Search

Purpose. The Gram-positive Staphylococcus aureus bacterium is one of the leading causes of infection in humans. The lack of specific noninvasive techniques for diagnosis of staphylococcal infection together with the severity of its associated complications support the need for new specific and selective diagnostic tools. This work presents the successful synthesis of an immunotracer that targets the α-toxin released by S. aureus. Methods. [89Zr]Zr-DFO-ToxAb was synthesized based on radiolabeling an anti-α-toxin antibody with zirconium-89. The physicochemical characterization of the immunotracer was performed by high-performance liquid chromatography (HPLC), radio-thin layer chromatography (radio-TLC), and electrophoretic analysis. Its diagnostic ability was evaluated in vivo by positron emission tomography/computed tomography (PET/CT) imaging in an animal model of local infection-inflammation (active S. aureus vs. heat-killed S. aureus) and infective osteoarthritis. Results. Chemical characterization of the tracer established the high radiochemical yield and purity of the tracer while maintaining antibody integrity. In vivo PET/CT image confirmed the ability of the tracer to detect active foci of S. aureus. Those results were supported by ex vivo biodistribution studies, autoradiography, and histology, which confirmed the ability of [89Zr]Zr-DFO-ToxAb to detect staphylococcal infectious foci, avoiding false-positives derived from inflammatory processes. Conclusions. We have developed an immuno-PET tracer capable of detecting S. aureus infections based on a radiolabeled antibody specific for the staphylococcal alpha toxins. The in vivo assessment of [89Zr]Zr-DFO-ToxAb confirmed its ability to selectively detect staphylococcal infectious foci, allowing us to discern between infectious and inflammatory processes.

In both clinical and preclinical scenarios, 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) is the radiotracer most widely used to study brain glucose metabolism with positron emission tomography (PET). In clinical practice, there is a worldwide standardized protocol for preparing patients for [18F]FDG-PET studies, which specifies the room lighting. However, this standard is typically not observed in the preclinical field, although it is well known that animal handling affects the biodistribution of [18F]FDG. The present study aimed to evaluate the effect of ambient lighting on brain [18F]FDG uptake in mice. Two [18F]FDG-PET studies were performed on each animal, one in light and one in dark conditions. Thermal video recordings were acquired to analyse animal motor activity in both conditions. [18F]FDG-PET images were analysed with the Statistical Parametric Mapping method. The results showed that [18F]FDG uptake is higher in darkness than in light condition in mouse nucleus accumbens, hippocampus, midbrain, hindbrain, and cerebellum. The SPM analysis also showed an interaction between the illumination condition and the sex of the animal. Mouse activity was significantly different (p = 0.01) between light conditions (632 ± 215 s of movement) and dark conditions (989 ± 200 s), without significant effect of sex (p = 0.416). We concluded that room illumination conditions during [18F]FDG uptake in mice affected the brain [18F]FDG biodistribution. Therefore, we highlight the importance to control this factor to ensure more reliable and reproducible mouse brain [18F]FDG-PET results.

In recent years, while the research budget and development times increased for different phases of drug development, the number of clinically approved new medicines declined. In fact, many promising drug candidates failed to demonstrate their full therapeutic potential in vivo. Reasons for unfavorable outcome include some intrinsic properties of drugs, like biodegradation, solubility, and systemic toxicity, as well as the ways in which they are administered or the time elapsed until therapeutic efficiency is demonstrated. Therefore, to develop the full therapeutic potential of drug candidates in vivo, there is a need for advanced drug delivery systems that would carry the drug specifically to the target and release it there at desired concentrations. In addition, there is a requirement for non-invasive biomedical imaging technologies allowing for rapid and sensitive evaluations of drug performance in vivo. This review will present recent developments in bioengineered drug delivery systems, highlighting the biomedical imaging tools needed to evaluate the success of drug delivery strategies.

This work proposes a method based on image analysis and machine and statistical learning to model and estimate osteocyte growth (in type I collagen scaffolds for bone regeneration systems) and the collagen degradation degree due to cellular growth. To achieve these aims, the mass of collagen -subjected to the action of osteocyte growth and differentiation from stem cells- was measured on 3 days during each of 2 months, under conditions simulating a tissue in the human body. In addition, optical microscopy was applied to obtain information about cellular growth, cellular differentiation, and collagen degradation. Our first contribution consists of the application of a supervised classification random forest algorithm to image texture features (the structure tensor and entropy) for estimating the different regions of interest in an image obtained by optical microscopy: the extracellular matrix, collagen, and image background, and nuclei. Then, extracellular-matrix and collagen regions of interest were determined by the extraction of features related to the progression of the cellular growth and collagen degradation (e.g., mean area of objects and the mode of an intensity histogram). Finally, these critical features were statistically modeled depending on time via nonparametric and parametric linear and nonlinear models such as those based on logistic functions. Namely, the parametric logistic mixture models provided a way to identify and model the degradation due to biological activity by estimating the corresponding proportion of mass loss. The relation between osteocyte growth and differentiation from stem cells, on the one hand, and collagen degradation, on the other hand, was determined too and modeled through analysis of image objects’ circularity and area, in addition to collagen mass loss. This set of imaging techniques, machine learning procedures, and statistical tools allowed us to characterize and parameterize type I collagen biodegradation when collagen acts as a scaffold in bone regeneration tasks. Namely, the parametric logistic mixture models provided a way to identify and model the degradation due to biological activity and thus to estimate the corresponding proportion of mass loss. Moreover, the proposed methodology can help to estimate the degradation degree of scaffolds from the information obtained by optical microscopy.

Paracoccidioidomycosis (PCM) is a primary pulmonary infection that often disseminates to other organs and systems. Involvement of the central nervous system (CNS) is rare and due to the fact that both clinical alertness and establishment of the diagnosis are delayed, the disease progresses causing serious problems. We report here a case of neuroparacoccidioidomycosis (NPCM), observed in a 55 year-old male, who consulted due to neurological symptoms (left hemiparesis, paresthesias, right palpebral ptosis, headache, vomiting and tonic clonic seizures) of a month duration. Upon physical examination, an ulcerated granulomatous lesion was observed in the abdomen. To confirm the diagnosis a stereotactic biopsy was taken; additionally, mycological tests from the ulcerated lesion and a bronchoalveolar lavage were performed. In the latter specimens, P. brasiliensis yeast cells were visualized and later on, the brain biopsy revealed the presence of the fungus. Treatment with itraconazole (ITZ) was initiated but clinical improvement was unremarkable; due to the fact that the patient was taking sodium valproate for seizure control, drug interactions were suspected and confirmed by absence of ITZ plasma levels. The latter medication was changed to clonazepam and after several weeks, clinical improvement began to be noticed and was accompanied by diminishing P. brasiliensis antigen and antibody titers. In the PCM endemic areas, CNS involvement should be considered more often and the efficacy of itraconazole therapy should also be taken into consideration.A paracoccidioidomicose (PCM) é infecção pulmonar primária que algumas vezes pode se disseminar a outros órgãos e sistemas. O envolvimento do sistema nervoso central (SNC) é raro e devido ao fato que a alerta clínica e o estabelecimento do diagnóstico são tardios, a doença progride e o paciente piora. Aquí apresentamos caso de neuroparacoccidioidomicose (NPCM) observada em homem de 55 anos de idade que referia sintomas neurológicos (hemiparalisia esquerda, parestesias, ptose pálpebral direita, dor de cabeça, vômito e convulsões) de um mes de duração. Ao exame físico, foi achada lesão ulcerada e granulomatosa no abdômen. Como o diagnóstico era duvidoso, foi indicada biopsia estereotáxica; além disso provas micológicas a partir da lesão ulcerada e um lavado broncoalveolar foram realizados. Nas últimas amostras P. brasiliensis foi observado e depois a biopsia do cérebro revelou a presença do fungo. O tratamento com itraconazol foi iniciado mas a melhoria clínica não foi detectável; devido ao fato que o paciente estava tomando valproato de sódio para o controle das convulsôes, foi suspeita interação entre os dois medicamentos, que foi confirmada pela ausência do nível plasmático do antimicótico. Este último medicamento foi trocado por clonazepam e depois de algumas semanas a melhoria clínica foi percebida e acompanhada pela diminuição dos títulos de antígenos e anticorpos do P. brasiliensis. Em áreas endêmicas, o envolvimento do SNC deve ser considerado em doentes com PCM e a eficácia do itraconazole deve ser considerada.

Abstract Introduction HIV treatment currently consists of daily oral antiretroviral therapy (ART). Cabotegravir + rilpivirine long-acting (CAB + RPV LA) is the first ART available in Spain administered every 2 months through intramuscular injection by a healthcare professional (HCP). The objective of this analysis was to assess potential healthcare resource use (HRU) and cost impact of implementing CAB + RPV LA vs. daily oral ART at National Health System (NHS) hospitals. Methods Online quantitative interviews and cost analysis were performed. Infectious disease specialists (IDS), hospital pharmacists (HP) and nurses were asked about their perception of potential differences in HRU between CAB + RPV LA vs. daily oral ART, among other concepts of interest. Spanish official tariffs were applied as unit costs to the HRU estimates (€2022). Results 120 responders (n = 40 IDS, n = 40 HP, n = 40 nurses) estimated an average number of annual visits per patient by speciality (IDS, HP, and nurse, respectively) of 3.3 vs. 3.7; 4.4 vs. 6.2; 6.1 vs. 3.9, for CAB + RPV LA vs. daily oral ART, and 3.0 vs. 3.2; 4.8 vs. 5.8; 6.9 vs. 4.9, respectively when adjusting by corresponding specialist responses. Estimation by the total sample led to an annual total cost per patient of €2,076 vs. €2,473, being €2,032 vs. €2,237 after adjusting by corresponding HCP, for CAB + RPV LA vs. daily oral ART. Conclusions These results suggest that the implementation of CAB + RPV LA in NHS hospitals would not incur in increased HRU-related costs compared to current daily oral ARTs, being potentially neutral or even cost-saving.

Auto-cascade refrigeration systems are the most employed systems for ultra-low temperature applications, especially for small capacity systems. Recent investigations have allowed to analyze them energetically and thermodynamically, starting a research line focused on enhancing their energy performance from experimental approaches. This work focuses on the energy optimization of a real auto-cascade system working with the mixture R600a/R1150 [70/30 %], which has been evaluated using two compressor models for R404A and R290 as well as the optimization of the two capillary tubes used in the system. Results indicate that overall efficiency of the R290 compressor is up to 21 % higher than with R404A, leading to COP increments between 35 and 81 %. Optimum capillary lengths have been determined in terms of COP and energy consumption, reaching similar values, however, the inner parameters of the system change as function of these lengths, which needs to be considered in prototypes design.

Abstract Introduction Insulin lispro 100 units/mL Jr KwikPen is the first prefilled, disposable, half‐unit insulin pen that delivers 0.5–30 units in increments of 0.5 units for the treatment of patients with diabetes. This study describes the profile of patients in Spain who initiated insulin therapy with Jr KwikPen in a real‐world setting. Methods This retrospective, observational study based on IQVIA's electronic medical records database included patients with Type 1 (T1D) or Type 2 (T2D) diabetes who initiated therapy with Jr KwikPen between May 2018 and December 2020. Sociodemographic, clinical, and treatment characteristics at treatment initiation were analysed descriptively. Results A total of 416 patients were included. The main characteristics of the T1D/T2D groups (N = 326/90), respectively were as follows: female sex, 61.7%/65.6%; mean age (standard deviation [SD]), 32.5 (20.7)/55.5 (16.6) years; body mass index, 20.9 (4.2)/25.2 (4.6) kg/m2 (N = 239/77); HbA1c, 7.8 (1.7)%/8.0 (1.5)% (N = 141/64); and presence of diabetes‐associated comorbidities, 27.9%/64.4%. Only 32.8% of patients with T1D were

This paper presents a recontextualization of Juan Rulfo’s Pedro Páramo as a ludic novel that can be further subcategorized as a horror survival narrative. In addition to stating the genre and textual modus operandi of the book, these classifications also hint to a quality that is reminiscent of a newer type of cultural text: a video game, to be specific. In general terms, this paper seeks to contribute to the expanding field of cultural studies by presenting an exercise that illustrates how emergent theory can be applied to the analysis of cultural texts to generate new interpretations. This study argues that Rulfo’s novel can be approached as a cultural text that can—and should—be read as a ludic object. This paper interjects narratology (Bárcenas, Herman, Franco), cultural studies (Klinger), film studies (Bruhm, Savoy), and video game theory (Kirkland, Nae) in order to create a functional analytic framework that allows for a reread of Pedro Páramo that creates a dialogue between literary studies and video game culture, while also expanding on the field of Mexican studies. As a point of departure, this paper rethinks the act of reading as an interactive practice comparable to playing a video game. By doing so, it becomes possible to view Pedro Páramo as a ludic novel in different terms from those generally applied to literary works. From that point on, this work presents a close read of Rulfo’s novel employing a comparative approach to scrutinize some of the basic narrative elements it shares with the horror survival video game series Silent Hill, ranging from the narrative units shared to the performative elements as it relates to the meaning formation processes through their respective user interactions.

Every year Europe produces about 58 million tonnes of plastic, and we generate 25 million tonnes of plastic waste. Only 30% of this is collected for recycling, with 39% incinerated and 31% ending up in landfills. The problem lies not only in the amounts of plastic recycled, but also in the quality of the recycling and the resulting secondary plastic. In economic terms, 95% of the value of plastic packaging – worth some 105 billion euros – is lost to the economy every year.The Plastics Strategy adopted by the European Commission in January 2018 set out how to get the economics right, presenting a vision for a smart, innovative and sustainable plastics industry. It argued that what is needed is a “New Plastics Economy” which must be a circular economy which eliminates waste, maximises value, and uses plastic efficiently. In doing so it will help protect our environment, reduce marine litter, greenhouse gas emissions and our dependence on imported fossil fuels.Plastic is here today and it is here to stay. The Plastic Strategy clearly emphasizes the value of plastic in our households and in our economies; indeed it is at pains not to demonise the material, whilst drawing attention to the damage caused by our failure to manage it properly.

Due to Regulation EU 517/2014 (F-Gas), the use of refrigerants with GWP higher than 150 was limited from 2015 on in small capacity refrigeration systems in Europe. Although refrigerants that dominate are R600a and R290 nowadays, which are classified as A3 by ASHRAE 34, literature points out that some refrigerant mixtures exist that could offer benefits from the point of view of COP and VCC, especially mixtures of hydrocarbons.This study tries to identify possible mixtures which could be used as alternatives to pure hydrocarbons, with the aim to increase the energetic behaviour of the systems and, if possible, to reduce the flammability characteristics. A thermodynamic screening of refrigerant mixtures (with the base refrigerants R290, R600a, R600, R1270, R152a, R32, R1234yf, R1234ze(E), R1233zd, R744 and R134a) is presented and detailed for two typologies of systems: single-stage systems with adiabatic capillary tube and single-stage systems with non-adiabatic capillary tube. The screening identifies the most promising refrigerant mixtures that will be tested later in experimental systems. Keywords: Hydrocarbons, Refrigerant, Stand-alone systems, Energy efficiency

The global COVID-19 spread has forced countries to implement non-pharmacological interventions (NPI) (i.e., mobility restrictions and testing campaigns) to preserve health systems. Spain is one of the most severely impacted countries, both clinically and economically. In an effort to support policy decision-making, we aimed to assess the impacts of different NPI on COVID-19 epidemiology, healthcare costs and Gross Domestic Product (GDP). A modified Susceptible-Exposed-Infectious-Removed epidemiological model was created to simulate the pandemic evolution. Its output was used to populate an economic model to quantify healthcare costs and GDP variation through a regression model which correlates NPI and GDP change from 42 countries. Thirteen scenarios combining different NPI were consecutively simulated in the epidemiological and economic models. Both increased testing and stringency could reduce cases, hospitalizations and deaths. While policies based on increased testing rates lead to higher healthcare costs, increased stringency is correlated with greater GDP declines, with differences of up to 4.4% points. Increased test sensitivity may lead to a reduction of cases, hospitalizations and deaths and to the implementation of pooling techniques that can increase throughput testing capacity. Alternative strategies to control COVID-19 spread entail differing economic outcomes. Decision-makers may utilize this tool to identify the most suitable strategy considering epidemiological and economic outcomes.

In the last century, the refrigerant R744 (carbon dioxide) has become an environmentally friendly solution in commercial refrigeration despite its particular issues related to the low critical temperature. The use of transcritical cycles in warm and hot countries reveals the necessity of adopting different configurations and technologies to improve this specific cycle. Among these, subcooling methods are well-known techniques to enhance the cooling capacity and the Coefficient of Performance (COP) of the cycle. In this work, an R600a dedicated mechanical subcooling system has been experimentally tested in an R744 transcritical system at different operating conditions. The results have been compared with those obtained using a suction-to-liquid heat exchanger (IHX) to determine the degree of improvement of the mechanical subcooling system. Using the experimental tests, a computational model has been developed and validated to predict the optimal subcooling degree and the cubic capacity of the mechanical subcooling compressor. Finally, the model has been used to analyze the effect of using different refrigerants in the mechanical subcooling unit finding that the hydrocarbon R290 and the HFC R152a are the most suitable fluids.

**Purpose:** To perform a cost-effectiveness analysis of radium-223 plus Best Supportive Care (BSC) compared to BSC in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and without previous docetaxel treatment in Spain. **Design and methods:** A Markov model was developed to compare radium-223 versus BSC and to accrue the health outcomes and costs of a simulated cohort of mCRPC patients. Quality-adjusted life year (QALY) and life year (LY) were selected as health outcomes to measure the effectiveness of treatment alternatives. Main health resource use and efficacy inputs were obtained from a randomized controlled trial comparing radium-223 versus placebo. Unit costs were retrieved from Spanish databases and published sources. One-way and probabilistic sensitivity analyses were carried out to assess uncertainty. **Results:** Total costs and QALYs were €65 067 and 1.12 QALYs for radium-223 and €55 437 and 0.77 QALYs for BSC. Therefore, incremental costs per QALY were €27 606. The sensitivity analysis showed that with a willingness-to-pay threshold of €30 000 per QALY, radium-223 would have a probability of 48% of being cost-effective compared to BSC. **Conclusions:** Although results must be assessed with caution, from the Spanish National Health System perspective and based on the results of the present analysis, radium-223 could be a suitable option of health resources’ utilization for end of life mCRPC without previous docetaxel treatment, subject to a moderate level of uncertainty.

Aim of the performed clinical study was to compare the accuracy and cost-effectiveness of PET/CT in the staging of non-small cell lung cancer (NSCLC). Material and Methods. Cross-sectional and prospective study including 103 patients with histologically confirmed NSCLC. All patients were examined using PET/CT with intravenous contrast medium. Those with disease stage ≤IIB underwent surgery (n=40). Disease stage was confirmed based on histology results, which were compared with those of PET/CT and positron emission tomography (PET) and computed tomography (CT) separately. 63 patients classified with ≥IIIA disease stage by PET/CT did not undergo surgery. The cost-effectiveness of PET/CT for disease classification was examined using a decision tree analysis. Results. Compared with histology, the accuracy of PET/CT for disease staging has a positive predictive value of 80%, a negative predictive value of 95%, a sensitivity of 94%, and a specificity of 82%. For PET alone, these values are 53%, 66%, 60%, and 50%, whereas for CT alone they are 68%, 86%, 76%, and 72%, respectively. Incremental cost-effectiveness of PET/CT over CT alone was €17,412 quality-adjusted life-year (QALY). Conclusion. In our clinical study, PET/CT using intravenous contrast medium was an accurate and cost-effective method for staging of patients with NSCLC.

La Teoría de la Metáfora de Lakoff y Johnson señala que parte de nuestra forma de comprender el mundo es metafórica, en el sentido de vincular patrones experienciales de un dominio cognitivo conocido con otro menos conocido. En este proceso participan ciertas estructuras imagen-esquemáticas, interrelacionadas y dinámicas, que surgen de nuestra propia experiencia corporal con el entorno. Considerando esto, podemos situar esta teoría dentro de las teorías cognitivas corporeizadas. Algunos investigadores han tomado la Teoría de la Metáfora Conceptual para explicar la experiencia y la cognición en el ámbito musical, donde se observan diferentes interpretaciones e implicancias. Proponemos, entonces, analizar diferentes componentes de la teoría, integrando los estudios en música ya existentes, a partir de cuatro niveles explicativos: (i) el origen corporeizado de los esquemas-imagen como un estrato profundo de base sensorio-motora; (ii) la proyección metafórica como un proceso que depende de esa experiencia corporal; (iii) la metáfora lingüística como descripciones verbales de una experiencia y comprensión metafórica; y (iv) las representaciones gráficas de los esquemas-imagen en la explicación teórica y la grafía como descripción de la experiencia musical.

Introdução: O leiomiossarcoma uterino corresponde a, aproximadamente, 30% dos sarcomas uterinos. A idade de maior incidência é por volta dos trinta e cinco anos, alcançando seu crescimento máximo aos cinquenta e cinco anos. Raramente envia metástases para o crânio e para os ossos. Apresentação do caso: Neste relato, descreve-se um caso raro de leiomiossarcoma uterino com metástase para o crânio e coluna. A paciente tinha um diagnóstico prévio de leiomiosarcoma uterino após histerectomia total ocorrida há cinco anos. A lesão craniana foi ressecada e as lesões da coluna foram abordadas com radioterapia. Conclusão: O leiomiossarcoma é normalmente acompanhado por metástases disseminadas e um prognóstico reservado. Metástases do crânio são geralmente vistas em um estágio avançado da doença. A cirurgia não pode alterar o curso da doença subjacente, mas pode aliviar o desconforto local. As opções de tratamento para as metástases espinais são variadas, e as indicações definitivas sobre eficácia não podem ser feitas. Ao nosso conhecimento, é o primeiro caso relatado com ambas as metástases apresentando-se simultaneamente.