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Reading should be the cornerstone of a school’s curriculum in order to build up the other skills. Despite the fact that reading tends to be an obligation and a hard task, it should be seen as a fun activity which will extend the student’s knowledge of the world. Reading efficiently in volves not only understanding, speed and fluency, but also the application of the student’s knowledge, thus promoting critical thinking. That is to say, the “ability to reach sound conclusions based on observation and information”. Due to the importance of acquiring reading skills in a foreign language, we see the necessity to stimulate students toward becoming efficient readers. That means avoiding word by word reading (Williams: 1984), and developing students’ abilities to understand and comprehend a text and to read fluently

People's subjective response to any thermal environment is commonly investigated by using rating scales describing the degree of thermal sensation, comfort, and acceptability. Subsequent analyses of results collected in this way rely on the assumption that specific distances between verbal anchors placed on the scale exist and that relationships between verbal anchors from different dimensions that are assessed (e.g. thermal sensation and comfort) do not change. Another inherent assumption is that such scales are independent of the context in which they are used (climate zone, season, etc.). Despite their use worldwide, there is indication that contextual differences influence the way the scales are perceived and therefore question the reliability of the scales’ interpretation. To address this issue, a large international collaborative questionnaire study was conducted in 26 countries, using 21 different languages, which led to a dataset of 8225 questionnaires. Results, analysed by means of robust statistical techniques, revealed that only a subset of the responses are in accordance with the mentioned assumptions. Significant differences appeared between groups of participants in their perception of the scales, both in relation to distances of the anchors and relationships between scales. It was also found that respondents’ interpretations of scales changed with contextual factors, such as climate, season, and language. These findings highlight the need to carefully consider context-dependent factors in interpreting and reporting results from thermal comfort studies or post-occupancy evaluations, as well as to revisit the use of rating scales and the analysis methods used in thermal comfort studies to improve their reliability.

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With evolution technology constant, it is natural that institutions are facing drastic changes of paradigms with regard to the way in which operate, are managed and delivered services in the modern technological infrastructure; having great impact on private and public administrative and operational organizations who must be accomplished efficiently manage resources according to user requirements. This article describes the analysis, design, implementation and testing in the computation laboratories of the Universidad Distrital Francisco José de Caldas (Bogotá, Colombia) of two prototypes of virtual desktops as a service (DaaS) for students and teachers, based on the requirements of some subjects of the curricular project of systems engineering, through the technologies Citrix VDI-in-a-box Systems and Oracle Virtual Machine. Based on this, an assessment is established to determine the best prototype to be implemented in the computer rooms based on criteria like mode of administration, characteristics that must comply with the infrastructure of virtualization (VDI), the type of persistence, among other issues. In this way, it is determined that VDI-in-a-box of Citrix System shas characteristics that adapt better than Oracle Virtual Machine according to the needs of the educational classroom.

Salmonella enterica serovar Enteritidis-ly-sing bacteriophages isolated from poultry or human sewage sources were used to reduce Salmonella Enteritidis in vitro and in experimentally infected chicks. Cocktails of 4 different bacteriophages obtained from commercial broiler houses (CB4Ø) and 45 bacteriophages from a municipal wastewater treatment plant (WT450) were evaluated. In experiment 1, an in vitro crop assay was conducted with selected bacteriophage concentrations (105 to 109 pfu/mL) to determine ability to reduce Salmonella Enteritidis in the simulated crop environment. Following 2 h at 37°C, CB4Ø or WT45Ø reduced Salmonella Enteritidis recovery by 1.5 or 5 log, respectively, as compared with control. However, CB4Ø did not affect total SE recovery after 6 h, whereas WT45Ø resulted in up to a 6-log reduction of Salmonella Enteritidis. In experiment 2, day-of-hatch chicks were challenged orally with 3 x 103 cfu/chick Salmonella Enteritidis and treated cloacally with 1 x 109 WT45Ø pfu/chick 1 h postchallenge. One hour later, chicks were treated or not with a commercially available probiotic (Floramax-B11). Both treatments significantly reduced Salmonella Enteritidis recovery from cecal tonsils at 24 h following vent lip application as compared with controls, but no additive effect was observed with the combination of bacteriophages and probiotic. In experiment 3, day-of-hatch chicks were challenged orally with 9 x 103 cfu/chick Salmonella Enteritidis and treated via oral gavage with 1 x 108 CB4Ø pfu/chick, 1.2 x 108 WT45Ø pfu/chick, or a combination of both, 1 h postchallenge. All treatments significantly reduced Salmonella Enteritidis recovered from cecal tonsils at 24 h as compared with untreated controls, but no significant differences were observed at 48 h following treatment. These data suggest that some bacteriophages can be efficacious in reducing SE colonization in poultry during a short period, but with the bacteriophages and methods presently tested, persistent reductions were not observed. [ABSTRACT FROM AUTHOR]

The nasal, oropharyngeal, and bronchial mucosa are primary contact points for airborne pathogens like Mycobacterium tuberculosis (Mtb), SARS-CoV-2, and influenza virus. While mucosal surfaces can function as both entry points and barriers to infection, mucosa-associated lymphoid tissues (MALT) facilitate early immune responses to mucosal antigens. MALT contains a variety of specialized epithelial cells, including a rare cell type called a microfold cell (M cell) that functions to transport apical antigens to basolateral antigen-presenting cells, a crucial step in the initiation of mucosal immunity. M cells have been extensively characterized in the gastrointestinal (GI) tract in murine and human models. However, the precise development and functions of human airway M cells is unknown. Here, using single-nucleus RNA sequencing (snRNA-seq), we generated an atlas of cells from the human adenoid and identified 16 unique cell types representing basal, club, hillock, and hematopoietic lineages, defined their developmental trajectories, and determined cell-cell relationships. Using trajectory analysis, we found that human airway M cells develop from progenitor club cells and express a gene signature distinct from intestinal M cells. Surprisingly, we also identified a heretofore unknown epithelial cell type demonstrating a robust interferon-stimulated gene signature. Our analysis of human adenoid cells enhances our understanding of mucosal immune responses and the role of M cells in airway immunity. This work also provides a resource for understanding early interactions of pathogens with airway mucosa and a platform for development of mucosal vaccines.

Over recent decades, anthropogenic forest fires have significantly altered vegetation dynamics in the Amazon region. While human activities primarily initiate these fires, their escalation is intricately linked to climatic conditions, particularly droughts induced by the warm El Niño phase. This study investigates the impact of meteorological and hydrological drought on forest fires in the Amazon, focusing on the role of groundwater and El Niño events. Utilizing comprehensive drought indicators at various soil depths and standardized precipitation indexes, the research spans from 2004 to 2016, revealing a consistent decrease in humidity conditions across surface soil moisture, root zone soil moisture, and groundwater storage levels. With its slower response to precipitation changes, groundwater emerges as a crucial factor influencing hydrological drought patterns in the Amazon. The spatial distribution of drought conditions is explored, highlighting areas with lower humidity concentrations in the northeast and a correlation between forest fires and positive rates of change in burned area fraction during El Niño events. Notably, the study underscores the substantial increase in burned area during the 2015-2016, characterized by a very strong El Niño. This nuanced understanding of groundwater dynamics and its interplay with El Niño events provides critical insights for developing a tailored fire risk index in the ecologically significant and vulnerable Amazon basin, subsidizing strategies for mitigating fire risk and enhancing preparedness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The COVID-19 pandemic has reshaped healthcare delivery worldwide., Objective: To explore potential changes in the reasons for visits and modality of care in primary care settings through the International Consortium of Primary Care Big Data Researchers (INTRePID)., Methods: We conducted a cross-sectional, retrospective study from 2018-2021. We examined visit volume, modality, and reasons for visits to primary care in Argentina, Australia, Canada, China, Peru, Norway, Singapore, Sweden, and the USA. The analysis involved a comparison between the pre-pandemic and pandemic periods., Results: There were more than 215 million visits from over 38 million patients during the study period in INTRePID primary care settings. Most INTRePID countries experienced a decline in monthly visit rates during the first year of the pandemic, with rate ratios (RR) and 95% confidence intervals (CI) ranging from RR:0.57 (95%CI:0.49-0.66) to RR:0.90 (95%CI:0.83-0.98), except for in Canada (RR:0.99, 95%CI:0.94-1.05) and Norway (RR:1.00, 95%CI:0.92-1.10), where rates remained stable and in Australia where rates increased (RR:1.19, 95%CI:1.11-1.28). Argentina, China, and Singapore had limited or no adoption of virtual care, whereas the remaining INTRePID countries varied in the extent of virtual care utilization. In Peru, virtual visits accounted for 7.34% (95%CI:7.33%-7.35%) of all interactions in the initial year of the pandemic, dipping to 5.22% (95%CI:5.21%-5.23%) in the subsequent year. However, in Canada 75.30% (95%CI:75.20%-75.40%) of the visits in the first year were virtual, decreasing to 62.77% (95%CI:62.66%-62.88%) in the second year. Diabetes, hypertension and/or hyperlipidemia and general health exams were in the top 10 reasons for visits in 2019 for all countries. Anxiety, depression and/or other mental health related reasons were among the top 10 reasons for virtual visits in all countries that had virtual care., Conclusions: The pandemic resulted in changes in reasons for visits to primary care, with virtual care mitigating visit volume disruptions in many countries., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KT receives a Chair in Family and Community Medicine Research in Primary Care at UHN and a Research Scholar award from the Department of Family and Community University of Toronto. She has received grants from the following organizations in the past 3 years: The Canadian Institutes of Health Research, Rathlyn Foundation Primary Care EMR Research and Discovery Fund, College of Family Physicians of Canada/Foundation for Advancing Family Medicine/CMA Foundation Heart and Stroke Foundation of Ontario, Department of Defense United States of America, St. Michael’s Hospital Foundation, Ontario Health Data Platform First Movers Fund, Queen’s University CSPC Research Initiation Grant, Diabetes Canada, Heart and Stroke Foundation and Brain Canada Heart-Brain IMPACT Award, CANSSI ICES Data Access Grant, North York General Hospital Exploration Fund, CFPC Janus Grant. MSCF receives honoraria and stocks from the Peruvian Cayetano Heredia University (Universidad Peruana Cayetano Heredia). SDL research group receives payments from the University of Oxford and the University of Surrey for conducting health services and primary care research. Moreover, they receive payments from pharmaceutical companies AstraZeneca, GSK, Sanofi, Seqirus, and Takeda for vaccine-related research. Additionally, SDL receives payments for membership on advisory boards for AstraZeneca, Sanofi, and Seqirus. RSK teaches at the Swedish advanced training program in quality improvement, Jonkoping Academy, and owns stocks in the Swedish healthcare company Ambea. AL received datasets and software from the University of Melbourne for data analysis in the present manuscript. He received remuneration as part of contracted wages from the University of Melbourne as part of his existing employment. JMN has received funding from the following organizations in the past 3 years: National Health and Medical Council, Medical Research Future Fund, Paul Ramsay Foundation, RACGP Foundation, and Astra Zeneca. This funding has all been provided to institutions, not personally. Related to use of general practice data, she holds shares in Torch Recruit, clinical trial recruitment software which is a spin off company from The University of Melbourne. WDP sits on the AT Still Research Advisory Board, for which he receives $1000 per year when meetings occur, although these meetings are irregular. He also serves voluntarily on the CO Aca. Fam Med. Leg. Com, Colorado Medicaid Provider Rate Review Com, and NAEPPCC Expert WG #4. He holds stocks in Johnson and Johnson, Eli Lilly, Novo Nordisk, Pfizer, Stryker, Amgen, Moderna, and Novartis, managed by independent advisors. Additionally, he receives supplies from Boehringer Ingelheim and AstraZeneca for COPD quality improvement studies and data analysis using secondary data. JMW was Past President at NAPCRG, an international primary care research organization holding an unpaid position. All other authors have declared that no competing interests exist. No funding sources were involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and the decision to submit the article for publication. The researchers are all independent of funders, and KT, AOB, MCL had full access to all the data and authors from each country had full access to the country-specific data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis., (Copyright: © 2024 Tu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: The majority of patients with respiratory illness are seen in primary care settings. Given COVID-19 is predominantly a respiratory illness, the INTernational ConsoRtium of Primary Care BIg Data Researchers (INTRePID), assessed the pandemic impact on primary care visits for respiratory illnesses., Design: Definitions for respiratory illness types were agreed on collectively. Monthly visit counts with diagnosis were shared centrally for analysis., Setting: Primary care settings in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden and the United States., Participants: Over 38 million patients seen in primary care settings in INTRePID countries before and during the pandemic, from January 1st, 2018, to December 31st, 2021., Main Outcome Measures: Relative change in the monthly mean number of visits before and after the onset of the pandemic for acute infectious respiratory disease visits including influenza, upper and lower respiratory tract infections and chronic respiratory disease visits including asthma, chronic obstructive pulmonary disease, respiratory allergies, and other respiratory diseases., Results: INTRePID countries reported a marked decrease in the average monthly visits for respiratory illness. Changes in visits varied from -10.9% [95% confidence interval (CI): -33.1 to +11.3%] in Norway to -79.9% (95% CI: -86.4% to -73.4%) in China for acute infectious respiratory disease visits and - 2.1% (95% CI: -12.1 to +7.8%) in Peru to -59.9% (95% CI: -68.6% to -51.3%) in China for chronic respiratory illness visits. While seasonal variation in allergic respiratory illness continued during the pandemic, there was essentially no spike in influenza illness during the first 2 years of the pandemic., Conclusion: The COVID-19 pandemic had a major impact on primary care visits for respiratory presentations. Primary care continued to provide services for respiratory illness, although there was a decrease in infectious illness during the COVID pandemic. Understanding the role of primary care may provide valuable information for COVID-19 recovery efforts and planning for future global emergencies., Competing Interests: JW holds the position of Vice President and is employed by the DARTNet Institute, a non-profit organization specializing in primary care research. AB and ML work for the University of Toronto and part of their salary is supported by grants. WP has received grant funding from NIMCH, sits on the advisory board of AT Still Research Foundation, has stock in Moderna, Johnson and Johnson, Eli Lilly, Novo Nordisk, Styker, Amgen, Novartis, and Pfizer; and received supplies from Boehringer Ingelheim and AstraZeneca. RK teaches at the Swedish advanced training program in quality improvement and owns stocks in the Swedish healthcare company Ambea. SL is the director of the Royal College of General Practitioners (RCGP) Research and Surveillance Center (RSC) as part of his academic post at Oxford. He has received payment to his research group for health services and primary care research from the University of Oxford and the University of Surrey and a wide range of grant funding through his university for vaccine-related research from AstraZeneca, GSK, Sanofi, Segirus and Takeda. MC-F receives honoraria and stocks from the Peruvian Cayetano Heredia University (Universidad Peruana Cayetano Heredia). KT receives a Chair in Family and Community Medicine Research in Primary Care at UHN and a Research Scholar award from the Department of Family and Community University of Toronto. KT received grants from the following organizations in the past 3 years: The Canadian Institutes of Health Research, Rathlyn Foundation Primary Care EMR Research and Discovery Fund, College of Family Physicians of Canada/Foundation for Advancing Family Medicine/CMA Foundation Heart and Stroke Foundation of Ontario, Department of Defense United States of America, St. Michael’s Hospital Foundation, Ontario Health Data Platform First Movers Fund, Queen’s University CSPC Research Initiation Grant, Diabetes Canada, Heart and Stroke Foundation and Brain Canada Heart-Brain IMPACT Award, CANSSI ICES Data Access Grant, North York General Hospital Exploration Fund, CFPC Janus Grant. All funding sources were not involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and the decision to submit the article for publication. The researchers are all independent of funders, and KT, AB, ML had full access to all the data and authors from each country had full access to the country-specific data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Westfall, Bonilla, Lapadula, Zingoni, Wong, Wensaas, Pace, Silva-Valencia, Scattini, Ng, Manski-Nankervis, Ling, Li, Heald, Laughlin, Kristiansson, Hallinan, Goh, Gaona, Flottorp, de Lusignan, Cuba-Fuentes, Baste and Tu.)

Two-photon excitation (TPE) microscopy with near-infrared (NIR) emission has emerged as a promising technique for deep-tissue optical imaging. Recent developments in fluorescence lifetime imaging with long-lived emission probes have further enhanced the spatial resolution and precision of fluorescence imaging, especially in complex systems with short-lived background signals. In this study, two innovative lysosome-targeting probes, Cz-NA and tCz-NA, are introduced. These probes offer a combination of advantages, including TPE (λ ex = 880 nm), NIR emission (λ em = 650 nm), and thermally activated delayed fluorescence (TADF) with long-lived lifetimes (1.05 and 1.71 µs, respectively). These characteristics significantly improve the resolution and signal-to-noise ratio in deep-tissue imaging. By integrating an acousto-optic modulator (AOM) device with TPE microscopy, the authors successfully applied Cz-NA in two-photon excited delayed fluorescence (TPEDF) imaging to track lysosomal adaptation and immune responses to inflammation in mice. This study sheds light on the relationship between lysosome tubulation, innate immune responses, and inflammation in vivo, providing valuable insights for the development of autofluorescence-free molecular probes in the future., (© 2024 Wiley‐VCH GmbH.)

Photodynamic immunotherapy (PDI) is an innovative approach to cancer treatment that utilizes photodynamic therapy (PDT) and photosensitizers (PSs) to induce immunogenic cell death (ICD). However, currently most commonly used PSs have restricted capabilities to generate reactive oxygen species (ROS) via a type-II mechanism under hypoxic environments, which limits their effectiveness in PDI. To overcome this, we propose a novel approach for constructing oxygen independent PSs based on stable organic free-radical molecules. By fine-tuning the characteristics of tris(2,4,6-trichlorophenyl)-methyl (TTM) radicals through the incorporation of electron-donating moieties, we successfully found that TTMIndoOMe could produce substantial amounts of ROS even in hypoxic environments. In vitro experiments showed that TTMIndoOMe could effectively produce O 2 ˙ - , kill tumor cells and trigger ICD. Moreover, in vivo experiments also demonstrated that TTMIndoOMe could further trigger anti-tumor immune response and exhibit a superior therapeutic effect compared with PDT alone. Our study offers a promising approach towards the development of next-generation PSs functioning efficiently even under hypoxic conditions and also paves the way for the creation of more effective PSs for PDI., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: The COVID-19 pandemic impacted mental health disorders, affecting both individuals with pre-existing conditions and those with no prior history. However, there is limited evidence regarding the pandemic's impact on mental health visits to primary care physicians. The International Consortium of Primary Care Big Data Researchers (INTRePID) explored primary care visit trends related to mental health conditions in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden, and the USA., Methods: We conducted an interrupted time series analysis in nine countries to examine changes in rates of monthly mental health visits to primary care settings from January 1st, 2018, to December 31st, 2021. Sub-group analysis considered service type (in-person/virtual) and six categories of mental health conditions (anxiety/depression, bipolar/schizophrenia/other psychotic disorders, sleep disorders, dementia, ADHD/eating disorders, and substance use disorder)., Findings: Mental health visit rates increased after the onset of the pandemic in most countries. In Argentina, Canada, China, Norway, Peru, and Singapore, this increase was immediate ranged from an incidence rate ratio of 1·118 [95% CI 1.053-1.187] to 2.240 [95% CI 2.057-2.439] when comparing the first month of pandemic with the pre-pandemic trend. Increases in the following months varied across countries. Anxiety/depression was the leading reason for mental health visits in most countries. Virtual visits were reported in Australia, Canada, Norway, Peru, Sweden, and the USA, accounting for up to 40% of the total mental health visits., Interpretation: Findings suggest an overall increase in mental health visits, driven largely by anxiety/depression. During the COVID-19 pandemic, many of the studied countries adopted virtual care in particular for mental health visits. Primary care plays a crucial role in addressing mental ill-health in times of crisis., Funding: Canadian Institutes of Health Research grant #173094 and the Rathlyn Foundation Primary Care EMR Research and Discovery Fund., Competing Interests: CL and AO receive a salary for research associate positions at the University of Toronto. JMW holds the position of Vice President Medical Affairs and is employed by the DARTNet Institute. SdeL serves as the director of the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) the primary care sentinel network and he receives funding from the UK Health Security Agency for this position. Seqirus and Roche provided a bursary for speaking. AstraZeneca provided a bursary to attend a European conference. Additionally, AstraZeneca, Sanofi, and Seqirus provided funding for Advisory Board membership. RSK has received payment from Qulturum Jönköping County for lectures and support from Region Uppsala to attend WONCA Sydney 2023. MSC-F is an Associate Professor at the Universidad Peruana Cayetano Heredia, and the Director of the Primary Health Care Research Center. Her salary is sourced from teaching, contracts and grants awarded to the university. She has received a grant from the National Council of Science and Technology of Peru. KT receives a Chair in Family and Community Medicine Research in Primary Care at UHN. She has received grants from the following organizations in the past 3 years: The Canadian Institutes of Health Research, Rathlyn Foundation Primary Care EMR Research and Discovery Fund, College of Family Physicians of Canada/Foundation for Advancing Family Medicine/CMA Foundation Heart and Stroke Foundation of Ontario, Department of Defense United States of America, St. Michael's Hospital Foundation, Ontario Health Data Platform First Movers Fund, Queen's University CSPC Research Initiation Grant, Diabetes Canada, Heart and Stroke Foundation and Brain Canada Heart-Brain IMPACT Award, CANSSI ICES Data Access Grant, North York General Hospital Exploration Fund, CFPC Janus Grant. Support for attending meetings is provided by the Rathlyn Foundation Primary Care EMR Research and Discovery Fund. None of the other authors have reported any other potential conflicts of interest., (© 2024 The Author(s).)

Objective: To understand how the COVID-19 pandemic has impacted sexual and reproductive health (SRH) visits., Design: An ecological study comparing SRH services volume in different countries before and after the onset of the COVID-19 pandemic., Setting: Seven countries from the INTernational ConsoRtium of Primary Care BIg Data Researchers (INTRePID) across four continents., Population: Over 3.8 million SRH visits to primary care physicians in Australia, China, Canada, Norway, Singapore, Sweden and the USA., Methods: Difference in average SRH monthly visits before and during the pandemic, with negative binomial regression modelling to compare predicted and observed number of visits during the pandemic for SRH visits., Main Outcome Measures: Monthly number of visits to primary care physicians from 2018 to 2021., Results: During the pandemic, the average volume of monthly SRH visits increased in Canada (15.6%, 99% CI 8.1-23.0%) where virtual care was pronounced. China, Singapore, Sweden and the USA experienced a decline (-56.5%, 99% CI -74.5 to -38.5%; -22.7%, 99% CI -38.8 to -6.5%; -19.4%, 99% CI -28.3 to -10.6%; and -22.7%, 99% CI -38.8 to -6.5%, respectively); while Australia and Norway showed insignificant changes (6.5%, 99% CI -0.7 to -13.8% and 1.7%, 99% CI -6.4 to -9.8%). The countries that maintained (Australia, Norway) or surpassed (Canada) pre-pandemic visit rates had the greatest use of virtual care., Conclusions: In-person SRH visits to primary care decreased during the pandemic. Virtual care seemed to counterbalance that decline. Although cervical cancer screening appeared insensitive to virtual care, strategies such as incorporating self-collected samples for HPV testing may provide a solution in a future pandemic., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

The JAK-STAT pathway plays a crucial role in the signaling cascade associated with various cytokines that have been implicated in the pathogenesis of inflammatory diseases and myeloproliferative neoplasms (MPN). Among the isoforms of JAKs, the JAK2 subtype is primarily responsible for the function of hematopoietic system cells, making it a significant target in the treatment of MPN. However, the precise regulatory role of JAK2 in inflammatory diseases requires further investigation and confirmation. The current study employed a selective JAK2 inhibitor, ZT55, derived from Isatis indigotica roots, to examine its regulatory effects on inflammatory and immune responses in delayed-type hypersensitivity (DTH) and arthritis in mice. To evaluate the efficacy of ZT55 treatment, DNFB-induced DTH and collagen-induced arthritis (CIA) mouse models were utilized. T cells were cultured and subsequently analyzed for proliferation and activation using flow cytometry and EdU assay. Additionally, the maturation and function of dendritic cells were assessed through flow cytometry and ELISA. Our findings indicate that ZT55 significantly reduced DNFB-induced DTH and attenuated inflammation, cartilage degradation, and bone destruction in CIA mice. Moreover, ZT55 was found to inhibit the proliferation and activation of T cells and the maturation of dendritic cells by regulating the JAK2-STAT3 signaling pathway. These results suggest that selectively targeting the JAK2 isoform could have anti-inflammatory and immunosuppressive effects by regulating the adaptive and innate immune responses via the JAK2-STAT3 signaling pathway. Therefore, ZT55 has the potential to be a promising pharmaceutical candidate for the treatment of inflammatory and autoimmune diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Monocytes are key effectors in autoimmunity-related diseases in the central nervous system (CNS) due to the critical roles of these cells in the production of proinflammatory cytokines, differentiation of T-helper (Th) cells, and antigen presentation. The JAK-STAT signaling is crucial for initiating monocytes induced immune responses by relaying cytokines signaling. However, the role of this pathway in modulating the communication between monocytes and Th cells in the pathogenesis of multiple sclerosis (MS) is unclear. Here, we show that the JAK1/2/3 and STAT1/3/5/6 subtypes involved in the demyelination mediated by the differentiation of pathological Th1 and Th17 and the CNS-infiltrating inflammatory monocytes in experimental autoimmune encephalomyelitis (EAE), a model for MS. JAK inhibition prevented the CNS-infiltrating CCR2-dependent Ly6C hi monocytes and monocyte-derived dendritic cells in EAE mice. In parallel, the proportion of GM-CSF + CD4 + T cells and GM-CSF secretion were decreased in pathological Th17 cells by JAK inhibition, which in turns converted CNS-invading monocytes into antigen-presenting cells to mediate tissue damage. Together, our data highlight the therapeutic potential of JAK inhibition in treating EAE by blocking the GM-CSF-driven inflammatory signature of monocytes., Competing Interests: The authors declare no conflicts of interest., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Objective: This study investigated early, real-world outcomes with cenobamate (CNB) in a large series of patients with highly drug-resistant epilepsy within a Spanish Expanded Access Program (EAP)., Method: This was a multicenter, retrospective, observational study in 14 hospitals. Inclusion criteria were age ≥18 years, focal seizures, and EAP authorization. Data were sourced from patient clinical records. Primary effectiveness endpoints included reductions (100%, ≥90%, ≥75%, and ≥50%) or worsening in seizure frequency at 3-, 6-, and 12-month visits and at the last visit. Safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation., Results: The study included 170 patients. At baseline, median epilepsy duration was 26 years and median number of seizures/month was 11.3. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 12 and 3, respectively. Mean CNB dosages/day were 176 mg, 200 mg, and 250 mg at 3, 6, and 12 months. Retention rates were 98.2%, 94.5%, and 87% at 3, 6, and 12 months. At last available visit, the rate of seizure freedom was 13.3%; ≥90%, ≥75%, and ≥50% responder rates were 27.9%, 45.5%, and 63%, respectively. There was a significant reduction in the number of seizures per month (mean: 44.6%; median: 66.7%) between baseline and the last visit (P < 0.001). Responses were maintained regardless of the number of prior or concomitant ASMs. The number of concomitant ASMs was reduced in 44.7% of patients. The cumulative percentage of patients with AEs and AEs leading to discontinuation were 68.2% and 3.5% at 3 months, 74.1% and 4.1% at 6 months, and 74.1% and 4.1% at 12 months. The most frequent AEs were somnolence and dizziness., Significance: In this highly refractory population, CNB showed a high response regardless of prior and concomitant ASMs. AEs were frequent but mostly mild-to-moderate, and few led to discontinuation., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Tolerogenic dendritic cells (tolDCs) facilitate the suppression of autoimmune responses by differentiating regulatory T cells (Treg). The dysfunction of immunotolerance results in the development of autoimmune diseases, such as rheumatoid arthritis (RA). As multipotent progenitor cells, mesenchymal stem cells (MSCs), can regulate dendritic cells (DCs) to restore their immunosuppressive function and prevent disease development. However, the underlying mechanisms of MSCs in regulating DCs still need to be better defined. Simultaneously, the delivery system for MSCs also influences their function. Herein, MSCs are encapsulated in alginate hydrogel to improve cell survival and retention in situ , maximizing efficacy in vivo . The three-dimensional co-culture of encapsulated MSCs with DCs demonstrates that MSCs can inhibit the maturation of DCs and the secretion of pro-inflammatory cytokines. In the collagen-induced arthritis (CIA) mice model, alginate hydrogel encapsulated MSCs induce a significantly higher expression of CD39 + CD73 + on MSCs. These enzymes hydrolyze ATP to adenosine and activate A 2A/2B receptors on immature DCs, further promoting the phenotypic transformation of DCs to tolDCs and regulating naïve T cells to Tregs. Therefore, encapsulated MSCs obviously alleviate the inflammatory response and prevent CIA progression. This finding clarifies the mechanism of MSCs-DCs crosstalk in eliciting the immunosuppression effect and provides insights into hydrogel-promoted stem cell therapy for autoimmune diseases., Competing Interests: The authors declare no conflicts of interest., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Around one-third of epilepsy patients develop drug-resistant seizures; early detection of seizures could help improve safety, reduce patient anxiety, increase independence, and enable acute treatment. In recent years, the use of artificial intelligence techniques and machine learning algorithms in different diseases, including epilepsy, has increased significantly. The main objective of this study is to determine whether the mjn-SERAS artificial intelligence algorithm developed by MJN Neuroserveis, can detect seizures early using patient-specific data to create a personalized mathematical model based on EEG training, defined as the programmed recognition of oncoming seizures before they are primarily initiated, usually within a period of a few minutes, in patients diagnosed of epilepsy. Retrospective, cross-sectional, observational, multicenter study to determine the sensitivity and specificity of the artificial intelligence algorithm. We searched the database of the Epilepsy Units of three Spanish medical centers and selected 50 patients evaluated between January 2017 and February 2021, diagnosed with refractory focal epilepsy who underwent video-EEG monitoring recordings between 3 and 5 days, a minimum of 3 seizures per patient, lasting more than 5 s and the interval between each seizure was greater than 1 h. Exclusion criteria included age <18 years, intracranial EEG monitoring, and severe psychiatric, neurological, or systemic disorders. The algorithm identified pre-ictal and interictal patterns from EEG data using our learning algorithm and was compared to a senior epileptologist's evaluation as a gold standard. Individual mathematical models of each patient were trained using this feature dataset. A total of 1963 h of 49 video-EEG recordings were reviewed, with an average of 39.26 h per patient. The video-EEG monitoring recorded 309 seizures as subsequently analyzed by the epileptologists. The mjn-SERAS algorithm was trained on 119 seizures and split testing was performed on 188 seizures. The statistical analysis includes the data from each model and reports 10 false negatives (no detection of episodes recorded by video-EEG) and 22 false positives (alert detected without clinical correlation or abnormal EEG signal within 30 min). Specifically, the automated mjn-SERAS AI algorithm achieved a sensitivity of 94.7% (95 %; CI 94.67-94.73), and an F-Score representing specificity of 92.2% (95 %; CI 92.17-92.23) compared to the reference performance represented by a mean (harmonic mean or average) and a positive predictive value of 91%, with a false positive rate of 0.55 per 24 h in the patient-independent model. This patient-specific AI algorithm for early seizure detection shows promising results in terms of sensitivity and false positive rate. Although the algorithm requires high computational requirements on specialized servers cloud for training and computing, its computational load in real-time is low, allowing its implementation on embedded devices for online seizure detection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Celastrol (CEL), a pentacyclic triterpene compound, has been proven to have a definite antipulmonary fibrosis effect. However, its direct targets for antipulmonary fibrosis remain unknown. In this study, we designed and synthesized a series of celastrol-based probes to identify the direct targets in human pulmonary fibroblasts using an activity-based protein profiling strategy. Among many fished targets, we identified a key protein, cullin-associated and neddylation-dissociated 1 (CAND1), which was involved in fibroblast-myofibroblast transformation (FMT). More importantly, we found that the inhibitory effect of celastrol on FMT is dependent on CAND1, through improving the interactions between CAND1 and Cullin1 to promote the activity of Skp1/Cullin1/F-box ubiquitin ligases. In silico studies and cysteine mutation experiments further demonstrated that Cys264 of CAND1 is the site for conjugation of celastrol. This reveals a new mechanism of celastrol against pulmonary fibrosis and may provide a novel therapeutic option for antipulmonary fibrosis.

Janus kinases (JAKs) play a critical role in immune responses by relaying signals from more than 50 cytokines, making them attractive therapeutic targets for autoimmune diseases. Although approved JAK inhibitors have demonstrated clinical efficacy, they target a broad spectrum of cytokines, which results in side effects. Therefore, next-generation inhibitors maintain efficacy, while sparing adverse events need to be developed. Among members of the JAK family, JAK3 only regulates a narrow spectrum of γc cytokines and becomes a potentially ideal target. Here, a highly JAK3-selective inhibitor Z583 is developed, which showed a potent inhibition of JAK3 with an IC 50 of 0.1 nM and exhibited a 4500-fold selectivity for JAK3 than other JAK subtypes. Furthermore, Z583 completely inhibited the γc cytokine signaling and sufficiently blocked the development of inflammatory response in RA model, while sparing hematopoiesis. Collectively, the highly selective JAK3 inhibitor Z583 is a promising candidate with significant therapeutic potential for autoimmune diseases.

Purpose: To describe demographic and clinical characteristics of chronic obstructive pulmonary disease patients managed in US primary care., Methods: This was an observational registry study using data from the Chronic Obstructive Pulmonary Disease (COPD) Optimum Patient Care DARTNet Research Database from which the Advancing the Patient Experience COPD registry is derived. Registry patients were aged ≥35 years at diagnosis. Electronic health record data were collected from both registries, supplemented with patient-reported information/outcomes from the Advancing the Patient Experience registry from 5 primary care groups in Texas, Ohio, Colorado, New York, and North Carolina (June 2019 through November 2020)., Results: Of 17,192 patients included, 1,354 were also in the Advancing the Patient Experience registry. Patients were predominantly female (56%; 9,689/17,192), White (64%; 9,732/15,225), current/ex-smokers (80%; 13,784/17,192), and overweight/obese (69%; 11,628/16,849). The most commonly prescribed maintenance treatments were inhaled corticosteroid with a long-acting β 2 -agonist (30%) and inhaled corticosteroid with a long-acting muscarinic antagonist (27%). Although 3% (565/17,192) of patitents were untreated, 9% (1,587/17,192) were on short-acting bronchodilator monotherapy, and 4% (756/17,192) were on inhaled corticosteroid monotherapy. Despite treatment, 38% (6,579/17,192) of patients experienced 1 or more exacerbations in the last 12 months. These findings were mirrored in the Advancing Patient Experience registry with many patients reporting high or very high impact of disease on their health (43%; 580/1,322), a breathlessness score 2 or more (45%; 588/1,315), and 1 or more exacerbation in the last 12 months (50%; 646/1,294)., Conclusions: Our findings highlight the high exacerbation, symptom, and treatment burdens experienced by COPD patients managed in US primary care, and the need for more real-life effectiveness trials to support decision making at the primary care level., (© 2022 Annals of Family Medicine, Inc.)

Introduction: Little is known about the variability in chronic obstructive pulmonary disease (COPD) management and how it may be affected by patient characteristics across different healthcare systems in the US. This study aims to describe demographic and clinical characteristics of people with COPD and compare management across five primary care medical groups in the US., Methods: This is a retrospective observational registry study utilizing electronic health records stored in the Advancing the Patient Experience (APEX) COPD registry. The APEX registry contains data from five US healthcare organizations located in Texas, Ohio, Colorado, New York, and North Carolina. Data on demographic and clinical characteristics of primary care patients with COPD between December 2019 and January 2020 were extracted and compared., Results: A total of 17,192 patients with COPD were included in analysis: Texas (n = 811), Ohio (n = 8722), Colorado (n = 472), New York (n = 1149) and North Carolina (n = 6038). The majority of patients at each location were female (>54%) and overweight/obese (>60%). Inter-location variabilities were noted in terms of age, race/ethnicity, exacerbation frequency, treatment pattern, and prevalence of comorbid conditions. Patients from the Colorado site experienced the lowest number of exacerbations per year while those from the New York site reported the highest number. Hypertension was the most common co-morbidity at 4 of 5 sites with the highest prevalence in New York. Depression was the most common co-morbidity in Ohio. Treatment patterns also varied by site; Colorado had the highest proportion of patients not on any treatment. ICS/LABA was the most commonly prescribed treatment except in Ohio, where ICS/LABA/LAMA was most common., Conclusions and Relevance: Our data show heterogeneity in demographic, clinical, and treatment characteristics of patients diagnosed with COPD who are managed in primary care across different healthcare organizations in the US., Competing Interests: Chester Fox declares no conflict of interest. Wilson Pace is on the advisory board for Mylan; stock from Eli Lilly, Novo Nordisk, Pfizer, Novartis, Johnson & Johnson, Stryker, Amgen, Gilead, and Sanofi. Elias Brandt, Gabriela Gaona, and Rachel Kent are employees of the DARTNet Institute. Amanda Ratigan is a consultant to Boehringer-Ingelheim, but at the time of this disclosure had received no funding directly or through any organization she works for from Boehringer-Ingelheim. Victoria Carter, Alexander Evans, Maja Kruszyk, Chantal Le Lievre, and Brooklyn Stanley are employees of Optimum Patient Care, a co-founder of the APEX COPD initiative. Chelsea Edwards was an employee of Optimum Patient Care Australia at the time that this study was conducted. Ku-Lang Chang declares no conflict of interest. MeiLan K Han reports personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Cipla, Chiesi, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, United Therapeutics, UpToDate, Altesa Biopharma, Medscape and Integrity. She has received either in kind research support or funds paid to the institution from the NIH, Novartis, Sunovion, Nuvaira, Sanofi, AstraZeneca, Boehringer Ingelheim, Gala Therapeutics, Biodesix, the COPD Foundation and the American Lung Association. She has participated in Data Safety Monitoring Boards for Novartis and Medtronic with funds paid to the institution. She has received stock options from Meissa Vaccines and Altesa Biopharma. Alan Kaplan is a member of the advisory board of, or speakers bureau for, AstraZeneca, Behring, Boehringer Ingelheim, Covis, Cipla, Grifols, GlaxoSmithKline, Merck Frosst, Novo Nordisk, Novartis, Pfizer, Purdue, Sanofi, Teva, and Trudel. Janwillem Kocks reports grants, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, grants and personal fees from Chiesi Pharmaceuticals, grants, personal fees and non-financial support from GSK, grants and non-financial support from Mundi Pharma, grants and personal fees from TEVA, grants and personal fees from Novartis, personal fees from MSD, personal fees from COVIS Pharma, grants from Valneva outside the submitted work; and Janwillem Kocks holds <5% shares of Lothar Medtec GmbH and 72.5% of shares in the General Practitioners Research Institute. Tessa Li Voti was an employee of Optimum Patient Care at the time this study was conducted. Cathy Mahle and Asif Shaikh are employees of Boehringer Ingelheim, a co-founder of the APEX COPD initiative. Barry Make reports funding from the NHLBI for the COPDGene study; grants and medical advisory boards from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, and Sunovion; personal fees for DSMB from Spiration and Shire/Baxalta; CME personal fees from WebMD, National Jewish Health, American College of Chest Physicians, Projects in Knowledge, Hybrid Communications, SPIRE Learning, Ultimate Medical Academy, Catamount Medical, Eastern Pulmonary Society, Catamount Medical Communications Medscape, Eastern VA Medical Center, Academy Continued Healthcare Learning, and Mt. Sinai Medical Center; royalites from Up-To-Date; medical advisory boards from Novartis, Phillips, Third Pole, Science 24/7, and Verona; grants from Pearl; outside the submitted work. Neil Skolnik is on advisory boards for AstraZeneca, Teva, Lilly, Boehringer Ingelheim, Sanofi, Janssen Pharmaceuticals, Intarcia, Mylan, and GlaxoSmithKline; Payment for lectures/speaking engagements from AstraZeneca and Boehringer Ingelheim; Research Support from Sanofi, AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline. Barbara P Yawn has served on COPD-related advisory boards for GlaxoSmithKline, AstraZeneca, Novartis, and Boehringer Ingelheim, Teva, receives consultancy fees from ndd Medical Technology and received COPD-related investigator-initiated research funds from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, and Novartis. David Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Thermo Fisher; consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, GlaxoSmithKline, Mylan, Mundipharma, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, Theravance and WebMD Global LLC; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance, British Lung Foundation, and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermo Fisher; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline., (© 2022 Fox et al.)

Background: Traditional Chinese herbal patches (TCHPs) characterized by good patient adherence and few side effects have been widely used in the clinic. However, their bioactive transdermal components, which are key to the quality and efficacy, have rarely been investigated., Purpose: Establishing an approach to probe the bioactive transdermal components of TCHPs, using Gutong patch (GTP) as a case study., Study Design and Methods: GTP constituents were identified using ultrahigh-pressure liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). The identified GTP constituents were transferred to an ultrahigh-pressure liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS) method in a dynamic multiple reaction monitoring (dMRM) mode for sensitively targeted analysis of transdermal components present at low concentrations. The ex vivo transdermal components were rapidly probed using a percutaneous permeation model and the release kinetics of marker components was assessed to evaluate the release behavior of GTP. The in vivo transdermal components were then studied in a rat model of arthritis and the changes in concentration of 15 representative bioactive transdermal components with time were well revealed., Results: A total of 120 phytochemical constituents have been identified in GTP extracts and 61 ex vivo transdermal components were targetedly detected. The release kinetics of GTP were evaluated by eight marker components and fitted to a zero-order kinetic model. In vivo, 62 and 40 transdermal components were observed in the skin and subcutaneous tissues of arthritic rats, respectively. The concentration-time changes of 15 representative transdermal components with documented bioactivities have been successfully exhibited after GTP administration., Conclusion: We established a feasible approach to probe the bioactive transdermal components of TCHPs efficiently. The integration of mass spectrometry profiling and targeted detection in dMRM mode enabled a comprehensive investigation of phytochemical constituents and their transdermal delivery, thus addressing the challenge of direct probing of diverse transdermal components present at low concentrations. This approach could be used to rapidly probe the bioactive components and understand the mechanism of TCHPs., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Inflammasomes are multi-protein macromolecular complexes that typically comprise of three units, a sensor, an adaptor and procaspase-1. The assembly of each inflammasome is dictated by a unique pattern recognition receptors (PRRs) in response to pathogen-associated molecular patterns (PAMPs) or other endogenous danger-associated molecular patterns (DAMPs) in the cytosol of the host cells, and promote the maturation and secretion of IL-1β and IL-18 during the inflammatory process. Specific inflammasomes are involved in the host defense response against different pathogens, and the latter have evolved multiple corresponding mechanisms to inhibit inflammasome activation. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome is the best understood in terms of molecular mechanisms, and is a promising therapeutic target in immune-related disorders. Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination of white matter in the central nervous system, increased levels of IL-1β in the cerebrospinal fluid (CSF) of relapsed patients, and deposition of caspase-1 in the spinal cord. The direct involvement of the NLRP3 inflammasome in the occurrence and development of MS was ascertained in the experimental autoimmune encephalomyelitis (EAE) animal model. In this review, we have focused on the mechanisms underlying activation of the NLRP3 inflammasome in MS or EAE, as well as inhibitors that specifically target the complex and alleviate disease progression, in order to unearth new therapeutic strategies against MS., (Copyright © 2021 Elsevier Inc. All rights reserved.)