d'innovation collaborative qui facilitent la cocréation de valeur publique. Les écosystèmes d'innovation étant un élément dynamique de ces mécanismes, il est nécessaire de systématiser les éléments conceptuels de leur influence sur le développement actuel des villes intelligentes. Cet article se concentre sur cet objectif, pour lequel on effectue une analyse basée sur une stratégie de recherche dans la base de données Google Scholar pour la période 2015-2021. La systématisation conceptuelle suit une méthodologie en trois étapes : i) la conceptualisation, qui distingue les définitions des villes intelligentes en mettant l'accent sur les écosystèmes d'innovation ; ii) le développement, qui approfondit les modèles théoriques qui mettent en évidence la façon dont la cocréation de valeur publique a lieu dans les environnements urbains actuels ; et iii) l'apprentissage, où les résultats de l'étude sont mis en évidence pour proposer des lignes directrices pour l'action. Il en résulte des régularités conceptuelles qui mettent en évidence l'importance d'analyser les villes intelligentes d'un point de vue innovant, collaboratif et centré sur les personnes. La principale contribution de cet article réside dans l'élaboration d'un modèle conceptuel général pour la cocréation de valeur publique dans les villes intelligentes, sur la base des résultats conceptuels obtenus, à partir desquels des recommandations sont également formulées, afin de favoriser leur mise en œuvre réussie.

The emergence and spread of carbapenemase-producing gram-negative bacteria is a major public health concern. We used data collected from microbiology laboratories as part of the PIRASOA program during 2014-2018 to study the epidemiology of carbapenemase-producing bacteria in Andalusia, Spain. Our findings highlight the importance of ongoing surveillance and epidemiologic studies for these bacteria.

Background: Epilepsy is one of the most common neurologic diseases, and around 30% of all epilepsies, particularly the temporal lobe epilepsy (TLE), are highly refractory to current pharmacological treatments. Abnormal synchronic neuronal activity, brain glucose metabolism alterations, neurodegeneration and neuroinflammation are features of epilepsy. Further, neuroinflammation has been shown to contribute to dysregulation of neuronal excitability and the progression of epileptogenesis. Flufenamic acid (FLU), a non-steroidal anti-inflammatory drug, is also characterized by its wide properties as a dose-dependent ion channel modulator. In this context, in vitro studies have shown that it abolishes seizure-like events in neocortical slices stimulated with a gamma-aminobutyric acid A (GABAA) receptor blocker. However, little is known about its effects in animal models. Thus, our goal was to assess the efficacy and safety of a relatively high dose of FLU in the lithium-pilocarpine rat model of status epilepticus (SE). This animal model reproduces many behavioral and neurobiological features of TLE such as short-term brain hypometabolism, severe hippocampal neurodegeneration and inflammation reflected by a marked reactive astrogliosis. Methods: FLU (100 mg/kg, i.p.) was administered to adult male rats, 150 min before SE induced by pilocarpine. Three days after the SE, brain glucose metabolism was assessed by 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]FDG) positron emission tomography (PET). Markers of hippocampal integrity, neurodegeneration and reactive astrogliosis were also evaluated. Results: FLU neither prevented the occurrence of the SE nor affected brain glucose hypometabolism as assessed by [18F]FDG PET. Regarding the neurohistochemical studies, FLU neither prevented neuronal damage nor hippocampal reactive astrogliosis. On the contrary, FLU increased the mortality rate and negatively affected body weight in the rats that survived the SE. Conclusions: Our results do not support an acute anticonvulsant effect of a single dose of FLU. Besides, FLU did not show short-term neuroprotective or anti-inflammatory effects in the rat lithium-pilocarpine model of SE. Moreover, at the dose administered, FLU resulted in deleterious effects.

To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients. We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing. A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported. Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations.

The American innovation economy, for all its ingenuity, does not engage large segments of the American public. Studies show that an individual's chances of becoming an inventor in the US are strongly linked to their socioeconomic class, race, and gender. As recently as 2019, women made up less than 13% of US inventors with patents, and only 18% of US businesses with patents are women-owned. White inventors filed patents at three times the rate of Black inventors. And Delgado and Murray's research has shown that innovation is highly geographically concentrated; between 2016 and 2020, 57% of all patents produced in the US originated in one of the top ten economic areas for patent activity, such as Silicon Valley, the Boston area, Houston, and Detroit.