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The nurse scheduling problem (NSP) has been a crucial and challenging research issue for hospitals, especially considering the serious deterioration in nursing shortages in recent years owing to long working hours, considerable work pressure, and irregular lifestyle, which are important in the service industry. This study investigates the NSP that aims to maximize nurse satisfaction with the generated schedule subject to government laws, internal regulations of hospitals, doctor-nurse pairing rules, shift and day off preferences of nurses, etc. The computational experiment results show that our proposed hybrid metaheuristic outperforms other metaheuristics and manual scheduling in terms of both computation time and solution quality. The presented solution procedure is implemented in a real-world clinic, which is used as a case study. The developed scheduling technique reduced the time spent on scheduling by 93% and increased the satisfaction of the schedule by 21%, which further enhanced the operating efficiency and service quality.
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Satisfação no Emprego , Admissão e Escalonamento de Pessoal , Humanos , Admissão e Escalonamento de Pessoal/organização & administração , Recursos Humanos de Enfermagem Hospitalar/organização & administração , Recursos Humanos de Enfermagem Hospitalar/psicologia , Eficiência Organizacional , MédicosRESUMO
It raises questions about the impact of lard on the health and the differences in individual responses. Therefore, we developed a model of mice fed with high fat (HF) from lard in 130 days. The weight of the mice was measured every two days. Glucose tolerance test and insulin tolerance tests were performed at 70 days and 130 days of experiment. At the end of the study, the fat tissue was collected to check the weight, and a blood sample was collected to check the blood lipids and liver enzymes. Surprisingly, mice responded variously to the HF by being classified into two groups, one group had significantly high gained weight (HG_HF) versus the mice fed a standard diet (STD) (p < 0.001), and another group (LG_HF) has not difference in body weight compared to the STD groups. This phenomenon in body weight is directly reflected by the white fat accumulation, but not by brown fat. Eating HF from lard for a long time can disrupt glucose tolerance and cause dyslipidemia in mice, even in the LG_HF group, but can not disrupt insulin tolerance and cause liver enzyme disorders. In summary, our findings are a wake-up call for many cases where eating HF from lard does not gain weight and not increase the white fat storage, but still has the potential to cause adverse health effects. Further studies are encouraged to understand the molecular mechanisms that causes the body to regulate its weight and responses when eating HF from lard, especially in the LG_HF group.
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Opium poppy is a crop of great commercial value as a source of several opium alkaloids for the pharmaceutical industries including morphine, codeine, thebaine, noscapine and papaverine. Most enzymes involved in benzylisoquinoline alkaloids (BIAs) biosynthesis in opium poppy have been functionally characterized, and opium poppy currently serves as a model system to study BIA metabolism in plants. BIA biosynthesis in opium poppy involves two biosynthetic gene clusters associated respectively with the morphine and noscapine branches. Recent reports have shown that genes in the same cluster are co-expressed, suggesting they might also be co-regulated. However, the transcriptional regulation of opium poppy BIA biosynthesis is not well studied. Opium poppy BIA biosynthesis involves three cell types associated with the phloem system: companion cells, sieve elements and laticifers. The transcripts and enzymes associated with BIA biosynthesis are distributed across cell types, requiring the translocation of key enzymes and pathway intermediates between cell types. Together, these suggest that the regulation of BIA biosynthesis in opium poppy is multilayered and complex, involving biochemical, genomic, and physiological mechanisms. In this review, we highlight recent advances in genome sequencing and single cell and spatial transcriptomics with a focus on how these efforts can improve our understanding of the genomic and cell-specific regulation of BIA biosynthesis. Such knowledge is vital for opium poppy genetic improvement and metabolic engineering efforts targeting the modulation of alkaloid yield and composition.
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The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This creates a hostile immune landscape that impedes effective immune responses. The interleukin-1 (IL-1) receptor antagonist (IL1RN), a key anti-inflammatory molecule, plays a significant role in suppressing IL-1-related immune and inflammatory responses. Our research investigates the oncogenic role of IL1RN in PCa, particularly its interactions with muscarinic acetylcholine receptor 4 (CHRM4), and its involvement in driving immunosuppressive pathways and M2-like macrophage polarization within the PCa TME. We demonstrate that following androgen deprivation therapy (ADT), the IL1RN-CHRM4 interaction in PCa activates the MAPK/AKT signaling pathway. This activation upregulates the transcription factors E2F1 and MYCN, stimulating IL1RN production and creating a positive feedback loop that increases CHRM4 abundance in both PCa cells and M2-like macrophages. This ADT-driven IL1RN/CHRM4 axis significantly enhances immune checkpoint markers associated with neuroendocrine differentiation and treatment-resistant outcomes. Higher serum IL1RN levels are associated with increased disease aggressiveness and M2-like macrophage markers in advanced PCa patients. Additionally, elevated IL1RN levels correlate with better clinical outcomes following immunotherapy. Clinical correlations between IL1RN and CHRM4 expression in advanced PCa patients and neuroendocrine PCa organoid models highlight their potential as therapeutic targets. Our data suggest that targeting the IL1RN/CHRM4 signaling could be a promising strategy for managing PCa progression and enhancing treatment responses.
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Regenerative medicine and cosmetics are currently two outstanding fields for drug discovery. Although many pharmaceutical products for regenerative medicine and cosmetics have received approval by official agencies, several challenges are still needed to overcome, especially financial and time issues. As a result, drug repositioning, which is the usage of previously approved drugs for new treatment, stands out as a promising approach to tackle these problems. Recently, increasing scientific evidence is collected to demonstrate the applicability of this novel method in the field of regenerative medicine and cosmetics. Experts in drug development have also taken advantage of novel technologies to discover new candidates for repositioning purposes following computational approach, one of two main approaches of drug repositioning. Therefore, numerous repurposed candidates have obtained approval to enter the market and have witnessed financial success such as minoxidil and fingolimod. The benefits of drug repositioning are undeniable for regenerative medicine and cosmetics. However, some aspects still need to be carefully considered regarding this method including actual effectiveness during clinical trials, patent regulations, data integration and analysis, publicly unavailable databases as well as environmental concerns and more effort are required to overcome these obstacles.
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Cosméticos , Reposicionamento de Medicamentos , Medicina Regenerativa , Medicina Regenerativa/economia , Humanos , Cosméticos/uso terapêutico , Cosméticos/economia , AnimaisRESUMO
BACKGROUND: At a global scale, the SARS-CoV-2 virus did not remain in its initial genotype for a long period of time, with the first global reports of variants of concern (VOCs) in late 2020. Subsequently, genome sequencing has become an indispensable tool for characterizing the ongoing pandemic, particularly for typing SARS-CoV-2 samples obtained from patients or environmental surveillance. For such SARS-CoV-2 typing, various in vitro and in silico workflows exist, yet to date, no systematic cross-platform validation has been reported. RESULTS: In this work, we present the first comprehensive cross-platform evaluation and validation of in silico SARS-CoV-2 typing workflows. The evaluation relies on a dataset of 54 patient-derived samples sequenced with several different in vitro approaches on all relevant state-of-the-art sequencing platforms. Moreover, we present UnCoVar, a robust, production-grade reproducible SARS-CoV-2 typing workflow that outperforms all other tested approaches in terms of precision and recall. CONCLUSIONS: In many ways, the SARS-CoV-2 pandemic has accelerated the development of techniques and analytical approaches. We believe that this can serve as a blueprint for dealing with future pandemics. Accordingly, UnCoVar is easily generalizable towards other viral pathogens and future pandemics. The fully automated workflow assembles virus genomes from patient samples, identifies existing lineages, and provides high-resolution insights into individual mutations. UnCoVar includes extensive quality control and automatically generates interactive visual reports. UnCoVar is implemented as a Snakemake workflow. The open-source code is available under a BSD 2-clause license at github.com/IKIM-Essen/uncovar.
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COVID-19 , Genoma Viral , SARS-CoV-2 , Fluxo de Trabalho , SARS-CoV-2/genética , Humanos , COVID-19/virologia , COVID-19/epidemiologia , Software , Reprodutibilidade dos TestesRESUMO
Neuroendocrine prostate cancer (PCa) (NEPC), an aggressive subtype that is associated with poor prognosis, may arise after androgen deprivation therapy (ADT). We investigated the molecular mechanisms by which ADT induces neuroendocrine differentiation in advanced PCa. We found that transmembrane protein 1 (MCTP1), which has putative Ca2+ sensing function and multiple Ca2+-binding C2 domains, was abundant in samples from patients with advanced PCa. MCTP1 was associated with the expression of the EMT-associated transcription factors ZBTB46, FOXA2, and HIF1A. The increased abundance of MCTP1 promoted PC3 prostate cancer cell migration and neuroendocrine differentiation and was associated with SNAI1-dependent EMT in C4-2 PCa cells after ADT. ZBTB46 interacted with FOXA2 and HIF1A and increased the abundance of MCTP1 in a hypoxia-dependent manner. MCTP1 stimulated Ca2+ signaling and AKT activation to promote EMT and neuroendocrine differentiation by increasing the SNAI1-dependent expression of EMT and neuroendocrine markers, effects that were blocked by knockdown of MCTP1. These data suggest an oncogenic role for MCTP1 in the maintenance of a rare and aggressive prostate cancer subtype through its response to Ca2+ and suggest its potential as a therapeutic target.
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Diferenciação Celular , Transição Epitelial-Mesenquimal , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Androgênios/metabolismo , Androgênios/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genéticaRESUMO
Human leucocyte antigen class I (HLA-I) molecules play a central role for both NK and T-cell responses that prevent serious human cytomegalovirus (HCMV) disease. To create opportunities for viral spread, several HCMV-encoded immunoevasins employ diverse strategies to target HLA-I. Among these, the glycoprotein US10 is so far insufficiently studied. While it was reported that US10 interferes with HLA-G expression, its ability to manipulate classical HLA-I antigen presentation remains unknown. In this study, we demonstrate that US10 recognizes and binds to all HLA-I (HLA-A, -B, -C, -E, -G) heavy chains. Additionally, impaired recruitment of HLA-I to the peptide loading complex was observed. Notably, the associated effects varied significantly dependending on HLA-I genotype and allotype: (i) HLA-A molecules evaded downregulation by US10, (ii) tapasin-dependent HLA-B molecules showed impaired maturation and cell surface expression, and (iii) ß2m-assembled HLA-C, in particular HLA-C*05:01 and -C*12:03, and HLA-G were strongly retained in complex with US10 in the endoplasmic reticulum. These genotype-specific effects on HLA-I were confirmed through unbiased HLA-I ligandome analyses. Furthermore, in HCMV-infected fibroblasts inhibition of overlapping US10 and US11 transcription had little effect on HLA-A, but induced HLA-B antigen presentation. Thus, the US10-mediated impact on HLA-I results in multiple geno- and allotypic effects in a so far unparalleled and multimodal manner.
During a viral infection, the immune system must discriminate between healthy and infected cells to selectively kill infected cells. Healthy cells have different types of molecules known collectively as HLA-I on their surface. These molecules present small fragments of proteins from the cell, called antigens, to patrolling immune cells, known as CTLs or natural killer cells. While CTLs ignore antigens from human proteins (which indicate the cell is healthy), they can bind to and recognize antigens from viral proteins, which triggers them to activate immune responses that kill the infected cell. However, some viruses can prevent infected cells from presenting HLA-I molecules on their surfaces as a strategy to evade the immune system. Natural killer cells have evolved to overcome this challenge. They bind to the HLA-I molecules themselves, which causes them to remain inactive. However, if the HLA-I molecules are missing, the NK cells can more easily switch on and kill the target cell. The human cytomegalovirus is a common virus that causes lifelong infection in humans. Although it rarely causes illness in healthy individuals, it can be life-threatening to newborn babies and for individuals with weakened immune systems. One human cytomegalovirus protein known as US10 was previously found to bind to HLA-I without reducing the levels of these molecules on the surface of the cell. However, its precise role remained unclear. Gerke et al. used several biochemical and cell biology approaches to investigate whether US10 manipulates the quality of the three types of HLA-I, which could impact both CTL and NK cell recognition. The experiments showed that US10 acted differently on the various kinds of HLA-I. To one type, it bound strongly within the cell and prevented it from reaching the surface. US10 also prevented another type of HLA-I from maturing properly and presenting antigens but did not affect the third type of HLA-I. These findings suggest that US10 interferes with the ability of different HLA-I types to present antigens in specific ways. Further research is needed to measure how US10 activity affects immune cells, which may ultimately aid the development of new therapies against human cytomegalovirus and other similar viruses.
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Citomegalovirus , Antígenos de Histocompatibilidade Classe I , Humanos , Citomegalovirus/genética , Citomegalovirus/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Genótipo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Ligação Proteica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Regulação da Expressão Gênica , Apresentação de Antígeno/genéticaRESUMO
Viral respiratory illness surveillance has traditionally focused on single pathogens (e.g., influenza) and required fever to identify influenza-like illness (ILI). We developed an automated system applying both laboratory test and syndrome criteria to electronic health records from 3 practice groups in Massachusetts, USA, to monitor trends in respiratory viral-like illness (RAVIOLI) across multiple pathogens. We identified RAVIOLI syndrome using diagnosis codes associated with respiratory viral testing or positive respiratory viral assays or fever. After retrospectively applying RAVIOLI criteria to electronic health records, we observed annual winter peaks during 2015-2019, predominantly caused by influenza, followed by cyclic peaks corresponding to SARS-CoV-2 surges during 2020-2024, spikes in RSV in mid-2021 and late 2022, and recrudescent influenza in late 2022 and 2023. RAVIOLI rates were higher and fluctuations more pronounced compared with traditional ILI surveillance. RAVIOLI broadens the scope, granularity, sensitivity, and specificity of respiratory viral illness surveillance compared with traditional ILI surveillance.
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Algoritmos , Registros Eletrônicos de Saúde , Infecções Respiratórias , Humanos , Infecções Respiratórias/virologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/diagnóstico , Estudos Retrospectivos , Influenza Humana/epidemiologia , Influenza Humana/diagnóstico , Influenza Humana/virologia , COVID-19/epidemiologia , COVID-19/diagnóstico , Vigilância da População/métodos , Massachusetts/epidemiologia , Adulto , Pessoa de Meia-Idade , SARS-CoV-2 , Masculino , Adolescente , Criança , Idoso , Feminino , Estações do Ano , Viroses/epidemiologia , Viroses/diagnóstico , Viroses/virologia , Pré-Escolar , Adulto JovemRESUMO
Objectives: To describe the status of using biological Disease Modifying Anti Rheumatic Drugs (bDMARDs) to treat rheumatoid arthritis (RA) and related factors. In addition, the study determined the impact of COVID-19 on the usage of bDMARDs. Methods: This is a cross-sectional study and included 219 RA patients over 18 years old. The KaplanMeier method and the log-rank test (p<0.05) were used to estimate the retention time and compare between different times. Cox regression analysis was used to determine the factors affecting the retention time of biological drugs (p<0.05). Results: Out of 1967 courses of treatment, there were 149 (7.6%) drug discontinuations, 760 (38.6%) doses extensions and 64 (3.3%) drug switch. Moderate disease level and choosing tumor necrosis factor (TNF) inhibitors initially were associated with retention time of COVID-19. Drug discontinuations and dose extensions increased after COVID-19 emergence. The retention time during COVID-19 was significantly different from that of pre-COVID-19. Gender, type of first-used bDMARD, conventional synthetic DMARDs (csDMARDs) and corticoid usage status, disease activity levels were associated with retention time. Conclusion: The presence of COVID-19 has a significant effect on usage status of the biologic drug. Further longitudinal studies are needed to clarify the relationship between COVID-19 and drug usage as well as related factors.(AU)
Objetivos: Describir el estado del uso de fármacos antirreumáticos modificadores de la enfermedad biológica (bDMARD) para tratar la artritis reumatoide (AR) y los factores relacionados. Además, el estudio determinó el impacto de COVID-19 en el uso de bDMARD. Métodos: Este es un estudio transversal que incluyó a 219 pacientes con AR mayores de 18 años. El método Kaplan-Meier y la prueba Log-rank (p<0,05) se usaron para estimar el tiempo de retención y compararlo entre diferentes tiempos. El análisis de regresión de Cox se utilizó para determinar los factores que afectan el tiempo de retención de los medicamentos biológicos (p<0,05). Resultados: De 1.967 cursos de tratamiento, hubo 149 (7,6%) interrupciones del fármaco, 760 (38,6%) extensiones de dosis y 64 (3,3%) cambios de fármaco. Nivel de enfermedad moderado y elección del factor de necrosis tumoral (TNF) inhibidores inicialmente se asociaron con el tiempo de retención de COVID-19. Las discontinuaciones de los medicamentos y las extensiones de las dosis aumentaron después de la aparición de COVID-19. El tiempo de retención durante COVID-19 fue significativamente diferente del pre-COVID-19. Género, tipo de bDMARD de primer uso, convencional DMARD sintéticos (csDMARDs) y el estado de uso de corticoides, los niveles de actividad de la enfermedad se asociaron con el tiempo de retención. Conclusión: La presencia de COVID-19 tiene un efecto significativo en el estado de uso del medicamento biológico. Se necesitan más estudios longitudinales para aclarar la relación entre COVID-19 y el uso de fármacos, así como los factores relacionados.(AU)
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Humanos , Masculino , Feminino , Artrite Reumatoide , /complicações , Antirreumáticos , Estimativa de Kaplan-Meier , Vietnã , Reumatologia , Doenças Reumáticas , /epidemiologia , Estudos TransversaisRESUMO
OBJECTIVES: To describe the status of using biological Disease Modifying Anti Rheumatic Drugs (bDMARDs) to treat rheumatoid arthritis (RA) and related factors. In addition, the study determined the impact of COVID-19 on the usage of bDMARDs. METHODS: This is a cross-sectional study and included 219 RA patients over 18 years old. The Kaplan-Meier method and the log-rank test (p<0.05) were used to estimate the retention time and compare between different times. Cox regression analysis was used to determine the factors affecting the retention time of biological drugs (p<0.05). RESULTS: Out of 1967 courses of treatment, there were 149 (7.6%) drug discontinuations, 760 (38.6%) doses extensions and 64 (3.3%) drug switch. Moderate disease level and choosing tumor necrosis factor (TNF) inhibitors initially were associated with retention time of COVID-19. Drug discontinuations and dose extensions increased after COVID-19 emergence. The retention time during COVID-19 was significantly different from that of pre-COVID-19. Gender, type of first-used bDMARD, conventional synthetic DMARDs (csDMARDs) and corticoid usage status, disease activity levels were associated with retention time. CONCLUSION: The presence of COVID-19 has a significant effect on usage status of the biologic drug. Further longitudinal studies are needed to clarify the relationship between COVID-19 and drug usage as well as related factors.
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Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , COVID-19 , Humanos , Adolescente , Vietnã , Estudos Transversais , Artrite Reumatoide/tratamento farmacológico , Antirreumáticos/uso terapêutico , Produtos Biológicos/uso terapêuticoRESUMO
The prevalence of metabolic disorders is increasing exponentially and has recently reached epidemic levels. Over the decades, a large number of therapeutic options have been proposed to manage these diseases but still show several limitations. In this circumstance, RNA therapeutics have rapidly emerged as a new hope for patients with metabolic diseases. 57 years have elapsed from the discovery of mRNA, a large number of RNA-based drug candidates have been evaluated for their therapeutic effectiveness and clinical safety under clinical studies. To date, there are seven RNA drugs for treating metabolic disorders receiving official approval and entering the global market. Their targets include hereditary transthyretin-mediated amyloidosis (hATTR), familial chylomicronemia syndrome, acute hepatic porphyria, primary hyperoxaluria type 1 and hypercholesterolemia, which are all related to liver proteins. All of these seven RNA drugs are antisense oligonucleotides (ASO) and small interfering RNA (siRNA). These two types of treatment are both based on oligonucleotides complementary to target RNA through Watson-Crick base-pairing, but their mechanisms of action include different nucleases. Such treatments show greatest potential among all types of RNA therapeutics due to consecutive achievements in chemical modifications. Another method, mRNA therapeutics also promise a brighter future for patients with a handful of drug candidates currently under development.
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Neuropatias Amiloides Familiares , Oligonucleotídeos Antissenso , Oligonucleotídeos , Humanos , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , RNA MensageiroRESUMO
The excretory system is responsible for removing wastes from the human body, which plays a crucial role in our lives. Current treatments for diseases related to this system have shown several limitations; therefore, there is a rising need for novel methods. In this circumstance, RNA-based therapeutics have rapidly emerged as new and promising candidates. In fact, to date, a handful of potential drugs have passed the development step and entered the clinical pipeline. Among them, one drug received FDA approval to enter the global market, which is Oxlumo (Lumasiran) for the treatment of primary hyperoxaluria type 1. For other excretory diseases, such as paroxysmal nocturnal hemoglobinuria, urothelial cancer or renal cancer, RNA-based candidates are also being tested under clinical trials. Currently, the most potential types of RNA therapeutics to treat disorders of the excretory system are those based on small interfering RNA (siRNA), antisense oligonucleotides (ASO) and messenger RNA (mRNA), Among them, siRNA therapeutics seem to be the most promising, including Oxlumo and two other developing drug candidates. This chapter will provide a general overview on the application of RNA therapeutics in disorders of the excretory system.
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Oligonucleotídeos Antissenso , Humanos , RNA Interferente Pequeno/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , RNA MensageiroRESUMO
BACKGROUND: People with HIV (PWH) may be at risk for more severe COVID-19 outcomes. We compared risk for severe COVID-19 in PWH with matched individuals without HIV. METHODS: We identified adults in Massachusetts with a positive SARS-CoV-2 test, March 2020-July 2022, using electronic medical record data from 3 large clinical practice groups. We then used regression models to compare outcomes among PWH versus propensity score-matched people without HIV (matched 20:1) for severe COVID-19 (pneumonia or acute respiratory distress syndrome), hospitalization, and hospital length of stay. RESULTS: We identified 171,058 individuals with COVID-19; among them, 768 PWH were matched to 15,360 individuals without HIV. Overall, severe COVID-19 and hospitalization were similar in PWH and those without HIV (severe COVID-19: 3.8% vs 3.0%, adjusted odds ratio [OR] 1.27, 95% confidence interval [CI]: 0.86-1.87; hospitalization: 12.1% vs 11.3%, adjusted OR: 1.08, 95% CI: 0.87 to 1.35). Compared with people without HIV, PWH with low CD4 T-cell counts (<200 cells/mm 3 ) had more severe COVID-19 (adjusted OR: 3.99, 95% CI: 2.06 to 7.74) and hospitalization (adjusted OR: 2.26, 95% CI: 1.35 to 3.80), but PWH with high CD4 counts had lower odds of hospitalization (adjusted OR: 0.73, 95% CI: 0.52 to 1.03). CONCLUSIONS: PWH with low CD4 T-cell counts had worse COVID-19 outcomes compared with people without HIV, but outcomes for those with high CD4 counts were similar to, or better than, those without HIV. It is unclear whether these findings are generalizable to settings where PWH have less access to and engagement with health care.
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COVID-19 , Infecções por HIV , Adulto , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Contagem de Linfócito CD4 , Registros Eletrônicos de SaúdeRESUMO
BACKGROUND/AIM: Adenosine deaminase family acting on RNA 1 (ADAR1) expression was examined to determine its correlation with endometriosis. The biological functions and inhibitory effects of ADAR1 knockdown were investigated in a human endometriotic cell line. MATERIALS AND METHODS: ADAR1 was examined in patients with and without endometriosis using reverse transcription polymerase chain reaction (RT-PCR), and the apoptotic expression of ADAR1 small interfering RNA (siRNA) was confirmed using flow cytometry. The biological functions and inhibitory effects of ADAR1 knockdown were investigated using RT-PCR in a 12Z immortalized human endometriotic cell line. RESULTS: ADAR1 expression was significantly higher in patients with endometriosis than in those without (p<0.001). ADAR1 siRNA increased early and late apoptosis, compared to the mock (24.83%) and control (19.96%) cells. ADAR1 knockdown led to apoptosis through MDA5, RIG-I, IRF3, IRF7, caspase 3, caspase 7, and caspase 8 expression in the cell lines. CONCLUSION: ADAR1 is a potential novel therapeutic target in endometriosis.
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Adenosina Desaminase , Endometriose , Feminino , Humanos , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Endometriose/genética , Linhagem Celular , RNA Interferente Pequeno/genética , Caspase 3RESUMO
Heparin recently has been discovered as a novel anti-cancer agent. The combinations of heparin with other agents was reported not only to reduce the undesired effects of free heparin and increase the cellular uptake of the delivered molecules, but also is the basis for the design and development of multi-stimulation response systems to improve their killing cancer cell efficiency at the target positions. This study aimed to design a redox and pH dual-responsive anticancer system based on heparin for cisplatin (CPT) therapy. Heparin was first cross-linked with Poloxamer 407 chains via disulfide bridges to form a redox-sensitive system Hep-P407. CPT was then encapsulated into the Hep-P407 system via the complex of Platin and carboxyl groups to form the redox/pH-responsive system CPT@Hep-P407. The obtained Hep-P407 systems were proved and characterized using specific techniques including1H-NMR, zeta potential, Dynamic Light Scattering (DLS) and Fourier-transform infrared spectroscopy. The dual-responsive behavior to redox and pH of CPT@Hep-P407 was proved through DLS, zeta andin vitrorelease analysis meanwhile its cytotoxicity was investigated using Resazurin assay. The CPT@Hep-P407 system is expected to be a promising redox/pH-responsive anticancer system based on heparin for CPT therapy.
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Cisplatino , Heparina , Polietilenoglicóis , Polietilenoimina , Nanogéis , Heparina/química , Oxirredução , Concentração de Íons de Hidrogênio , Sistemas de Liberação de Medicamentos/métodosRESUMO
BACKGROUND: The short-term association between increasing temperatures and injury has been described in high-income countries, but less is known for low-income and-middle-income countries, including Vietnam. METHODS: We used emergency injury visits (EIV) data for 2017-2019 from 733 hospitals and clinics in Hanoi, Vietnam to examine the effects of daily temperature on EIV. Time-series analysis with quasi-Poisson models was used to estimate a linear relative risk increase (RRI) for overall populations and ones stratified by age and sex. Exposure-response curves estimated non-linear associations as an RR between daily temperature and injury. Models were adjusted for the day of week, holidays, daily relative humidity, daily particulate matter, and long-term and seasonal trends. RESULTS AND CONCLUSIONS: A total of 39 313 EIV were recorded averaging 36 injuries daily. Injuries more likely occurred in males and those aged 15-44, and aged 44-60. For linear effects, a 5°C increase in same day mean temperature was associated with an overall increased EIV (RRI 4.8; 95% CI 2.3 to 7.3) with males (RRI 5.9; 95% CI 3.0 to 8.9) experiencing a greater effect than females (RRI 3.0; 95% CI -0.5 to 6.5). Non-linear effects showed an increase in EIV at higher temperatures compared with the threshold temperature of 15°C, with the greatest effect at 33°C (RR 1.3; 95% CI 1.2 to 1.6). Further research to investigate temperature-injury among different populations and by the cause of injury is warranted.
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Temperatura Alta , Material Particulado , Masculino , Feminino , Humanos , Temperatura , Vietnã/epidemiologia , Material Particulado/análise , RiscoRESUMO
Lichens produce secondary metabolites that have many pharmaceutical activities such as antimicrobial, antioxidant, antiviral, anticancer, antigenotoxic, anti-inflammatory, analgesic and antipyretic activities. However, there is limited research on their efflux pump inhibitory activities. Twelve phytochemicals were isolated from Usnea aciculifera, and their activity of AcrAB-TolC efflux pump inhibition was evaluated. Four potential compounds, which are diffractaic acid (2), 8' -O- methylstictic acid (5), 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 2,4-dimethoxy-3,6-dimethylbenzoate (8) and 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 2-hydroxy-4-methoxy-3,6-dimethylbenzoate (9), were found by virtual screening using pharmacophore and 2D-QSAR model. Compound 8 exhibited AcrB inhibition activity in vitro with an accumulation H33342 percentage compared with untreated control of 202% at a concentration of 50 µM and increased the antibacterial activity of levofloxacin by four-fold at a concentration of 200 µM. By molecular docking and molecular dynamics (MD) simulation, the binding affinity of depside and depsidone derivatives to AcrB was also clarified. Despite the poor docking score to the AcrB binding site, compound 8 was the most stable among the four complexes at 20 ns of MD simulation. The analysis of long MD at 100 ns indicated that compound 8 interacts strongly with the residues in the distal pocket, creating a stable complex with ΔGbind of -31.51 kcal.mol-1. According to the ADMETlab 2.0 web server's predictions of pharmacokinetics and toxicities, compound 8 has the potential for drug development.Communicated by Ramaswamy H. Sarma.
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Efflux pumps have been reported as one of the significant mechanisms by which bacteria evade the effects of multiple antibiotics. The tripartite efflux pump MexAB-OprM in Pseudomonas aeruginosa is one of the most significant multidrug efflux systems due to its broad resistance to antibiotics such as chloramphenicol, fluoroquinolones, lipophilic ß-lactam antibiotics, nalidixic acid, novobiocin, rifampicin, and tetracycline. A promising strategy to overcome this resistance mechanism is to combine antibiotics with efflux pump inhibitors (EPIs), which can increase their intracellular concentration to enhance their biological activities. Based on 143 EPIs with chemically diverse skeletons, the 3D pharmacophore and 2D-QSAR modelings were developed and used for the virtual screening on 9.2 million compounds including ZINC15, DrugBank, and Traditional Chinese Medicine databases to identify new EPIs. The molecular docking was also performed to evaluate the binding affinity of potential EPIs to the distal-binding pocket of MexB and resulted in 611 potential EPIs. The structure-activity relationship analyses suggested that nitrogen heterocyclic compounds, piperazine and pyridine scaffolds, and amide derivatives are the most favorable chemically features for MexAB inhibitory activities. The results from molecular dynamics analysis in 100 ns indicated that ZINC009296881 and ZINC009200074 were the most potential MexB inhibitors with strong binding affinity to the distal pocket and MM/GBSA ∆Gbind values of - 38.97 and - 30.19 kcal mol-1, respectively. The predicted pharmacokinetic properties and toxicity of these compounds indicated their potential oral drugs. Multistep virtual screening of EPIs for MexAB-OprM, efflux pump multidrug resistant of P. aeruginosa.
RESUMO
BACKGROUND AND OBJECTIVES: When a patient is admitted for seizure-like activity, in addition to obtaining a thorough history and physical exam, the evaluation may include a neurology consultation, EEG, and brain MRI. The cost of an inpatient MRI is significant and only 2% of MRIs yield clinically significant findings. At our institution, there was a 20% increase in patients undergoing inpatient MRI from 2018 to 2020. Our aim: Decrease the percentage of patient encounters receiving inpatient brain MRIs for seizure evaluation from 50% to 40% in 6 months by safely shifting MRIs to the outpatient setting. METHODS: Initially, provider variability in ordering practices of MRIs was analyzed. Stakeholders were gathered and a local guideline was developed to standardize MRI utilization. A process map was created and highlighted barriers to obtaining an outpatient MRI. A new standard process was developed that streamlined and automated processes, and reduced delays and reliance on patients' families. RESULTS: Since implementation of the new clinical guideline, the percentage of inpatient MRIs ordered for patient encounters presenting with seizures and seizure-like episodes decreased from a mean of 50% to 26%. Significant reductions occurred for patients with complex febrile seizures, provoked but afebrile seizures, and unprovoked seizures. The MRI guideline recommendations were followed in 93% of encounters in the final 12 months. None of the patients who underwent outpatient MRI required readmission for acute findings. CONCLUSIONS: In this project, the percentage of inpatient MRIs was safely decreased with the implementation of a clinical guideline and standardized process.