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1.
J Biopharm Stat ; : 1-13, 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31707908

RESUMO

In medical product development, there has been an increased interest in utilizing real-world data which have become abundant with recent advances in biomedical science, information technology, and engineering. High-quality real-world data may be analyzed to generate real-world evidence that can be utilized in the regulatory and healthcare decision-making. In this paper, we consider the case in which a single-arm clinical study, viewed as the primary data source, is supplemented with patients from a real-world data source containing both clinical outcome and covariate data at the patient-level. Propensity score methodology is used to identify real-world data patients that are similar to those in the single-arm study in terms of the baseline characteristics, and to stratify these patients into strata based on the proximity of the propensity scores. In each stratum, a composite likelihood function of a parameter of interest is constructed by down-weighting the information from the real-world data source, and an estimate of the stratum-specific parameter is obtained by maximizing the composite likelihood function. These stratum-specific estimates are then combined to obtain an overall population-level estimate of the parameter of interest. The performance of the proposed approach is evaluated via a simulation study. A hypothetical example based on our experience is provided to illustrate the implementation of the proposed approach.

2.
J Biopharm Stat ; 29(5): 749-759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31590626

RESUMO

A question that routinely arises in medical device clinical studies is the homogeneity across demographic subgroups, geographical regions, or investigational sites of the enrolled patients in terms of treatment effects or outcome variables. The main objective of this paper is to discuss statistical concepts and methods for the assessment of such homogeneity and to provide the practitioner a statistical framework and points to consider in conducting homogeneity assessment. Demographic subgroups, geographical regions, and investigational sites are discussed separately as each has its unique issues. Specific considerations are also given to randomized controlled trials, non-randomized comparative studies, and single-arm studies. We point out that judicious use of statistical methods, in conjunction with sound clinical judgment, is essential in handling the issue of homogeneity of treatment effect in medical device clinical studies.

3.
Nat Commun ; 10(1): 4594, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597914

RESUMO

Cranial lymphatic vessels (LVs) are involved in the transport of fluids, macromolecules and central nervous system (CNS) immune responses. Little information about spinal LVs is available, because these delicate structures are embedded within vertebral tissues and difficult to visualize using traditional histology. Here we show an extended vertebral column LV network using three-dimensional imaging of decalcified iDISCO+-clarified spine segments. Vertebral LVs connect to peripheral sensory and sympathetic ganglia and form metameric vertebral circuits connecting to lymph nodes and the thoracic duct. They drain the epidural space and the dura mater around the spinal cord and associate with leukocytes. Vertebral LVs remodel extensively after spinal cord injury and VEGF-C-induced vertebral lymphangiogenesis exacerbates the inflammatory responses, T cell infiltration and demyelination following focal spinal cord lesion. Therefore, vertebral LVs add to skull meningeal LVs as gatekeepers of CNS immunity and may be potential targets to improve the maintenance and repair of spinal tissues.


Assuntos
Linfonodos/fisiologia , Vasos Linfáticos/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Coluna Vertebral/fisiologia , Ducto Torácico/fisiologia , Animais , Processamento de Imagem Assistida por Computador/métodos , Linfonodos/anatomia & histologia , Vasos Linfáticos/anatomia & histologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Microscopia de Fluorescência , Traumatismos da Medula Espinal/patologia , Coluna Vertebral/anatomia & histologia , Ducto Torácico/anatomia & histologia
4.
J Biopharm Stat ; 29(5): 731-748, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31530111

RESUMO

We are now at an amazing time for medical product development in drugs, biological products and medical devices. As a result of dramatic recent advances in biomedical science, information technology and engineering, ``big data'' from health care in the real-world have become available. Although big data may not necessarily be attuned to provide the preponderance of evidence to a clinical study, high-quality real-world data can be transformed into scientific evidence for regulatory and healthcare decision-making using proven analytical methods and techniques, such as propensity score methodology and Bayesian inference. In this paper, we extend the Bayesian power prior approach for a single-arm study (the current study) to leverage external real-world data. We use propensity score methodology to pre-select a subset of real-world data containing patients that are similar to those in the current study in terms of covariates, and to stratify the selected patients together with those in the current study into more homogeneous strata. The power prior approach is then applied in each stratum to obtain stratum-specific posterior distributions, which are combined to complete the Bayesian inference for the parameters of interest. We evaluate the performance of the proposed method as compared to that of the ordinary power prior approach by simulation and illustrate its implementation using a hypothetical example, based on our regulatory review experience.

5.
J Biopharm Stat ; 29(4): 580-591, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257999

RESUMO

Observational (non-randomized) comparative studies have been adopted in the pre-market safety/effectiveness evaluation of medical devices. There has been an increased interest in utilizing this design with the growing available real-world data. However, in such studies, biases that are introduced in every stage and aspect of study need to be addressed. Otherwise, the objectivity of study design and validity of study results will be compromised. In this paper, challenges and opportunities are discussed from the regulatory perspective. Considerations and good statistical practice to mitigate the potential bias are presented.

6.
Ther Innov Regul Sci ; : 2168479019830385, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30813775

RESUMO

There is an increasing demand for utilization of external data, such as historical study data and patient registry data, to augment the control group in a randomized controlled trial. While such a study design could reduce the time and cost, how to maintain the study validity and integrity is one major statistical challenge that needs to be carefully addressed. We discuss a study design quality process to enhance the study validity and integrity when using this approach. The discussed quality process is tailored to the confirmatory study using a 2-stage design with an emphasis on the interaction process among stakeholders. In an example, the quality process covers a 2-step assessment of the similarity in patient characteristics between the current study and the external data source, and between the treatment and augmented control groups.

7.
J Biopharm Stat ; 29(1): 143-150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29985744

RESUMO

Noninferiority trials are commonly utilized to evaluate the safety and effectiveness of medical devices. It could happen that the noninferiority hypothesis is rejected while the performance of the active control is clinically not satisfactory. This may pose a great challenge when making a regulatory decision. To avoid such a difficult situation, we propose to conduct a companion test to assess the performance of the active control when testing the main noninferiority hypothesis and to incorporate such a test into the study design. Under our proposal, the noninferiority of the investigational device to the active control can only be claimed when both hypotheses are rejected. The operating characteristics of the proposed study design based on these two tests can be fully evaluated at the design stage. This proposed approach is aimed to facilitate regulatory decision making in a more transparent manner.

8.
Chin J Nat Med ; 16(7): 499-504, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30080648

RESUMO

Two previously undescribed steroidal compounds, 16, 23-epoxy-22, 26-epimino-cholest-22(N), 23, 25(26)-trien-3ß-ol-3-O-ß-D-glucopyranosyl-(1→2)-ß-D-glucopyranosyl-(1→4)-ß-D-galactopyranoside (1) and 26-O-ß-D-glucopyranosyl-(25R)-5α-furost-20(22)-en-3ß, 26-diol (2), together with 7 known ones including 26-O-ß-D-glucopyranosyl-(25R)-5, 20(22)-dien-furost-3ß, 26-diol (3), (25R)-5-en-spirost-3ß-ol-O-ß-D-glucopyranosyl-(1→4)-[α-L-rhmanopyranosyl-(1→2)]-ß-D-galactopyranoside (4), funkioside D (5), aspidistrin (6), tigogenin-3-O-ß-D-lucotrioside (7), desglucolanatigonin II (8), and degalactotigonin (9), were isolated from Solanum lyratum Thunb. Their cytotoxic activities were tested in two cancer cell lines by MTT method. One of the steroidal glycosides (6) showed significant cytotoxic activity against gastric cancer SGC7901 and liver cancer BEL-7402 cells.


Assuntos
Alcaloides/toxicidade , Antineoplásicos/isolamento & purificação , Antineoplásicos/toxicidade , Glicosídeos/toxicidade , Extratos Vegetais/toxicidade , Solanum/química , Esteróis/toxicidade , Alcaloides/química , Alcaloides/isolamento & purificação , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glicosídeos/química , Glicosídeos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Fitosteróis/química , Fitosteróis/isolamento & purificação , Fitosteróis/toxicidade , Extratos Vegetais/química , Plantas Medicinais/química , Esteróis/química , Esteróis/farmacologia
9.
Angew Chem Int Ed Engl ; 57(11): 2894-2898, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29356328

RESUMO

Although two-dimensional (2D) carbon materials are widely investigated, a well-defined 2D carbon nanosheet with an ordered mesostructure has rarely been realized. Monolayer-ordered mesoporous carbon nanosheets (OMCNS) were prepared through confinement assembly of resol and F127 in the interlayer of montmorillonite (MONT). The nanoscale distance of the interlayer space of MONT only allow the assembly of resol and F127 in the same plane, leading to ordered mesopores perpendicular to carbon nanosheets, and favor the formation of sp2 carbon, resulting in a high degree of graphitization. The mesopores on the carbon nanosheets provide efficient ion diffusion, and the high degree of graphitization provides a fast electron-transport route, enabling OMCNS as excellent electrode materials for electric double layer capacitors.

10.
Exp Ther Med ; 14(6): 6052-6058, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29285156

RESUMO

Renal tubular cell apoptosis and tubular dysfunction is an important process underlying diabetic nephropathy (DN). Understanding the mechanisms underlying renal tubular epithelial cell survival is important for the prevention of kidney damage associated with glucotoxicity. Curcumin has been demonstrated to possess potent anti-apoptotic properties. However, the roles of curcumin in renal epithelial cells are yet to be defined. The present study investigated advanced glycation or glycoxidation end-product (AGE)-induced toxicity in renal tubular epithelial cells via several complementary assays, including cell viability, cell apoptosis and cell autophagy in the NRK-52E rat kidney tubular epithelial cell line. The extent of apoptosis was significantly increased in the NRK-52E cells following treatment with AGEs. The results also indicated that curcumin reversed this effect by promoting autophagy through the phosphoinositide 3-kinase/AKT serine/threonine kinase signaling pathway. These conclusions suggested that curcumin exerts a renoprotective effect in the presence of AGEs, at least in part by activating autophagy in NRK-52E cells. Collectively, these findings indicate that curcumin not only exerts renoprotective effects, however may also act as a novel therapeutic strategy for the treatment of diabetic nephropathy.

11.
Biomed Pharmacother ; 93: 352-358, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28651236

RESUMO

Tanshinone I from tanshen has been used in traditional Chinese medicine for treating cardiovascular diseases and inflammatory diseases. Given the link between inflammation and Type 2 diabetes mellitus (T2DM), we suspect that tanshinone I may have a beneficial effect on T2DM. This study was to investigate the potential effects of tanshinone I on T2DM and its underlying mechanism. T2DM was thus induced in Sprague-Dawley (SD) rats using streptozotocin (STZ) and high-fat diet. It was observed that T2DM rats had higher levels of total cholesterol (TC), nonesterified fatty acids (NEFAs), total triglyceride (TG) and total low density lipoprotein cholesterol (LDL-C) compared with normal, healthy SD rats. Treatment with tanshinone I decreased these levels and lowered blood glucose level in T2DM rats. In addition, enzyme-linked immunosorbent assay (ELISA) analysis showed that T2DM rats had elevated levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Furthermore, Western blot analysis revealed that T2DM rats had enhanced nuclear translocation of NF-κB as well as elevated phosphorylation of Ser307 in IRS-1(insulin receptor substrate 1). Treatment by tanshinone I lowered the levels of IL-6 and TNF-α, decreased nuclear translocation of NF-κB as well as phosphorylation of Ser307 in IRS-1. These results demonstrated that tanshinone I could alleviate T2DM syndrome in rats.


Assuntos
/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina/fisiologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Interleucina-6/metabolismo , Medicina Tradicional Chinesa/métodos , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-28421123

RESUMO

The chickpea, a food and medicine used by the people of Xinjiang, has a beneficial hypoglycemic effect. To better utilize this national resource and develop hypoglycemic agents from components of the chickpea, a series of new derivatives of isoflavone compounds from the chickpea were synthesized. An insulin-resistant (IR) HepG2 cell model was used to screen the hypoglycemic activities of these compounds. And the structure-activity relationships of these compounds were explored. Additionally, several combinations of these compound displayed higher hypoglycemic activity than any single compound, and they had similar hypoglycemic activity to that of the positive control group (p > 0.05). In addition, combination 3 and combination 6 exerted different effects on the insulin sensitivity of H4IIE cells stimulated with resistin. And the results indicated that combination 3 would have higher hypoglycemic activity. These findings demonstrate the characteristics of multiple components and targets of Chinese herbal medicine. This evidence may provide new ideas for the development of hypoglycemic drugs.

13.
Chemistry ; 22(46): 16668-16674, 2016 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-27704674

RESUMO

High-performance electrical double-layer capacitors (EDLCs) require carbon electrode materials with high specific surface area, short ion-diffusion pathways, and outstanding electrical conductivity. Herein, a general approach combing the molten-salt method and chemical activation to prepare N-doped carbon nanosheets with high surface area (654 m2 g-1 ) and adjustable porous structure is presented. Owing to their structural features, the N-doped carbon nanosheets exhibited superior capacitive performance, demonstrated by a maximum capacitance of 243 F g-1 (area-normalized capacitance up to 37 µF cm-2 ) at a current density of 0.5 A g-1 in aqueous electrolyte, high rate capability (179 F g-1 at 20 A g-1 ), and excellent cycle stability. This method provides a new route to prepare porous and heteroatom-doped carbon nanosheets for high-performance EDLCs, which could also be extended to other polymer precursors and even waste biomass.

14.
J Biopharm Stat ; 26(6): 1136-1145, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27540636

RESUMO

Regulatory decisions are made based on the assessment of risk and benefit of medical devices at the time of pre-market approval and subsequently, when post-market risk-benefit balance needs reevaluation. Such assessments depend on scientific evidence obtained from pre-market studies, post-approval studies, post-market surveillance studies, patient perspective information, as well as other real world data such as national and international registries. Such registries provide real world evidence and are playing a more and more important role in enhancing the safety and effectiveness evaluation of medical devices. While these registries provide large quantities of data reflecting real world practice and can potentially reduce the cost of clinical trials, challenges arise concerning (1) data quality adequate for regulatory decision-making, (2) bias introduced at every stage and aspect of study, (3) scientific validity of study designs, and (4) reliability and interpretability of study results. This article will discuss related statistical and regulatory challenges and opportunities with examples encountered in medical device regulatory reviews.


Assuntos
Aprovação de Equipamentos , Regulamentação Governamental , Sistema de Registros , Viés , Confiabilidade dos Dados , Tomada de Decisões , Humanos , Reprodutibilidade dos Testes , Projetos de Pesquisa , Medição de Risco
15.
Chemistry ; 22(12): 4256-62, 2016 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-26849174

RESUMO

Porous carbon with high specific surface area (SSA), a reasonable pore size distribution, and modified surface chemistry is highly desirable for application in energy storage devices. Herein, we report the synthesis of nitrogen-containing mesoporous carbon with high SSA (1390 m(2) g(-1)), a suitable pore size distribution (1.5-8.1 nm), and a nitrogen content of 4.7 wt % through a facile one-step self-assembly process. Owing to its unique physical characteristics and nitrogen doping, this material demonstrates great promise for application in both supercapacitors and encapsulating sulfur as a superior cathode material for lithium-sulfur batteries. When deployed as a supercapacitor electrode, it exhibited a high specific capacitance of 238.4 F g(-1) at 1 A g(-1) and an excellent rate capability (180 F g(-1), 10 A g(-1)). Furthermore, when an NMC/S electrode was evaluated as the cathode material for lithium-sulfur batteries, it showed a high initial discharge capacity of 1143.6 mA h g(-1) at 837.5 mA g(-1) and an extraordinary cycling stability with 70.3% capacity retention after 100 cycles.

16.
Artigo em Inglês | MEDLINE | ID: mdl-24521495

RESUMO

The complete mitochondrial genome (14,414 bp) of the blood-feeding leech Hirudo nipponia, which was an important natural medicinal resource, was sequenced and characterized. The genome encodes 13 protein-coding genes, 2 rRNAs and 22 tRNAs. The content of A + T was 72.60% for H. nipponia (31.69% A, 40.91% T, 15.45% G and 11.95% C). All protein-coding genes started with ATN except for nad3 and nad5, which used GTG as start codon. Eight protein-coding genes stopped with termination codon TAA. Five protein-coding genes used incomplete stop codon TA or T. The A + T-rich region was located between tRNA-Arg and tRNA-His with a length of 83 bp. This is the first report about completely sequenced mitochondrial genome from the family Hirudinidae. The complete mitochondrial genomes of H. nipponia would be useful for the exploration of Hirudinea polygenetic relationships.


Assuntos
Genoma Mitocondrial/genética , Sanguessugas/genética , Análise de Sequência de DNA , Animais , Genes de RNAr , Anotação de Sequência Molecular , Dados de Sequência Molecular , Fases de Leitura Aberta/genética , Filogenia , RNA de Transferência/genética
17.
Mitochondrial DNA A DNA Mapp Seq Anal ; 27(3): 1924-5, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-25329287

RESUMO

Erpobdella octoculata (Linnaeus, 1758; Hirudinea: Arhynchobdellida: Erpobdellidae) is a very common and morphologically variable macrophagous predators of aquatic invertebrates. Here we determined the complete mitochondrial DNA (mtDNA) sequence of this species, as the first representative of the suborder Erpobdelliformes. This genome is 14,407 bp in length with an A + T content of 71.55%, containing 37 typical animal mitochondrial genes and a non-coding region (NCR). It has high AT content and the same gene arrangement pattern as those of typical annelids. The complete mtDNA sequence of E. octoculata provides useful genetic markers for identification, ecological and evolutionary studies of leeches.


Assuntos
Genoma Mitocondrial , Sanguessugas/genética , Sequenciamento Completo do Genoma , Animais , Composição de Bases/genética , Pareamento de Bases/genética , Sequência de Bases , Genes Mitocondriais , RNA de Transferência/genética
18.
ACS Appl Mater Interfaces ; 7(40): 22284-91, 2015 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-26399912

RESUMO

Graphene is considered a promising electrochemical capacitors electrode material due to its high surface area and high electrical conductivity. However, restacking interactions between graphene nanosheets significantly decrease the ion-accessible surface area and impede electronic and ionic transfer. This would, in turn, severely hinder the realization of high energy density. Herein, we report a strategy for preparation of few-layer graphene material with abundant crumples and high-level nitrogen doping. The two-dimensional graphene nanosheets (CNG) feature high ion-available surface area, excellent electronic and ion transfer properties, and high packing density, permitting the CNG electrode to exhibit excellent electrochemical performance. In ionic liquid electrolyte, the CNG electrode exhibits gravimetric and volumetric capacitances of 128 F g(-1) and 98 F cm(-3), respectively, achieving gravimetric and volumetric energy densities of 56 Wh kg(-1) and 43 Wh L(-1). The preparation strategy described here provides a new approach for developing a graphene-based supercapacitor with high gravimetric and volumetric energy densities.

19.
J Biopharm Stat ; 24(5): 994-1010, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25013971

RESUMO

Due to the special nature of medical device clinical studies, observational (nonrandomized) comparative studies play important roles in the premarket safety/effectiveness evaluation of medical devices. While historical data collected in earlier investigational device exemption studies of a previously approved medical device have been used to form control groups in comparative studies, high-quality registry data are emerging to provide opportunities for the premarket evaluation of new devices. However, in such studies, various biases could be introduced in every stage and aspect of study and may compromise the objectivity of study design and validity of study results. In this article, challenges and opportunities in the design of such studies using propensity score methodology are discussed from regulatory perspectives.


Assuntos
Aprovação de Equipamentos , Equipamentos e Provisões , Estudos Observacionais como Assunto/métodos , Projetos de Pesquisa , Grupos Controle , Aprovação de Equipamentos/normas , Humanos , Estudos Observacionais como Assunto/estatística & dados numéricos , Pontuação de Propensão , Tamanho da Amostra , Amostragem , Resultado do Tratamento
20.
Zhong Yao Cai ; 36(6): 874-9, 2013 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-24380266

RESUMO

OBJECTIVE: To explore the phylogenetic relationships among medicinal leeches and their closely related species by comparing their ITS gene fragments. METHODS: 8 different leech species, including Whitmania pigra, Whitmania acranulata, Whitmania laevis, Hirudo nipponia, Poecilobdella manillensis, Poecilobdella javanica, Poecilobdella hubeiensis and Erpobdella octoculata were collected as the materials for study. After the total DNA of all samples was extracted, amplified by PCR and cloned, their ITS sequence, AT content, variable sites and evolutionary relationships were analyzed. RESULTS: The length of ITS was 948-981 bp with 210 variable sites and 43 inserts on/deletion. The average G + C content was high up to 56.0%-57.8%. The aligned ITS sequence demonstrated that their ITS genes were relatively conserved in species. Data analysis showed that the relationship between E. octoculata and P. javanica was closer than others, their genetic distance was only 0.007. Through the phylogenetic tree analysis, three species of Haemopidae and four species of Hirudinidae were obviously clustered into two branches. CONCLUSION: The results support the taxonomic status of Haemopidae and Hirudinidae, and provide sufficient evidences that Erpobdella octoculata and Poecilobdella javanica should not be assigned to two genera, of which the taxonomic system should be further researched.


Assuntos
DNA Espaçador Ribossômico/genética , Sanguessugas/genética , Animais , Sequência de Bases , Evolução Molecular , Sanguessugas/classificação , Dados de Sequência Molecular , Filogenia , Alinhamento de Sequência , Análise de Sequência de DNA
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