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This study aimed to evaluate the 1-year mortality rate among older patients with COVID-19 discharged from hospital and to identify risk factors associated with this outcome. Using a COVID-19 dataset from the Korean National Health Insurance System, this study's evaluation period spanned from October 8, 2020, through December 31, 2021. The primary outcome was the 1-year mortality rate following hospital discharge. A logistic regression model was employed for multivariable analysis to estimate the odds ratios for the outcomes, and the Kaplan-Meier method was used to analyze differences in 1-year survival rates. Among the 66,810 COVID-19 patients aged 60 years or older who were hospitalized during the study period, the in-hospital mortality rate was 4.8% (n = 3219). Among the survivors (n = 63,369), the 1-year mortality rate was 4.9% (n = 3093). Non-survivors, compared to survivors, were significantly older (79.2 ± 9.5 vs. 68.9 ± 7.8, P < 0.001) and exhibited a lower rate of COVID-19 vaccination (63.0% vs. 91.7%, P < 0.001). Additionally, non-survivors experienced a higher incidence of organ dysfunction, along with a greater proportion of required mechanical ventilation (14.6% vs. 1.0%, P < 0.001) and extracorporeal membrane oxygenation (4.0% vs. 0.1%, P < 0.001). Multivariable logistic regression analysis identified older age, male sex, cardiovascular disease, immunosuppression, organ dysfunction, illness severity, and corticosteroid use during hospitalization as factors associated with death within 1 year after hospital discharge. However, vaccination was found to have a long-term protective effect against death among COVID-19 survivors. The 1-year mortality rate after hospital discharge for older COVID-19 patients was comparable to the in-hospital mortality rate for these patients in Korea. The long-term mortality rate among hospitalized older COVID-19 patients was influenced by demographic factors and the severity of illness experienced during hospitalization.
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COVID-19 , Mortalidade Hospitalar , Hospitalização , Sobreviventes , Humanos , COVID-19/mortalidade , COVID-19/epidemiologia , Idoso , República da Coreia/epidemiologia , Masculino , Feminino , Idoso de 80 Anos ou mais , Fatores de Risco , Pessoa de Meia-Idade , Hospitalização/estatística & dados numéricos , Sobreviventes/estatística & dados numéricos , SARS-CoV-2/isolamento & purificação , Estudos de CoortesRESUMO
PURPOSE: Allergen exposure is the most potent factor in allergen sensitization, which affects the exacerbation and severity of allergic diseases. Due to industrialization and climate change, the pattern of allergen sensitization has changed over time, and the incidence of allergic diseases has also increased. This study investigated the status of allergen sensitization in the Korean population and its effects on allergic diseases. METHODS: A total of 2,386 participants aged ≥ 10 years, who underwent 7 specific immunoglobulin E tests for aeroallergens (Dermatophagoides farinae [Der f], dog dander, cat epithelium, birch, oak, Japanese hop, and ragweed), were selected among the participants of the 2019 Korean National Health and Nutrition Examination Survey. We compared the demographic characteristics, combined allergic diseases, and sinusitis symptoms between the atopic and non-atopic groups. RESULTS: The prevalence of allergen sensitization in the general Korean population was 45%, and Der f was the most frequent cause of sensitization (39.9%). The prevalence of sensitization to indoor allergens was highest among teenagers and those belonging to the 20- to 29-year age group (P < 0.001). In contrast, there was a high prevalence of sensitization to outdoor allergens among individuals belonging to the age group of 60-69 years. The prevalence of atopic dermatitis (odds ratio [OR], 2.559; 95% confidence interval [CI], 1.689-3.878), allergic rhinitis (OR, 3.075; 95% CI, 2.426-3.897), and otitis media (OR, 1.481; 95% CI, 1.092-2.007) significantly increased by allergen sensitization. Patients with allergen sensitization were more likely to experience the symptoms of rhinitis and sinusitis. CONCLUSIONS: The study findings confirmed that allergen sensitization occurs in approximately half of the general Korean population and affects the prevalence and symptoms of allergic diseases. This suggests that active allergy tests and diagnosis of allergic diseases are necessary in Koreans.
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Recently, cases of antifreeze poisoning in companion animals, particularly cats, have surged in the Republic of Korea. Ethylene glycol (EG), the toxic primary component of antifreeze, is metabolized into glycolic acid (GA), leading to severe metabolic acidosis, acute kidney injury, and death. Traditional detection methods, although effective, are often time-consuming owing to complex sample preparation. This study involved a novel analytical method utilizing GC-MS for EG and LC-MS/MS for GA detection, which streamlined the detection process by eliminating the need for derivatization. The method was validated for accuracy and reliability, enabling the rapid and precise identification of EG and GA in biological samples. This study also included the successful application of this method in a case where initial exposure to antifreeze was not apparent, which highlighted the effectiveness of this method in diagnosing poisoning even in cases where clinical history is unclear. The development of this rapid diagnostic approach addresses the urgent need for the efficient detection of antifreeze poisoning, improving animal welfare and supporting forensic investigations.
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Etilenoglicol , Glicolatos , Animais , Etilenoglicol/intoxicação , Gatos , República da Coreia , Cromatografia Gasosa-Espectrometria de Massas/métodos , Espectrometria de Massas em Tandem/métodos , Reprodutibilidade dos Testes , Cromatografia Líquida/métodosRESUMO
We utilized amino acid (AA) and carbon stable isotope analyses to characterize phytoplankton-derived organic matter (OM) and trace the sources of organic carbon in the Amundsen Sea. Carbon isotope ratios of particulate organic carbon (δ13C-POC) range from -28.7‱ to -23.1‱, indicating that particulate organic matter originated primarily from phytoplankton. The dissolved organic carbon isotope (δ13C-DOC) signature (-27.1 to -21.0‱) observed in the sea-ice melting system suggests that meltwater contributes to the DOC supply of the Amundsen Sea together with OM produced by phytoplankton. A negative correlation between the degradation index and δ13C-POC indicates that the quality of OM significantly influences isotopic fractionation (r2 = 0.59, p < 0.001). The AA distribution in the Amundsen Sea (5.43 ± 3.19 µM) was significantly larger than previously reported in the Southern Ocean and was associated with phytoplankton biomass (r2 = 0.49, p < 0.01). Under conditions dominated by P. antarctica (DI = 2.29 ± 2.30), OM exhibited greater lability compared to conditions co-dominated by diatoms and D. speculum (DI = 0.04 ± 3.64). These results highlight the important role of P. antarctica in influencing the properties of OM, suggesting potential impacts on carbon cycling and microbial metabolic activity in the Amundsen Sea.
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Aminoácidos , Isótopos de Carbono , Carbono , Fitoplâncton , Fitoplâncton/metabolismo , Isótopos de Carbono/análise , Aminoácidos/metabolismo , Aminoácidos/análise , Carbono/metabolismo , Oceanos e Mares , Água do Mar/química , Biomassa , Diatomáceas/metabolismoAssuntos
Anticorpos Monoclonais Humanizados , Azetidinas , Tratamento Farmacológico da COVID-19 , Pirazóis , Respiração Artificial , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Estudos de Coortes , Pirazóis/uso terapêutico , Pessoa de Meia-Idade , Idoso , Azetidinas/uso terapêutico , Azetidinas/administração & dosagem , Purinas/uso terapêutico , Sulfonamidas/uso terapêutico , COVID-19RESUMO
Knowledge gaps about how the ocean melts Antarctica's ice shelves, borne from a lack of observations, lead to large uncertainties in sea level predictions. Using high-resolution maps of the underside of Dotson Ice Shelf, West Antarctica, we reveal the imprint that ice shelf basal melting leaves on the ice. Convection and intermittent warm water intrusions form widespread terraced features through slow melting in quiescent areas, while shear-driven turbulence rapidly melts smooth, eroded topographies in outflow areas, as well as enigmatic teardrop-shaped indentations that result from boundary-layer flow rotation. Full-thickness ice fractures, with bases modified by basal melting and convective processes, are observed throughout the area. This new wealth of processes, all active under a single ice shelf, must be considered to accurately predict future Antarctic ice shelf melt.
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Point defects play a crucial role in determining the properties of atomically thin semiconductors. This work demonstrates the controlled formation of different types of defects and their comprehensive optical characterization using hyperspectral line imaging (HSLI). Distinct optical responses are observed in monolayer semiconductors grown under different stoichiometries using metal-organic chemical vapor deposition. HSLI enables the simultaneous measurement of 400 spectra, allowing for statistical analysis of optical signatures at close to a centimeter scale. The study discovers that chalcogen-rich samples exhibit remarkable optical uniformity due to reduced precursor accumulation compared to the metal-rich case. The utilization of HSLI as a facile and reliable characterization tool pushes the boundaries of potential applications for atomically thin semiconductors in future devices.
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Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival in vivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclear factor κB (NF-κB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD.
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Sobrevivência Celular , Neurônios Dopaminérgicos , NF-kappa B , Fator de Necrose Tumoral alfa , Proteína Supressora de Tumor p53 , Neurônios Dopaminérgicos/metabolismo , Animais , Humanos , NF-kappa B/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Camundongos , Sobrevivência Celular/efeitos dos fármacos , Transdução de Sinais , Doença de Parkinson/metabolismo , Células-Tronco Pluripotentes/metabolismo , Apoptose , Modelos Animais de Doenças , Sistemas CRISPR-CasRESUMO
Background: Limited data are available on the relationship of disseminated intravascular coagulation (DIC) with mortality in patients receiving extracorporeal membrane oxygenation (ECMO). Thus, we investigated the association of DIC score and antithrombin (AT) III with clinical outcomes in patients undergoing ECMO. Methods: We analyzed 703 patients who underwent ECMO between January 2014 and May 2022 at Samsung Medical Center. The DIC score was calculated using laboratory findings within 24 h of the ECMO initiation, and ≥ 5 was defined as overt DIC. In addition, the AT III level was measured to identify the correlation with the DIC score. Results: Among the study patients, 169 (24.0%) were diagnosed with overt DIC (DIC group) during early maintenance therapy. In-hospital mortality was significantly higher in the DIC group than in the non-DIC group (55.0% vs. 36.5%, p < 0.001). Bleeding events were significantly higher in the group of patients with a DIC score of 7 or 8 than in the other group (20.8% vs. 8.4%, p = 0.038). DIC score negatively correlated with AT III level (r = -0.417, p < 0.001). The predictive performance of AT III for overt DIC had statistical significance with a c-static of 0.81 (95% confidence interval (CI), 0.77-0.84, p < 0.001). Conclusion: Overt DIC was associated with higher in-hospital mortality and a tendency to bleed in ECMO patients. Furthermore, AT III plasma levels can easily predict overt DIC in patients undergoing ECMO. These findings suggest that monitoring AT III plasma levels may be important in the management of ECMO.
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AIMS: To develop antifungal lactic acid bacteria (LAB) and investigate their antifungal mechanisms against Aspergillus flavus in aflatoxin (AF) production. METHODS AND RESULTS: We isolated 179 LABs from cereal-based fermentation starters and investigated their antifungal mechanism against A. flavus through liquid chromatography-mass spectrometry and co-culture analysis techniques. Of the 179 isolates, antifungal activity was identified in Pediococcus pentosaceus, Lactobacillus crustorum, and Weissella paramesenteroides. These LABs reduced AF concentration by (i) inhibiting mycelial growth, (ii) binding AF to the cell wall, and (iii) producing antifungal compounds. Species-specific activities were also observed, with P. pentosaceus inhibiting AF production and W. paramesenteroides showing AF B1 binding activity. In addition, crucial extracellular metabolites for selecting antifungal LAB were involved in the 2',3'-cAMP-adenosine and nucleoside pathways. CONCLUSIONS: This study demonstrates that P. pentosaceus, L. crustorum, and W. paramesenteroides are key LAB strains with distinct antifungal mechanisms against A. flavus, suggesting their potential as biological agents to reduce AF in food materials.
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Antifúngicos , Aspergillus flavus , Técnicas de Cocultura , Lactobacillales , Metabolômica , Aspergillus flavus/metabolismo , Aspergillus flavus/crescimento & desenvolvimento , Aspergillus flavus/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Lactobacillales/metabolismo , Lactobacillales/crescimento & desenvolvimento , Fermentação , Aflatoxinas/biossíntese , Grão Comestível/microbiologia , Pediococcus pentosaceus/metabolismo , Antibiose , Microbiologia de AlimentosRESUMO
A Gram-stain-negative, yellow-pigmented, strictly aerobic, non-flagellated, motile by gliding, rod-shaped bacterium, designated strain YSD2104T, was isolated from a coastal sediment sample collected from the southeastern part of the Yellow Sea. Phylogenetic analysis based on the 16S rRNA gene sequences revealed that strain YSD2104T was closely related to three type strains, Lutimonas vermicola IMCC1616T (97.4â%), Lutimonas saemankumensis SMK-142T (96.9â%), and Lutimonas halocynthiae RSS3-C1T (96.8â%). Strain YSD2104T has a single circular chromosome of 3.54 Mbp with a DNA G+C content of 38.3âmol%. The average nucleotide identity and digital DNA-DNA hybridization values between strain YSD2104T and the three type strains (L. vermicola IMCC1616 T, L. saemankumensis SMK-142T, and L. halocynthiae RSS3-C1T) were 74.0, 86.2 and 73.6â%, and 17.9, 30.3 and 17.8â%, respectively. Growth was observed at 20-30â°C (optimum, 30â°C), at pH 6.5-8.5 (optimum, pH 7.0), and with NaCl concentrations of 1.5-3.5â% (optimum, 2.5â%). The major carotenoid was zeaxanthin, and flexirubin-type pigment was not produced. The major respiratory quinone was menaquinone-6. The major fatty acids (>10â%) were iso-C15â:â0, iso-C15â:â1 G, iso-C17â:â0 3-OH, summed feature 3 (C16â:â1 ω6c and/or C16â:â1 ω7c), and summed feature 9 (iso-C17â:â1 ω9c and/or 10-methyl C16â:â0). The major polar lipids were phosphatidylethanolamine, one unidentified aminophospholipid, two unidentified aminolipids, and eight unidentified lipids. Conclusively, based on this polyphasic approach, we classified strain YSD2104T (=KCTC 102008T=JCM 36287T) as representing a novel species of the genus Lutimonas and proposed the name Lutimonas zeaxanthinifaciens sp. nov.
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Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano , Ácidos Graxos , Sedimentos Geológicos , Hibridização de Ácido Nucleico , Filogenia , RNA Ribossômico 16S , Água do Mar , Análise de Sequência de DNA , Vitamina K 2 , Zeaxantinas , Sedimentos Geológicos/microbiologia , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , Vitamina K 2/análogos & derivados , Vitamina K 2/análise , Água do Mar/microbiologia , ChinaRESUMO
Genetic code expansion involves introducing non-canonical amino acids (ncAAs) with unique functional groups into proteins to broaden their applications. Orthogonal aminoacyl tRNA synthetase (aaRS), essential for genetic code expansion, facilitates the charging of ncAAs to tRNA. In this study, we developed a new aaRS mutant from Methanosaeta concilii tyrosyl-tRNA synthetase (Mc TyrRS) to incorporate para-azido-L-phenylalanine (AzF). The development involved initial site-specific mutations in Mc TyrRS, followed by random mutagenesis. The new aaRS mutant with amber suppression was isolated through fluorescence-activated cell sorting. The M. concilii aaRS mutant structure was further analyzed to interpret the effect of mutations. This research provides a novel orthogonal aaRS evolution pipeline for highly efficient ncAA incorporation that will contribute to developing novel aaRS from various organisms.
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BACKGROUND: Limited data are available on the mortality rates of patients receiving extracorporeal membrane oxygenation (ECMO) support for coronavirus disease 2019 (COVID-19). We aimed to analyze the relationship between COVID-19 and clinical outcomes for patients receiving ECMO. METHODS: We retrospectively investigated patients with COVID-19 pneumonia requiring ECMO in 19 hospitals across Korea from January 1, 2020 to August 31, 2021. The primary outcome was the 90-day mortality after ECMO initiation. We performed multivariate analysis using a logistic regression model to estimate the odds ratio (OR) of 90-day mortality. Survival differences were analyzed using the Kaplan-Meier (KM) method. RESULTS: Of 127 patients with COVID-19 pneumonia who received ECMO, 70 patients (55.1%) died within 90 days of ECMO initiation. The median age was 64 years, and 63% of patients were male. The incidence of ECMO was increased with age but was decreased after 70 years of age. However, the survival rate was decreased linearly with age. In multivariate analysis, age (OR, 1.048; 95% confidence interval [CI], 1.010-1.089; P = 0.014) and receipt of continuous renal replacement therapy (CRRT) (OR, 3.069; 95% CI, 1.312-7.180; P = 0.010) were significantly associated with an increased risk of 90-day mortality. KM curves showed significant differences in survival between groups according to age (65 years) (log-rank P = 0.021) and receipt of CRRT (log-rank P = 0.004). CONCLUSION: Older age and receipt of CRRT were associated with higher mortality rates among patients with COVID-19 who received ECMO.
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COVID-19 , Oxigenação por Membrana Extracorpórea , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , COVID-19/terapia , Estudos Retrospectivos , Morte , Fatores de RiscoRESUMO
The chronic use of the novel synthetic cathinone mexedrone, like other psychoactive drugs, can be considered addictive, with a high potential for abuse and the ability to cause psychological dependence in certain users. However, little is known about the neurobehavioral effects of mexedrone in association with its potential for abuse. We investigated the abuse potential for mexedrone abuse through multiple behavioral tests. In addition, serotonin transporter (SERT) levels were measured in the synaptosome of the dorsal striatum, and serotonin (5-HT) levels were measured in the dorsal striatum of acute mexedreone (50 mg/kg)-treated mice. To clarify the neuropharmacological mechanisms underlying the locomotor response of mexedrone, the 5-HT2A receptor antagonist M100907 (0.5 or 1.0 mg/kg) was administered prior to the acute injection of mexedrone in the locomotor activity experiment in mice. Mexedrone (10-50 mg/kg) produced a significant place preference in mice and mexedrone (0.1-0.5 mg/kg/infusion) maintained self-administration behavior in rats in a dose-dependent manner. In the drug discrimination experiment, mexedrone (5.6-32 mg/kg) was fully substituted for the discriminative stimulus effects of cocaine in rats. Mexedrone increased locomotor activity, and these effects were reversed by pretreatment with M100907. Acute mexedrone significantly increased c-Fos expression in the dorsal striatum and decreased SERT levels in the synaptosome of the dorsal striatum of mice, resulting in an elevation of 5-HT levels. Taken together, our results provide the possibility that mexedrone has abuse potential, which might be mediated, at least in part, by the activation of the serotonergic system in the dorsal striatum.
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Cocaína , Fluorbenzenos , Metanfetamina/análogos & derivados , Piperidinas , Catinona Sintética , Ratos , Camundongos , Masculino , Animais , Ratos Sprague-Dawley , Serotonina/metabolismo , Cocaína/farmacologia , Relação Dose-Resposta a DrogaRESUMO
Idiopathic Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which is associated with neuroinflammation and reactive gliosis. The underlying cause of PD and the concurrent neuroinflammation are not well understood. In this study, we utilize human and murine neuronal lines, stem cell-derived dopaminergic neurons, and mice to demonstrate that three previously identified genetic risk factors for PD, namely SATB1, MIR22HG, and GBA, are components of a single gene regulatory pathway. Our findings indicate that dysregulation of this pathway leads to the upregulation of glucocerebrosides (GluCer), which triggers a cellular senescence-like phenotype in dopaminergic neurons. Specifically, we discovered that downregulation of the transcriptional repressor SATB1 results in the derepression of the microRNA miR-22-3p, leading to decreased GBA expression and subsequent accumulation of GluCer. Furthermore, our results demonstrate that an increase in GluCer alone is sufficient to impair lysosomal and mitochondrial function, thereby inducing cellular senescence. Dysregulation of the SATB1-MIR22-GBA pathway, observed in both PD patients and normal aging, leads to lysosomal and mitochondrial dysfunction due to the GluCer accumulation, ultimately resulting in a cellular senescence-like phenotype in dopaminergic neurons. Therefore, our study highlights a novel pathway involving three genetic risk factors for PD and provides a potential mechanism for the senescence-induced neuroinflammation and reactive gliosis observed in both PD and normal aging.
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Proteínas de Ligação à Região de Interação com a Matriz , MicroRNAs , Doença de Parkinson , Humanos , Camundongos , Animais , Neurônios Dopaminérgicos/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Glucosilceramidas/metabolismo , Gliose , Doenças Neuroinflamatórias , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Senescência Celular/genética , Fatores de Transcrição/metabolismo , FenótipoRESUMO
Genome-scale metabolic model (GEM) can be used to simulate cellular metabolic phenotypes under various environmental or genetic conditions. This study utilized the GEM to observe the internal metabolic fluxes of recombinant Escherichia coli producing gamma-aminobutyric acid (GABA). Recombinant E. coli was cultivated in a fermenter under three conditions: pH 7, pH 5, and additional succinic acids. External fluxes were calculated from cultivation results, and internal fluxes were calculated through flux optimization. Based on the internal flux analysis, glycolysis and pentose phosphate pathways were repressed under cultivation at pH 5, even though glutamate dehydrogenase increased GABA production. Notably, this repression was halted by adding succinic acid. Furthermore, proper sucA repression is a promising target for developing strains more capable of producing GABA.
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Escherichia coli , Ácido gama-Aminobutírico , Escherichia coli/genética , Escherichia coli/metabolismo , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/biossíntese , Concentração de Íons de Hidrogênio , Fermentação , Glicólise , Ácido Succínico/metabolismo , Via de Pentose Fosfato , Análise do Fluxo Metabólico , Modelos Biológicos , Reatores Biológicos/microbiologia , Glutamato Desidrogenase/metabolismo , Glutamato Desidrogenase/genética , Engenharia Metabólica/métodosRESUMO
The spread of carbapenem-resistant Enterobacterales (CRE) poses a public health threat worldwide. We aimed to compare the mortality rates between the carbapenemase-producing (CP) and non-CP CRE bacteremia. We conducted a retrospective cohort study in patients with CRE bacteremia after propensity score (PS) matching. We performed a Kaplan-Meier curve analysis to identify the cumulative hazard for 30-day mortality. There were 318 patients with CRE between January 1, 2018, and December 31, 2022. There were 252 patients with CP-CRE and 66 with non-CP-RE, respectively. Before PS matching, the 30-day mortality rates were 40.9% in the non-CP-CRE group and 53.2% in the CP-CRE group (p = 0.097). In patients in the intensive care unit (ICU), the mortality rates were 49.0% in the non-CP-CRE group and 57.1% in the CP-CRE group (p = 0.340). After PS matching, the hazard ratio (HR) for mortality in the CP-CRE group was 1.49 (95% confidence interval [CI] 0.74-3.03), p = 0.266). In ICU patients, the HR of CP-CRE was 1.11 (95% CI 0.36-3.39, p = 0.860). The Kaplan-Meier curve for 30-day mortality showed no difference in cumulative hazard. After PS matching, there was no difference in 30-day mortality between patients with CP-CRE and non-CP-CRE bacteremia.
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Bacteriemia , Humanos , Pontuação de Propensão , Estudos Retrospectivos , Bacteriemia/tratamento farmacológico , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêuticoRESUMO
COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDA-approved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection. We also identified the inflammatory and cellular senescence signature and low levels of SARS-CoV-2 transcripts in human substantia nigra tissue of COVID-19 patients. Furthermore, we observed reduced numbers of neuromelanin+ and tyrosine-hydroxylase (TH)+ DA neurons and fibers in a cohort of severe COVID-19 patients. Our findings demonstrate that hPSC-derived DA neurons are susceptible to SARS-CoV-2, identify candidate neuroprotective drugs for COVID-19 patients, and suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.
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COVID-19 , Células-Tronco Pluripotentes , Humanos , SARS-CoV-2 , Neurônios Dopaminérgicos , Sistema Nervoso CentralRESUMO
Prime editing (PE) allows for precise genome editing in human pluripotent stem cells (hPSCs), such as introducing single nucleotide modifications, small deletions, or insertions at a specific genomic locus, a strategy that shows great promise for creating "Disease in a dish" models. To improve the effectiveness of prime editing in hPSCs, we systematically compared and combined the "inhibition of mismatch repair pathway and p53" on top of the "PEmax" to generate an all-in-one "PE-Plus" prime editor. We show that PE-Plus conducts the most efficient editing among the current PE tools in hPSCs. We further established an inducible prime editing platform in hPSCs by incorporating the all-in-one PE vector into a safe-harbor locus and demonstrated temporal control of precise editing in both hPSCs and differentiated cells. By evaluating disease-associated mutations, we show that this platform allows efficient creation of both monoallelic and biallelic disease-relevant mutations in hPSCs. In addition, this platform enables the efficient introduction of single or multiple edits in one step, demonstrating potential for multiplex editing. Therefore, our method presents an efficient and controllable multiplex prime editing tool in hPSCs and their differentiated progeny.
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BACKGROUND: Only some studies have directly compared and analyzed the roles of activated partial thromboplastin time (aPTT) and activated clotting time (ACT) in coagulation monitoring during argatroban administration. OBJECTIVES: This study aims to assess the correlation of argatroban dose with ACT and aPTT values and to identify the optimal coagulation test for argatroban dose adjustment. METHODS: We evaluated 55 patients on extracorporeal membrane oxygenation (ECMO) who received argatroban for more than 72 hours. The correlation between argatroban dose and aPTT and ACT values was evaluated. To compare argatroban dose and bleeding events according to liver dysfunction, the patients were divided into 2 groups based on alanine aminotransferase and total bilirubin. RESULTS: Among the 55 patients, a total of 459 doses and coagulation tests were evaluated. The aPTT and ACT values showed a weak correlation with argatroban dose, with the Pearson correlation coefficients of 0.261 (P < 0.001) and 0.194 (P = 0.001), respectively. The agreement between the target 150 to 180 seconds for ACT and 55 to 75 seconds for aPTT was observed in 140 patients (46.1%). Twenty-four patients (43.6%) had liver dysfunction when they started argatroban. The median argatroban dose was lower in the liver dysfunction group than in the control group (0.094 mcg/kg/min vs 0.169 mcg/kg/min, P = 0.020). Difference was not observed between the 2 groups in the amount of red blood cell (0.47 vs 0.43 pack, P = 0.909) and platelet (0.60 vs 0.08 pack, P = 0.079) transfusion per day. CONCLUSION AND RELEVANCE: A weak correlation was observed between argatroban dose and the aPTT and ACT values. However, the agreement between aPTT and ACT was only 46.1% regarding the scope of target range. Further research is necessary to determine how to assess the optimal argatroban dose for patients administered argatroban while undergoing ECMO at the intensive care unit.