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The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.
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Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Pneumonia Viral/metabolismo , Proteômica/métodos , Células A549 , Enzima de Conversão de Angiotensina 2 , Animais , Antivirais/farmacologia , COVID-19 , Células CACO-2 , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação , Pneumonia Viral/virologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Receptor Tirosina Quinase AxlRESUMO
A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
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Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Reposicionamento de Medicamentos , Terapia de Alvo Molecular , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Mapas de Interação de Proteínas , Proteínas Virais/metabolismo , Animais , Antivirais/classificação , Antivirais/farmacologia , Betacoronavirus/genética , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , COVID-19 , Chlorocebus aethiops , Clonagem Molecular , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imunidade Inata , Espectrometria de Massas , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Ligação Proteica , Biossíntese de Proteínas/efeitos dos fármacos , Domínios Proteicos , Mapeamento de Interação de Proteínas , Receptores sigma/metabolismo , SARS-CoV-2 , Proteínas Ligases SKP Culina F-Box/metabolismo , Células Vero , Proteínas Virais/genética , Tratamento Farmacológico da COVID-19RESUMO
At its October 2023 meeting, the Advisory Committee on Immunization Practices* (ACIP) approved the Recommended Adult Immunization Schedule for Ages 19 Years or Older, United States, 2024. The adult immunization schedule, which can be found on the CDC immunization schedule website (https://www.cdc.gov/vaccines/schedules), is published annually to consolidate and summarize updates to ACIP recommendations on the vaccination of adults and to assist health care providers in implementing current ACIP recommendations. The 2024 immunization schedule includes several changes to the cover page, tables, notes, and appendix from the 2023 immunization schedule. In addition, the 2024 adult immunization schedule includes a new addendum section that summarizes new or updated ACIP recommendations that will occur before the next annual update to the adult immunization schedule. Health care providers are advised to use the cover page, tables, notes, appendix, and addendum together to determine recommended vaccinations for patient populations.
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Comitês Consultivos , Imunização , Adulto , Humanos , Centers for Disease Control and Prevention, U.S. , Esquemas de Imunização , Estados Unidos , VacinaçãoRESUMO
At its October 2023 meeting, the Advisory Committee on Immunization Practices* (ACIP) approved the Recommended Child and Adolescent Immunization Schedule for Ages 18 Years or Younger, United States, 2024. The child and adolescent immunization schedule, which can be found on the CDC immunization schedule website (https://www.cdc.gov/vaccines/schedules), is published annually to consolidate and summarize updates to ACIP recommendations on the vaccination of children and adolescents and to assist health care providers in implementing current ACIP recommendations. The 2024 immunization schedule includes several changes to the cover page, tables, notes, and appendix from the 2023 immunization schedule. In addition, the 2024 child and adolescent immunization schedule includes a new addendum section to summarize new or updated ACIP recommendations that will occur before the next annual update to the child and adolescent immunization schedule. Health care providers are advised to use the cover page, tables, notes, appendix, and addendum together to identify the recommended immunizations for patient populations.
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Comitês Consultivos , Imunização , Adolescente , Criança , Humanos , Lactente , Centers for Disease Control and Prevention, U.S. , Esquemas de Imunização , Estados Unidos , VacinaçãoRESUMO
INTRODUCTION: Scarce data exist about clinical/radiological differences between acute ischemic strokes diagnosed in the emergency room (AISER) and stroke chameleons (SCs). We aimed at describing the differences observed in a comprehensive stroke center in Chile. METHODS: Prospective observational study of patients with ischemic stroke syndromes admitted to the emergency room (ER) of Clínica Alemana between December 2014 and October 2023. RESULTS: 1,197 patients were included; of these 63 (5.2%, 95% CI: 4.1-6.6) were SC; these were younger (p < 0.001), less frequently hypertensive (p = 0.03), and they also had lower systolic (SBP) (p < 0.001), diastolic blood pressures (DBP) (p = 0.011), and NIHSS (p < 0.001). Clinically, they presented less frequently gaze (p = 0.008) and campimetry alterations (p = 0.03), facial (p < 0.001) and limb weakness (left arm [p = 0.004], right arm (p = 0.041), left leg (p = 0.001), right leg p = 0.0029), sensory abnormalities (p < 0.001), and dysarthria (p < 0.001). Neuroradiological evaluations included less frequently large vessel occlusions (p = 0.01) and other stroke locations (p = 0.005); they also differed in their etiologies (p < 0.001). Brainstem strokes (p < 0.001) and extinction/inattention symptoms (p < 0.001) were only seen in AISER. In multivariate analysis, younger age (OR: 0.945; 95% CI: 0.93-0.96), DBP (OR: 0.97; 95% CI, 0.95-0.99), facial weakness (OR: 0.39; 95% CI: 0.19-0.78), sensory abnormities (OR: 0.16.18; 95% CI, 0.05-0.4), infratentorial location (OR: 0.36; 95% CI, 0.15-0.78), posterior circulation involvement (OR: 3.02; 95% CI, 1.45-6.3), cardioembolic (OR: 3.5; 95% CI, 1.56-7.99), and undetermined (OR: 2.42; 95% CI, 1.22-4.7; 95%) etiologies, remained statistically significant. A stepwise analysis including only clinical elements present on the patient's arrival to the ER, demonstrates that age (OR: 0.95; 95% CI: 0.94-0.97), DBP (OR: 0.97; 95% CI, 0.95-0.99), the presence of atrial fibrillation (OR: 2.22; 95% CI, 1.04-4.75, NIHSS (OR: 0.88; 95% CI, 0.71-0.89) and the presence in NIHSS of 1a level of consciousness (OR: 5.66; CI: 95% 1.8-16.9), 1b level of consciousness questions (OR: 3.023; 95% CI, 1.35-6.8), facial weakness (OR: 0.3; CI: 95% 0.17-0.8), and sensory abnormalities (OR: 0.27; 95% CI, 0.1-0.72) remained statistically significant. CONCLUSION: SC had clinical and radiological differences compared to AISER. An additional relevant finding is that neurological symptoms in a patient with atrial fibrillation, even with a negative diffusion-weighted imaging, should be carefully evaluated as a potential stroke until other causes are satisfactorily ruled out.
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Photophysics and photochemistry of a potential light-activated cytotoxic dirhodium complex [Rh2(µ-O2CCH3)2(bpy)(dppz)](O2CCH3)2, where bpy = 2,2'-bipyridine, dppz = dipyrido[3,2-a:2',3'-c]phenazine (Complex 1 or Rh2) in aqueous solutions was studied by means of stationary photolysis and time-resolved methods in time range from hundreds of femtoseconds to microseconds. According to the literature, Complex 1 demonstrates both oxygen-dependent (due to singlet oxygen formation) and oxygen-independent cytotoxicity. Photoexchange of an acetate ligand to a water molecule was the only observed photochemical reaction, which rate was increased by oxygen removal from solutions. Photoexcitation of Complex 1 results in the formation of the lowest triplet electronic excited state, which lifetime is less than 10 ns. This time is too short for diffusion-controlled quenching of the triplet state by dissolved oxygen resulting in 1O2 formation. We proposed that singlet oxygen is produced by photoexcitation of weakly bound van der Waals complexes [Rh2 O2], which are formed in solutions. If this is true, no oxygen-independent light-induced cytotoxicity of Complex 1 exists. Residual cytotoxicity deaerated solutions are caused by the remaining [Rh2 O2] complexes.
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Antineoplásicos , Oxigênio Singlete , Fotoquímica , Antineoplásicos/farmacologia , Antineoplásicos/química , OxigênioRESUMO
The review discusses electrochemical methods for analysis of drug interactions with DNA. The electroanalysis method is based on the registration of interaction-induced changes in the electrochemical oxidation potential of heterocyclic nitrogenous bases in the DNA molecule and in the maximum oxidation current amplitude. The mechanisms of DNA-drug interactions can be identified based on the shift in the electrooxidation potential of heterocyclic nitrogenous bases toward more negative (cathodic) or positive (anodic) values. Drug intercalation into DNA shifts the electrochemical oxidation potential to positive values, indicating thermodynamically unfavorable process that hinders oxidation of nitrogenous bases in DNA. The potential shift toward the negative values indicates electrostatic interactions, e.g., drug binding in the DNA minor groove, since this process does not interfere with the electrochemical oxidation of bases. The concentration-dependent decrease in the intensity of electrochemical oxidation of DNA bases allows to quantify the type of interaction and calculate the binding constants.
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DNA , Testes Farmacogenômicos , DNA/metabolismo , Interações MedicamentosasRESUMO
Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo.
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Aedes/virologia , Antivirais/farmacologia , Febre de Chikungunya/transmissão , Vírus Chikungunya/genética , Vírus Defeituosos/genética , Genoma Viral , Replicação Viral , Animais , Febre de Chikungunya/imunologia , Febre de Chikungunya/virologia , Vírus Chikungunya/crescimento & desenvolvimento , Vírus Chikungunya/isolamento & purificação , Humanos , Mosquitos Vetores/virologiaRESUMO
Using sphygmomanometers to measure blood pressure is a common practice in the healthcare context. The disinfection and maintenance of these devices is essential in clinical practice to prevent the proliferation of microorganisms. The aim of this study was to determine the presence of pathogenic microorganisms in sphygmomanometer cuffs in the clinical setting. A cross-sectional study was carried out. Five types of healthcare centers, selected through convenience sampling, participated in this study. Samples were collected from the inside of sphygmomanometer cuffs, and labeled and delivered to the laboratory for analysis. The samples were incubated in an oven at 35.5 °C for 24 h. A total CFU count was carried out on the plates that were cataloged as positive. Colonies that showed growth were identified using the matrix-assisted laser desorption/ionization-mass spectrometry technology. Of the total sample, (N = 372), 69.1% were positive and were isolated. In 30.9% (n = 115), no bacterial development was found within 48 h. A total of 257 microorganisms were found. The mean number of colony-forming units was 29.62 (SD = 32.33). The socio-health centers had the highest amount of bacterial contamination in the cuffs. In regards to the type of microorganisms, 31.5% (n = 81) found were Bacillus cereus, followed by 26.8% (n = 69) of Staphylococcus hominis and 9.7% (n = 25) were Pantoea agglomerans, among others. Statistically significant differences were found between the type of microorganism and the hours elapsed since the last disinfection (X2(19) = 44.582; p = 0.001). Statistically significant differences were found between the time elapsed since the last disinfection and the type of sphygmomanometer (X2 (2) = 117.752; p = 0.000). Despite the fact that most hospitals and health centers have established infection control policies and protocols, the results of this study indicate the presence of pathogenic microorganisms in blood pressure cuffs in the clinical setting.
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Determinação da Pressão Arterial , Esfigmomanômetros , Pressão Sanguínea/fisiologia , Estudos Transversais , Determinação da Pressão Arterial/métodos , Esfigmomanômetros/microbiologia , Bacillus cereusRESUMO
A study of luminescence and photochromic properties of (E)-2,3-bis(2,5-dimethylthiophen-3-yl)-5-(4-(pyrrolidin-1-yl)benzylidene)cyclopent-2-en-1-one, which is a diarylethene with a push-pull system between carbonyl and dimethylamino groups, was performed using time-resolved methods. The intramolecular charge transfer (ICT) process as well as 6π-electrocyclization and E-/Z-isomerization contribute to the complex light-induced properties of this molecule. Formation of unexpected short-lived intermediates was detected in the time range from 100 fs to 100 µs. A model based on two processes (additional photocyclization and interconversion between conformers) was proposed to rationalize this result. The key intermediates existing in the picosecond time domain are so-called precursors, which are proposed for both parallel (p) and anti-parallel (ap) isomers of the open form. In general, fast light-induced processes for the fluorescent diarylcyclopentenones are much more complicated than for the parent cyclopentenone-based DAE.
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OBJECTIVES: The use of intraosseous (IO) access is recommended in cardiac arrest when peripheral venous access is not accessible. Various methodologies exist that are used for teaching and learning about cannulation of the IO route both in education and in research. The purpose of the present study was to compare self-efficacy in the cannulation technique for IO access through different techniques. METHODS: A randomized comparative study was conducted. A total of 118 nursing students participated. The participants were randomly distributed into 2 intervention groups: chicken bone and egg. A checklist was used for data collection to evaluate the IO cannulation technique in nursing students and another to analyze self-efficacy. RESULTS: The average total score of self-efficacy for all participants was 8.84 (standard deviation (SD) = 0.98). No statistically significant differences were found when comparing the total self-efficacy score and the intervention group ( U = 1604.500; z = -0.733; P = 0.463). No statistically significant differences were found between both groups for the average total score of the procedure ( U = 6916.500; z = -0.939; P = 0.348). The egg group carried out the IO cannulation procedure in a significantly less amount of time (M = 126.88, SD = 82.18) than the chicken bone group (M = 183.77, SD = 108.28), finding statistically significant differences ( U = 4983.500; z = -5.326; P < 0.001). CONCLUSIONS: Using an egg to teach and learn about IO access could be considered a methodology that is equally effective as using a chicken bone, with the advantage of achieving IO access in a lesser amount of time.
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Serviços Médicos de Emergência , Parada Cardíaca , Criança , Humanos , Cateterismo , Coleta de Dados , Serviços Médicos de Emergência/métodos , Parada Cardíaca/terapia , Infusões Intraósseas , AutoeficáciaRESUMO
The interactions of dsDNA with new targeted drug delivery derivatives of doxorubicin (DOX), such as DOX embedded into phospholipid nanoparticles (NPhs) and DOX with the NGR targeted peptide-modified NPhs were studied electrochemically by differential pulse voltammetry technique. Screen-printed electrodes (SPEs), modified with stable fine dispersions of carbon nanotubes (CNTs), were used for quantitative electrochemical investigations of direct electrochemical oxidation of guanine, adenine, and thymine heterocyclic bases of dsDNA, and their changes in the presence of DOX nanoderivatives. Analysing the shifts of peak potentials of nucleobases in the presence of drug, we have shown that the doxorubicin with NGR targeted peptide changed the mode of interaction in DNA-drug complexes from intercalative to electrostatic. Binding constants (Kb) of DNA-drug complexes were calculated in accordance with adenine, guanine, and thymine oxidation signals. Based on our experiments, we have proven that the surface modification of a drug delivery system with NGR targeted peptide dramatically changed the mechanism of interaction of drug with genetic material. DNA-mediated drug toxicity was calculated based on the concentration-dependent "response" of heterocyclic nucleobases on drug influence. DOX, DOX-loaded phospholipid nanoparticles (NPhs), and DOX with NGR addressed peptide-modified NPhs were moderately toxic in the concentration range of 0.5-290 µM.
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Nanopartículas , Nanotubos de Carbono , Fosfolipídeos , Timina , Doxorrubicina/farmacologia , Doxorrubicina/química , Peptídeos , Sistemas de Liberação de Medicamentos/métodos , DNA/química , Nanopartículas/química , Adenina , GuaninaRESUMO
This study aimed to evaluate staff nurses' perspectives on the use of face masks in effective communication and relationship management skills with patients in the hospital setting. The study surveyed registered nurses (RNs) who work with adult patients in different hospital units. An online survey was completed by RNs who were selected by convenience sampling. RNs' communication with patients was perceived as moderately affected by the use of face masks. Statistically significant differences were found when comparing communication with years of professional experience. Participants who had over 10 years of experience reported having greater difficulty in their communication with patients when using face masks. The effect of provider-patient relationship on effective nurse-patient face-mask communication was statistically significant and negative. This study shows that some participants found face masks used in the clinical setting may affect nurse-patient communication, as well as the nurses' ability to manage their relationships with patients. The findings of this study support the need for targeted research into effective communication strategies when face mask use is needed in the healthcare setting.
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Comunicação , Relações Enfermeiro-Paciente , Adulto , Humanos , Estudos Transversais , Pacientes , HospitaisRESUMO
BACKGROUND AND PURPOSE: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients. METHODS: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150-180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1-24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage. RESULTS: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71-0.82]; P<0.001 and 0.86 [95% CI, 0.76-0.98]; P=0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93-1.04]; P=0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06-1.31]; P=0.002 and 1.34 [1.11-1.62]; P=0.002) but not with magnitude of SBP reduction (1.05 [0.98-1.14]; P=0.184). CONCLUSIONS: Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616.
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Pressão Sanguínea , Hipertensão , AVC Isquêmico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertensão/terapia , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/prevenção & controle , AVC Isquêmico/etiologia , AVC Isquêmico/fisiopatologia , AVC Isquêmico/terapia , Pessoa de Meia-Idade , Estudos Prospectivos , Ativador de Plasminogênio Tecidual/efeitos adversosRESUMO
Corynebacterium striatum, a common constituent of the human skin microbiome, is now considered an emerging multidrug-resistant pathogen of immunocompromised and chronically ill patients. However, little is known about the molecular mechanisms in the transition from colonization to the multidrug-resistant (MDR) invasive phenotype in clinical isolates. This study performed a comprehensive pan-genomic analysis of C. striatum, including isolates from "normal skin microbiome" and from MDR infections, to gain insights into genetic factors contributing to pathogenicity and multidrug resistance in this species. For this, three novel genome sequences were obtained from clinical isolates of C. striatum of patients from Brazil, and other 24 complete or draft C. striatum genomes were retrieved from GenBank, including the ATCC6940 isolate from the Human Microbiome Project. Analysis of C. striatum strains demonstrated the presence of an open pan-genome (α = 0.852803) containing 3816 gene families, including 15 antimicrobial resistance (AMR) genes and 32 putative virulence factors. The core and accessory genomes included 1297 and 1307 genes, respectively. The identified AMR genes are primarily associated with resistance to aminoglycosides and tetracyclines. Of these, 66.6% are present in genomic islands, and four AMR genes, including aac(6')-ib7, are located in a class 1-integron. In conclusion, our data indicated that C. striatum possesses genomic characteristics favorable to the invasive phenotype, with high genomic plasticity, a robust genetic arsenal for iron acquisition, and important virulence determinants and AMR genes present in mobile genetic elements.
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Antibacterianos , Corynebacterium , Humanos , Fenótipo , Fatores de Virulência/genética , Farmacorresistência Bacteriana Múltipla/genética , Testes de Sensibilidade MicrobianaRESUMO
Here, we examine in silico the infection dynamics and interactions of two Zika virus (ZIKV) genomes: one is the full-length ZIKV genome (wild type [WT]), and the other is one of the naturally occurring defective viral genomes (DVGs), which can replicate in the presence of the WT genome, appears under high-MOI (multiplicity of infection) passaging conditions, and carries a deletion encompassing part of the structural and NS1 protein-coding region. Ordinary differential equations (ODEs) were used to simulate the infection of cells by virus particles and the intracellular replication of the WT and DVG genomes that produce these particles. For each virus passage in Vero and C6/36 cell cultures, the rates of the simulated processes were fitted to two types of observations: virus titer data and the assembled haplotypes of the replicate passage samples. We studied the consistency of the model with the experimental data across all passages of infection in each cell type separately as well as the sensitivity of the model's parameters. We also determined which simulated processes of virus evolution are the most important for the adaptation of the WT and DVG interplay in these two disparate cell culture environments. Our results demonstrate that in the majority of passages, the rates of DVG production are higher inC6/36 cells than in Vero cells, which might result in tolerance and therefore drive the persistence of the mosquito vector in the context of ZIKV infection. Additionally, the model simulations showed a slower accumulation of infected cells under higher activation of the DVG-associated processes, which indicates a potential role of DVGs in virus attenuation. IMPORTANCE One of the ideas for lessening Zika pathogenicity is the addition of its natural or engineered defective virus genomes (DVGs) (have no pathogenicity) to the infection pool: a DVG is redirecting the wild-type (WT)-associated virus development resources toward its own maturation. The mathematical model presented here, attuned to the data from interplays between WT Zika viruses and their natural DVGs in mammalian and mosquito cells, provides evidence that the loss of uninfected cells is attenuated by the DVG development processes. This model enabled us to estimate the rates of virus development processes in the WT/DVG interplay, determine the key processes, and show that the key processes are faster in mosquito cells than in mammalian ones. In general, the presented model and its detailed study suggest in what important virus development processes the therapeutically efficient DVG might compete with the WT; this may help in assembling engineered DVGs for ZIKV and other flaviviruses.
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Vírus Defeituosos , Interações entre Hospedeiro e Microrganismos , Infecção por Zika virus/virologia , Zika virus , Aedes , Animais , Chlorocebus aethiops , Vírus Defeituosos/crescimento & desenvolvimento , Vírus Defeituosos/patogenicidade , Células Vero , Replicação Viral , Zika virus/crescimento & desenvolvimento , Zika virus/patogenicidadeRESUMO
BACKGROUND: It has been reported that acute stroke services were compromised during COVID-19 due to various pandemic-related issues. We aimed to investigate these changes by recruiting centers from different countries. METHODS: Eight countries participated in this cross-sectional, observational, retrospective study by providing data from their stroke data base. We compared 1 year before to 1 year during COVID-19 as regards onset to door (OTD), door to needle (DTN), door to groin (DTG), duration of hospital stay, National Institute of Health Stroke Scale (NIHSS) at baseline, 24 h, and at discharge as well as modified Rankin score (mRS) on discharge and at 3 months follow-up. RESULTS: During the pandemic year, there was a reduction in the number of patients, median age was significantly lower, admission NIHSS was higher, hemorrhagic stroke increased, and OTD and DTG showed no difference, while DTN time was longer, rtPA administration was decreased, thrombectomy was more frequent, and hospital stay was shorter. mRS was less favorable on discharge and at 3 months. CONCLUSION: COVID-19 showed variable effects on stroke services. Some were negatively impacted as the number of patients presenting to hospitals, DTN time, and stroke outcome, while others were marginally affected as the type of management.
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COVID-19 , Acidente Vascular Cerebral , Estudos Transversais , Humanos , Estudos Retrospectivos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/terapia , Terapia Trombolítica , Tempo para o Tratamento , Resultado do TratamentoRESUMO
Percutaneous transendocardial injections of therapeutic agents into the myocardium may not always be effective. We used an animal model for assessing the efficacy of the injections using linoleic acid as a testing agent. Efficacious delivery into the myocardium of a beating heart was indicated by rapidly developed local myocardial necrosis and wall motion abnormalities using echocardiography. We employed this experimental model to test our innovative technology, an acoustically active injection catheter. The Doppler ultrasound-guided acoustically active injection catheter effectively delivers the substance to the myocardium but needs further technical improvements to minimize an unwanted systemic distribution of the agent.
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Cateterismo Cardíaco , Catéteres , Animais , Modelos Animais de Doenças , Injeções , Ultrassonografia DopplerRESUMO
OBJECTIVES: Low adherence to a Mediterranean diet (MeDi) is associated with increased incidence, mortality, and severity of acute ischemic strokes (AIS). Nevertheless, the explanatory factors associated with such results are unclear. Our aim was to investigate stroke risk factors associated with adherence to a MeDi in a prospective cohort of AIS patients. MATERIALS AND METHODS: Patients admitted from February 2017 to February 2020 were included in this study. Adherence was measured using the 14-point Mediterranean Diet Adherence Screener (MEDAS). Demographic and clinical characteristics were compared with adherence with a univariate analysis. A binomial regression was used to investigate the independent association of premorbid factors and MeDi components with adherence. RESULTS: There were 413 patients. Mean age was 68.6 (17.4), 176 (42.6%) women. Median MEDAS score was 6 (IQR 4-7) points. 253 patients (61.2%) had a low adherence (MEDAS ≤ 6). In the univariate analysis, a low MEDAS was associated with lower education, diabetes, sedentary lifestyle, greater body mass index (BMI), lower alcohol consumption, and higher LDLc. In the regression analysis, younger age, lower education, functional disability, hypertension, sedentary lifestyle, and higher BMI were associated with lower MEDAS scores. Six MeDi components had particularly low patient adherence: seafood, legumes, olive oil, nuts, wine, and fruit. DISCUSSION: These data indicate low adherence to MeDi in younger patients who are less educated and have existing cardiovascular risk factors, in particular hypertension, sedentary lifestyle, and higher BMI. Some components of the diet had a particularly low adherence. CONCLUSIONS: Tailoring diet prevention interventions to these specific populations, focusing on components with known less adherence, could improve adherence to a MeDi and the opportunity for secondary stroke prevention.
Assuntos
Dieta Mediterrânea , AVC Isquêmico , Cooperação e Adesão ao Tratamento , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Hospitais , Humanos , AVC Isquêmico/dietoterapia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Cooperação e Adesão ao Tratamento/estatística & dados numéricosRESUMO
BACKGROUND: Knowledge about stroke symptoms, correct decision in front of a stroke case and recognition of stroke risk factors are crucial to fight against stroke burden. We aimed to assess the stroke awareness among a sample of the Chilean population. METHODS: A closed-ended questions structured survey was applied in November 2019 using a computer-assisted telephone interviewing system. Probabilistic sample, random selection and stratification for region was used. Multivariate logistic regression model was used to estimate the association between participants' characteristics and responses. RESULTS: Of 706 participants, only 74.4% (95% CI 70.9-77.5) recognized at least one typical stroke symptom. Most (586, 82.4% 95% CI 75.2-89.7) chose to contact the emergency ambulance or directly go to the emergency department in case of a stroke symptom and recognized at least one risk factor (692, 97.9% CI 96.7-98.8). In multivariable analysis, sociodemographic characteristics associated to a worse recognition of at least one stroke symptom were being men (OR 0.67, 95% CI 0.47-0.96), being 55 years old or older (OR 0.59 95% CI 0.37-0.93) and from the lowest socioeconomic level (SES) (OR 0.33 95% CI 0.16-0.67). Female sex was associated with lower stroke risk factor knowledge (OR 0.64 95% IC 0.47-0.87). Participants who recognized at least one typical stroke symptom and would promptly seek care at an emergency department differed significantly between SES (p=0.001) and age groups (p=0.035). CONCLUSIONS: We found insufficient knowledge about stroke symptoms and best decisions making in the Chilean population. We describe gaps that can be targeted in future stroke awareness campaigns. There is a need to strengthen tailored stroke education particularly for underserved populations.