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11.
Many important pharmaceutical agents, including vancomycin, bleomycin, cyclosporin, and several antibiotics, are produced by non‐ribosomal peptide synthetase (NRPS) enzymes in microorganisms. The NRPS pathway produces an extensive library of products using multienzyme complexes acting in an assembly‐line fashion. Engineering an NRPS system to produce an even greater variety of products, some of which may also have beneficial therapeutic value, would be an enormous advantage. Several approaches have been successful in generating novel NRPS products: mutational biosynthesis during which nonnatural substrates are fed to an organism; domain and module swapping between different species to generate hybrid enzymes; and rational site‐directed mutagenesis, based either on phylogeny or computational prediction, intended to switch substrate specificity and produce altered products. This review will highlight the progress in these areas and describe research in the future that will extend the capacity for re‐engineering NRPS systems. Drug Dev. Res. 66:9–18, 2006. © 2006 Wiley‐Liss, Inc. 相似文献
12.
随着生物医用材料研制和医学的迅速发展,以及生活水平、医疗保健、康复水平的提高,人们对自身组织、器官及骨骼缺损的修复和置换方面的要求日益提高,尤其对人造骨骼和人工关节的需求越来越广泛。由于计算机断层成像技术CT(computed tomography)已经成为显示和研究人体内部结构非常有用的手段,将计算机辅助设计技术CAD(Computer aided design)和计算机辅助工程CAE(Computer aided Engineering)等相关技术应用于人造骨骼和内置假体的设计,不仅可以提高产品的设计质量,同时,结合CT和计算机三维重建方法, 相似文献
13.
Design and conduct of occupational epidemiology studies: III. Design aspects of case-control studies
Currently available approaches for the design of occupational case-control studies are reviewed. An accompanying paper reviews methods of analysis. We commence by drawing a distinction between cohort-based and registry-based studies. Methods for selecting cases and controls are then reviewed, including cumulative incidence and incidence density sampling, matching, sources of controls, and issues in control selection. Finally, the advantages and disadvantages of the case-control approach are summarized. 相似文献
14.
J. M. McGree J. A. Eccleston S. B. Duffull 《Journal of pharmacokinetics and pharmacodynamics》2009,36(2):101-123
We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional
nature of such models, differences in predicted responses are a consequence of different assumptions about how the models
interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques
have been explored in the literature where it was found that the sequential and FO approaches can produce biased results.
It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal
design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected
Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into
our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical
and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates
formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed
and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature.
We consider design for situations where all responses are continuous and extend this methodology to the case where a response
may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such
responses will offer little information about all parameters and hence a sequential optimization, in the form of product design
optimality, may yield near optimal designs. 相似文献
15.
16.
We focus on the Fisher information matrix used for design evaluation and optimization in nonlinear mixed effects multiple response models. We evaluate the appropriateness of its expression computed by linearization as proposed for a single response model. Using a pharmacokinetic–pharmacodynamic (PKPD) example, we first compare the computation of the Fisher information matrix with approximation to one derived from the observed matrix on a large simulation using the stochastic approximation expectation–maximization algorithm (SAEM). The expression of the Fisher information matrix for multiple responses is also evaluated by comparison with the empirical information obtained through a replicated simulation study using the first‐order linearization estimation methods implemented in the NONMEM software (first‐order (FO), first‐order conditional estimate (FOCE)) and the SAEM algorithm in the MONOLIX software. The predicted errors given by the approximated information matrix are close to those given by the information matrix obtained without linearization using SAEM and to the empirical ones obtained with FOCE and SAEM. The simulation study also illustrates the accuracy of both FOCE and SAEM estimation algorithms when jointly modelling multiple responses and the major limitations of the FO method. This study highlights the appropriateness of the approximated Fisher information matrix for multiple responses, which is implemented in PFIM 3.0, an extension of the R function PFIM dedicated to design evaluation and optimization. It also emphasizes the use of this computing tool for designing population multiple response studies, as for instance in PKPD studies or in PK studies including the modelling of the PK of a drug and its active metabolite. Copyright © 2009 John Wiley & Sons, Ltd. 相似文献
17.
18.
Phase II clinical trials are performed to investigate whether a novel treatment shows sufficient promise of efficacy to justify its evaluation in a subsequent definitive phase III trial, and they are often also used to select the dose to take forward. In this paper we discuss different design proposals for a phase II trial in which three active treatment doses and a placebo control are to be compared in terms of a single‐ordered categorical endpoint. The sample size requirements for one‐stage and two‐stage designs are derived, based on an approach similar to that of Dunnett. Detailed computations are prepared for an illustrative example concerning a study in stroke. Allowance for early stopping for futility is made. Simulations are used to verify that the specified type I error and power requirements are valid, despite certain approximations used in the derivation of sample size. The advantages and disadvantages of the different designs are discussed, and the scope for extending the approach to different forms of endpoint is considered. Copyright © 2008 John Wiley & Sons, Ltd. 相似文献
19.
Donald B. Penzien PhD ; Frank Andrasik PhD ; Brian M. Freidenberg PhD ; Timothy T. Houle PhD ; Alvin E. Lake III PhD; Gay L. Lipchik PhD ; Kenneth A. Holroyd PhD ; Richard B. Lipton MD ; Douglas C. McCrory MD ; Justin M. Nash PhD ; Robert A. Nicholson PhD ; Scott W. Powers PhD ABPP ; Jeanetta C. Rains PhD ; David A. Wittrock PhD 《Headache》2005,45(S2):S110-S132
Guidelines for design of clinical trials evaluating behavioral headache treatments were developed to facilitate production of quality research evaluating behavioral therapies for management of primary headache disorders. These guidelines were produced by a Workgroup of headache researchers under auspices of the American Headache Society. The guidelines are complementary to and modeled after guidelines for pharmacological trials published by the International Headache Society, but they address methodologic considerations unique to behavioral and other nonpharmacological treatments. Explicit guidelines for evaluating behavioral headache therapies are needed as the optimal methodology for behavioral (and other nonpharmacologic) trials necessarily differs from the preferred methodology for drug trials. In addition, trials comparing and integrating drug and behavioral therapies present methodological challenges not addressed by guidelines for pharmacologic research. These guidelines address patient selection, trial design for behavioral treatments and for comparisons across multiple treatment modalities (eg, behavioral vs pharmacologic), evaluation of results, and research ethics. Although developed specifically for behavioral therapies, the guidelines may apply to the design of clinical trials evaluating many forms of nonpharmacologic therapies for headache. 相似文献
20.
This article identifies common characteristics of educationally related programs that form a common basis for understanding and working with gifted programs. Special approaches and programs for educational enrichment as well as specific activities that have been successful are discussed. 相似文献