RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a variety of clinical manifestations, many of which originate from altered immune responses, either locally or systemically. Immune cell cross-talk occurs mainly in lymphoid organs. However, systemic cell interaction specific to coronavirus disease 2019 has not been well characterized. Here, by employing single-cell RNA sequencing and imaging flow cytometry analysis, we unraveled, in peripheral blood, a heterogeneous group of cell complexes formed by the adherence of CD14+ monocytes to different cytotoxic lymphocytes, including SARS-CoV-2-specific CD8+ T cells, γδ T cells, and natural killer T cells. These lymphocytes attached to CD14+ monocytes that showed enhanced inflammasome activation and pyroptosis-induced cell death in progression stage; in contrast, in the convalescent phase, CD14+ monocytes with elevated antigen presentation potential were targeted by cytotoxic lymphocytes, thereby restricting the excessive immune activation. Collectively, our study reports previously unrecognized cell-cell interplay in the SARS-CoV-2-specific immune response, providing new insight into the intricacy of dynamic immune cell interaction representing antiviral defense.
Assuntos
COVID-19 , Monócitos , SARS-CoV-2 , Linfócitos T Citotóxicos , Humanos , COVID-19/imunologia , COVID-19/virologia , Monócitos/imunologia , SARS-CoV-2/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Inflamassomos/imunologia , Piroptose/imunologia , Células T Matadoras Naturais/imunologia , Masculino , Comunicação Celular/imunologia , Análise de Célula ÚnicaRESUMO
BACKGROUND: We examined effects of single-nucleotide variants (SNVs) of IL1RN, the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021. RESULTS: Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P = .0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P = .052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P = .030). CONCLUSIONS: The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms.
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COVID-19 , Síndrome da Liberação de Citocina , Haplótipos , Proteína Antagonista do Receptor de Interleucina 1 , Polimorfismo de Nucleotídeo Único , SARS-CoV-2 , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/sangue , COVID-19/mortalidade , COVID-19/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , SARS-CoV-2/genética , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/mortalidade , Adulto , Genótipo , Biomarcadores/sangueRESUMO
BACKGROUND: Despite advances in medical therapy for heart failure with reduced ejection fraction (HFrEF), major gaps in medication adherence to guideline-directed medical therapies (GDMT) remain. Greater continuity of care may impact medication adherence and reduced hospitalizations. METHODS: We conducted a cross-sectional study of adults with a diagnosis of HF and EF ≤40% with ≥2 outpatient encounters between January 1, 2017 and January 10, 2021, prescribed ≥1 of the following GDMT: 1) Beta Blocker, 2) Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker/Angiotensin Receptor Neprilysin Inhibitor, 3) Mineralocorticoid Receptor Antagonist, 4) Sodium Glucose Cotransporter-2 Inhibitor. Continuity of care was calculated using the Bice-Boxerman Continuity of Care Index (COC) and the Usual Provider of Care (UPC) index, categorized by quantile. The primary outcome was adherence to GDMT, defined as average proportion of days covered ≥80% over 1 year. Secondary outcomes included all-cause and HF hospitalization at 1-year. We performed multivariable logistic regression analyses adjusted for demographics, insurance status, comorbidity index, number of visits and neighborhood SES index. RESULTS: Overall, 3,971 individuals were included (mean age 72 years (SD 14), 71% male, 66% White race). In adjusted analyses, compared to individuals in the highest COC quartile, individuals in the third COC quartile had higher odds of GDMT adherence (OR 1.26, 95% CI 1.03-1.53, P = .024). UPC tertile was not associated with adherence (all P > .05). Compared to the highest quantiles, the lowest UPC and COC quantiles had higher odds of all-cause (UPC: OR 1.53, 95%CI 1.23-1.91; COC: OR 2.54, 95%CI 1.94-3.34) and HF (UPC: OR 1.81, 95%CI 1.23-2.67; COC: OR 1.77, 95%CI 1.09-2.95) hospitalizations. CONCLUSIONS: Continuity of care was not associated with GDMT adherence among patients with HFrEF but lower continuity of care was associated with increased all-cause and HF-hospitalizations.
Assuntos
Continuidade da Assistência ao Paciente , Insuficiência Cardíaca , Adesão à Medicação , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Masculino , Feminino , Adesão à Medicação/estatística & dados numéricos , Estudos Transversais , Continuidade da Assistência ao Paciente/estatística & dados numéricos , Idoso , Pessoa de Meia-Idade , Hospitalização/estatística & dados numéricos , Antagonistas Adrenérgicos beta/uso terapêutico , Volume Sistólico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêuticoRESUMO
Given the high prevalence of avian leukosis virus subgroup K (ALV-K) in chickens in China, the positive rate of ALV-K in local chickens in Henan province was investigated, and the genetic region encoding the glycoprotein gp85 of isolates from positive chickens was analyzed. The positive rate of ALV-K in local chickens in Henan was found to be 87.2% (41/47). Phylogenetic analysis of gp85 sequences revealed six clusters that differed in their host range regions (hr1 and hr2) and variable regions (vr1, vr2, and vr3). Evidence of recombination of hr1, hr2, vr1, vr2, and vr3 was observed between the different clusters. The isolate HN23LS02 appears to have obtained its hr1 and hr2 regions from separate lineages via recombination but without having a significant affect on the replication capacity of the virus.
Assuntos
Vírus da Leucose Aviária , Leucose Aviária , Galinhas , Especificidade de Hospedeiro , Filogenia , Doenças das Aves Domésticas , Recombinação Genética , Proteínas do Envelope Viral , Animais , Vírus da Leucose Aviária/genética , Vírus da Leucose Aviária/classificação , Vírus da Leucose Aviária/isolamento & purificação , Galinhas/virologia , Leucose Aviária/virologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Doenças das Aves Domésticas/virologia , ChinaRESUMO
Haematopoietic stem and progenitor cells (HSPCs) give rise to all blood lineages that support the entire lifespan of vertebrates1. After HSPCs emerge from endothelial cells within the developing dorsal aorta, homing allows the nascent cells to anchor in their niches for further expansion and differentiation2-5. Unique niche microenvironments, composed of various blood vessels as units of microcirculation and other niche components such as stromal cells, regulate this process6-9. However, the detailed architecture of the microenvironment and the mechanism for the regulation of HSPC homing remain unclear. Here, using advanced live imaging and a cell-labelling system, we perform high-resolution analyses of the HSPC homing in caudal haematopoietic tissue of zebrafish (equivalent to the fetal liver in mammals), and reveal the role of the vascular architecture in the regulation of HSPC retention. We identify a VCAM-1+ macrophage-like niche cell population that patrols the inner surface of the venous plexus, interacts with HSPCs in an ITGA4-dependent manner, and directs HSPC retention. These cells, named 'usher cells', together with caudal venous capillaries and plexus, define retention hotspots within the homing microenvironment. Thus, the study provides insights into the mechanism of HSPC homing and reveals the essential role of a VCAM-1+ macrophage population with patrolling behaviour in HSPC retention.
Assuntos
Células Endoteliais/citologia , Células-Tronco Hematopoéticas/citologia , Macrófagos/metabolismo , Nicho de Células-Tronco , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Microambiente Celular , Integrinas/genética , Integrinas/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
In order to obtain the inorganic efficient antibacterial agents, the means of ion doping and morphology construction in this research are used to enhance the antibacterial property of nano-MgO, which is according to the "oxidative damage mechanism" and "contact mechanism". In this work, the nano-textured Sc2O3-MgO are synthesized by doping Sc3+ in nano-MgO lattice through calcining at 600 °C. When the Sc3+ content reaches 10%, the nanotextures on the powders surface are pretty clearly visible and uniform, and the specific surface area and the oxygen vacancy are ideal, so that the 10% Sc3+-doped powders (SM-10) has the excellent antibacterial property against E. coli and S. aureus (MBC = 0.03 mg/mL). The efficient antibacterial agents in this research have a better antibacterial effect than the 0% Sc3+-doped powders (SM-0, MBC = 0.20 mg/mL) and the commercial nano-MgO (CM, MBC = 0.40 mg/mL), which have application prospects in the field of antibacterial.
Assuntos
Nanopartículas , Nanopartículas/química , Antibacterianos/farmacologia , Antibacterianos/química , Staphylococcus aureus , Escherichia coli , OxigênioRESUMO
Due to their high porosity, large specific surface area, and structural similarity with the extracellular matrix (ECM), electrospun nanofiber membranes are often endowed with the antibacterial properties for biomedical applications. The purpose of this study was to synthesize nano-structured Sc2O3-MgO by doping Sc3+, calcining at 600 °C, and then loading it onto the PCL/PVP substrates with electrospinning technology with the aim of developing new efficient antibacterial nanofiber membranes for tissue engineering. A scanning electron microscope (SEM) and energy dispersive X-ray spectrometer (EDS) were used to study the morphology of all formulations and analyze the types and contents of the elements, and an X-ray diffraction (XRD), thermogravimetric analysis (TGA), and Fourier transform attenuated total reflection infrared spectroscopy (ATR-FTIR) were used for further analysis. The experimental results showed that the PCL/PVP (SMCV-2.0) nanofibers loaded with 2.0 wt% Sc2O3-MgO were smooth and homogeneous with an average diameter of 252.6 nm; the antibacterial test indicated that a low load concentration of 2.0 wt% Sc2O3-MgO in PCL/PVP (SMCV-2.0) showed a 100% antibacterial rate against Escherichia coli (E. coli).
Assuntos
Infecções por Escherichia coli , Nanofibras , Humanos , Óxido de Magnésio , Nanofibras/química , Escherichia coli , Antibacterianos/farmacologia , Antibacterianos/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Lung adenocarcinoma (LADC) is the most prevalent lung cancer sub-type, and targeted therapy developed in recent years has made progress in its treatment. Erdafitinib, a potent and selective pan-FGFR tyrosine kinase inhibitor, has been confirmed to be effective for the treatment of LADC; however, the molecular mechanism responsible for this effect is unclear. The in vitro study showed that erdafitinib exhibited an outstanding anti-cancer activity in human LADC cell line A549 by inducing S-phase cell-cycle arrest and cell apoptosis. The mechanistic study based on the transcriptomic data revealed that erdafitinib exerted its anti-cancer effect by affecting the cell cycle-related pathway, and CDK2 was the regulatory target of this drug. In addition, CDK2 overexpression significantly attenuated the anti-cancer effect of erdafitinib by affecting the transcriptional activity and expression of E2F1, as well as the expression of CDK1. The in vivo study showed that erdafitinib presented an obvious anti-cancer effect in the A549 xenograft mice model, which was accompanied by the reduced expression of CDK2. Thus, this study demonstrates the anti-cancer effect of erdafitinib against LADC for the first time based on in vitro and in vivo models, whose activity is achieved by targeting CDK2 and regulating downstream E2F1-CDK1 signaling. This study may be helpful for expanding the clinical application of erdafitinib in treating LADC.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Animais , Apoptose , Carcinogênese/genética , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis , QuinoxalinasRESUMO
BACKGROUND: The discoidin domain receptor 1 (DDR1) is activated by collagens, upregulated in injured and fibrotic kidneys, and contributes to fibrosis by regulating extracellular matrix production, but how DDR1 controls fibrosis is poorly understood. DDR1 is a receptor tyrosine kinase (RTK). RTKs can translocate to the nucleus via a nuclear localization sequence (NLS) present on the receptor itself or a ligand it is bound to. In the nucleus, RTKs regulate gene expression by binding chromatin directly or by interacting with transcription factors. METHODS: To determine whether DDR1 translocates to the nucleus and whether this event is mediated by collagen-induced DDR1 activation, we generated renal cells expressing wild-type or mutant forms of DDR1 no longer able to bind collagen. Then, we determined the location of the DDR1 upon collagen stimulation. Using both biochemical assays and immunofluorescence, we analyzed the steps involved in DDR1 nuclear translocation. RESULTS: We show that although DDR1 and its natural ligand, collagen, lack an NLS, DDR1 is present in the nucleus of injured human and mouse kidney proximal tubules. We show that DDR1 nuclear translocation requires collagen-mediated receptor activation and interaction of DDR1 with SEC61B, a component of the Sec61 translocon, and nonmuscle myosin IIA and ß-actin. Once in the nucleus, DDR1 binds to chromatin to increase the transcription of collagen IV, a major collagen upregulated in fibrosis. CONCLUSIONS: These findings reveal a novel mechanism whereby activated DDR1 translates to the nucleus to regulate synthesis of profibrotic molecules.
Assuntos
Colágeno Tipo IV/genética , Colágeno Tipo I/metabolismo , Receptor com Domínio Discoidina 1/metabolismo , Túbulos Renais Proximais/metabolismo , Actinas/metabolismo , Injúria Renal Aguda/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Núcleo Celular , Cromatina/metabolismo , Colágeno Tipo I/farmacologia , Colágeno Tipo IV/metabolismo , Receptor com Domínio Discoidina 1/genética , Humanos , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Cadeias Pesadas de Miosina/metabolismo , Sinais de Localização Nuclear , Proteína 4 de Ligação ao Retinoblastoma/metabolismo , Canais de Translocação SEC/metabolismo , Transcrição GênicaRESUMO
It was recently shown that ZnO nanoparticles (NPs) could induce endoplasmic reticulum (ER) stress in human umbilical vein endothelial cells (HUVECs). If ER stress is associated the toxicity of ZnO NPs, the presence of ER stress inducer thapsigargin (TG) should alter the response of HUVECs to ZnO NP exposure. In this study, we addressed this issue by assessing cytotoxicity, oxidative stress and inflammatory responses in ZnO NP exposed HUVECs with or without the presence of TG. Moreover, TiO2 NPs were used to compare the effects. Exposure to 32 µg/mL ZnO NPs (p < 0.05), but not TiO2 NPs (p > 0.05), significantly induced cytotoxicity as assessed by WST-1 and neutral red uptake assay, as well as intracellular ROS. ZnO NPs dose-dependently increased the accumulation of intracellular Zn ions, and ZnSO4 induced similar cytotoxic effects as ZnO NPs, which indicated a role of Zn ions. The release of inflammatory proteins tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) or the adhesion of THP-1 monocytes to HUVECs was not significantly affected by ZnO or TiO2 NP exposure (p > 0.05). The presence of 250 nM TG significantly induced cytotoxicity, release of IL-6 and THP-1 monocyte adhesion (p < 0.01), but did not significantly affect intracellular ROS or release of TNFα (p > 0.05). ANOVA analysis indicated no interaction between exposure to ZnO NPs and the presence of TG on almost all the endpoints (p > 0.05) except neutral red uptake assay (p < 0.01). We concluded ER stress is probably not associated with ZnO NP exposure induced oxidative stress and inflammatory responses in HUVECs.
Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Nanopartículas/toxicidade , Tapsigargina/toxicidade , Titânio/toxicidade , Óxido de Zinco/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/ultraestrutura , Humanos , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Propriedades de Superfície , Tapsigargina/química , Titânio/química , Óxido de Zinco/químicaRESUMO
Antibacterial and active packaging materials have gained significant research attention in response to the growing interest in food packaging. In this investigation, we developed hydrogel packaging materials with antibacterial and antioxidant properties by incorporating chitooligosaccharide (COS) and fish skin gelatin (FSG) nanofiber membranes, which readily absorbed water and exhibited swelling characteristics. The nanofiber membranes were fabricated by electrospinning technology, embedding COS within FSG, and subsequently crosslinked through the Maillard reaction facilitated by the addition of glucose. The behavior of conductivity, viscosity, and surface tension in the spinning solutions was analyzed to understand their variation patterns. Scanning electron microscopy (SEM) results revealed that the crosslinked COS/FSG nanofiber membranes possessed a uniform yet disordered fiber structure, with the diameter of the nanofibers increasing as the COS content increased. Remarkably, when the COS content reached 25 %, the COS/FSG nanofiber membranes (CF-C-25) exhibited a suitable fiber diameter of 437.16 ± 63.20 nm. Furthermore, the thermal crosslinking process involving glucose supplementation enhanced the hydrophobicity of CF-C-25. Upon hydration, the CF-H-25 hydrogel displayed a distinctive porous structure, exhibiting a remarkable swelling rate of 954 %. Notably, the inclusion of COS significantly augmented the antibacterial and antioxidant properties of the hydrogel-based nanofiber membranes. CF-H-25 demonstrated an impressive growth inhibition of 90.56 ± 5.91 % against E. coli, coupled with excellent antioxidant capabilities. In continuation, we performed a comprehensive analysis of the total colony count, pH, TVB-N, and TBA of crucian carp. The CF-H-25 hydrogel proved highly effective in extending the shelf life of crucian carp by 2-4 days, suggesting its potential application as an edible membrane for aquatic product packaging.
Assuntos
Quitosana , Nanofibras , Oligossacarídeos , Sulfanilamidas , Animais , Nanofibras/química , Gelatina/química , Antioxidantes/farmacologia , Antioxidantes/química , Escherichia coli , Hidrogéis/farmacologia , Antibacterianos/farmacologia , Quitina , GlucoseRESUMO
The toxicity of Mg(OH)2 nanoparticles (NPs) as antibacterial agents to a normal biological system is unclear, so it is necessary to evaluate their potential toxic effect for safe use. In this work, the administration of these antibacterial agents did not induce pulmonary interstitial fibrosis as no significant effect on the proliferation of HELF cells was observed in vitro. Additionally, Mg(OH)2 NPs caused no inhibition of the proliferation of PC-12 cells, indicating that the brain's nervous system was not affected by Mg(OH)2 NPs. The acute oral toxicity test showed that the Mg(OH)2 NPs at 10,000 mg/kg induced no mortality during the administration period, and there was little toxicity in vital organs according to a histological analysis. In addition, the in vivo acute eye irritation test results showed little acute irritation of the eye caused by Mg(OH)2 NPs. Thus, Mg(OH)2 NPs exhibited great biosafety to a normal biological system, which was critical for human health and environmental protection.
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Cerebral ischemic stroke remains one of the most serious neurological disorders that pose threats to human health, causing a large amount of long-term disability or even death throughout the world. Based on its physiologic and pathological features, there are limited available therapeutic options for effective ischemic stroke management. Encouragingly, a rapid advancement of nanobiotechnology is bringing new insights into exploring more alternative strategies against cerebral ischemic stroke, which can cleverly overcome the limitations related to conventional treatment methods. Therefore, this review focuses on the recent achievements of nanobiotechnology for ischemic stroke management, which emphasizes diverse targeted delivery strategies using various nanoplatforms including liposomes, micelles, polymeric nanoparticles, nanogels, inorganic nanomaterials, and cell-derived nano-vectors based on the pathophysiological features of ischemic stroke. Moreover, different therapeutic approaches against ischemic stroke such as neuroprotection, anti-inflammation, thrombolysis, increased blood-brain barrier penetration and reactive oxygen species scavenging are highlighted. Meanwhile, this review discusses how these versatile nanoplatforms were designed to assist in the treatment of ischemic stroke. Based on this, challenges, opportunities, and future perspectives using nanobiotechnology through rational design for effective ischemic stroke management are revealed.
Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/tratamento farmacológico , Lipossomos , Barreira Hematoencefálica , NeuroproteçãoRESUMO
Objective: To explore the regulation of the inflammatory response in acute SARS-CoV-2 infection, we examined effects of single nucleotide variants (SNVs) of IL1RN , the gene encoding the anti-inflammatory IL-1 receptor antagonist (IL-1Ra), on the cytokine release syndrome and mortality. Methods: We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021 at NYU Langone's Tisch Hospital. CTA and TTG haplotypes formed from three SNVs (rs419598, rs315952, rs9005) and the individual SNVs of the IL1RN gene were assessed for association with laboratory markers of the cytokine release syndrome (CRS) and mortality. Results: Mortality in the population was 15.3%, and was lower in women than men (13.1% vs.17.3%, p<0.0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra relative to TTG carriers. Decreased mortality among CTA-1/2 carriers was observed in male patients between the ages of 55-74 [9.2% vs. 17.9%, p=0.001]. Evaluation of individual SNVs of the IL1RN gene (rs419598, rs315952, rs9005) indicated that carriers of the IL1RN rs419598 CC SNV exhibited lower inflammatory biomarker levels, and was associated with reduced mortality compared to the CT/TT genotype in men (OR 0.49 (0.23 - 1.00); 0.052), with the most pronounced effect observed between the ages of 55-74 [5.5% vs. 18.4%, p<0.001]. Conclusion: The IL1RN haplotype CTA, and sequence variant of rs419598 are associated with attenuation of the cytokine release syndrome and decreased mortality in males with acute SARS-CoV2 infection. The data suggest that IL1RN modulates the COVID-19 cytokine release syndrome via endogenous " anti-inflammatory" mechanisms. Significance statement: We provide evidence that variants of IL1RN modulate the severity of SARS-CoV-2 infection. The IL1RN CTA haplotype and rs419598 CC single nucleotide variant are associated with decreased plasma levels of inflammatory markers, interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-2 (IL-2), C-reactive protein (CRP), D-dimer, ferritin, and procalcitonin, in association with higher levels of IL-1Ra and IL-10, anti-inflammatory proteins. Both haplotype CTA and rs419598 CC genotype are associated with a significant reduction in the mortality of men. These data provide genetic evidence that inflammasome activation and the IL-1 pathway plays an important role in the mortality and morbidity associated with severe SARS-CoV-2 infection, and that genetic regulation of inflammatory pathways by variants of IL1RN merits further evaluation in severe SARS-CoV-2 infection.
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PURPOSE: Clinic-based or community-based interventions can improve adherence to guideline-directed medication therapies (GDMTs) among patients with heart failure (HF). However, opportunities for such interventions are frequently missed, as providers may be unable to recognise risk patterns for medication non-adherence. Machine learning algorithms can help in identifying patients with high likelihood of non-adherence. While a number of multilevel factors influence adherence, prior models predicting non-adherence have been limited by data availability. We have established an electronic health record (EHR)-based cohort with comprehensive data elements from multiple sources to improve on existing models. We linked EHR data with pharmacy refill data for real-time incorporation of prescription fills and with social determinants data to incorporate neighbourhood factors. PARTICIPANTS: Patients seen at a large health system in New York City (NYC), who were >18 years old with diagnosis of HF or reduced ejection fraction (<40%) since 2017, had at least one clinical encounter between 1 April 2021 and 31 October 2022 and active prescriptions for any of the four GDMTs (beta-blocker, ACEi/angiotensin receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonist (MRA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i)) during the study period. Patients with non-geocodable address or outside the continental USA were excluded. FINDINGS TO DATE: Among 39 963 patients in the cohort, the average age was 73±14 years old, 44% were female and 48% were current/former smokers. The common comorbid conditions were hypertension (77%), cardiac arrhythmias (56%), obesity (33%) and valvular disease (33%). During the study period, 33 606 (84%) patients had an active prescription of beta blocker, 32 626 (82%) had ACEi/ARB/ARNI, 11 611 (29%) MRA and 7472 (19%) SGLT2i. Ninety-nine per cent were from urban metropolitan areas. FUTURE PLANS: We will use the established cohort to develop a machine learning model to predict medication adherence, and to support ancillary studies assessing associates of adherence. For external validation, we will include data from an additional hospital system in NYC.
Assuntos
Insuficiência Cardíaca , Farmácia , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adolescente , Masculino , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Determinantes Sociais da Saúde , Antagonistas de Receptores de Angiotensina/uso terapêutico , Registros Eletrônicos de Saúde , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Anti-Hipertensivos/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Adesão à Medicação , Volume Sistólico , Antagonistas de Receptores de Mineralocorticoides/uso terapêuticoRESUMO
Importance: Medication nonadherence is common among patients with heart failure with reduced ejection fraction (HFrEF) and can lead to increased hospitalization and mortality. Patients living in socioeconomically disadvantaged areas may be at greater risk for medication nonadherence due to barriers such as lower access to transportation or pharmacies. Objective: To examine the association between neighborhood-level socioeconomic status (nSES) and medication nonadherence among patients with HFrEF and to assess the mediating roles of access to transportation, walkability, and pharmacy density. Design, Setting, and Participants: This retrospective cohort study was conducted between June 30, 2020, and December 31, 2021, at a large health system based primarily in New York City and surrounding areas. Adult patients with a diagnosis of HF, reduced EF on echocardiogram, and a prescription of at least 1 guideline-directed medical therapy (GDMT) for HFrEF were included. Exposure: Patient addresses were geocoded, and nSES was calculated using the Agency for Healthcare Research and Quality SES index, which combines census-tract level measures of poverty, rent burden, unemployment, crowding, home value, and education, with higher values indicating higher nSES. Main Outcomes and Measures: Medication nonadherence was obtained through linkage of health record prescription data with pharmacy fill data and was defined as proportion of days covered (PDC) of less than 80% over 6 months, averaged across GDMT medications. Results: Among 6247 patients, the mean (SD) age was 73 (14) years, and majority were male (4340 [69.5%]). There were 1011 (16.2%) Black participants, 735 (11.8%) Hispanic/Latinx participants, and 3929 (62.9%) White participants. Patients in lower nSES areas had higher rates of nonadherence, ranging from 51.7% in the lowest quartile (731 of 1086 participants) to 40.0% in the highest quartile (563 of 1086 participants) (P < .001). In adjusted analysis, patients living in the lower 2 nSES quartiles had significantly higher odds of nonadherence when compared with patients living in the highest nSES quartile (quartile 1: odds ratio [OR], 1.57 [95% CI, 1.35-1.83]; quartile 2: OR, 1.35 [95% CI, 1.16-1.56]). No mediation by access to transportation and pharmacy density was found, but a small amount of mediation by neighborhood walkability was observed. Conclusions and Relevance: In this retrospective cohort study of patients with HFrEF, living in a lower nSES area was associated with higher rates of GDMT nonadherence. These findings highlight the importance of considering neighborhood-level disparities when developing approaches to improve medication adherence.
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Insuficiência Cardíaca , Adulto , Humanos , Masculino , Feminino , Idoso , Estudos Retrospectivos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Volume Sistólico , Classe Social , PrescriçõesRESUMO
Objectives: Our objective was to analyze changes in lifestyle patterns of Chinese college students at home during the COVID-19 outbreak. Methods: According to a structured online questionnaire covering socio- demographic information, anthropometric data, and changes in food intake, physical activity, and sleep during the COVID-19 outbreak, the relationships between the above data before and during the outbreak were analyzed. Results: Among the 781 participants, 38.5% had significantly increased their total food intake and 29.1% had significantly decreased their physical activity. Overall, 44% of participants reported weight gain. The average weight gain was 0.7±2.5 kg. The main causes of weight gain were increased food intake (p < .001), decreased physical activity (p < .01), and an excessive increase or reduction in sleep duration (p < .024). Conclusion: During the COVID-19 outbreak, college students' food intake was found to be increased and physical activity decreased; sleep duration was irregular, and all these factors influenced weight gain.
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COVID-19 , China/epidemiologia , Surtos de Doenças , Humanos , Estilo de Vida , Estudantes , Aumento de PesoRESUMO
Background Angiotensin receptor neprilysin inhibitors (ARNI) reduce mortality and hospitalization for patients with heart failure. However, relatively high copayments for ARNI may contribute to suboptimal adherence, thus potentially limiting their benefits. Methods and Results We conducted a retrospective cohort study within a large, multi-site health system. We included patients with: ARNI prescription between November 20, 2020 and June 30, 2021; diagnosis of heart failure or left ventricular ejection fraction ≤40%; and available pharmacy or pharmacy benefit manager copayment data. The primary exposure was copayment, categorized as $0, $0.01 to $10, $10.01 to $100, and >$100. The primary outcome was prescription fill nonadherence, defined as the proportion of days covered <80% over 6 months. We assessed the association between copayment and nonadherence using multivariable logistic regression, and nonbinarized proportion of days covered using multivariable Poisson regression, adjusting for demographic, clinical, and neighborhood-level covariates. A total of 921 patients met inclusion criteria, with 192 (20.8%) having $0 copayment, 228 (24.8%) with $0.01 to $10 copayment, 206 (22.4%) with $10.01 to $100, and 295 (32.0%) with >$100. Patients with higher copayments had higher rates of nonadherence, ranging from 17.2% for $0 copayment to 34.2% for copayment >$100 (P<0.001). After multivariable adjustment, odds of nonadherence were significantly higher for copayment of $10.01 to $100 (odds ratio [OR], 1.93 [95% CI, 1.15-3.27], P=0.01) or >$100 (OR, 2.58 [95% CI, 1.63-4.18], P<0.001), as compared with $0 copayment. Similar associations were seen when assessing proportion of days covered as a proportion. Conclusions We found higher rates of not filling ARNI prescriptions among patients with higher copayments, which persisted after multivariable adjustment. Our findings support future studies to assess whether reducing copayments can increase adherence to ARNI and improve outcomes for heart failure.
Assuntos
Insuficiência Cardíaca , Neprilisina , Humanos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Combinação de Medicamentos , Neprilisina/antagonistas & inibidores , Estudos Retrospectivos , Volume Sistólico , Tetrazóis/uso terapêutico , Resultado do Tratamento , Valsartana/uso terapêutico , Função Ventricular EsquerdaRESUMO
The multifunctional polyethylene terephthalate (PET) fabrics were successfully prepared through a dip-coating technology to endow the flame retardant and antibacterial properties of PET fabrics, which are extensively used in many fields. The flame retardant and antibacterial agent was synthesized by a double drop-reverse precipitation method and surface-modified by the mixtures of titanate coupling agents and stearic acid to result in a good compatibility of the hydrophilic nano-Mg(OH)2 and the hydrophobic PET fabrics. The results indicated that the suitable synthesis conditions of nano-Mg(OH)2 are: Mg2+ concentration 1.5 mg/mL, reaction temperature 50 °C and reaction time 50 min, and the optimal modification conditions of nano-Mg(OH)2 are: modifier ratio 5/5, modification temperature 70 °C and modification time 40 min. The flame retardant test and the antibacterial test showed that the multifunctional PET fabrics had excellent flame retardant and antibacterial properties.
RESUMO
Lung adenocarcinoma (LADC), the most common type of lung cancer, is still one of the most aggressive and rapidly fatal tumor types, even though achievements in new therapeutic approaches have been developed. Elaiophylin as a C2 symmetrically glycosylated 16 macrolides has been reported to be a late-stage autophagy inhibitor with a potent anti-tumor effect on various cancers. This study investigated the anti-tumor effect of elaiophylin on human LADC for the first time in in vitro and in vivo models. The in vitro study in LADC A549 cells showed that elaiophylin significantly inhibited cell viability and induced cell apoptosis through the suppression of mitophagy and induction of cellular and mitochondrial oxidative stress. Proteomic analysis and molecular docking assay implicated that SIRT1 was likely the direct target of elaiophylin in A549 cells. Further mechanistic study verified that elaiophylin reduced Nrf2 deacetylation, expression, and transcriptional activity as well as cytoplasm translocation by downregulating SIRT1 expression and deacetylase activity. Additionally, SIRT1/Nrf2 activation could attenuate elaiophylin-induced mitophagy inhibition and oxidative stress. The in vivo study in the A549-xenograft mice model showed that the anti-tumor effect of elaiophylin was accompanied by the decreased expressions of SIRT1, Nrf2, Parkin, and PINK1. Thus, the present study reports that elaiophylin has potent anti-tumor properties in LADC, which effect is likely mediated through suppressing the SIRT1/Nrf2 signaling. In conclusion, elaiophylin may be a novel drug candidate for LADC and SIRT1 may be a new therapeutic target for such devastating malignancy.