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Abstract B cell chronic lymphocytic leukaemia (B‐CLL) presenting with cutaneous infiltration is rare, and when it occurs, it presents most commonly on the head and neck. We present the case of an 80‐year‐old woman with a 2‐month history of erythema, swelling and pain affecting all her toes. She had a history of B‐CLL diagnosed 20 years previously that had remained stable under observation without treatment. A toe skin biopsy showed a diffuse infiltrate of lymphoid cells occupying the dermis composed of small mature lymphoid cells with a monotonous appearance. On immunohistochemistry, the neoplastic lymphoid cells stained positive for the B‐cell marker CD20. Overall, the morphology and immunophenotype were consistent with cutaneous involvement by chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). We concluded that her symptoms were directly caused by skin infiltration of B‐CLL.

Resumen: Introducción: la formación médica de los alumnos del rotatorio de 6.° curso del grado de medicina es desigual dependiendo de las rotaciones que elijan. El Proyecto U de Universitario permite unificar los conocimientos. Métodos: proyecto prospectivo multidisciplinar creado para alumnos de 6.° curso del grado de Medicina que se formaron en el Área Sanitaria V del Principado de Asturias. Se diseñaron talleres prácticos y sesiones usando técnicas de simulación, videos interactivos, role-playing y presentaciones. Se valoró la asistencia y satisfacción. Este proyecto fue certificado como Proyecto de Innovación docente de la Universidad de Oviedo (julio 2023). Resultados: hubo gran asistencia y alto aprovechamiento. La satisfacción media fue excelente-muy satisfactoria. La valoración de los profesores osciló entre 8 y10/10 puntos. Conclusión: el Proyecto U de Universitario completa la formación de los alumnos de 6.o curso del grado de Medicina y es un proyecto muy bien valorado por los alumnos de grados de ciencias de la salud. Abstract: Introduction: The medical training of students in the 6th year rotation of the Degree in Medicine is unequal depending on the rotations they choose. The University U Project allows for the unification of knowledge. Methods: Multidisciplinary prospective project created for students of the 6th year of the Degree of Medicine who were trained in Health Area V of the Principality of Asturias. Practical workshops and sessions were designed using simulation techniques, interactive videos, role-playing and presentations. Attendance and satisfaction were evaluated. This project was certified as a Teaching Innovation Project of the University of Oviedo (July 2023). Results: A high attendance and high achievement was achieved. Average satisfaction was excellent-very satisfactory. The evaluation of the professors ranged between 8 and 10/10 points. Conclusion: The University U Project completes the training of students in the 6th year of the degree of medicine and is a project very well valued by students of health sciences degrees.

Abstract Urea is a commonly used nitrogen fertiliser synthesised from ammonia and carbon dioxide using thermal catalysis. This process results in high carbon dioxide emissions associated with the required amounts of ammonia. Electrocatalysis provides an alternative method to urea production with reduced carbon emissions while utilising waste products like nitrate. This manuscript reports on urea synthesis from the electroreduction of nitrate and carbon dioxide using CuOxZnOy electrodes under mild conditions. Catalysts with different ratios of CuO and ZnO, synthesised via flame spray pyrolysis, were explored for the reaction. The results revealed that all the CuOxZnOy electrocatalyst compositions produce urea, but the efficiency strongly depends on the metal ratio composition of the catalysts. The CuO50ZnO50 composition had the best performance in terms of selectivity (41% at −0.8 V vs RHE) and activity (0.27 mA/cm2 at −0.8 V vs RHE) towards urea production. Thus, this material is one of the most efficient electrocatalysts for urea production reported so far. This study systematically evaluates bimetallic catalysts with varying compositions for urea synthesis from carbon dioxide and nitrate.

Abstract Co-electrolysis of carbon oxides and nitrogen oxides promise to simultaneously help restore the balance of the C and N cycles while producing valuable chemicals such as urea. However, co-electrolysis processes are still largely inefficient and numerous knowledge voids persist. Here, we provide a solid thermodynamic basis for modelling urea production via co-electrolysis. First, we determine the energetics of aqueous urea produced under electrochemical conditions based on experimental data, which enables an accurate assessment of equilibrium potentials and overpotentials. Next, we use density functional theory (DFT) calculations to model various co-electrolysis reactions producing urea. The calculated reaction free energies deviate significantly from experimental values for well-known GGA, meta-GGA and hybrid functionals. These deviations stem from errors in the DFT-calculated energies of molecular reactants and products. In particular, the error for urea is approximately -0.25 ± 0.10 eV. Finally, we show that all these errors introduce large inconsistencies in the calculated free-energy diagrams of urea production via co-electrolysis, such that gas-phase corrections are strongly advised.

The chromenopyridine scaffold represents an important class of heterocyclic compounds exhibiting a broad spectrum of biological properties. This review describes novel and efficient procedures for the synthesis of this scaffold. Herein, several methods were detailed and grouped according to their starting material (e.g., salicylaldehydes, chromones, chromanones and coumarins) and respective biological activity, when reported. This review highlights the potential of the reported synthetic strategies for preparing chromenopyridine derivatives with promising biological activity, paving the way for further developments in drug discovery.

Background: Preterm newborns require the use of the best and most current strategies to treat and prevent both acute pathology and associated sequelae. This study aimed to compare the differences in the management of preterm newborns over 10 years in a tertiary hospital in Spain and its impact on height, weight, and neurological development in the medium term. Methods: We conducted a retrospective, observational, and analytical study examining the management and clinical variables in preterm newborns under 32 weeks of gestational age who were born in our hospital in 2011 and 2021. Results: Twenty-six newborns were included in the study. Significant differences in magnesium sulfate use, continuous positive airway pressure immediately after birth, and non-invasive mechanical ventilation during hospitalization were observed. Differences were found in the use of parenteral nutrition and the timing of initiation of enteral feeding. We did not observe differences in the neurological or weight evolution in the medium term. Conclusions: Significant differences in managing preterm newborns in these 10 years were observed. Lower mortality and alterations in central nervous system ultrasound and, significantly, less growth retardation during admission in 2021 have been observed; however, it does not manifest with improvement in long-term somatometrics or neurological prognosis.

Introduction and objectives: During the COVID-19 pandemic, the follow-up of patients treated with vitamin K antagonists (VKAs) may have been affected. This study aims to compare how these patients were monitored preand post-COVID-19 pandemic and understand the impact of non-face-to-face appointments on their follow-up. Methods: We conducted a retrospective cohort study in a Portuguese Health Center. The study included patients treated with VKAs and followed at the Health Center for international normalized ratio (INR) monitoring between March 2019 and March 2021. Data collected: sex, age, type of VKA; INR; date of INR assessment, type of appointment (face-to-face or phone/e-mail). Rosendaal’s method was used to calculate pre-COVID-19 and post-COVID-19 time in therapeutic range (TTR). Good TTR control was defined if values ≥ 70%. Results: 44 patients were included. The mean TTR in the pre-COVID-19 period was 64.55% (95% CI: 58.10 - 71.00%). The post-COVID-19 mean was slightly higher (+ 2.26%), 66.81% (95% CI: 59.66 - 73.97%), but the difference was not statistically significant (p = 0.576). The use of non-face-to-face appointments did not contribute to worsening post-pandemic TTR, showing no lower follow-up than during pre-pandemic period in which all contacts were face-to-face [CI (95%) -0.397 - 0.196 for a reference range -0.489 - 0.693]. Conclusions: The TTR value in both periods was similar and lower than the value defined for effective hypocoagulation. The use of non-face-to-face consultation in the post-COVID-19 period does not seem to have influenced the quality of hypocoagulation.

Approximately 20% of lung adenocarcinomas harbor activating mutations at KRAS, an oncogene with the ability to alter the tumor immune microenvironment. In this retrospective study, we examined 103 patients with KRAS-mutant lung adenocarcinoma who were treated with immunotherapy-based regimens and we evaluated the clinical outcomes according to PD-L1 expression and the type of KRAS mutation. Among all patients included, 47% carried KRAS G12C mutation whereas 53% harbored KRAS non-G12C mutations. PD-L1 status was available for 77% of cases, with higher expression among KRAS G12C tumors (p = 0.01). Better overall survival and progression-free survival were observed in high PD-L1 expression tumors, regardless of KRAS mutation type. The heterogeneous nature of KRAS-mutant tumors and the presence of other co-mutations may contribute to different outcomes to immunotherapy-based strategies.

Abstract The interest in electrochemical processes to produce ammonia has increased in recent years. The motivation for this increase is the attempt to reduce the carbon emissions associated with its production, since ammonia is responsible for 1.8% of the global CO2 emissions. Moreover, green ammonia is also seen as a possible transportation fuel in various renewable energy transition scenarios. Several electrochemical processes are being investigated such as N2, NO3–, or NO conversion. Since nitrates are an attractive source of nitrogen, due to their role as water contaminants and facility to break N‐O bonds, this mini review is focused on the electrocatalytic synthesis of ammonia from NO3− reduction. Here, we summarized the important work on reaction mechanisms and electrocatalysts for this reaction.

Abstract Background Specific serum biomarkers of cartilage metabolism such as cartilage oligomeric matrix protein (sCOMP) and procollagen type II C-terminal propeptide (sPIICP) as well as hyaluronan (sHA), a biomarker of synovitis, have been implicated in the pathophysiology of knee osteoarthritis (OA). However, the associations of these biomarkers with the severity of the disease and OA risk factors, including age and obesity remain inconclusive. This analysis examines the associations between these serum biomarkers and the radiographic severity of OA and knee pain, as wells as obesity, the age and gender of the participants, and other OA risk factors. Methods From 44 patients with early knee OA and 130 patients with late knee OA we analyzed the radiographic severity of the disease using the Kellgren and Lawrence (KL) grading system. Moreover, 38 overweight healthy individuals were used as a control group. Specific information was collected from all participants during their recruitment. The levels of the three serum biomarkers were quantified using commercially available ELISA kits. Serum biomarkers were analyzed for associations with the average KL scores and pain in both knees, as well as with specific OA risk factors. Results The levels of sCOMP were elevated in patients with severe late OA and knee pain and correlated weakly with OA severity. A weakly correlation of sHA levels and OA severity OA was observed. We demonstrated that only sPIICP levels were markedly decreased in patients with late knee OA suggesting the alterations of cartilage metabolism in this arthritic disease. Moreover, we found that sPIICP has the strongest correlation with obesity and the severity of OA, as well as with the knee pain at rest and during walking regardless of the severity of the disease. ROC analysis showed that the area under the ROC curve (AUC) was 0.980 (95% CI: 0.945–0.995; p

As a model organism, Drosophila is uniquely placed to contribute to our understanding of how brains control complex behavior. Not only does it have complex adaptive behaviors, but also a uniquely powerful genetic toolkit, increasingly complete dense connectomic maps of the central nervous system and a rapidly growing set of transcriptomic profiles of cell types. But this also poses a challenge: Given the massive amounts of available data, how are researchers to Find, Access, Integrate and Reuse (FAIR) relevant data in order to develop an integrated anatomical and molecular picture of circuits, inform hypothesis generation, and find reagents for experiments to test these hypotheses? The Virtual Fly Brain (virtualflybrain.org) web application & API provide a solution to this problem, using FAIR principles to integrate 3D images of neurons and brain regions, connectomics, transcriptomics and reagent expression data covering the whole CNS in both larva and adult. Users can search for neurons, neuroanatomy and reagents by name, location, or connectivity, via text search, clicking on 3D images, search-by-image, and queries by type (e.g., dopaminergic neuron) or properties (e.g., synaptic input in the antennal lobe). Returned results include cross-registered 3D images that can be explored in linked 2D and 3D browsers or downloaded under open licenses, and extensive descriptions of cell types and regions curated from the literature. These solutions are potentially extensible to cover similar atlasing and data integration challenges in vertebrates.

Abstract Extracellular vesicles (EVs) large‐scale production is a crucial point for the translation of EVs from discovery to application of EV‐based products. In October 2021, the International Society for Extracellular Vesicles (ISEV), along with support by the FET‐OPEN projects, “The Extracellular Vesicle Foundry” (evFOUNDRY) and “Extracellular vesicles from a natural source for tailor‐made nanomaterials” (VES4US), organized a workshop entitled “massivEVs” to discuss the potential challenges for translation of EV‐based products. This report gives an overview of the topics discussed during “massivEVs”, the most important points raised, and the points of consensus reached after discussion among academia and industry representatives. Overall, the review of the existing EV manufacturing, upscaling challenges and directions for their resolution highlighted in the workshop painted an optimistic future for the expanding EV field.

Introduction: Cardiac Rehabilitation (CR) is a multifactorial intervention, usually composed of structured physical exercise, psychological support and health education. The structuring in the different phases of CR for this specific population has not been deeply studied, with gaps in the scientific evidence regarding health gains resulting from CR programs. The caregiver / family literature is also scarce. The aim of this study is to identify in which domains rehabilitation nurses can intervene in order to develop health gains in heart transplant recipients and their caregivers/family. Method: To make this intervention operational, Doran's The Quality Health Outcomes Model will be used, in the component of results sensitive to nursing care. Two studies will be carried out concurrently, one aimed at the cardiac rehabilitation of the transplanted person (phases 1, 2 and 3) and the other focusing on the cardiac rehabilitation of the caregiver / family. The methodologies used will be the scoping review, the case report, the exploratory study and the randomized clinical study (with intervention group and control group). Discussion/Expected Results: The Rehabilitation Nursing in Cardiac Transplant Program (ERtxC) will be built and implemented, in its different phases, during the years 2021 and 2022. It is estimated that the program can be accessed by 150 heart transplant patients and their respective families / caregiver. Conclusion: At the end of the year 2022, it is estimated to have reached the end of this program, with the respective assessment of health gains. After validation of this program, an attempt will be made to permanently create this offer in a systematic way for all people undergoing heart transplantation in Portugal.

Mycobacterium avium subsp. paratuberculosis (MAP) may play a role in the pathology of human inflammatory bowel disease (IBD). Previously, we found a high frequency (98% in patients with active disease) of MAP DNA detection in the blood of Portuguese Crohn's Disease patients, suggesting this cohort has high exposure to MAP organisms. Water is an important route for MAP dissemination, in this study we therefore aimed to assess MAP contamination within water sources in Porto area (the residential area of our IBD study cohort). Water and biofilms were collected in a wide variety of locations within the Porto area, including taps connected to domestic water sources and from municipal water distribution systems. Baseline samples were collected in early autumn plus further domestic water samples in early winter, to assess the effect of winter rainfall. DNA was extracted from all 131 samples and IS900-based nested PCR used to assess the frequency of MAP presence. Our results show high MAP positivity in municipal water sources (20.7% of water samples and 41.4% of biofilm samples) and even higher amongst domestic sources (30.8% of water samples and 50% of biofilm samples). MAP positivity in biofilms correlated with positivity in water samples from the same sources. A significantly higher frequency of MAP-positivity was observed during winter rains as compared with samples collected in autumn prior to the winter rainfall period (61.9% versus 30.8%). We conclude that domestic and municipal water sources of Porto region have a high burden of MAP contamination and this prevalence increases with rainfall. We hypothesize that human exposure to MAP from local water supplies is commonplace and represents a major route for MAP transmission and challenge which, if positively linked to disease pathology, may contribute to the observed high prevalence of IBD in Porto district.

Male breast cancer is a rare disease, representing approximately 1% of all breast cancers, but its incidence appears to be increasing over the years. As normal male breast does not develop acini and lobules, lobular carcinoma is very rare, accounting for 1% - 2% of all cases of male breast cancer. Pleomorphic lobular carcinoma is an aggressive variant of invasive lobular carcinoma with only six cases of male breast reported in the literature until now, and none with associated Paget’s disease. We report a case of an invasive pleomorphic lobular carcinoma with axillary lymph node involvement and associated Paget’s disease in a high-risk man. Low awareness among men and a lack of a screening program often lead to a late diagnosis of male breast cancer, and consequently, at a later stages of disease, with lower survival rates compared to women. Early diagnosis is essential in order to improve patient outcomes and achieve better survival rates in men.

Abstract Aims In Portugal, in the last 5 years, no study has published recent data regarding outcomes of patients with acute decompensated heart failure (ADHF). We aimed to determine the characteristics and outcomes of a large contemporaneous Portuguese cohort of ADHF patients admitted to our emergency department (ED). Methods and results We conducted a retrospective, study of all 1024 patients admitted to our ED with a discharge diagnosis of ADHF from November 2016 to December 2017. Baseline clinical data and outcomes {in‐hospital, 30 day, and follow‐up all‐cause mortality, and readmissions; median follow‐up, 5 months; interquartile range [(IQR), 3–11 months]} were determined. Mean age was 78 ± 10 years, and 53% were male; of the 1024 patients, 554 (54%) were hospitalized. The median hospitalization length was 9 (IQR, 5–15) days, and in‐hospital mortality was 12.7%. Hospitalized patients were predominantly men (56% vs. 47%; P

The first hours of life of a sick or premature newborn are crucial for its prognosis and therefore delivery should take place in a center prepared for that degree of complexity. When this condition is not met, the newborn must be transferred in an optimal and safe way to the center that can offer the necessary care. The training, staffing, organization and coordination of the neonatal transport team are essential to guarantee a safe transfer. Being aware of the interest and the advances that are currently taking place in this area of ​​pediatrics, the Standards Commission and the Neonatal Transport Commission of the Spanish Society of Neonatology have prepared this document. In it, both the provision of human and material resources necessary as well as the bases of clinical stabilization in transport to carry out the neonatal transfer in a safe way and proportionate to the needs of the critical newborn have been exhaustively reviewed and detailed. Resumen: Las primeras horas de vida de un recién nacido enfermo o prematuro son cruciales para su pronóstico y por lo tanto el parto debería acontecer en un centro preparado para ese grado de complejidad. Cuando no se cumple esta condición, el recién nacido debe ser trasladado de un modo óptimo y seguro al centro que pueda ofrecerle los cuidados necesarios. La formación, dotación, organización y coordinación del equipo de transporte neonatal son indispensables para garantizar un traslado en condiciones. Siendo conscientes del interés y los avances que en la actualidad se están produciendo en esta área de la pediatría, la Comisión de Estándares y la Comisión de Transporte Neonatal de la Sociedad Española de Neonatología han elaborado el presente documento. En él, se ha revisado y detallado de forma exhaustiva tanto la dotación de recursos humanos y materiales necesarios como las bases de la estabilización clínica en transporte para llevar a cabo el traslado neonatal de forma segura y proporcionada a las necesidades del recién nacido crítico.

Os estereótipos e preconceitos possibilitam a diferenciação e separação entre culturas, levando por vezes a problemas de aceitação e adaptação. Os meios de comunicação fazem parte da vida quotidiana, sendo, atualmente, indispensáveis para a transmissão de conhecimento dentro e entre comunidades. A transmissão de informação parece por vezes recorrer ao uso de estereótipos e preconceitos para influenciar o público para uma determinada opinião, ou, simplesmente, facilitar a compreensão de um evento. Neste contexto, o objetivo deste artigo é apurar se e de que modo os meios de comunicação portugueses, em particular a crónica jornalística, transmitem e conservam estereótipos e preconceitos sobre a China e os chineses. Deste modo, inicia-se o mesmo com uma breve base teórica para a análise de textos retirados de revistas portuguesas, procedendo-se ao levantamento de estereótipos e preconceitos sobre os chineses neles presentes. Propõe-se que a linguagem usada pelos autores de crónicas, influenciada pelos estereótipos sobre os chineses, contribui para a manutenção de ‘ideias feitas’ na sociedade.

The hemibrain connectome provides large-scale connectivity and morphology information for the majority of the central brain of Drosophila melanogaster. Using this data set, we provide a complete description of the Drosophila olfactory system, covering all first, second and lateral horn-associated third-order neurons. We develop a generally applicable strategy to extract information flow and layered organisation from connectome graphs, mapping olfactory input to descending interneurons. This identifies a range of motifs including highly lateralised circuits in the antennal lobe and patterns of convergence downstream of the mushroom body and lateral horn. Leveraging a second data set we provide a first quantitative assessment of inter- versus intra-individual stereotypy. Comparing neurons across two brains (three hemispheres) reveals striking similarity in neuronal morphology across brains. Connectivity correlates with morphology and neurons of the same morphological type show similar connection variability within the same brain as across two brains.

Resumen: Introducción: En noviembre de 2014, se detectó un brote de Klebsiella pneumoniae productora de betalactamasas de espectro extendido en la unidad de cuidados intensivos neonatales de un hospital terciario. Objetivo: El objetivo fue describir las características clínicas, epidemiológicas y microbiológicas del brote, analizar los factores de riesgo asociados y presentar las medidas preventivas y de control implementadas para su erradicación. Métodos: Estudio de casos y controles. Se realizaron análisis univariantes y bivariantes, considerándose estadísticamente significativo un valor de p < 0,05. Las medidas preventivas y de control se centraron en la necesidad de determinar la magnitud del problema, en la comunicación efectiva, la evaluación de los procedimientos sanitarios y la educación sobre la seguridad del paciente. Se realizó caracterización molecular y fenotípica de muestras clínicas. Resultados: La muestra de estudio consistió en 51 neonatos, de los que 17 fueron casos y los 34 restantes controles. La distribución de casos por peso al nacer fue: 2 con peso > 2.500 g (11,8%), 4 con peso de 1.500-2.500 g (23,5%), 5 con peso de 1.000-1.500 g (29,4%) y 5 con peso < 1.000 g (29,4%). En un caso no se había registrado el peso al nacer en la historia clínica. Los factores de riesgo estadísticamente significativos para la colonización/infección fueron: presencia de catéter venoso (OR = 5,0 [IC 95% 1,4-17,8]; p = 0,016); nutrición parenteral (OR = 6,8 [IC 95%: 1,8-25,7]; p = 0,006); sondaje vesical (OR = 5,9 [IC 95% 1,2-30,0]; p = 0,028) y peso al nacer (p = 0,035). Encontramos diferencias estadísticamente significativas en la estancia hospitalaria media (p = 0,004) y los días de estancia en la unidad de cuidados intensivos neonatales (p = 0,002). Se encontró resistencia a antimicrobianos tipo betalactamasas de espectro extendido CTX-M-14 en los 17 casos. Conclusión: Han de reforzarse las iniciativas de trabajo sobre la seguridad de los pacientes, especialmente aquellas aplicables a intervenciones con el potencial de aumentar el riesgo de colonización/infección por K. pneumoniae productora de betalactamasas de espectro extendido en la unidad de cuidados intensivos neonatales, como las asociadas a la inserción, cuidado y mantenimiento de catéter venoso, la nutrición parenteral y el sondaje vesical. Abstract: Introduction: In November 2014, an extended-spectrum beta-lactamase producing Klebsiella pneumoniae outbreak was detected in the neonatal intensive care unit of a tertiary care hospital. Objective: Our aim was to determine the clinical, epidemiological and microbiological characteristics of the outbreak, to analyse the identified risk factors and to describe the preventive and control measures implemented for its eradication. Methods: We conducted a case-control study. We performed Univariate and bivariate analyses, defining statistical significance as a p-value of less than 0.05. The implemented preventive and control measures were aimed at establishing the magnitude of the outbreak, effective communication, the evaluation of health care processes and education on patient safety. Clinical samples were collected for molecular and phenotypic characterization. Findings: The sample consisted of 51 newborns, of who 17 were cases and the remaining 34 controls. The distribution of cases by birth weight was: 2 cases (11.8%) greater than 2500 g, 4 cases (23.5%) between 1500 and 2500 g, 5 cases (29.4%) between 1000 and 1500 g, and 5 cases (29.4%) less than 1000 g. In one case, the birth weight was not documented in the health record. The following risk factors for colonization or infection were statistically significant in our study: presence of a central venous catheter (OR, 5.0 [95% CI, 1.4-17.8]; P = .016); parenteral nutrition (OR, 6.8 [95% CI, 1.8-25.7]; P = .006); urinary catheterization (OR, 5.9 [95% CI, 1.2-30.0]; P = .028) and birth weight (P = .035). We found statistically significant differences in the mean total length of stay in hospital (P = .004) and length of stay in the NICU (P = .002). All 17 cases presented antimicrobial resistance with presence of extended-spectrum beta-lactamase type CTX-M-14. Conclusion: Workplace interventions focused on patient safety need to be reinforced, especially those concerning practices with the potential to increase the extrinsic risk of colonization or infection by extended-spectrum beta-lactamase -producing K. pneumoniae in the NICU, such as the insertion, care and maintenance of central venous catheter, parenteral nutrition and urinary catheterization.

Introduction: In November 2014, an extended-spectrum beta-lactamase producing Klebsiella pneumoniae outbreak was detected in the neonatal intensive care unit of a tertiary care hospital. Objective: Our aim was to determine the clinical, epidemiological and microbiological characteristics of the outbreak, to analyse the identified risk factors and to describe the preventive and control measures implemented for its eradication. Methods: We conducted a case-control study. We performed univariate and bivariate analyses, defining statistical significance as a P-value of less than 0.05. The implemented preventive and control measures were aimed at establishing the magnitude of the outbreak, effective communication, the evaluation of health care processes and education on patient safety. Clinical samples were collected for molecular and phenotypic characterisation. Findings: The sample consisted of 51 newborns, of who 17 were cases and the remaining 34 controls. The distribution of cases by birth weight was: 2 cases (11.8%) greater than 2500 g, 4 cases (23.5%) between 1500 and 2500 g, 5 cases (29.4%) between 1000 and 1500 g, and 5 cases (29.4%) less than 1000 g. In one case, the birth weight was not documented in the health record. The following risk factors for colonisation or infection were statistically significant in our study: presence of a central venous catheter (OR, 5.0 [95% CI, 1.4–17.8]; P = .016); parenteral nutrition (OR, 6.8 [95% CI, 1.8–25.7]; P = .006); urinary catheterization (OR, 5.9 [95% CI, 1.2–30.0]; P = .028) and birth weight (P = .035). We found statistically significant differences in the mean total length of stay in hospital (P = .004) and length of stay in the NICU (P = .002). All 17 cases presented antimicrobial resistance with presence of extended-spectrum beta-lactamase type CTX-M-14. Conclusion: Workplace interventions focused on patient safety need to be reinforced, especially those concerning practices with the potential to increase the extrinsic risk of colonisation or infection by extended-spectrum beta-lactamase-producing K. pneumoniae in the NICU, such as the insertion, care and maintenance of central venous catheter, parenteral nutrition and urinary catheterization. Resumen: Introducción: En noviembre de 2014, se detectó un brote de Klebsiella pneumoniae productora de betalactamasas de espectro extendido en la unidad de cuidados intensivos neonatales de un hospital terciario. Objetivo: El objetivo fue describir las características clínicas, epidemiológicas y microbiológicas del brote, analizar los factores de riesgo asociados y presentar las medidas preventivas y de control implementadas para su erradicación. Métodos: Estudio de casos y controles. Se realizaron análisis univariantes y bivariantes, considerándose estadísticamente significativo un valour de p < 0,05. Las medidas preventivas y de control se centraron en la necesidad de determinar la magnitud del problema, en la comunicación efectiva, la evaluación de los procedimientos sanitarios y la educación sobre la seguridad del paciente. Se realizó caracterización molecular y fenotípica de muestras clínicas. Resultados: La muestra de estudio consistió en 51 neonatos, de los que 17 fueron casos y los 34 restantes controles. La distribución de casos por peso al nacer fue: 2 con peso > 2.500 g (11,8%), 4 con peso de 1.500–2.500 g (23,5%), 5 con peso de 1.000–1.500 g (29,4%) y 5 con peso < 1.000 g (29,4%). En un caso no se había registrado el peso al nacer en la historia clínica. Los factores de riesgo estadísticamente significativos para la colonización/infección fueron: presencia de catéter venoso (OR = 5,0 [IC 95% 1,4–17,8]; p = 0,016); nutrición parenteral (OR = 6,8 [IC 95%: 1,8–25,7]; p = 0,006); sondaje vesical (OR = 5,9 [IC 95% 1,2–30,0]; p = 0,028) y peso al nacer (p = 0,035). Encontramos diferencias estadísticamente significativas en la estancia hospitalaria media (p = 0,004) y los días de estancia en la unidad de cuidados intensivos neonatales (p = 0,002). Se encontró resistencia a antimicrobianos tipo betalactamasas de espectro extendido CTX-M-14 en los 17 casos. Conclusión: Han de reforzarse las iniciativas de trabajo sobre la seguridad de los pacientes, especialmente aquellas aplicables a intervenciones con el potencial de aumentar el riesgo de colonización/infección por K. pneumoniae productora de betalactamasas de espectro extendido en la unidad de cuidados intensivos neonatales, como las asociadas a la inserción, cuidado y mantenimiento de catéter venoso, la nutrición parenteral y el sondaje vesical.

Renal cell carcinoma is the most lethal cancer of the urological system due to late diagnosis and treatment resistance. Propolis, a beehive product, is a valuable natural source of compounds with bioactivities and may be a beneficial addition to current anticancer treatments. A Portuguese propolis sample, its fractions (n-hexane, ethyl acetate, n-butanol and water) and three subfractions (P1–P3), were tested for their toxicity on A498, 786-O and Caki-2 renal cell carcinoma cell lines and the non-neoplastic HK2 kidney cells. The ethyl acetate fraction showed the strongest toxicity against A498 (IC50 = 0.162 µg mL−1) and 786-O (IC50 = 0.271 µg mL−1) cells. With similar toxicity against 786-O, P1 (IC50 = 3.8 µg mL−1) and P3 (IC50 = 3.1 µg mL−1) exhibited greater effect when combined (IC50 = 2.5 µg mL−1). Results support the potential of propolis and its constituents as promising coadjuvants in renal cell carcinoma treatment.

Background: Neonatal sepsis is a condition with high mortality and morbidity that contributes to high rates of antibiotic therapy at birth. In addition, very low birth weight newborns (VLBWN) are particularly vulnerable. Interleukin 6 (IL-6) seems to be an early and effective marker that could help a better selection of patients to be treated. This study aimed to evaluate the use of antibiotics in the first 72 hours of life in VLBW infants before and after using IL-6 as an infection marker. Also, we wanted to analyze the differences in morbidity and mortality during admission and other factors associated with the decision to start antibiotic treatment. Methods: We conducted a cohort retrospective study. We included VLBWN born in our hospital or admitted before 72 hours of life in two two-year periods (2007-2008 and 2011-2012). Results: Antibiotics use during the first 72 hours of life was analyzed as the primary variable, which was reduced by 20% on the second period (p = 0.002). Regarding the analysis of secondary variables, we found no significant differences in mortality during hospital admission and the incidence of nosocomial sepsis, enterocolitis, or invasive fungal infection. The multivariate analysis indicated extreme prematurity and the study group as the most strongly related factors to the start of antibiotic therapy. Conclusions: IL-6 was a useful marker of infection to reduce the use of antibiotic therapy in VLBW infants without increasing mortality.

Making inferences about the computations performed by neuronal circuits from synapse-level connectivity maps is an emerging opportunity in neuroscience. The mushroom body (MB) is well positioned for developing and testing such an approach due to its conserved neuronal architecture, recently completed dense connectome, and extensive prior experimental studies of its roles in learning, memory, and activity regulation. Here, we identify new components of the MB circuit in Drosophila, including extensive visual input and MB output neurons (MBONs) with direct connections to descending neurons. We find unexpected structure in sensory inputs, in the transfer of information about different sensory modalities to MBONs, and in the modulation of that transfer by dopaminergic neurons (DANs). We provide insights into the circuitry used to integrate MB outputs, connectivity between the MB and the central complex and inputs to DANs, including feedback from MBONs. Our results provide a foundation for further theoretical and experimental work.

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly’s brain.

To analyse neuron data at scale, neuroscientists expend substantial effort reading documentation, installing dependencies and moving between analysis and visualisation environments. To facilitate this, we have developed a suite of interoperable open-source R packages called the natverse. The natverse allows users to read local and remote data, perform popular analyses including visualisation and clustering and graph-theoretic analysis of neuronal branching. Unlike most tools, the natverse enables comparison across many neurons of morphology and connectivity after imaging or co-registration within a common template space. The natverse also enables transformations between different template spaces and imaging modalities. We demonstrate tools that integrate the vast majority of Drosophila neuroanatomical light microscopy and electron microscopy connectomic datasets. The natverse is an easy-to-use environment for neuroscientists to solve complex, large-scale analysis challenges as well as an open platform to create new code and packages to share with the community.

To sustain their high proliferation rates, most cancer cells rely on glycolytic metabolism, with production of lactic acid. For many years, lactate was seen as a metabolic waste of glycolytic metabolism; however, recent evidence has revealed new roles of lactate in the tumor microenvironment, either as metabolic fuel or as a signaling molecule. Lactate plays a key role in the different models of metabolic crosstalk proposed in malignant tumors: among cancer cells displaying complementary metabolic phenotypes and between cancer cells and other tumor microenvironment associated cells, including endothelial cells, fibroblasts, and diverse immune cells. This cell metabolic symbiosis/slavery supports several cancer aggressiveness features, including increased angiogenesis, immunological escape, invasion, metastasis, and resistance to therapy. Lactate transport is mediated by the monocarboxylate transporter (MCT) family, while another large family of G protein-coupled receptors (GPCRs), not yet fully characterized in the cancer context, is involved in lactate/acidosis signaling. In this mini-review, we will focus on the role of lactate in the tumor microenvironment, from metabolic affairs to signaling, including the function of lactate in the cancer–cancer and cancer–stromal shuttles, as well as a signaling oncometabolite. We will also review the prognostic value of lactate metabolism and therapeutic approaches designed to target lactate production and transport.

Mucormycosis is a rare fungal infection caused by Mucorales order fungi. The rhino-cerebral form of mucormycosis is most commonly seen in patients with diabetes mellitus, whereas, pulmonary mucormycosis is a rare manifestation in patients with haematological malignancy and transplant recipients. We report a case of pulmonary mucormycosis presenting with a late acute onset diabetes on a patient immunosuppressed with a low dose of steroids.We aim to illustrate the need for a high clinical suspicion for the diagnosis of mucormycosis and to report the importance of early and aggressive inhiation of antifungal therapy.

The tryptophan hydroxylase 2 (TPH2) enzyme catalyzes the first step of serotonin biosynthesis. Serotonin is known for its role in several homeostatic systems related to sleep, mood, and food intake. As the reaction catalyzed by TPH2 is the rate-limiting step of serotonin biosynthesis, mutations in TPH2 have been associated with several psychiatric disorders (PD). This work undertakes an in silico analysis of the effects of genetic mutations in the human TPH2 protein. Ten algorithms were used to predict the functional and stability effects of the TPH2 mutations. ConSurf was used to estimate the evolutionary conservation of TPH2 amino acids. GROMACS was used to perform molecular dynamics (MD) simulations of TPH2 WT and P260S, R303W, and R441H, which had already been associated with the development of PD. Forty-six TPH2 variants were compiled from the literature. Among the analyzed variants, those occurring at the catalytic domain were shown to be more damaging to protein structure and function. The ConSurf analysis indicated that the mutations affecting the catalytic domain were also more conserved throughout evolution. The variants S364K and S383F were predicted to be deleterious by all the functional algorithms used and occurred at conserved positions, suggesting that they might be deleterious. The MD analyses indicate that the mutations P206S, R303W, and R441H affect TPH2 flexibility and essential mobility at the catalytic and oligomerization domains. The variants P206S, R303W, and R441H also exhibited alterations in dimer binding affinity and stability throughout the simulations. Thus, these mutations may impair TPH2 functional interactions and, consequently, its function, leading to the development of PD. Furthermore, we developed a database, SNPMOL (http://www.snpmol.org/), containing the results presented in this paper. Understanding the effects of TPH2 mutations on protein structure and function may lead to improvements in existing treatments for PD and facilitate the design of further experiments.

A large number of applications for fibroblast activation protein inhibitors (FAPI)-based PET agents have been evaluated in conditions ranging from cancer to non-malignant diseases such as myocardial infarction. In particular, 68Ga-FAPI-46 was reported to have a high specificity and affinity for FAP-expressing cells, a fast and high accumulation in tumor lesions/injuries together with a fast body clearance when investigated in vivo. Due to the increasing interest in the use of the agent both preclinically and clinically, we developed an automated synthesis for the production of 68Ga-FAPI-46 on a Trasis AiO platform. The new synthetic procedure, which included the processing of the generator eluate using a strong cation exchange resin and a final purification step through an HLB followed by a QMA cartridge, yielded 68Ga-FAPI-46 with high radiochemical purity (>98%) and apparent molar activity (271.1 ± 105.6 MBq/nmol). Additionally, the in vitro and in vivo properties of the product were assessed on glioblastoma cells and mouse model. Although developed for the preparation of 68Ga-FAPI-46 for preclinical use, our method can be adapted for clinical production as a reliable alternative to the manual (i.e., cold kit) or modular systems preparations already described in the literature.

Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore, may confound the uptake of choline radiotracer [18F]fluoromethyl-[1,2-2H4]-choline ([18F]-D4-FCH). The aim of this study was to investigate how hypoxia affects the choline radiotracer dynamics. Three underlying mechanisms by which hypoxia could potentially alter the uptake of the choline radiotracer, [18F]-D4-FCH, were investigated: 18F-D4-FCH import, CHKA phosphorylation activity, and the efflux of [18F]-D4-FCH and its phosphorylated product [18F]-D4-FCHP. The effects of hypoxia on [18F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer MDA-MB-231 cells. The mechanisms of radiotracer efflux were assessed by the cell uptake and immunofluorescence in vitro and examined in vivo (n = 24). The mathematical modelling methodology was further developed to verify the efflux hypothesis using [18F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (n = 17). We report a novel finding involving the export of phosphorylated [18F]-D4-FCH and [18F]-D4-FCHP via HIF-1α-responsive efflux transporters, including ABCB4, when the HIF-1α level is augmented. This is supported by a graphical analysis of human data with a compartmental model (M2T6k + k5) that accounts for the efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting the consideration of efflux in the modelling of radiotracer dynamics.

Animals exhibit innate behaviours to a variety of sensory stimuli including olfactory cues. In Drosophila, one higher olfactory centre, the lateral horn (LH), is implicated in innate behaviour. However, our structural and functional understanding of the LH is scant, in large part due to a lack of sparse neurogenetic tools for this region. We generate a collection of split-GAL4 driver lines providing genetic access to 82 LH cell types. We use these to create an anatomical and neurotransmitter map of the LH and link this to EM connectomics data. We find ~30% of LH projections converge with outputs from the mushroom body, site of olfactory learning and memory. Using optogenetic activation, we identify LH cell types that drive changes in valence behavior or specific locomotor programs. In summary, we have generated a resource for manipulating and mapping LH neurons, providing new insights into the circuit basis of innate and learned olfactory behavior.

Introducción: El síndrome de HELLP es un grave trastorno hipertensivo del embarazo con importantes problemas neonatales en los hijos de las madres afectadas. El objetivo de este trabajo fue conocer las características de estos neonatos y su evolución. Métodos: Se llevó a cabo un estudio observacional descriptivo y retrospectivo de los neonatos hijos de madre con síndrome de HELLP, nacidos en un hospital universitario entre el 1° de enero de 2008 y el 31 de diciembre de 2013. Se estudiaron 33 neonatos procedentes de 28 gestaciones (cinco gemelares). Se realizó un análisis descriptivo y comparativo entre grupos, y posteriormente un análisis de multivarianza de factores asociados con la mortalidad dentro de la serie. Resultados: De 33 recién nacidos estudiados (2.2/1,000 recién nacidos totales), dos fueron mortinatos (6.1% del total) y cuatro fallecieron tras el nacimiento (12.9% de los neonatos vivos), con una mortalidad perinatal total del 18.2%; 28 neonatos terminaron la gestación antes de la semana 37 (84.8%) y 11 antes de la semana 32 (33.3%); siete neonatos pesaron menos de 1,500 g (cuatro de ellos menos de 1,000 g). De los 31 recién nacidos vivos, 13 neonatos tenían peso menor al percentil 10 para su edad gestacional (41.9%), 20 precisaron reanimación neonatal (64.5%) y 14 presentaban leucopenia neonatal (45.2%). En la regresión logística final, la mortalidad neonatal se asoció con la gran prematuridad, independientemente del bajo peso, leucopenia o necesidad de reanimación neonatal. Conclusiones: Los hijos de madre con síndrome de HELLP presentan elevada mortalidad asociada con la alta prematuridad, independientemente de la presencia de leucopenia, bajo peso para edad gestacional o necesidad de reanimación neonatal.

Objetivos: Realizar uma revisão sobre adesão à terapêutica na população portuguesa visando descrever o âmbito (quantidade, foco e natureza) da atividade de investigação original. Fontes de dados: Foram pesquisados estudos sobre adesão à terapêutica na MEDLINE, Web of Science, SciELO e B-on. Métodos de revisão: A revisão foi realizada em dezembro de 2014. Nas fontes de dados foram pesquisados estudos sobre adesão à terapêutica na população portuguesa cuja recolha de dados fosse igual ou posterior a 2005 e/ou se a publicação ocorreu até ao final de 2014. Resultados: Obtiveram-se 82 publicações, das quais foram selecionadas 26. Os resultados indicam um maior número de estudos em populações do Norte e da região de Lisboa e Vale do Tejo; a aparente inexistência de estudos sobre iniciação do tratamento e apenas um estudo sobre descontinuação; uma variabilidade nos métodos de recolha de dados e nas medidas utilizadas para avaliar a adesão à terapêutica, com os inquéritos dirigidos aos doentes como a principal fonte de informação; taxas de adesão entre os 41,6% e os 89%, dependentes da doença ou condição estudada. Conclusões: Os diferentes métodos de recolha de dados e medidas de avaliação da adesão, os curtos períodos de recolha de dados, a análise quase exclusiva da implementação do tratamento, não analisando os fatores que influenciam a sua iniciação e descontinuação, dificultam a monitorização da adesão à terapêutica na população portuguesa.

Case summary An 18-month-old female domestic shorthair cat was referred for investigation of a 6 month period of regurgitation. Contrast radiography indicated an intramural oesophageal structure. Ultrasound-guided fine-needle aspiration of the area retrieved viscous fluid containing high numbers of squamous epithelial cells. Computed tomography disclosed a thin-walled contrast-enhancing structure containing non-enhancing homogenous contents. Exploratory thoracotomy confirmed an intramural cystic oesophageal structure, which was resected. Histopathological analysis of the resected tissue demonstrated an intramural oesophageal duplication cyst. A 12 month follow-up period has seen complete resolution of the cat’s clinical signs. Relevance and novel information This is the first report of successful oesophageal duplication cyst removal in a cat. Oesophageal duplication cysts should be included on the differential list for dysphagia and regurgitation in cats. Complete surgical removal in this cat carried a good long-term outcome.

Chitosan was acetylated during 2, 5 and 10h and physical gels were obtained at different polymer concentrations in N,N-dimethylacetamide containing 5% of LiCl. Acetylation was confirmed by infrared spectroscopy and 13C NMR, and degrees of acetylation in the range of 0.82-0.91 were determined by NMR. The O-acetylation degree (0.12-0.15) was exclusively determined by a volumetric method. Rheological studies showed that the storage modulus values were smaller for the more acetylated samples and increased with the temperature and the polymer concentration. All the gels presented storage modulus superior to loss modulus, evidencing more elastic than viscous characteristics. The results obtained in this work suggest a gelation process based on a balance between O and N-acetylation and intermolecular bonds.

Objective In the presence of risk factors of neonatal sepsis of vertical transmission, antibiotic treatment is usually started. The main purpose of this study was to evaluate the usefulness of Interleukin 6 (IL6) to avoid unnecessary antibiotic treatment. Study design We conducted a prospective study among patients admitted to the Neonatal Intensive Care Unit. In total, 73 patients were included. Infants were classified as belonging to one of three subgroups: infected, not-infected and control group. Values of IL6, C reactive protein and Procalcitonin were collected. We calculated the optimal cut-off point using the receiver operating curve. Likelihood ratio and odds ratio has been calculated, as well as classical parameters of diagnostic efficiency. Results Significantly higher serum IL6 levels were detected in the infected group. Septic neonates were 5-fold more likely to have a positive IL6 than healthy newborns and their post-test probability was 9-fold higher than pre-test probability. A negative IL6 concentration virtually ruled out sepsis despite the presence of risk factor for vertical sepsis. Conclusion IL6 could be used to ruling out sepsis in asymptomatic neonates with risk factor for vertical sepsis, avoiding excessive antibiotic treatment.