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We conducted a multicenter and retrospective study to describe the use of botulinum toxin type A (BoNT-A) to treat post-stroke spasticity (PSS). Data were extracted from free-text in electronic health records (EHRs) in five Spanish hospitals. We included adults diagnosed with PSS between January 2015 and December 2019, stratified into BoNT-A-treated and untreated groups. We used EHRead® technology, which incorporates natural language processing and machine learning, as well as SNOMED CT terminology. We analyzed demographic data, stroke characteristics, BoNT-A use patterns, and other treatments. We reviewed the EHRs of 1,233,929 patients and identified 2190 people with PSS with a median age of 69 years; in total, 52.1% were men, 70.7% had cardiovascular risk factors, and 63.2% had suffered an ischemic stroke. Among the PSS patients, 25.5% received BoNT-A at least once. The median time from stroke to spasticity onset was 205 days, and the time from stroke to the first BoNT-A injection was 364 days. The primary goal of BoNT-A treatment was pain control. Among the study cohort, rehabilitation was the most common non-pharmacological treatment (95.5%). Only 3.3% had recorded monitoring scales. In conclusion, a quarter of patients with PSS received BoNT-A mainly for pain relief, typically one year after the stroke. Early treatment, disease monitoring, and better data documentation in EHRs are crucial to improve PSS patients’ care.

Summary: SARS-CoV-2 infection and vaccination elicit potent immune responses. Our study presents a comprehensive multimodal single-cell analysis of blood from COVID-19 patients and healthy volunteers receiving the SARS-CoV-2 vaccine and booster. We profiled immune responses via transcriptional analysis and lymphocyte repertoire reconstruction. COVID-19 patients displayed an enhanced interferon signature and cytotoxic gene upregulation, absent in vaccine recipients. B and T cell repertoire analysis revealed clonal expansion among effector cells in COVID-19 patients and memory cells in vaccine recipients. Furthermore, while clonal αβ T cell responses were observed in both COVID-19 patients and vaccine recipients, expansion of clonal γδ T cells was found only in infected individuals. Our dataset enables side-by-side comparison of immune responses to infection versus vaccination, including clonal B and T cell responses. Our comparative analysis shows that vaccination induces a robust, durable clonal B and T cell responses, without the severe inflammation associated with infection.

Summary: Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.

Background: The optimal treatment for patients with osteoarthritis (OA) of the knees and meniscal injuries has been extensively analyzed. Most research studies of patients treated by arthroscopic surgery have shown satisfactory results in the short and medium term. Objective: To evaluate if arthroscopic knee surgery provides additional benefit over a 3-year period in middle-aged patients with meniscal and knee-locking symptoms and to demonstrate that arthroscopic surgery of osteoarthritic knees improves patient function and satisfaction. Methods: A retrospective analysis was performed on 50 consecutive patients (51 knees) with a diagnosis of OA, treated with arthroscopic surgery. Radiological lesions were classified using the Kellgren-Lawrence scale, and the extent of OA was classified using the International Cartilage Repair Society (IRCS) classification. The results were evaluated using a postoperative knee scale that contains three parameters. The follow-up period was three years. Results: The patients had 64.7% good results, 21.56% regular results, and 13.72% bad results. The best results were obtained in patients with mild and moderate OA and symptoms of mechanical joint injury. The effect of predictive factors was uncertain due to the small sample size in subgroup analyses. Conclusion: Treatment with arthroscopic surgery can improve function and activity levels in patients with mild and moderate OA, allowing the best results to be obtained in those with symptoms of pain and blockage due to loose bodies or meniscal tears. In clinical relevance, arthroscopic surgery in knee OA produces significant improvement in selected patients that allows to improve pain, mobility and function. Level of Evidence: level IV; retrospective longitudinal cohort study.

Background: The optimal treatment for patients with osteoarthritis (OA) of the knees and meniscal injuries has been extensively analyzed. Most research studies of patients treated by arthroscopic surgery have shown satisfactory results in the short and medium term. Objective: To evaluate if arthroscopic knee surgery provides additional benefit over a 3-year period in middle-aged patients with meniscal and knee-locking symptoms and to demonstrate that arthroscopic surgery of osteoarthritic knees improves patient function and satisfaction. Methods: A retrospective analysis was performed on 50 consecutive patients (51 knees) with a diagnosis of OA, treated with arthroscopic surgery. Radiological lesions were classified using the Kellgren-Lawrence scale, and the extent of OA was classified using the International Cartilage Repair Society (IRCS) classification. The results were evaluated using a postoperative knee scale that contains three parameters. The follow-up period was three years. Results: The patients had 64.7% good results, 21.56% regular results, and 13.72% bad results. The best results were obtained in patients with mild and moderate OA and symptoms of mechanical joint injury. The effect of predictive factors was uncertain due to the small sample size in subgroup analyses. Conclusion: Treatment with arthroscopic surgery can improve function and activity levels in patients with mild and moderate OA, allowing the best results to be obtained in those with symptoms of pain and blockage due to loose bodies or meniscal tears. In clinical relevance, arthroscopic surgery in knee OA produces significant improvement in selected patients that allows to improve pain, mobility and function. Level of Evidence: level IV; retrospective longitudinal cohort study.

Abstract Background Leishmaniasis is a vector-borne disease caused by several species from genus Leishmania. An increase in the number of cases related to human movement has been informed in the last years. Due to the increase of suspicious leishmaniasis cases arriving in Cuba during 2017, a general analysis is presented herein. Methods Clinical samples were collected from 5 patients suspicious of leishmaniasis, received from January to December 2017 at the Institute of Tropical Medicine Pedro Kourí, Cuba. Skin lesion samples were analyzed using different diagnostic assays: direct smear, histological examination, and molecular analysis for species identification. Epidemiological and demographic data were requested from each case and analyzed. Treatment and follow up of patient was also performed. Results Five cases were confirmed as Leishmania infection according to microscopic observation and molecular methods results. PCR-18S, PCR-N/RFLP and PCR-F/RFLP identified the following species: L. panamensis (2 cases), L. braziliensis (1 case), L.panamensis/L.guyanensis (1 case), L. mexicana complex (1 case). In treated patients, drugs were well tolerated, cure were documented and no relapse have been currently reported (3 years later). Conclusions Clinical characteristics, demographic data, and epidemiological features of infection for each case evidence the potential risk related with travel to endemic areas of leishmaniasis. Keyworks Cutaneous leishmaniasis, Epidemiology, Imported cases.

La limitación al ejercicio de los derechos humanos debe encerrar una alta preocupación al constituir un acto del poder estatal que puede generar eventualmente acciones arbitrarias o dictatoriales que socaven el estado de derecho por ello, adquiere radical importancia establecer su instrumentación y regulación con específica exactitud dentro de las estructuras constitucionales o legales.

Introduction: Immune checkpoint inhibitor (ICI) therapy is markedly improving the prognosis of patients with several types of cancer. On the other hand, the growth in the use of these drugs in oncology is associated with an increase in multiple immune-related adverse events (irAEs), whose optimal prevention and management remain unclear. In this context, there is a need for reliable and validated biomarkers to predict the occurrence of irAEs in patients treated with ICIs. Thus, the main objective of this study is to evaluate the diagnostic performance of a sensitive routinely available panel of autoantibodies consisting of antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibodies to identify patients at risk of developing irAEs.Methods and Analysis: A multicenter, prospective, observational, cohort study has been designed to be conducted in patients diagnosed with cancer amenable to ICI therapy. Considering the percentage of ICI-induced irAEs to be 25% and a loss to follow-up of 5%, it has been estimated that a sample size of 294 patients is required to detect an expected sensitivity of the autoantibody panel under study of 0.90 with a confidence interval (95%) of no less than 0.75. For 48 weeks, patients will be monitored through the oncology outpatient clinics of five hospitals in Spain. Immune-related adverse events will be defined and categorized according to CTCAE v. 5.0. All the patients will undergo ordinary blood tests at specific moments predefined per protocol and extraordinary blood tests at the time of any irAE being detected. Ordinary and extraordinary samples will be frozen and stored in the biobank until analysis in the same autoimmunity laboratory when the whole cohort reaches week 48. A predictive model of irAEs will be constructed with potential risk factors of immune-related toxicity including the autoantibody panel under study.Ethics and Dissemination: This protocol was reviewed and approved by the Ethical Committee of the Basque Country and the Spanish Agency of Medicines and Medical Devices. Informed consent will be obtained from all participants before their enrollment. The authors declare that the results will be submitted to an international peer-reviewed journal for their prompt dissemination.

AbstractBackground The aim of this study was to assess the diagnostic performance of an autoantibody battery in patients receiving immune checkpoint inhibitors who experienced immune-related adverse events (irAEs).Methods We retrospectively analyzed several variables potentially related to irAEs, namely, demographic, clinical, and laboratory characteristics, including an autoantibody battery (antinuclear, anti-neutrophil cytoplasmic, anti-thyroid antibodies and rheumatoid factor).Results Sixty-nine patients (48 men; 61.8 ± 10.9 years at baseline) diagnosed with stage-4 solid-organ cancer and treated with nivolumab were followed up for 12 ± 10.3 months. Thirty-two irAEs were detected in 26 patients (37.5%). Adverse events occurred more commonly in women (62% vs. 27%, p = .006), and younger patients (irAEs: 58.1 ± 9.8, no irAEs: 64.1 ± 10.9 years, p = .024). Autoantibody battery results were available for 26 patients and were more frequently positive in patients with irAEs (87% vs. 30%, p = .009). The positive predictive value, negative predictive value, and diagnostic accuracy of the battery were 82.3%, 77.8%, and 80.8%, respectively. Among the 64 patients with an evaluable response, 23 (38.5%) experienced tumour progression, this being less frequent in patients with irAEs (19% vs. 48.5%, p = .03). Overall survival was higher in patients developing irAEs (HR = 1.88, p = .05).Conclusion Positivity in a readily available autoantibody battery may be associated with the occurrence of irAEs.KEY MESSAGESPositivity in an accessible and inexpensive autoantibody battery including antinuclear, anti-neutrophil cytoplasmic, anti-thyroid antibodies and rheumatoid factor may be associated with the occurrence of immune-related adverse events.Patients with cancer on immune checkpoint inhibitors experiencing immune-related adverse events showed a lower risk of progression and better overall survival than patients not experiencing this type of adverse effect.

La gerencia sostenible es un modelo de gestión capaz de plantear alternativas de solución a muchas de las problemáticas empresariales, bajo un enfoque estructural que entrelaza el crecimiento económico de la organización con el concepto de responsabilidad social. Por esta razón, su implementación se convierte en una estrategia necesaria para contribuir a la sustentabilidad del planeta. En este sentido, el presente documento expone un análisis conceptual y descriptivo de los aspectos más relevantes que involucra la gerencia sostenible como modelo de gestión eficaz, a fin de impulsar desde el ámbito académico la necesidad e importancia de adoptar este tipo de estrategias que mejoran tanto la productividad como la competitividad de la empresa, a la vez que benefician a la sociedad y el medioambiente.

This study addresses the planning procedures for the installation of the mooring systems that support the floating offshore wind turbines in a wind farm. It considers the logistics of the installation process and discusses the important role of the weather windows in the planning of those operations at a preliminary stage of the project. The case study is based on a wind farm array of 47 Telwind floating wind turbine platforms, to be located in Lannion (France), with a potential of 470 MW. The study includes the transport and logistics requirements of different mooring components, such as chains, connectors and drag anchors; the description of the installation operations considering the typology of vessels that are necessary in these manoeuvres; as well as the planning and costs associated with the transport and installation. Given the diversity of elements and operations involved in the installation procedure, it is demonstrated that the research results of duration and costs of this type of operations are only possible to obtain using a simulation tool.

Simultaneous measurement of surface proteins and gene expression within single cells using oligo-conjugated antibodies offers high-resolution snapshots of complex cell populations. Signal from oligo-conjugated antibodies is quantified by high-throughput sequencing and is highly scalable and sensitive. We investigated the response of oligo-conjugated antibodies towards four variables: concentration, staining volume, cell number at staining, and tissue. We find that staining with recommended antibody concentrations causes unnecessarily high background and amount of antibody used can be drastically reduced without loss of biological information. Reducing staining volume only affects antibodies targeting abundant epitopes used at low concentrations and is counteracted by reducing cell numbers. Adjusting concentrations increases signal, lowers background, and reduces costs. Background signal can account for a major fraction of total sequencing and is primarily derived from antibodies used at high concentrations. This study provides new insight into titration response and background of oligo-conjugated antibodies and offers concrete guidelines to improve such panels.

Abstract Exosome production from cancer-associated fibroblasts seems to be an important driver of tumor progression. We report the first in-depth biotype characterization of ncRNAs, analyzed by Next Generation Sequencing and Bioinformatics, expressed in established primary human normal and cancer-associated fibroblasts (CAFs) from cancer and normal mucosa tissues from 9 colorectal cancer patients, and/or packaged in their derived exosomes. Differential representation and enrichment analyses based on these ncRNAs revealed a significant number of differences between the ncRNA content of exosomes and the expression patterns of the normal and cancer-associated fibroblast cells. ncRNA regulatory elements are specifically packaged in CAF-derived exosomes, supporting a specific cross-talk between CAFs and colon cancer cells and/or other stromal cells, mediated by exosomes. These sncRNAs are potential biomarkers present in cancer-associated fibroblast-derived exosomes, which should thereby contribute to developing new non-invasive diagnostic, prognostic and predictive methods for clinical applications in management of cancer patients.

Cancer-associated fibroblasts (CAFs) are one of the major players in tumor-stroma crosstalk. Findings in experimental studies suggest important roles for CAFs in regulation of tumor growth, metastasis and drug response (Hanahan and Coussens, 2012). Furthermore, their clinical relevance is supported by new findings from tumor analyses, demonstrating the prognostic and response-predictive significance of CAF-derived markers or gene signatures (Berdiel-hacer et al., 2014; Finak et al., 2008; Navab et al., 2011; Paulsson and Micke, 2014). CAFs are a heterogeneous pool of cell subsets with distinct functions which needs to be better defined by their marker expressions. The development of a methodology for the establishment of fibroblast primary cultures derived from human colon tumors allowed us to characterize their functional and molecular properties (Herrera et al., 2013). In addition, the different molecular mechanisms through which CAFs affect tumor growth and metastasis are still to be clarified. Therefore, functional and molecular characterization of the cancer-associated fibroblasts is essential to fully understand their role in tumor progression.

Cellular adaptation to hypoxia is a protective mechanism for neurons and relevant to cancer. Treatment with desferrioxamine (DFO) to induce hypoxia reduced the viability of human neuronal NMB cells. Surviving/attached cells exhibited profound increases of expression of the human kappa-opioid receptor (hKOR) and hypoxia inducible factor-1α (HIF-1α). The functional relationship between hKOR and HIF-1α was investigated using RT-PCR, Western blot, luciferase reporter, mutagenesis, siRNA and receptor-ligand binding assays. In surviving neurons, DFO increased HIF-1α expression and its amount in the nucleus. DFO also dramatically increased hKOR expression. Two (designated as HIFC and D) out of four potential HIF response elements of the hKOR gene (HIFA–D) synergistically mediated the DFO response. Mutation of both elements completely abolished the DFO-induced effect. The CD11 plasmid (containing HIFC and D with an 11 bp spacing) produced greater augmentation than that of the CD17 plasmid (HIFC and D with a 17 bp-spacing), suggesting that a proper topological interaction of these elements synergistically enhanced the promoter activity. HIF-1α siRNA knocked down the increase of endogenous HIF-1α messages and diminished the DFO-induced increase of hKOR expression. Increased hKOR expression resulted in the up-regulation of hKOR protein. In conclusion, the adaptation of neuronal hKOR under hypoxia was governed by HIF-1, revealing a new mechanism of hKOR regulation.

In the title compound, alternatively called α-hydroxy-γ-alkylidenebutenolide, C12H16O3, two independent molecules (A and B) crystallize in the asymmetric unit in each of which the 5,6-dihydrobenzo ring has an envelope conformation. The torsion angle along the butadiene chain in the γ-alkylidenebutenolide core is −177.9 (2)° for molecule A and 179.9 (2)° for molecule B. In the crystal, O—H...O hydrogen bonds between hydroxyl and carbonyl groups of adjacent independent molecules form dimers with R22(10) loops.

Climate change threatens archaeological sites and cultural landscapes globally. While to date, awareness and action around cultural heritage and climate change adaptation planning has focused on Europe and North America, in this article, the authors address adaptation policy and measures for heritage sites in low- and middle-income countries. Using a review of national adaptation plans, expert survey and five case studies, results show the varied climate change adaptation responses across four continents, their strengths and weaknesses, and the barriers to be addressed to ensure better integration of cultural heritage in climate change adaptation planning. Keywords: climate change, adaptation plans, cultural heritage, policy making, place-based solutions, community engagement, Introduction Climate change threatens archaeological resources globally. Many sites have already been affected and this number will only increase in the future. Current management practices and mechanisms are unlikely to [...]