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Abstract Background The relationship between collapse and a diagnosis of hypoadrenocorticism is not well understood in dogs. Hypothesis To assess the prevalence of episodes of collapse in dogs screened for hypoadrenocorticism, and to assess the prevalence of confirmed hypoadrenocorticism in dogs presenting with reported collapse. Animals Seventy‐three client‐owned dogs with resting cortisol concentrations were measured and presented to a University teaching hospital for collapse. Methods Retrospective review of medical records of dogs at a single center. Results The prevalence of episodes of collapse in dogs that had a resting cortisol measurement was 73/856 (8.5%; 95% confidence interval [95% CI], 6.7%‐10.6%). Resting cortisol concentration was 2 μg/dL (>55 nmol/L). The most common diagnosis was vasovagal syncope (10/73), followed by sick sinus syndrome and third‐degree atrioventricular block (2/73). The final diagnosis was unknown in 24/73 dogs. Conclusions and Clinical Importance Hypoadrenocorticism was the final diagnosis in 1 of 73 dogs presented to a teaching hospital either in a collapsed state or with a previous history of episodes of collapse. No dog presenting as cardiovascularly stable for intermittent collapse was found to have hypoadrenocorticism.

RESUMEN Objetivo: Valorar si en nuestra población los factores de riesgo cardiovascular (FRCV) se correlacionan con la severidad de la COVID-19 en pacientes hospitalizados. Material y Métodos: Estudio de cohortes retrospectivo de pacientes con COVID-19 ingresados entre los meses de abril y diciembre del 2020 en un centro terciario en el sur de España. Se valoró la asociación entre los FRCV y la severidad del SARS-COV2. Se consideró como COVID severo aquel que ingresó en la Unidad de Cuidados Intensivos (UCI) o que falleció. Resultados: Se analizaron 608 pacientes ingresados con diagnóstico de neumonía por COVID-19, la mediana de edad fue de 73 años (RIC: 64-81) años. Los pacientes fueron predominantemente varones (55,8%). La hipertensión arterial fue el FRCV más común (83,7%), seguido de la dislipemia (50,2%), diabetes (43,1%), obesidad (32,9%) y tabaquismo (15,6%). Durante la estancia un total del 25,8% de los pacientes tuvieron un pronóstico desfavorable: un 7,9% precisó ingreso en UCI y un 22,9% fallecieron. En el análisis multivariante resultaron variables independientes para padecer un COVID severo el género masculino (OR: 1,697; IC 95%: 1,138-2,532), la edad avanzada (OR: 1,697; IC 95%: 1,138-2,532), y la obesidad (OR: 1,634; IC95%: 1,370-1,947). Conclusión. Existe una gran prevalencia de FRCV en los pacientes ingresados por COVID 19 de nuestra población. La obesidad, junto con la edad avanzada y el género masculino se asocian con una mayor gravedad y mortalidad hospitalaria en los pacientes ingresados con SARS-CoV 2. ABSTRACT Objective: To assess whether cardiovascular risk factors (CVRF) are correlated with the severity of COVID-19 in hospitalized patients in our population. Material and Methods: Retrospective cohort study of patients with COVID-19 admitted between the months of April and December 2020 in a tertiary center in southern Spain. The association between CVRF and the severity of SARS-COV2 was assessed. Severe COVID was considered to be one who was admitted to the Intensive Care Unit (ICU) or who died. Results: 608 patients admitted with a diagnosis of COVID-19 pneumonia were analyzed, the median age was 73 years (IQR: 64-81) years. The patients were predominantly male (55.8%). Hypertension was the most common CVRF (83.7%), followed by dyslipidemia (50.2%), diabetes mellitus (43.1%), obesity (32.9%), and smoking (15.6%). During the stay, a total of 25.8% of the patients had an unfavorable prognosis: 22.9% died and 7.9% required admission in the ICU. In the multivariate analysis, significant independent variables were found for suffering from severe COVID: male sex (OR: 1,697; IC 95%: 1,138-2,532), age (OR: 1.697; CI 95%: 1,138-2,532), and obesity (OR: 1,634; 95% CI: 1,370-1,947). Conclusions: There is a high prevalence of CVRF in patients hospitalized for COVID 19 in our population. Obesity, along with older age and male gender, are associated with greater severity and hospital mortality in patients admitted with SARS-CoV-2

Abstract Simultaneously recording network activity and ultrastructural changes of the synapse is essential for advancing understanding of the basis of neuronal functions. However, the rapid millisecond‐scale fluctuations in neuronal activity and the subtle sub‐diffraction resolution changes of synaptic morphology pose significant challenges to this endeavor. Here, specially designed graphene microelectrode arrays (G‐MEAs) are used, which are compatible with high spatial resolution imaging across various scales as well as permit high temporal resolution electrophysiological recordings to address these challenges. Furthermore, alongside G‐MEAs, an easy‐to‐implement machine learning algorithm is developed to efficiently process the large datasets collected from MEA recordings. It is demonstrated that the combined use of G‐MEAs, machine learning (ML) spike analysis, and 4D structured illumination microscopy (SIM) enables monitoring the impact of disease progression on hippocampal neurons which are treated with an intracellular cholesterol transport inhibitor mimicking Niemann–Pick disease type C (NPC), and show that synaptic boutons, compared to untreated controls, significantly increase in size, leading to a loss in neuronal signaling capacity.

While pesticide use is subject to strict regulatory oversight worldwide, it remains a main concern for environmental protection, including biodiversity conservation. This is partly due to the current regulatory approach that relies on separate assessments for each single pesticide, crop use, and non-target organism group at local scales. Such assessments tend to overlook the combined effects of overall pesticide usage at larger spatial scales. Integrative landscape-based approaches are emerging, enabling the consideration of agricultural management, the environmental characteristics, and the combined effects of pesticides applied in a same or in different crops within an area. These developments offer the opportunity to deliver informative risk predictions relevant for different decision contexts including their connection to larger spatial scales and to combine environmental risks of pesticides, with those from other environmental stressors. We discuss the needs, challenges, opportunities and available tools for implementing landscape-based approaches for prospective and retrospective pesticide Environmental Risk Assessments (ERA). A set of “building blocks” that emerged from the discussions have been integrated into a conceptual framework. The framework includes elements to facilitate its implementation, in particular: flexibility to address the needs of relevant users and stakeholders; means to address the inherent complexity of environmental systems; connections to make use of and integrate data derived from monitoring programs; and options for validation and approaches to facilitate future use in a regulatory context. The conceptual model can be applied to existing ERA methodologies, facilitating its comparability, and highlighting interoperability drivers at landscape level. The benefits of landscape-based pesticide ERA extend beyond regulation. Linking and validating risk predictions with relevant environmental impacts under a solid science-based approach will support the setting of protection goals and the formulation of sustainable agricultural strategies. Moreover, landscape ERA offers a communication tool on realistic pesticide impacts in a multistressors environment for stakeholders and citizens.

The paper analyses the effects of public subsidies to private R&D in Spain. We carried out an evaluation assessment of the program aid of the Centre for the Development for Industrial Technology (CDTI) from 2015 to 2020. CDTI is the main public agency in Spain that grants public support for firms to carry out R&D projects. We combine information on public grants from CDTI with the Technological Innovation Panel (PITEC) that integrates information from the survey on innovation and R&D activities of companies (Innovation Survey). The sample is an unbalanced panel containing 57,988 observations of which 9,116 (16%) correspond to beneficiary companies. We use a mixed approach of Differences-in-Differences with propensity score matching (DD-PSM) in the common support to control for some of the biases that occur when analysing causal effects. We find that public support has positive effects on firms’ R&D resources (i.e. internal R&D investment and job creation) - input additionality- and cooperation -behavioural additionality. However, the impact of public support on firms’ technological outputs varies importantly across sectors, having a positive effect limited to traditional-oriented sectors.

Abstract Drug studies targeting neuronal ion channels are crucial to understand neuronal function and develop therapies for neurological diseases. The traditional method to study neuronal ion‐channel activities heavily relies on the whole‐cell patch clamp as the industry standard. However, this technique is both technically challenging and labour‐intensive, while involving the complexity of keeping cells alive with low throughput. Therefore, the shortcomings are limiting the efficiency of ion‐channel‐related neuroscience research and drug testing. Here, this work reports a new system of integrating neuron membranes with organic microelectrode arrays (OMEAs) for ion‐channel‐related drug studies. This work demonstrates that the supported lipid bilayers (SLBs) derived from both neuron‐like (neuroblastoma) cells and primary neurons are integrated with OMEAs for the first time. The increased expression of voltage‐gated calcium (CaV) ion channels on differentiated SH‐SY5Y SLBs compared to non‐differentiated ones is sensed electrically. Also, dose‐response of the CaV ion‐channel blocking effect on primary cortical neuronal SLBs from rats is monitored. The dose range causing ion channel blocking is comparable to literature. This system overcomes the major challenges from traditional methods (e.g., patch clamp) and showcases an easy‐to‐test, rapid, ultra‐sensitive, cell‐free, and high‐throughput platform to monitor dose‐dependent ion‐channel blocking effects on native neuronal membranes.

Abstract In cancer patients, psychological distress, which encompasses anxiety, depression, and somatization, arises from the complex interplay of emotional and behavioral reactions to the diagnosis and treatment, significantly influencing their functionality and quality of life. The aim was to investigate factors associated with psychological distress in cancer patients. This prospective and multicenter study, conducted by the Spanish Society of Medical Oncology (SEOM), included two cohorts of patients with cancer (localized resected or advanced unresectable). They completed surveys assessing psychological distress (BSI-18) before and after cancer treatment and coping (MINI-MAC) and spirituality (FACIT-sp) prior to therapy. A multivariable logistic regression analysis and a Structural Equation Modeling (SEM) were conducted. Between 2019 and 2022, 1807 patients were evaluated, mostly women (54%), average age 64 years. The most frequent cancers were colorectal (30%), breast (25%) and lung (18%). Men had lower levels of anxiety and depression (OR 0.66, 95% CI 0.52–0.84; OR 0.72, 95% CI 0.56–0.93). Colorectal cancer patients experienced less anxiety (OR 0.63, 95% CI 0.43–0.92), depression (OR 0.55, 95% CI 0.37–0.81), and somatization (OR 0.59, 95% CI 0.42–0.83). Patients with localized cancer and spiritual beliefs had reduced psychological distress, whereas those with anxious preoccupation had higher level. SEM revealed a relationship between psychological distress and coping strategies, emphasizing how baseline anxious preoccupation exacerbates post-treatment distress. This study suggests that age, sex, extension and location of cancer, coping and spirituality influence psychological distress in cancer patients.

Abstract Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

Abstract Streptococcus suis is a zoonotic pathogen that causes a major health problem in the pig production industry worldwide. Spain is one of the largest pig producers in the world. This work aimed to investigate the genetic and phenotypic features of invasive S. suis isolates recovered in Spain. A panel of 156 clinical isolates recovered from 13 Autonomous Communities, representing the major pig producers, were analysed. MLST and serotyping analysis revealed that most isolates (61.6%) were assigned to ST1 (26.3%), ST123 (18.6%), ST29 (9.6%), and ST3 (7.1%). Interestingly, 34 new STs were identified, indicating the emergence of novel genetic lineages. Serotypes 9 (27.6%) and 1 (21.8%) prevailed, followed by serotypes 7 (12.8%) and 2 (12.2%). Analysis of 13 virulence-associated genes showed significant associations between ST, serotype, virulence patterns, and clinical features, evidencing particular virulence traits associated with genetic clusters. The pangenome was generated, and the core genome was distributed in 7 Bayesian groups where each group included a variable set of over- and under-represented genes of different categories. The study provides comprehensive data and knowledge to improve the design of new vaccines, antimicrobial treatments, and bacterial typing approaches.

A key obstacle to achieving a fully renewable energy system is energy storage. A promising solution involves generating green hydrogen by using wind power. In parallel, as some wind power plants near the end of their operational life, crucial decisions about their future must be made. In this context, hybrid solutions emerge as promising renewable systems, offering resilient and cost-effective approaches. This paper provides a methodology for the optimal selection of wind-hydrogen hybrid systems, combining repowered wind power plants and green hydrogen production. The methodology aims to maximize the power and hydrogen generation; promoting the industrial sector cooperation and minimizing costs and emissions in line with Sustainable Development Goals 7, 9, and 13. The methodology is evaluated in three scenarios considering a real case study: (i) only repowering, (ii) repowering with energy surplus for hydrogen production purposes, and (iii) repowering with specific wind turbines focused on hydrogen production. From the results, the third scenario achieves the objectives of the previous Sustainable Development Goals, maximizing the clean energy generation (160—240 GWh/year of electricity, and 1500—3000 ton H2/year), CO2 emissions (up to 15%), and minimizing the hybrid solution costs up to 130,000e. Further successful hybrid solutions and implementations require significant additional investments in research, development, and deployment on a global scale, along with supportive policies and regulatory frameworks to encourage adoption and development.

Cada año crece el número de mujeres marroquíes que se desplaza de forma temporal a España para trabajar en la explotación agrícola de frutos rojos. En el año 2022 fueron 19.000 mujeres. Sin embargo, esta actividad ha generado preocupación social debido a las denuncias continuas por parte de las trabajadoras por vulneración de derechos, así como por abusos sexuales. El objetivo de este artículo es la exposición de la violación de derechos laborales existente con base en la construcción de un perfil de contratación y la emergente respuesta de resistencia por parte de las mujeres migrantes en la provincia. La metodología parte de un punto de vista feminista y se realiza un estudio etnográfico, desde febrero a abril de 2022, donde el eje principal serán los relatos de las mujeres marroquíes. Entre las conclusiones descubrimos cómo la búsqueda de un perfil de contratación basado en elementos discriminatorios que garanticen el retorno de las trabajadoras.

Abstract Coagulase-negative staphylococci (CoNS) are currently considered typical microorganisms causing infective endocarditis (IE) in patients with prosthetic valves. The objective was to determine variables associated with IE in patients with CoNS bacteremia. We performed an analysis of the clinical characteristics of patients with CoNS bacteremia admitted to a university hospital in Madrid (Spain) from 2021 to December 2022 according to the occurrence of IE. This study is an evaluation of a bacteremia registry. During the study period, 106 patients with CoNS bacteremia were detected. In 85 patients an echocardiogram was performed during hospital admission to rule out IE. Among them, 12 episodes were detected that met IE criteria (14.2%). Of the 6 patients with heart valve prostheses, 5 patients (83.3%) had IE (p

Abstract Monomeric alpha-synuclein (aSyn) is a well characterised protein that importantly binds to lipids. aSyn monomers assemble into amyloid fibrils which are localised to lipids and organelles in insoluble structures found in Parkinson’s disease patient’s brains. Previous work to address pathological aSyn-lipid interactions has focused on using synthetic lipid membranes, which lack the complexity of physiological lipid membranes. Here, we use physiological membranes in the form of synaptic vesicles (SV) isolated from rodent brain to demonstrate that lipid-associated aSyn fibrils are more easily taken up into iPSC-derived cortical i3Neurons. Lipid-associated aSyn fibril characterisation reveals that SV lipids are an integrated part of the fibrils and while their fibril morphology differs from aSyn fibrils alone, the core fibril structure remains the same, suggesting the lipids lead to the increase in fibril uptake. Furthermore, SV enhance the aggregation rate of aSyn, yet increasing the SV:aSyn ratio causes a reduction in aggregation propensity. We finally show that aSyn fibrils disintegrate SV, whereas aSyn monomers cause clustering of SV using small angle neutron scattering and high-resolution imaging. Disease burden on neurons may be impacted by an increased uptake of lipid-associated aSyn which could enhance stress and pathology, which in turn may have fatal consequences for neurons.

Abstract Background Non‐traumatic spinal cord hemorrhage (NTSH) is an uncommon cause of myelopathy in dogs. Objectives Describe the clinical characteristics, concurrent medical conditions and underlying causes, magnetic resonance imaging (MRI) findings and outcome in dogs with NTSH. Animals Dogs diagnosed with NTSH using gradient echo T2‐weighted (GRE) sequences with or without histopathological confirmation of hemorrhage were included. Dogs with a traumatic cause were excluded, including those with compressive intervertebral disc extrusion. Methods Retrospective descriptive study; the databases of 2 referral hospitals were searched between 2013 and 2021. Results Twenty‐three dogs met inclusion criteria. The onset of signs was acute and progressive in 70% of cases; spinal hyperesthesia was variable (48%). Hemorrhage was identified in the thoracolumbar spinal segments in 65% of dogs. An underlying cause was identified in 65% of cases. Angiostrongylus vasorum represented 18% of the total cohort, followed by steroid‐responsive meningitis arteritis (SRMA; 13%). Overall, 64% of dogs had a good or excellent outcome, regardless of cause; which was increased to 100% for SRMA, 75% for A. vasorum and 75% for idiopathic NTSH. Outcome was not associated with neurological severity. Recovery rate was 67% and 50% for nociception‐intact and nociception‐negative dogs, respectively. Conclusions Larger prospective studies would be required to define prognostic factors for dogs with NTSH, but outcome appeared to be most influenced by the underlying cause, as opposed to neurological severity at presentation.

Although the fetal head position has traditionally been evaluated by digital examination (DE), it has a failure rate ranging between 20 and 70%; hence, intrapartum transabdominal ultrasonography (TUS) has become relevant. We aimed to evaluate the utility of the TUS to identify the fetal head positions in vacuum-assisted deliveries. We performed a prospective observational study including 101 pregnant patients in active labor who required a vacuum-assisted delivery. The fetal head position was assessed by a DE and a TUS prior to vacuum cup placement. After delivery, the optimal vacuum cup placement was evaluated as the distance between the chignon and the flexion point ≤2 cm. The general concordance rate between the DE and TUS was 72.2%, with the poorest concordance rate for occiput posterior positions at 46.1%. In five cases (4.9%), it was not possible to determine the fetal head position through the DE. The correlation was higher in low and medium planes, with 77% and 68.1% concordance rates, respectively, while it was lower in high planes (60%). In 90.1% of cases, the vacuum cup placement was optimal. Our findings show that intrapartum transabdominal ultrasonography is a useful technique to identify the fetal head position allowing optimal placement of the vacuum cup necessary for correct vacuum-assisted delivery.

Abstract Background Adjuvant regional anesthesia is often selected for patients or procedures with high risk of pulmonary complications after general anesthesia. The benefit of adjuvant regional anesthesia to reduce postoperative pulmonary complications remains uncertain. In a prospective observational multicenter study, patients scheduled for non-cardiothoracic surgery with at least one postoperative pulmonary complication surprisingly received adjuvant regional anesthesia more frequently than those with no complications. We hypothesized that, after adjusting for surgical and patient complexity variables, the incidence of postoperative pulmonary complications would not be associated with adjuvant regional anesthesia. Methods We performed a secondary analysis of a prospective observational multicenter study including 1202 American Society of Anesthesiologists physical status 3 patients undergoing non-cardiothoracic surgery. Patients were classified as receiving either adjuvant regional anesthesia or general anesthesia alone. Predefined pulmonary complications within the first seven postoperative days were prospectively identified. Groups were compared using bivariable and multivariable hierarchical logistic regression analyses for the outcome of at least one postoperative pulmonary complication. Results Adjuvant regional anesthesia was performed in 266 (22.1%) patients and not performed in 936 (77.9%). The incidence of postoperative pulmonary complications was greater in patients receiving adjuvant regional anesthesia (42.1%) than in patients without it (30.9%) (site adjusted p = 0.007), but this association was not confirmed after adjusting for covariates (adjusted OR 1.37; 95% CI, 0.83–2.25; p = 0.165). Conclusion After adjusting for surgical and patient complexity, adjuvant regional anesthesia versus general anesthesia alone was not associated with a greater incidence of postoperative pulmonary complications in this multicenter cohort of non-cardiothoracic surgery patients.

Association of mRNA translation with the mitotic spindle is thought to be involved in localized production of cell fate determinants. Here, the authors show Vasa facilitates asymmetric translation, which contributes to differential regulation during sea urchin embryogenesis.

Introduction The evaluation of staging and activity of invasive fungal infection (IFI) is used to adjust the type and duration of antifungal therapy (AT). Typically anatomy-based imaging is used. Positron emission tomography/CT with 18F-fluorodeoxyglucose (18F-FDG PET/CT) not only evaluates more than one body area in one session, but adds functional information to the anatomic data provided by usual imaging techniques and can potentially improve staging of IFI and monitoring of the response to therapy. Our objective is to analyse the impact of the systematic use of 18F-FDG PET/CT in IFI diagnostic and therapeutic management.Methods and analysis Multicentre prospective cohort study of IFI with performance of systematic 18F-FDG PET/CT at diagnosis and follow-up that will be carried out in 14 Spanish tertiary hospitals. It is planned to include 224 patients with IFI over a 2-year study period. Findings and changes in management before and after 18F-FDG PET/CT will be compared. Additionally, the association of initial quantitative 18F-FDG PET/CT parameters with response to therapy will be evaluated.The primary endpoint is to compare the yield of 18F-FDG PET/CT with standard management without 18F-FDG PET/CT in IFI at initial assessment (staging) and in monitoring the response to treatment.The impact of the results of 18F-FDG PET/CT on the diagnostic-therapeutic management of patients with IFI (added value), as well as the prognostic ability of different quantification parameters of 18F-FDG PET/CT will be secondary endpoints.Ethics and dissemination The Clinical Research Ethics Committee of Puerta de Hierro-Majadahonda University Hospital approved the protocol of the study at the primary site. We plan to publish the results in high-impact journals.Trial registration number NCT05688592.

BackgroundIt remains unclear how inpatient physical activity after major abdominal surgery affects outcomes. Accelerometer research may provide further evidence for postoperative mobilization. ObjectiveWe aimed to summarize the current literature evaluating the impact of accelerometer-measured postoperative physical activity on outcomes after major abdominal surgery. MethodsWe searched PubMed and Google Scholar in October 2021 to conduct a systematic review. Studies were included if they used accelerometers to measure inpatient physical behaviors immediately after major abdominal surgery, defined as any nonobstetric procedures performed under general anesthesia requiring hospital admission. Studies were eligible only if they evaluated the effects of physical activity on postoperative outcomes such as postoperative complications, return of gastrointestinal function, hospital length of stay, discharge destination, and readmissions. We excluded studies involving participants aged

ABSTRACT Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

Abstract Background Resting cortisol concentrations are routinely measured in dogs with chronic gastrointestinal signs to rule out hypoadrenocorticism based on a concentration >2 μg/dL (>55 nmol/L). Hypothesis/Objectives To assess the cross‐sectional prevalence of hypoadrenocorticism in a group of dogs with chronic gastrointestinal signs presented to a referral internal medicine service. Animals Two‐hundred and eighty‐two client‐owned dogs with chronic gastrointestinal signs and with resting cortisol concentration testing performed. Methods Retrospective review of medical records (final diagnosis, resting cortisol concentration, and adenocorticotropic hormone [ACTH] stimulation test results) of a referral population of dogs between May 2013 and September 2017. Results Resting cortisol concentration was 2 μg/dL (>55 nmol/L). Overall, the most common diagnosis was chronic primary inflammatory enteropathy (176/282, 62.4%), followed by extragastrointestinal neoplasia (17/282, 6%), protein‐losing enteropathy, pancreatitis and megaesophagus (10/282, 3.5% each). Conclusions and Clinical Importance Although dogs with hypoadrenocorticism can present with chronic gastrointestinal signs, it was the final diagnosis in only 1 of 282 dogs presenting to a referral internal medicine service for signs of chronic enteropathy. Repeated resting cortisol concentration may be considered as a test to try and exclude hypoadrenocorticism.

Abstract Background Total-RNA sequencing (total-RNA-seq) allows the simultaneous study of both the coding and the non-coding transcriptome. Yet, computational pipelines have traditionally focused on particular biotypes, making assumptions that are not fullfilled by total-RNA-seq datasets. Transcripts from distinct RNA biotypes vary in length, biogenesis, and function, can overlap in a genomic region, and may be present in the genome with a high copy number. Consequently, reads from total-RNA-seq libraries may cause ambiguous genomic alignments, demanding for flexible quantification approaches. Results Here we present Multi-Graph count (MGcount), a total-RNA-seq quantification tool combining two strategies for handling ambiguous alignments. First, MGcount assigns reads hierarchically to small-RNA and long-RNA features to account for length disparity when transcripts overlap in the same genomic position. Next, MGcount aggregates RNA products with similar sequences where reads systematically multi-map using a graph-based approach. MGcount outputs a transcriptomic count matrix compatible with RNA-sequencing downstream analysis pipelines, with both bulk and single-cell resolution, and the graphs that model repeated transcript structures for different biotypes. The software can be used as a python module or as a single-file executable program. Conclusions MGcount is a flexible total-RNA-seq quantification tool that successfully integrates reads that align to multiple genomic locations or that overlap with multiple gene features. Its approach is suitable for the simultaneous estimation of protein-coding, long non-coding and small non-coding transcript concentration, in both precursor and processed forms. Both source code and compiled software are available at https://github.com/hitaandrea/MGcount .

The gold standard for the diagnosis of pelvic congestion syndrome (PCS) is venography (VG), although transvaginal ultrasound (TVU) might be a noninvasive, nonionizing alternative. Our aim is to determine whether TVU is an accurate and comparable diagnostic tool for PCS. An observational prospective study including 67 patients was carried out. A TVU was performed on patients, measuring pelvic venous vessels parameters. Subsequentially, a VG was performed, and results were compared for the test calibration of TVU. Out of the 67 patients included, only 51 completed the study and were distributed in two groups according to VG results: 39 patients belonging to the PCS group and 12 to the normal group. PCS patients had a larger venous plexus diameter (15.1 mm vs. 12 mm; p = 0.009) and higher rates of crossing veins in the myometrium (74.35% vs. 33.3%; p = 0.009), reverse or altered flow during Valsalva (58.9% vs. 25%; p = 0.04), and largest pelvic vein ≥ 8 mm (92.3% vs. 25%). The sensitivity and specificity of TVU were 92.3% (95% CI: 78.03–97.99%) and 75% (95% CI: 42.84–93.31%), respectively. In conclusion, transvaginal ultrasonography, with the described methodology, appears to be a promising tool for the diagnosis of PCS, with acceptable sensitivity and specificity.

OBJECTIVES:. The use of hyperoxemia during cardiac surgery remains controversial. We hypothesized that intraoperative hyperoxemia during cardiac surgery is associated with an increased risk of postoperative pulmonary complications. DESIGN:. Retrospective cohort study. SETTING:. We analyzed intraoperative data from five hospitals within the Multicenter Perioperative Outcomes Group between January 1, 2014, and December 31, 2019. We assessed intraoperative oxygenation of adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Hyperoxemia pre and post CPB was quantified as the area under the curve (AUC) of Fio2 above 0.21 in minutes when the corresponding peripheral oxygen saturation was greater than 92% measured by pulse oximetry. We quantified hyperoxemia during CPB as the AUC of Pao2 greater than 200 mm Hg measured by arterial blood gas. We analyzed the association of hyperoxemia during all phases of cardiac surgery with the frequency of postoperative pulmonary complications within 30 days, including acute respiratory insufficiency or failure, acute respiratory distress syndrome, need for reintubation, and pneumonia. PATIENTS:. Twenty-one thousand six hundred thirty-two cardiac surgical patients. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. During 21,632 distinct cardiac surgery cases, 96.4% of patients spent at least 1 minute in hyperoxemia (99.1% pre-CPB, 98.5% intra-CPB, and 96.4% post-CPB). Increasing exposure to hyperoxemia was associated with an increased risk of postoperative pulmonary complications throughout three distinct surgical periods. During CPB, increasing exposure to hyperoxemia was associated with an increased odds of developing postoperative pulmonary complications (p < 0.001) in a linear manner. Hyperoxemia before CPB (p < 0.001) and after CPB (p = 0.02) were associated with increased odds of developing postoperative pulmonary complications in a U-shaped relationship. CONCLUSIONS:. Hyperoxemia occurs almost universally during cardiac surgery. Exposure to hyperoxemia assessed continuously as an AUC during the intraoperative period, but particularly during CPB, was associated with an increased incidence of postoperative pulmonary complications.

Background Postoperative pulmonary complications (PPCs) are a major cause of morbidity and mortality after open abdominal surgery. Optimized perioperative lung expansion may minimize the synergistic factors responsible for the multiple-hit perioperative pulmonary dysfunction. This ongoing study will assess whether an anesthesia-centered bundle focused on perioperative lung expansion results in decreased incidence and severity of PPCs after open abdominal surgery. Methods Prospective multicenter randomized controlled pragmatic trial in 750 adult patients with at least moderate risk for PPCs undergoing prolonged (≥2 hour) open abdominal surgery. Participants are randomized to receive either a bundle intervention focused on perioperative lung expansion or usual care. The bundle intervention includes preoperative patient education, intraoperative protective ventilation with individualized positive end-expiratory pressure to maximize respiratory system compliance, optimized neuromuscular blockade and reversal management, and postoperative incentive spirometry and early mobilization. Primary outcome is the distribution of the highest PPC severity by postoperative day 7. Secondary outcomes include the proportion of participants with: PPC grades 1–2 through POD 7; PPC grades 3–4 through POD 7, 30 and 90; intraoperative hypoxemia, rescue recruitment maneuvers, or cardiovascular events; and any major extrapulmonary postoperative complications. Additional secondary and exploratory outcomes include individual PPCs by POD 7, length of postoperative oxygen therapy or other respiratory support, hospital resource use parameters, Patient-Reported Outcomes Measurements (PROMIS®) questionnaires for dyspnea and fatigue collected before and at days 7, 30 and 90 after surgery, and plasma concentrations of lung injury biomarkers (IL6, IL-8, RAGE, CC16, Ang-2) analyzed from samples obtained before, end of, and 24 hours after surgery. Discussion Participant recruitment for this study started January 2020; results are expected in 2024. At the conclusion of this trial, we will determine if this anesthesia-centered strategy focused on perioperative lung expansion reduces lung morbidity and healthcare utilization after open abdominal surgery. Trial registration ClinicalTrial.gov NCT04108130.

Abstract To assess the effectiveness and safety of the Preserflo Microshunt (PMS) implantation combined with cataract surgery in open-angle glaucoma (OAG) patients. Retrospective, open-label study conducted on insufficiently controlled OAG patients, who underwent a PMS implant procedure with mitomycin-C 0.2%, either alone or in combination with cataract surgery, and were followed for at least 12 months. Success was defined as an intraocular pressure (IOP) ≤ 18 mmHg and a reduction of at least 20% without (complete) or with (qualified) hypotensive medication. Fifty-eight eyes were included in the study, 35 eyes underwent PMS alone and 23 underwent PMS + Phaco. In the overall study sample, mean IOP was significantly lowered from 21.5 ± 3.3 mmHg at baseline to 14.6 ± 3.5 mmHg at month 12 (p

Abstract We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activity. We show that phenylethynyl biguanidium salts possess higher ability to cross hydrophobic barriers, improve mitochondrial accumulation and anticancer activity. Mechanistically, the most active compound, 1b, like metformin, activated AMPK, decreased the NAD+/NADH ratio and mitochondrial respiration, but at 800-fold lower concentration. In vivo studies show that compound 1b significantly inhibits the growth of pancreatic cancer xenografts in mice, while biguanides currently in clinical trials had little activity.

Summary: Background: Better understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management. Methods: Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed. Findings: The median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering of ordinal score over time revealed distinct disease course trajectories. Risk factors associated with prolonged hospitalization or death by day 28 included age ≥ 65 years (odds ratio [OR], 2.01; 95% CI 1.28–3.17), Hispanic ethnicity (OR, 1.71; 95% CI 1.13–2.57), elevated baseline creatinine (OR 2.80; 95% CI 1.63– 4.80) or troponin (OR 1.89; 95% 1.03–3.47), baseline lymphopenia (OR 2.19; 95% CI 1.61–2.97), presence of infiltrate by chest imaging (OR 3.16; 95% CI 1.96–5.10), and high SARS-CoV2 viral load (OR 1.53; 95% CI 1.17–2.00). Fatal cases had the lowest ratio of SARS-CoV-2 antibody to viral load levels compared to other trajectories over time (p=0.001). 589 survivors (51%) completed at least one survey at follow-up with 305 (52%) having at least one symptom consistent with PASC, most commonly dyspnea (56% among symptomatic patients). Female sex was the only associated risk factor for PASC. Interpretation: Integration of PCR cycle threshold, and antibody values with demographics, comorbidities, and laboratory/radiographic findings identified risk factors for 28-day outcome severity, though only female sex was associated with PASC. Longitudinal clinical phenotyping offers important insights, and provides a framework for immunophenotyping for acute and long COVID-19. Funding: NIH.

High-Performance Computing (HPC) systems need to be constantly monitored to ensure their stability. The monitoring systems collect a tremendous amount of data about different parameters or Key Performance Indicators (KPIs), such as resource usage, IO waiting time, etc. A proper analysis of this data, usually stored as time series, can provide insight in choosing the right management strategies as well as the early detection of issues. In this paper, we introduce a methodology to cluster HPC jobs according to their KPI indicators. Our approach reduces the inherent high dimensionality of the collected data by applying two techniques to the time series: literature-based and variance-based feature extraction. We also define a procedure to visualize the obtained clusters by combining the two previous approaches and the Principal Component Analysis (PCA). Finally, we have validated our contributions on a real data set to conclude that those KPIs related to CPU usage provide the best cohesion and separation for clustering analysis and the good results of our visualization methodology.

Head and neck cancers are often diagnosed at later stages with poor outcomes. Mesenchymal stem cells (MSC) are recruited to primary tumor sites where they can have pro- and antitumorigenic influence. In trying to better understand the dynamics between MSC and cancer cells, we found that head and neck cancer-MSC exposure resulted in mesenchymal features, elevated proliferation rate, and were more motile, like the same cells that fused with MSC. We orthotopically grafted the parental head and neck cancer cells, those fused with MSC, or those exposed to MSC into the tongues of mice. The cancer cells originally incubated with MSC developed larger more aggressive tumors compared to the parental cell line. RNA sequencing analysis revealed the expression of genes associated with drug resistance in the cancer cells exposed to MSC compared to parental cancer cells. Strikingly, MSC exposed cancer cell lines developed paclitaxel resistance that could be maintained up to 30 d after the initial co-incubation period. The secretory profile of the MSC suggested IL-6 to be a potential mediator of epigenetic imprinting on the head and neck cancer cells. When the MSC-imprinted cancer cells were exposed to the demethylation agent, 5-aza-2’deoxycytidine, it restored the expression of the drug resistance genes to that of parental cells. This study demonstrated that the recognized recruitment of MSC to tumors could impart multiple protumorigenic properties including chemotherapy resistance like that observed in the relatively rare event of cancer/MSC cell fusion.

In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.

Understanding the immune response to dengue virus (DENV) is essential for developing a dengue vaccine that is protective against all 4 DENV serotypes. We evaluated the immune response after vaccination (live attenuated tetravalent dengue vaccine TV005 or trivalent admixture) and after challenge with DEN2Δ30 (Tonga/74) to better understand the importance of homotypic immunity in vaccine protection. Significant increases in IP-10 expression were observed following receipt of either the trivalent or tetravalent vaccine. After challenge, a large increase in IP-10 expression was observed in the placebo and trivalent admixture groups but not in the tetravalent vaccine group. MCP-1, IL-1RA, and MIP-1β exhibited a similar pattern as IP-10. These results demonstrate protective effects of trivalent and tetravalent vaccines against DENV and suggest that the tetravalent vaccine has a better protective effect compared with the trivalent admixture. We also explored the postvaccination and postchallenge immune response differences between Black and White participants. White participants responded to vaccine differently than Black participants; Black participants receiving trivalent and tetravalent vaccines responded strongly and White participants responded only transiently in trivalent group. In response to challenge, White participants elicited a stronger response than Black participants. These results may explain why White participants may have a more vigorous DENV immune response than Black participants, as reported in literature.

ABSTRACT Our group was the first to describe direct antagonism of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway by dengue virus (DENV) in human cells, and here, we report new findings on the characterization of the interaction between the DENV nonstructural protein 2B (NS2B)-NS3 (NS2B3) protease complex and STING. We demonstrate interactions between NS2B and the transmembrane domains of human STING and between NS3 and a portion of the cytoplasmic C-terminal domain of human STING. One significant obstacle we face today in the DENV field is the lack of small animal models available that can effectively recapitulate DENV pathogenesis in the early events of infection. The existing mouse models are either immunocompromised mice lacking interferon (IFN) receptors or “humanized” mice reconstituted with human stem cells. However, both approaches fail to capture important aspects of human pathogenesis because they lack critical innate immunity components or have deficiencies in immune cell development or maintenance. As an important step toward developing an immunocompetent mouse model for DENV, we have generated two chimeric human-mouse STING constructs that have promise in retaining both cleavability by NS2B3 and signaling capacity in the mouse. IMPORTANCE This article characterizes the interaction between human STING and DENV viral protease complex NS2B3 by constructing serial deletion mutants of STING. Our findings suggest that DENV nonstructural protein NS2B interacts with the transmembrane domains and NS3 with the C-terminal cyclic dinucleotide binding domain of human STING. Furthermore, as there exists no ideal immunocompetent murine model that can simultaneously support robust DENV replication and recapitulate the clinical manifestation of dengue disease observed in humans, we expressed and characterized two promising human-mouse chimeric STING constructs that can be used for developing a relevant transgenic mouse model to study dengue in the future. Both constructs can activate normal IFN responses in the overexpression system and be cleaved under infection conditions. We believe our findings offer a roadmap to the further development of a murine model that can greatly facilitate antiviral discoveries and vaccine research for DENV.

Summary: The tetravalent dengue vaccine candidate, TAK-003, induces a functional antibody response, but the titers of antibodies against the four serotypes of the dengue virus (DENV) can vary. Here, through a transcriptomic analysis on whole blood collected from recipients of a two-dose schedule of TAK-003, we examine gene expression, splicing, and transcript isoform-level changes for both protein-coding and noncoding genes to broaden our understanding of the immune response. Our analysis reveals a dynamic pattern of vaccine-associated regulation of long noncoding RNAs (lncRNAs), differential splicing of interferon-stimulated gene exons, and gene expression changes related to multiple signaling pathways that detect viral infection. Co-expression networks isolate immune cell-type-related and interferon-response modules that represent specific biological processes that correlate with more robust antibody responses. These data provide insights into the early determinants of the variable immune response to the vaccine, highlighting the significance of splicing and isoform-level gene regulatory mechanisms in defining vaccine immunogenicity.

The B Corp movement is becoming increasingly important nationally and internationally. In fact, the number of certified companies has radically increased (34,78%) from 2017 (2300 B-Corp companies) to 2019 (3100 B-Corp companies). Taking this fact into consideration, the aim of this study is to present a research protocol for conducting a systematic review of literature on B Corp companies. First, the inclusion and exclusion criteria applied that allow reaching the final sample of 45 articles are specified. The codes that will be used in the analysis phase are also made explicit.

El análisis de la literatura especializada en la educación empresarial permite ver las dudas existentes en torno a su validez y la dificultad de comparación y generalización de los resultados obtenidos por las investigaciones previas sobre esta educación, al no existir un consenso en su definición y terminología. Por tanto, el objetivo de este trabajo es establecer y delimitar una definición que integre las diferentes perspectivas existentes en la literatura previa y se consiga, de este modo, un lenguaje unificado que contribuya a definir programas formativos que alcancen los objetivos deseados, aumenten las intenciones empresariales y mejoren las competencias empresariales

Major advances in information and communication technologies (ICTs) make citizens to be considered as sensors in motion. Carrying their mobile devices, moving in their connected vehicles or actively participating in social networks, citizens provide a wealth of information that, after properly processing, can support numerous applications for the benefit of the community. In the context of smart communities, the INRISCO [1] proposal intends for (i) the early detection of abnormal situations in cities (i.e., incidents), (ii) the analysis of whether, according to their impact, those incidents are really adverse for the community; and (iii) the automatic actuation by dissemination of appropriate information to citizens and authorities. Thus, INRISCO will identify and report on incidents in traffic (jam, accident) or public infrastructure (e.g., works, street cut), the occurrence of specific events that affect other citizens' life (e.g., demonstrations, concerts), or environmental problems (e.g., pollution, bad weather). It is of particular interest to this proposal the identification of incidents with a social and economic impact, which affects the quality of life of citizens.

There is a consensus about the good sensing characteristics of Twitter to mine and uncover knowledge in financial markets, being considered a relevant feeder for taking decisions about buying or holding stock shares and even for detecting stock manipulation. Although Twitter hashtags allow to aggregate topic-related content, a specific mechanism for financial information also exists: Cashtag (consisting of the company ticker preceded by $) is a supporting mechanism to track financial tweets referring to a company listed in a stock market. However, according to our experiments and due to the lack of conventions in cashtags usage, the irruption of cryptocurrencies has resulted in a significant degradation on the cashtag-based aggregation of posts. Unfortunately, Twitter' users may use homonym tickers to refer to cryptocurrencies and to companies in stock markets, which means that filtering by cashtag may result on both posts referring to stock companies and cryptocurrencies. This research proposes automated classifiers to distinguish conflicting cashtags and, so, their container tweets by analyzing the distinctive features of tweets referring to stock companies and cryptocurrencies. As experiment, this paper analyses the interference between cryptocurrencies and company tickers in the London Stock Exchange (LSE), specifically, companies in the main and alternative market indices FTSE-100 and AIM-100. Heuristic-based as well as supervised classifiers are proposed and their advantages and drawbacks, including their ability to self-adapt to Twitter usage changes, are discussed. The experiment confirms a significant distortion in collected data when colliding or homonym cashtags exist, i.e., the same $ acronym to refer to company tickers and cryptocurrencies. According to our results, the distinctive features of posts including cryptocurrencies or company tickers support accurate classification of colliding tweets (homonym cashtags) and Independent Models, as the most detached classifiers from training data, have the potential to be trans-applicability (in different stock markets) while retaining performance.

Addressing the biodiversity crisis requires renewed collaborative approaches. Large carnivores are ambassador species, and as such they can aid the protection of a wide range of species, including evolutionarily distinct and threatened ones, while being popular for conservation marketing. However, conflicts between carnivores and people present a considerable challenge to biodiversity conservation. Our cross disciplinary essay brings together original research to discuss key issues in the conservation of large carnivores as keystone species for biodiversity rich, healthy ecosystems. Our findings suggest the need to promote coexistence through challenging ‘wilderness’ myths; to consider coexistence/conflict as a continuum; to include varied interest groups in decision making; to address fear through positive mediated experiences, and to explore further partnerships with zoos. As wide-reaching institutions visited by over 700 million people/year worldwide, zoos combine knowledge, emotion and social context creating ideal conditions for the development of care towards nature, pro-environmental behaviors and long-term connections between visitors and carnivores. Based on current research, we provide evidence that large carnivores and zoos are both powerful catalysts for public engagement with biodiversity conservation, recognizing barriers and suggesting future ways to collaborate to address biodiversity loss.

Con el fin de reducir el impacto que tiene al depositar los desechos sólidos en el ambiente y conociendo la problemática que hay en Panamá en temas de basura, se plantea la utilización del plástico como elemento reforzador del concreto en la construcción de elementos de acera. Para tal efecto se construyeron especímenes y se sometieron a pruebas para determinar si es viable la implementación de este método. Para la mezcla se utilizó 9 Kg/m3 de plástico, en la que este porcentaje fue escogido con referencia a los ensayos realizados en la investigación Estudio de Propiedades Mecánicas del Concreto reforzado con fibras de polipropileno reciclado, trabajo realizado por el Ingeniero Carlos González.

Two novel crystal forms of bis(oxonium) ethane-1,2-disulfonate, 2H3O−·C2H4O6S22−, are reported. Polymorph II has monoclinic (P21/n) symmetry, while the symmetry of form III is triclinic (P\overline{1}). Both structures display extensive networks of O—H...O hydrogen bonds. While this network in Form II is similar to that observed for the previously reported Form I [Mootz & Wunderlich (1970). Acta Cryst. B26, 1820–1825; Sartori et al. (1994). Z. Naturforsch. 49, 1467–1472] and extends in all directions, in Form III it differs significantly, forming layers parallel to the ab plane. The sulfonate molecule in all three forms adopts a nearly identical geometry. The other observed differences between the forms, apart from the hydrogen-bonding network, are observed in the crystal density and packing index.