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TLR signaling in B cells triggers their activation and differentiation independent of help from T cells. Plasmacytoid dendritic cells (pDCs) cooperate with B cells to boost TLR-stimulated T-independent humoral immunity; however, the molecular mechanisms remain elusive. In this study, we demonstrate that in the mouse system, the adjuvant effects of pDCs also occurred following challenge with pathogens and that follicular (FO) B cells were more sensitive to pDC-induced enhancement than were marginal zone (MZ) B cells. Moreover, pDCs migrated to the FO zones and interacted with FO B cells upon stimulation in vivo. CXCL10, a ligand for CXCR3 expressed on pDCs, was superinduced in the coculture system and facilitated the cooperative activation of B cells. Moreover, pDCs also promoted TLR-stimulated autoantibody production in FO B and MZ B cells. Ingenuity Pathway Analysis and gene set enrichment analysis revealed that type I IFN (IFN-I)-mediated JAK-STAT and Ras-MAPK pathways were highly enriched in R848-stimulated B cells cocultured with pDCs compared with B cells alone. Whereas IFN-I receptor 1 deficiency reduced pDC-enhanced B cell responses, STAT1 deficiency displayed a more pronounced defect. One of the STAT1-dependent but IFN-I-independent mechanisms was TLR-induced STAT1-S727 phosphorylation by p38 MAPK. Serine 727 to alanine mutation attenuated the synergism between pDCs and B cells. In conclusion, we uncover a molecular mechanism for pDC-enhanced B cell response and define a crucial role of the IFN-I/TLR-mediated signaling pathway through a p38 MAPK-STAT1 axis in controlling T-independent humoral immunity and providing a novel therapeutic target for treating autoimmune diseases.
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Interferón Tipo I , Proteínas Quinasas p38 Activadas por Mitógenos , Ratones , Animales , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Transducción de Señal , Interferón Tipo I/metabolismo , Fosforilación , Células DendríticasRESUMEN
OBJECTIVES: Observational studies link elevated plasma homocysteine (Hcy) with vascular disease. Our aim was to assess the gender difference in the association between the plasma tHcy level and brain atrophy and identify the possible influencer. We employed Mendelian randomization (MR) to explore the causal relationship between plasma tHcy level, estradiol level, and brain atrophy. METHODS: A total of 687 patients with brain atrophy were included, and gender-specific subgroup analyses in association between tHcy and brain atrophy are conducted. From genome-wide association studies, we selected genetic variants (P < 5 × 10-8) for the plasma tHcy level and estradiol level. We investigated the degree of brain atrophy (including gray matter volume and total brain volume) in the UK biobank (n = 7,916). The inverse variance-weighted and several sensitivity MR regression analyses were carried out. RESULTS: The plasma tHcy level was significantly associated with brain atrophy for females, but not for males. An MR study showed that there was little evidence of the causal link between elevated plasma tHcy and brain atrophy. On the other hand, we found evidence to support causality for genetically decreased estradiol with higher risk of brain atrophy. Furthermore, genetic predisposition to elevated plasma tHcy was associated with a lower estradiol level. CONCLUSIONS: The influence of estradiol on the association between tHcy and brain atrophy deserves further investigation.
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Estudio de Asociación del Genoma Completo , Enfermedades Neurodegenerativas , Masculino , Femenino , Humanos , Análisis de la Aleatorización Mendeliana , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Enfermedades Neurodegenerativas/patología , Atrofia/patología , EstradiolRESUMEN
BACKGROUND: Use of machine learning to estimate exposure effects introduces a dependence between the results of an empirical study and the value of the seed used to fix the pseudo-random number generator. METHODS: We used data from 10,038 pregnant women and a 10% subsample (N = 1,004) to examine the extent to which the risk difference for the relation between fruit and vegetable consumption and preeclampsia risk changes under different seed values. We fit an augmented inverse probability weighted estimator with two Super Learner algorithms: a simple algorithm including random forests and single layer neural networks and a more complex algorithm with a mix of tree-based, regression based, penalized and simple algorithms. We evaluated the distributions of risk differences, standard errors, and p values that result from 5,000 different seed value selections. RESULTS: Our findings suggest important variability in the risk difference estimates, as well as an important effect of the stacking algorithm used. The interquartile range width (IQRw) of the risk differences in the full sample with the simple algorithm was 13 per 1000. However, all other IQRs were roughly an order of magnitude lower. The medians of the distributions of risk differences differed according to the sample size and the algorithm used. CONCLUSIONS: Our findings add another dimension of concern regarding the potential for "p-hacking", and further warrants the need to move away from simplistic evidentiary thresholds in empirical research. When empirical results depend on pseudo-random number generator seed values, caution is warranted in interpreting these results.
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The self-assembly of the lanthanide metal-organic frameworks presents a formidable challenge but profound significance. Compared with the metal-organic frameworks based on 4f-3d ions, the chemistry of 4f-3p metal-organic frameworks has not been fully explored so far. In this study, two lanthanide-aluminum-based clusters [Ln6Al(IN)10(µ3-OH)5(µ3-O)3(H2O)8]·xH2O (x = 2, Ln = Gd, abbreviated as Gd6Al; x = 2.5, Ln = Eu, abbreviated as Eu6Al; HIN = isonicotinic acid) have been meticulously designed and obtained by hydrothermal reaction at low pH. The crystallographic study revealed that both Gd6Al and Eu6Al clusters exhibit an unprecedented sandwiched metal-organic framework holding a highly ordered honeycomb network. To our knowledge, it is the first case of Ln-Al-based cluster-organic frameworks. Furthermore, magnetic investigation of Gd6Al manifests a decent magnetic entropy change of -ΔSmmax = 28.8 J kg-1 K-1 at 2 K for ΔH = 7.0 T. Significantly, the introduction of AlIII ions into the lanthanide metal-organic frameworks displays excellent solid-state luminescent capability with a lifetime of 371.6 µs and quantum yield of 6.64%. The construction and investigation of these two Ln-Al clusters represent great progress in the 4f-3p metal-organic framework.
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Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed that CYTH1 depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with the CYTH1 knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Ratones , Animales , Leucemia Mieloide Aguda/tratamiento farmacológico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Moléculas de Adhesión Celular , Progresión de la Enfermedad , Línea Celular TumoralRESUMEN
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have obvious advantages over MSC therapy. But the strong procoagulant properties of MSC-EVs pose a potential risk of thromboembolism, an issue that remains insufficiently explored. In this study, we systematically investigated the procoagulant activity of large EVs derived from human umbilical cord MSCs (UC-EVs) both in vitro and in vivo. UC-EVs were isolated from cell culture supernatants. Mice were injected with UC-EVs (0.125, 0.25, 0.5, 1, 2, 4 µg/g body weight) in 100 µL PBS via the tail vein. Behavior and mortality were monitored for 30 min after injection. We showed that these UC-EVs activated coagulation in a dose- and tissue factor-dependent manner. UC-EVs-induced coagulation in vitro could be inhibited by addition of tissue factor pathway inhibitor. Notably, intravenous administration of high doses of the UC-EVs (1 µg/g body weight or higher) led to rapid mortality due to multiple thrombus formations in lung tissue, platelets, and fibrinogen depletion, and prolonged prothrombin and activated partial thromboplastin times. Importantly, we demonstrated that pulmonary thromboembolism induced by the UC-EVs could be prevented by either reducing the infusion rate or by pre-injection of heparin, a known anticoagulant. In conclusion, this study elucidates the procoagulant characteristics and mechanisms of large UC-EVs, details the associated coagulation risk during intravenous delivery, sets a safe upper limit for intravenous dose, and offers effective strategies to prevent such mortal risks when high doses of large UC-EVs are needed for optimal therapeutic effects, with implications for the development and application of large UC-EV-based as well as other MSC-EV-based therapies.
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Lung injury has been a serious medical problem that requires new therapeutic approaches and biomarkers. Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) that exist widely in eukaryotes. CircRNAs are single-stranded RNAs that form covalently closed loops. CircRNAs are significant gene regulators that have a role in the development, progression, and therapy of lung injury by controlling transcription, translating into protein, and sponging microRNAs (miRNAs) and proteins. Although the study of circRNAs in lung injury caused by pulmonary toxicants is just beginning, several studies have revealed their expression patterns. The function that circRNAs perform in relation to pulmonary toxicants (severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2), drug abuse, PM2.5, and cigarette smoke) is the main topic of this review. A variety of circRNAs can serve as potential biomarkers of lung injury. In this review, the biogenesis, properties, and biological functions of circRNAs were concluded, and the relationship between circRNAs and pulmonary toxicants was discussed. It is expected that the new ideas and potential treatment targets that circRNAs provide would be beneficial to research into the molecular mechanisms behind lung injury.
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Lesión Pulmonar , MicroARNs , Humanos , ARN Circular/genética , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/genética , Lesión Pulmonar/terapia , Pulmón/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Biomarcadores/metabolismoRESUMEN
With advances in next-generation sequencing technology, there is growing evidence that the gut microbiome plays a key role in the host's innate and adaptive immune system. Gut microbes and their metabolites directly or indirectly regulate host immune cells. Crucially, dysregulation of the gut microbiota is often associated with many immune system diseases. In turn, microbes modulate disease immunotherapy. Data from preclinical to clinical studies suggest that the gut microbiota may influence the effectiveness of tumor immunotherapy, particularly immune checkpoint inhibitors (ICIs). In addition, the most critical issue now is a COVID-19 vaccine that generates strong and durable immunity. A growing number of clinical studies confirm the potential of gut microbes to enhance the efficacy of COVID-19 vaccines. However, it is still unclear how gut bacteria interact with immune cells and what treatments are based on gut microbes. Here, we outline recent advances in the effects and mechanisms of the gut microbiota and its metabolites (tryptophan metabolites, bile acids, short-chain fatty acids, and inosine) on different immune cells (dendritic cells, CD4+T cells, and macrophages). It also highlights innovative intervention strategies and clinical trials of microbiota-based checkpoint blocking therapies for tumor immunity, and ongoing efforts to maintain the long-term immunogenicity of COVID-19 vaccines. Finally, the challenges to be overcome in this area are discussed. These provide an important basis for further research and clinical translation of gut microbiota.
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COVID-19 , Microbioma Gastrointestinal , Inmunoterapia , Humanos , Microbioma Gastrointestinal/inmunología , Inmunoterapia/métodos , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/terapia , Vacunas contra la COVID-19/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Animales , SARS-CoV-2/inmunología , Neoplasias/inmunología , Neoplasias/terapiaRESUMEN
BACKGROUND: The prevalence of hypertensive heart disease (HHD) is high and there is currently no easy way to detect early HHD. Explore the application of radiomics using cardiac magnetic resonance (CMR) non-enhanced cine sequences in diagnosing HHD and latent cardiac changes caused by hypertension. METHODS: 132 patients who underwent CMR scanning were divided into groups: HHD (42), hypertension with normal cardiac structure and function (HWN) group (46), and normal control (NOR) group (44). Myocardial regions of the end-diastolic (ED) and end-systolic (ES) phases of the CMR short-axis cine sequence images were segmented into regions of interest (ROI). Three feature subsets (ED, ES, and ED combined with ES) were established after radiomic least absolute shrinkage and selection operator feature selection. Nine radiomic models were built using random forest (RF), support vector machine (SVM), and naive Bayes. Model performance was analyzed using receiver operating characteristic curves, and metrics like accuracy, area under the curve (AUC), precision, recall, and specificity. RESULTS: The feature subsets included first-order, shape, and texture features. SVM of ED combined with ES achieved the highest accuracy (0.833), with a macro-average AUC of 0.941. AUCs for HHD, HWN, and NOR identification were 0.967, 0.876, and 0.963, respectively. Precisions were 0.972, 0.740, and 0.826; recalls were 0.833, 0.804, and 0.863, respectively; and specificities were 0.989, 0.863, and 0.909, respectively. CONCLUSIONS: Radiomics technology using CMR non-enhanced cine sequences can detect early cardiac changes due to hypertension. It holds promise for future use in screening for latent cardiac damage in early HHD.
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Diagnóstico Precoz , Hipertensión , Imagen por Resonancia Cinemagnética , Humanos , Femenino , Masculino , Imagen por Resonancia Cinemagnética/métodos , Persona de Mediana Edad , Hipertensión/diagnóstico por imagen , Hipertensión/complicaciones , Máquina de Vectores de Soporte , Cardiopatías/diagnóstico por imagen , Anciano , Adulto , Teorema de Bayes , Curva ROC , Interpretación de Imagen Asistida por Computador/métodos , RadiómicaRESUMEN
The increasing incidence of environmental concerns related to excessive use of pesticides, such as imidacloprid and carbendazim, poses risks to pollinators, water bodies, and human health, prompting regulatory scrutiny and bans in developed countries. In this study, we propose a portable smartphone-based biosensor for rapid and label-free colorimetric detection by using the gold-decorated polystyrene microparticles (Ps-AuNP) functionalized with specific aptamers to imidacloprid and carbendazim on a microfluidic paper-based analytical device (µ-PAD). Four aptamers were selected for the detection of these pesticides and their sensitivity and selectivity performance was evaluated. The sensitivity results show a detection limit for imidacloprid of 3.12 ppm and 1.56 ppm for carbendazim. The aptamers also exhibited high selectivity performance against other pesticides, such as thiamethoxam, fenamiphos, isoproturon, and atrazine. However, the platform presented cross-selectivity when detecting imidacloprid, carbendazim, and linuron, which is discussed herein. Overall, we present a promising platform for simple, on-site, and rapid colorimetric screening of specific pesticides, while highlighting the challenges of aptasensors in achieving selectivity amidst diverse molecular structures.
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Bencimidazoles , Carbamatos , Neonicotinoides , Nitrocompuestos , Plaguicidas , Oro/química , Plaguicidas/análisis , Teléfono InteligenteRESUMEN
Lateral flow assay (LFA) color signal quantification methods were developed by utilizing both International Commission on Illumination (CIE) LAB (CIELAB) color space and grayscale intensity differences. The CIELAB image processing procedure included calibration, test, control band detection, and color difference calculation, which can minimize the noise from the background. The LFA platform showcases its ability to accurately discern relevant colorimetric signals. The rising occurrence of infectious outbreaks from foodborne pathogens like Salmonella typhimurium presents significant economic, healthcare, and public health risks. The study introduces an aptamer-based lateral flow (ABLF) platform by using inkjet printing for specially detecting S. typhimurium. The ABLF utilized gold-decorated polystyrene microparticles, functionalized with specific S. typhimurium aptamers (Ps-AuNPs-ssDNA). The platform demonstrates a detection limit of 102 CFU mL-1 in buffer solutions and 103 CFU mL-1 in romaine lettuce tests. Furthermore, it sustained performance for over 8 weeks at room temperature. The ABLF platform and analysis methods are expected to effectively resolve the low-sensitivity problems of the former LFA systems and to bridge the gap between lab-scale platforms to market-ready solutions by offering a simple, cost-effective, and consistent approach to detecting foodborne pathogens in real samples.
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Aptámeros de Nucleótidos , Colorimetría , Oro , Nanopartículas del Metal , Salmonella typhimurium , Salmonella typhimurium/aislamiento & purificación , Colorimetría/métodos , Colorimetría/instrumentación , Oro/química , Aptámeros de Nucleótidos/química , Nanopartículas del Metal/química , Límite de Detección , Microbiología de Alimentos , Lactuca/microbiología , Lactuca/química , Impresión , Poliestirenos/química , Técnicas Biosensibles/métodosRESUMEN
Based on the systematic deconstruction of multi-dimensional and multi-target biological networks, modular pharmacology explains the complex mechanism of diseases and the interactions of multi-target drugs. It has made progress in the fields of pathogenesis of disease, biological basis of disease and traditional Chinese medicine(TCM) syndrome, pharmacological mechanism of multi-target herbs, compatibility of formulas, and discovery of new drug of TCM compound. However, the complexity of multi-omics data and biological networks brings challenges to the modular deconstruction and analysis of the drug networks. Here, we constructed the "Computing Platform for Modular Pharmacology" online analysis system, which can implement the function of network construction, module identification, module discriminant analysis, hub-module analysis, intra-module and inter-module relationship analysis, and topological visualization of network based on quantitative expression profiles and protein-protein interaction(PPI) data. This tool provides a powerful tool for the research on complex diseases and multi-target drug mechanisms by means of modular pharmacology. The platform may have broad range of application in disease modular identification and correlation mechanism, interpretation of scientific principles of TCM, analysis of complex mechanisms of TCM and formulas, and discovery of multi-target drugs.
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Medicamentos Herbarios Chinos , Medicina Tradicional China , Humanos , Biología Computacional/métodos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Farmacología/métodos , Mapas de Interacción de Proteínas/efectos de los fármacosRESUMEN
Traditional Chinese medicine proteins(TCMPs) not only have nutritional values and biological activities but also serve as key enzymes in the synthesis of pharmacodynamic components in traditional Chinese medicines. They play a role in the synthesis of pharmacodynamic components by regulating biosynthesis and selective synthesis pathways and controlling drug quality and stability. The recent years have witnessed great progress in the research on the structures and functions of proteins using various methods and technologies. However, the research on the structures and functions of TCMPs lags behind. Therefore, it is urgent to study the structures and functions of TCMPs using modern means to promote the discovery of innovative drugs based on TCMPs and clarify the synthesis pathways of pharmacodynamic components. This study introduces the latest techniques for studying protein structures and functions, including spectroscopy, mass spectrometry, nuclear magnetic resonance, X-ray crystal diffraction, microscopy, and structure prediction. Furthermore, this paper introduces the methods for protein functional studies, including liquid chromatography-mass spectrometry, co-immunoprecipitation, yeast two-hybrid, and pull-down assay. By systematically reviewing these techniques and methods, this paper provides technical references for the structural identification and functional studies of TCMPs, with the aim of promoting the in-depth exploration of the structures and functions of TCMPs.
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Medicamentos Herbarios Chinos , Medicina Tradicional China , Medicamentos Herbarios Chinos/química , Proteínas/química , Proteínas/metabolismo , Humanos , Espectrometría de MasasRESUMEN
Limbal stem cell deficiency (LSCD) is one of the leading factors negatively affecting the success of keratoplasty, and its treatment remains an urgent problem in ophthalmology. With the development of regenerative medicine, one of the promising approaches is the transplantation of tissue-engineered constructs from cultured limbal stem cells (LSCs) in biopolymer carriers. PURPOSE: This study was conducted to develop an experimental model of LSCD and evaluate the effectiveness of transplantation of a tissue-engineered construct consisting of cultured cells containing a population of LSCs and a collagen carrier. MATERIAL AND METHODS: The study was performed on 12 rabbits and included several stages. At the first stage, the physiological effects of collagen matrix implantation into the limbal zone were studied. At the second stage, tissue-engineered constructs consisting of LSCs on a collagen matrix were formed and their effect on the regeneration processes in the experimental LSCD model was analyzed. The animals were divided into 2 groups: surgical treatment (transplantation of the tissue-engineered construct) was used in the experimental group, and conservative treatment was used in the control group. Slit-lamp biomicroscopy with photo-registration, fluorescein corneal staining, optical coherence tomography of the anterior segment of the eye, and impression cytology were used to assess the results. RESULTS: No side reactions were observed after implantation of the collagen matrix into the limbal zone. One month after surgical treatment of the LSCD model in the experimental group, complete epithelization with minor manifestations of epitheliopathy was observed. In the control group, erosion of the corneal epithelium was noted. The time of corneal epithelization in the experimental and control groups was 9.2±2.95 and 46.20±12.07 days, respectively (p=0.139). According to the data of impression cytology, in the experimental group there were no goblet cells in the central part of the cornea, which indicates the restoration of corneal type epithelial cells, in contrast to the control group. CONCLUSION: Transplantation of a tissue-engineered construct from cultured limbal cells on a collagen membrane should be considered as a promising method for the treatment of limbal stem cell deficiency.
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Enfermedades de la Córnea , Modelos Animales de Enfermedad , Limbo de la Córnea , Trasplante de Células Madre , Células Madre , Ingeniería de Tejidos , Conejos , Animales , Ingeniería de Tejidos/métodos , Limbo de la Córnea/citología , Enfermedades de la Córnea/terapia , Enfermedades de la Córnea/cirugía , Trasplante de Células Madre/métodos , Células Cultivadas , Tomografía de Coherencia Óptica/métodos , Resultado del Tratamiento , Deficiencia de Células Madre LimbaresRESUMEN
Galactose is an abundant and essential sugar used for the biosynthesis of many macromolecules in different organisms, including plants. Galactose metabolism is tightly and finely controlled, since excess galactose and its derivatives are inhibitory to plant growth. In Arabidopsis (Arabidopsis thaliana), root growth and pollen germination are strongly inhibited by excess galactose. However, the mechanism of galactose-induced inhibition during pollen germination remains obscure. In this study, we characterized a plasma membrane-localized transporter, Arabidopsis Sugars Will Eventually be Exported Transporter 5, that transports glucose and galactose. SWEET5 protein levels started to accumulate at the tricellular stage of pollen development and peaked in mature pollen, before rapidly declining after pollen germinated. SWEET5 levels are responsible for the dosage-dependent sensitivity to galactose, and galactokinase is essential for these inhibitory effects during pollen germination. However, sugar measurement results indicate that galactose flux dynamics and sugar metabolism, rather than the steady-state galactose level, may explain phenotypic differences between sweet5 and Col-0 in galactose inhibition of pollen germination.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Galactoquinasa/metabolismo , Galactoquinasa/farmacología , Galactosa/metabolismo , Galactosa/farmacología , Germinación , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Monosacáridos/genética , Proteínas de Transporte de Monosacáridos/metabolismo , PolenRESUMEN
Fiber-optic sensors are an indispensable element of modern sensing technologies by virtue of their low cost, excellent electromagnetic immunity, and remote sensing capability. Optical Vernier effect is widely used to enhance sensitivity of fiber-optic sensors but requires bulky and complex cascaded interferometers. Here we propose and experimentally demonstrate an ultracompact (â¼2 mm by â¼2 mm) Vernier-effect-improved sensor by only using a single microfiber-knot resonator. With the Vernier effect achieved by controlling the optical beating with the spectral ripple of a super light emitting diode (SLED), we show â¼20x sensitivity enhancement for quantitative temperature monitoring. Our sensor creates a new practical method to realize Vernier effect in fiber-optic sensors and beyond.
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AIMS: The contemporary prescription patterns of antidiabetic drugs following guideline changes recommending metformin as first-line gestational diabetes (GDM) pharmacotherapy is underexplored. We aimed to examined use of metformin and insulin during pregnancy among women with GDM over 20 years in the United Kingdom. METHODS: We conducted a population-based cohort study using linked data from the Clinical Practice Research Datalink, its pregnancy register and Hospital Episode Statistics from 1998 to 2017. We included pregnancies of women without prior diabetes history who received GDM diagnosis or initiated an antidiabetic drug after 20 weeks gestation. Patient-level and practice-level characteristics were compared between metformin initiators and insulin initiators. We described trends of initiating metformin as first-line treatment and described time to initiation of rescue insulin overall, and by body mass index among metformin initiators. RESULTS: Our cohort included 5633 pregnancies from 5393 women with GDM, of whom 38.9% initiated pharmacotherapy (41% insulin, 59% metformin). Metformin prescriptions (as opposed to insulin) increased substantially, from <5% of pregnancies before 2007 to 42.5% in 2008. Over 85% of pregnancies that were prescribed pharmacotherapy were prescribed metformin as first-line treatment in 2015. Among metformin initiators, 16% initiated rescue insulin, typically occurring within 40 days of metformin initiation. Choice of GDM pharmacotherapy varied by characteristics, including smoking, obesity, race/ethnicity and general practice regions. CONCLUSIONS: Metformin was the most prescribed medication for GDM, with large increases over the past 2 decades. The increasing use of oral-antidiabetic drugs during pregnancy, consistent with other regions, highlights the need for future studies examining effectiveness and safety of antidiabetic drug use during pregnancy.
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Diabetes Gestacional , Hipoglucemiantes , Insulina , Metformina , Embarazo en Diabéticas , Femenino , Humanos , Embarazo , Estudios de Cohortes , Diabetes Gestacional/tratamiento farmacológico , Diabetes Gestacional/epidemiología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Metformina/uso terapéutico , Embarazo en Diabéticas/tratamiento farmacológico , Embarazo en Diabéticas/epidemiología , Mujeres EmbarazadasRESUMEN
BACKGROUND: While the benefits of levothyroxine are well-established for overt hypothyroidism, they are unclear for subclinical hypothyroidism (SCH) among pregnant women. OBJECTIVE: To estimate the effect of initiation of levothyroxine on pregnancy loss among women with SCH with an emulated target trial using observational data. METHODS: We emulated a target trial using the United Kingdom's Clinical Practice Research Datalink to account for the staggered timing of diagnosis and treatment of SCH and the time of entry of women into prenatal care. We emulated multiple nested trials (at each gestational week) and used an intention-to-treat approach to define levothyroxine use (≥1 prescription in the 7 days prior to trial entry), with eligible users matched to non-users (1:4) on time of diagnosis, gestational week of the first eligible trial and high-dimensional propensity score. Pregnancy losses included spontaneous abortion and stillbirth. A pooled logistic regression model with bootstrap resampling was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Based on 159,177 eligible person-trials (5781 women), the matched cohort included 181 initiators and 640 non-initiators of levothyroxine, with 57 pregnancy losses occurring during follow-up. Overall, the mean age of women was 32.2 years (SD 5.4), 25% were obese, 8% had type 2 diabetes and about 50% were nulliparous. After matching, women who initiated levothyroxine versus not had higher thyroid-stimulating levels during pregnancy and were more likely to have a history of hypothyroidism. The cumulative incidence of pregnancy loss was lower in initiators versus non-initiators of levothyroxine. The adjusted HR for pregnancy loss was 0.87 (95% CI 0.22, 1.56). CONCLUSIONS: Although our assessment of the effect of initiation of levothyroxine for SCH in pregnancy precludes any definitive conclusions due to wide confidence intervals, this study illustrates the feasibility of using the target trial emulation framework to examine the effectiveness of medication use in pregnancy.
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The self-assembly of the high-nuclearity Ln-exclusive nanoclusters is challenging but of significance due to its aesthetically pleasing architectures and far-reaching latent applications in magnetic cooling technologies. Herein, two novel high-nuclearity lanthanide nanoclusters were successfully synthesized under solvothermal conditions, formulated as {[Gd18(IN)20(HCOO)8(µ6-O)(µ3-OH)24(H2O)4]·4H2O}n and {[Eu18(IN)16(HCOO)8(CH3COO)4(µ6-O)(µ3-OH)24(H2O)4]·5H2O}n (abbreviated as Gd18 and Eu18, HIN = isonicotinic acid). Both of them possess novel and exquisite windmill-shaped cationic cores in the family of high-nuclearity Ln-exclusive nanoclusters. Remarkably, the adjacent second building units are interconnected into a three-dimensional (3D) metal-organic framework by IN- ligands. As expected, the abundant existence of GdIII ions endows Gd18 with a favorable magnetic entropy change at 2.0 K for ΔH = 7.0 T (-ΔSmmax = 40.0 J kg-1 K-1), and Eu18 displays the typical luminescence of EuIII ions.
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BACKGROUND: Along with increasing research on acupuncture for chronic pain, the validity of sham acupuncture (SA) has also been argued. METHODS: Nine databases were searched for randomized controlled trials (RCTs) from the inception dates of the databases to July 5, 2022. With Markov Chain Monte Carlo methods, a Bayesian multiple-treatment network meta-analysis (NMA) with random-effects model was conducted. RESULTS: A total of 62 RCTs with 6,806 patients and four kinds of treatments (real acupuncture [RA], non-acupuncture [NA], penetrative SA [PSA], and non-penetrative SA [NPSA]) were included. The results indicated that both NPSA and PSA were not superior to NA in improving chronic pain (NPSA: mean difference [MD]= -4.77, 95% confidence interval [CI] -11.09 to 1.52; PSA: MD= -4.96, 95% CI -10.38 to 0.48). After NPSA and PSA were combined into the SA group, the weak trend of pain relief from SA was still not statistically significant (MD= -4.91, 95% CI -9.93 to 0.05). NPSA and PSA had similar effects (MD= 0.18, 95% CI -5.45 to 5.81). RA was significantly associated with pain relief, compared with NPSA and PSA (NPSA: MD= -12.03, 95% CI -16.62 to -7.41; PSA: MD= -11.85, 95% CI -15.48 to -8.23). The results were generally consistent regardless of pain phenotype, frequency, duration, acupuncture methods, analgesic intake, or detection bias. CONCLUSION: These results suggested that acupuncture was significantly associated with reduced chronic pain. The two kinds of placebo acupuncture, NPSA and PSA, have similar effects. Both NPSA and PSA, with a weak but not significant effect, are appropriate to be inert placebo controls in RCTs for chronic pain.