RESUMO
An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.
Assuntos
Tratamento Farmacológico da COVID-19 , Glicoproteína da Espícula de Coronavírus , Humanos , Ligação Proteica , SARS-CoV-2RESUMO
BACKGROUND: Despite the progression of dialysis techniques, the mortality of hemodialysis (HD) patients is still high in China. Here, a retrospective study was performed to investigate the neglected risk factors of all-cause mortality during maintenance HD (MHD). METHODS: We investigated 117 MHD patients who died between 2011 and 2016 in the Second Xiangya Hospital of Central South University HD center. In order to analyze the risk factors of 48 months all-cause death, the methods of Kaplan-Meier and Cox regression were used. RESULTS: Multivariate analyses of adjusted age and gender showed that MHD patients with estimated glomerular filtration rate <7 or >10 mL/min/1.73 m2 and anemia (hemoglobin <100 g/L) at the initiation of dialysis are independently associated with the higher death risk. Using central venous catheter vascular access, cerebrovascular comorbidities, diabetes, low-flux dialyzer, and dialysis frequency ≤2 times weekly were also the independent risk factors of death within 48 months. CONCLUSIONS: This study indicated that the status of HD initiation is a risk factor of long-term survival in MHD patients, which were usually ignored for lacking of nephrology care prior and could potentially be identified and modified to improve the survival prognosis. Video Journal Club "Cappuccino with Claudio Ronco" at https://www.karger.com/Journal/ArticleNews/223997?sponsor=52.
Assuntos
Causas de Morte , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Diálise Renal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Estimativa de Kaplan-Meier , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Diálise Renal/efeitos adversos , Diálise Renal/métodos , Análise de Sobrevida , Adulto JovemRESUMO
Some existing confidence interval methods and hypothesis testing methods in the analysis of a contingency table with incomplete observations in both margins entirely depend on an underlying assumption that the sampling distribution of the observed counts is a product of independent multinomial/binomial distributions for complete and incomplete counts. However, it can be shown that this independency assumption is incorrect and can result in unreliable conclusions because of the under-estimation of the uncertainty. Therefore, the first objective of this paper is to derive the valid joint sampling distribution of the observed counts in a contingency table with incomplete observations in both margins. The second objective is to provide a new framework for analyzing incomplete contingency tables based on the derived joint sampling distribution of the observed counts by developing a Fisher scoring algorithm to calculate maximum likelihood estimates of parameters of interest, the bootstrap confidence interval methods, and the bootstrap testing hypothesis methods. We compare the differences between the valid sampling distribution and the sampling distribution under the independency assumption. Simulation studies showed that average/expected confidence-interval widths of parameters based on the sampling distribution under the independency assumption are shorter than those based on the new sampling distribution, yielding unrealistic results. A real data set is analyzed to illustrate the application of the new sampling distribution for incomplete contingency tables and the analysis results again confirm the conclusions obtained from the simulation studies.
Assuntos
Intervalos de Confiança , Interpretação Estatística de Dados , Algoritmos , Distribuição Binomial , Criança , Feminino , Humanos , Funções Verossimilhança , Mães/estatística & dados numéricos , Doenças do Sistema Nervoso/complicações , Projetos de Pesquisa , Sons Respiratórios/etiologia , Fumar/efeitos adversos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Incomplete data often arise in various clinical trials such as crossover trials, equivalence trials, and pre and post-test comparative studies. Various methods have been developed to construct confidence interval (CI) of risk difference or risk ratio for incomplete paired binary data. But, there is little works done on incomplete continuous correlated data. To this end, this manuscript aims to develop several approaches to construct CI of the difference of two means for incomplete continuous correlated data. METHODS: Large sample method, hybrid method, simple Bootstrap-resampling method based on the maximum likelihood estimates (B 1) and Ekbohm's unbiased estimator (B 2), and percentile Bootstrap-resampling method based on the maximum likelihood estimates (B 3) and Ekbohm's unbiased estimator (B 4) are presented to construct CI of the difference of two means for incomplete continuous correlated data. Simulation studies are conducted to evaluate the performance of the proposed CIs in terms of empirical coverage probability, expected interval width, and mesial and distal non-coverage probabilities. RESULTS: Empirical results show that the Bootstrap-resampling-based CIs B 1, B 2, B 4 behave satisfactorily for small to moderate sample sizes in the sense that their coverage probabilities could be well controlled around the pre-specified nominal confidence level and the ratio of their mesial non-coverage probabilities to the non-coverage probabilities could be well controlled in the interval [0.4, 0.6]. CONCLUSIONS: If one would like a CI with the shortest interval width, the Bootstrap-resampling-based CIs B 1 is the optimal choice.
Assuntos
Asma/tratamento farmacológico , Intervalos de Confiança , Fumarato de Formoterol/administração & dosagem , Modelos Estatísticos , Administração por Inalação , Asma/diagnóstico , Asma/epidemiologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Funções Verossimilhança , Masculino , Razão de Chances , Sensibilidade e EspecificidadeRESUMO
Under the assumption of missing at random, eight confidence intervals (CIs) for the difference between two correlated proportions in the presence of incomplete paired binary data are constructed on the basis of the likelihood ratio statistic, the score statistic, the Wald-type statistic, the hybrid method incorporated with the Wilson score and Agresti-Coull (AC) intervals, and the Bootstrap-resampling method. Extensive simulation studies are conducted to evaluate the performance of the presented CIs in terms of coverage probability and expected interval width. Our empirical results evidence that the Wilson-score-based hybrid CI and the Wald-type CI together with the constrained maximum likelihood estimates perform well for small-to-moderate sample sizes in the sense that (i) their empirical coverage probabilities are quite close to the prespecified confidence level, (ii) their expected interval widths are shorter, and (iii) their ratios of the mesial non-coverage to non-coverage probabilities lie in interval [0.4, 0.6]. An example from a neurological study is used to illustrate the proposed methodologies.
Assuntos
Intervalos de Confiança , Modelos Estatísticos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Simulação por Computador , Estudos Cross-Over , Interpretação Estatística de Dados , Humanos , Análise por Pareamento , Meningite/complicações , Meningite/tratamento farmacológico , Método de Monte Carlo , Exame Neurológico/estatística & dados numéricosRESUMO
Matched-pair design is often used in clinical trials to increase the efficiency of establishing equivalence between two treatments with binary outcomes. In this article, we consider such a design based on rate ratio in the presence of incomplete data. The rate ratio is one of the most frequently used indices in comparing efficiency of two treatments in clinical trials. In this article, we propose 10 confidence-interval estimators for the rate ratio in incomplete matched-pair designs. A hybrid method that recovers variance estimates required for the rate ratio from the confidence limits for single proportions is proposed. It is noteworthy that confidence intervals based on this hybrid method have closed-form solution. The performance of the proposed confidence intervals is evaluated with respect to their exact coverage probability, expected confidence interval width, and distal and mesial noncoverage probability. The results show that the hybrid Agresti-Coull confidence interval based on Fieller's theorem performs satisfactorily for small to moderate sample sizes. Two real examples from clinical trials are used to illustrate the proposed confidence intervals.
Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Intervalos de Confiança , Análise por Pareamento , Modelos Estatísticos , Antieméticos/administração & dosagem , Antieméticos/uso terapêutico , Humanos , Funções Verossimilhança , Hemissuccinato de Metilprednisolona/administração & dosagem , Hemissuccinato de Metilprednisolona/uso terapêutico , Metoclopramida/administração & dosagem , Metoclopramida/uso terapêutico , Tamanho da Amostra , Vômito/prevenção & controleRESUMO
OBJECTIVE: To explore the efficacy of intranasal treatment by immunosuppressant tacrolimus for allergic asthma and its mechanism in mice. METHODS: 24 female BALB/c mice were randomly divided into 4 groups: group A (negative control), group B (model control), group C (low dose treatment), and group D (high dose treatment). Mice in group A were treated with saline (100 microl). Other groups were sensitized intraperitoneally with allergen extracts of Dermatophagoides farinae (Der f) absorbed to Al(OH)3 at day 0, 7, and 14. From day 28, groups A, B, C, and D were intranasally treated with saline, PBS, 0.01% tacrolimus, and 0.1% tacrolimus, respectively, once per day for 7 d, and followed by intranasal challenge with 50 microl Der f extracts in the mean time. 24 h after the last challenge, the airway hyper-responsiveness (AHR) were detected. At 48 h after the last challenge, the mice were sacrificed, the bronchoalveolar lavage fluid (BALF) was collected, the lungs and spleen were aseptically removed. The total cell number and cell classification of BALF were recorded. The level of interleukin-4 (IL-4), interleukin-5 (IL-5), interferon-gamma (IFN-gamma) in BALF and in spleen cells culture supernatants was detected by ELISA. The lung inflammation and mucus secretion were observed in mice by HE (haematoxylin and eosin) staining and AB (Alcian Blue) staining. RESULTS: Compared with group B, AHR (P < 0.05) and airway inflammation in group D significantly reduced. The number of total cells [(29.92 +/- 5.20) x 10(4)/ml] (P < 0.05) and eosinophils [(4.33 +/- 0.75) x 10(4)/ml] (P < 0.01) in group D greatly decreased than those of group B [(59.33 +/- 5.99) x 10(4)/ml and (22.67 +/- 5.65) x 10(4)/ml]. The level of IL-4 [(22.49 +/- 4.96) pg/ml] (P < 0.05), IL-5 [(43.90 +/- 13.15) pg/ml] (P < 0.01) and IFN-gamma [(10.17 +/- 1.09) pg/ml] (P < 0.05) in BALF significantly decreased (P < 0.05) than those of group B [(57.02 +/- 7.38), (133.49 +/- 15.63) and (15.32 +/- 3.23) pg/ml, respectively]. The level of IL-4 [(22.54 +/- 4.58) pg/ml], IL-5 [(3631 +/- 20.85) pg/ml] and IFN-gamma [(11.28 +/- 1.79) pg/ml] in spleen cell culture supernatant all significantly decreased (P < 0.05) than those of group B [(56.34 +/- 6.21), (72.3 +/- 6.23) and (18.82 +/- 1.88) pg/ml, respectively]. There was no significant difference between group C and group B. CONCLUSION: Tacrolimus shows certain immune therapeutic effect on dust mite sensitized mice, and this effect may be attributed to its inhibition on T lymphocyte factor secretion.
Assuntos
Asma/terapia , Imunossupressores/uso terapêutico , Tacrolimo/uso terapêutico , Administração Intranasal , Alérgenos/administração & dosagem , Animais , Antígenos de Dermatophagoides/administração & dosagem , Líquido da Lavagem Broncoalveolar , Feminino , Imunossupressores/administração & dosagem , Inflamação , Interferon gama/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Tacrolimo/administração & dosagemRESUMO
In this article, we consider confidence interval construction for proportion ratio in paired samples. Previous studies usually reported that score-based confidence intervals consistently outperformed other asymptotic confidence intervals for correlated proportion difference and ratio. However, score-based confidence intervals may not possess closed-form solutions and iterative procedures are therefore required. This article investigates the problem of confidence interval construction for ratio of two correlated proportions based on a hybrid method. Briefly, the hybrid method simply combines two separate confidence intervals for two individual proportions to produce a hybrid confidence interval for the ratio of the two individual proportions in paired studies. Most importantly, confidence intervals based on this hybrid method possess explicit solutions. Our simulation studies indicate that hybrid Wilson score confidence intervals based on Fieller's theorem performs well. The proposed confidence intervals will be illustrated with three real examples.
Assuntos
Intervalos de Confiança , Modelos EstatísticosRESUMO
This paper investigates homogeneity test of rate ratios in stratified matched-pair studies on the basis of asymptotic and bootstrap-resampling methods. Based on the efficient score approach, we develop a simple and computationally tractable score test statistic. Several other homogeneity test statistics are also proposed on the basis of the weighted least-squares estimate and logarithmic transformation. Sample size formulae are derived to guarantee a pre-specified power for the proposed tests at the pre-given significance level. Empirical results confirm that (i) the modified score statistic based on the bootstrap-resampling method performs better in the sense that its empirical type I error rate is much closer to the pre-specified nominal level than those of other tests and its power is greater than those of other tests, and is hence recommended, whilst the statistics based on the weighted least-squares estimate and logarithmic transformation are slightly conservative under some of the considered settings; (ii) the derived sample size formulae are rather accurate in the sense that their empirical powers obtained from the estimated sample sizes are very close to the pre-specified nominal powers. A real example is used to illustrate the proposed methodologies.
Assuntos
Modelos Estatísticos , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Análise dos Mínimos Quadrados , Método de Monte Carlo , Adulto JovemRESUMO
A stratified matched-pair study is often designed for adjusting a confounding effect or effect of different trails/centers/ groups in modern medical studies. The relative risk is one of the most frequently used indices in comparing efficiency of two treatments in clinical trials. In this paper, we propose seven confidence interval estimators for the common relative risk and three simultaneous confidence interval estimators for the relative risks in stratified matched-pair designs. The performance of the proposed methods is evaluated with respect to their type I error rates, powers, coverage probabilities, and expected widths. Our empirical results show that the percentile bootstrap confidence interval and bootstrap-resampling-based Bonferroni simultaneous confidence interval behave satisfactorily for small to large sample sizes in the sense that (i) their empirical coverage probabilities can be well controlled around the pre-specified nominal confidence level with reasonably shorter confidence widths; and (ii) the empirical type I error rates of their associated test statistics are generally closer to the pre-specified nominal level with larger powers. They are hence recommended. Two real examples from clinical laboratory studies are used to illustrate the proposed methodologies.