首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   29594篇
  免费   2302篇
  国内免费   64篇
耳鼻咽喉   239篇
儿科学   1056篇
妇产科学   900篇
基础医学   3679篇
口腔科学   526篇
临床医学   5302篇
内科学   4991篇
皮肤病学   408篇
神经病学   2735篇
特种医学   554篇
外科学   2531篇
综合类   446篇
一般理论   67篇
预防医学   4157篇
眼科学   371篇
药学   1692篇
中国医学   26篇
肿瘤学   2280篇
  2023年   159篇
  2022年   109篇
  2021年   422篇
  2020年   433篇
  2019年   740篇
  2018年   766篇
  2017年   574篇
  2016年   678篇
  2015年   759篇
  2014年   962篇
  2013年   1487篇
  2012年   2059篇
  2011年   2081篇
  2010年   1135篇
  2009年   1042篇
  2008年   1973篇
  2007年   2134篇
  2006年   2110篇
  2005年   1999篇
  2004年   1871篇
  2003年   1800篇
  2002年   1681篇
  2001年   293篇
  2000年   273篇
  1999年   265篇
  1998年   362篇
  1997年   247篇
  1996年   239篇
  1995年   272篇
  1994年   243篇
  1993年   232篇
  1992年   176篇
  1991年   160篇
  1990年   153篇
  1989年   151篇
  1988年   132篇
  1987年   117篇
  1986年   119篇
  1985年   142篇
  1984年   129篇
  1983年   133篇
  1982年   149篇
  1981年   137篇
  1980年   141篇
  1979年   66篇
  1978年   65篇
  1977年   57篇
  1976年   63篇
  1975年   55篇
  1974年   53篇
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
1.
2.
Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.  相似文献   
3.

Few studies have examined the views of policy makers regarding the impact of mental health stigma on the development and implementation of mental health policies. This study aimed to address this knowledge gap by exploring policymakers’ and policy advisors’ perspectives regarding the impact of mental health stigma on the development and implementation of mental health programmes, strategies, and services in Singapore. In all 13 participants were recruited for the study comprising practicing policymakers, senior staff of organisations involved in implementing the various mental health programmes, and policy advisors. Data was collected through semi-structured interviews, which were transcribed verbatim and analysed using reflexive thematic analysis. Data analysis revealed three superordinate themes related to challenges experienced by the policymakers/advisors when dealing with mental health policy and implementation of programmes. These themes included stigma as a barrier to mental health treatment, community-level barriers to mental health recovery, and mental health being a neglected need. Policymakers/advisors demonstrated an in-depth and nuanced understanding of the barriers (consequent to stigma) to mental healthcare delivery and access. Policymakers/advisors were able to associate the themes related to the stigma towards mental illness with help-seeking barriers based on personal experiences, knowledge, and insight gained through the implementation of mental health programmes and initiatives.

  相似文献   
4.
Breast Cancer Research and Treatment - The NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in...  相似文献   
5.
6.
7.
A flexible and dynamically adjustable behavior is crucial to adapt to a continuously changing environment. In order to optimally adapt, we need to learn from the consequences of our behavior. We usually learn through different kinds of prediction errors, which occur when we experience unexpected situations due to false predictions. With this literature review, we intended to contribute to current etiological models that ascribe various positive symptoms (particularly delusions and hallucinations) in patients with schizophrenia to false prediction errors and deficient predictive learning. We discuss alterations in the electrophysiological measure of the error‐related negativity/error negativity (ERN/Ne) as a global deficit and a trait in schizophrenia, as they have been observed in different samples of patients with schizophrenia, in individuals at high‐risk and individuals with subclinical schizotypal traits. As the ERN/Ne can itself be considered the result of predictive processes (evaluation of current action outcomes as worse than expected), we propose that the reported alterations indicate that patients suffering from schizophrenic illnesses fail to adequately classify the outcomes of their actions as better or worse than expected due to a deficit in self‐monitoring. Furthermore, we discuss results in further action‐monitoring components, such as the correct response negativity (CRN)—a smaller negativity elicited by correct responses; and error positivity (Pe)—a later positivity assumed to reflect conscious error processing. The reported results show normal Pe amplitudes and normal post‐error adjustments (adaptations after committed error to improve performance), indicating an intact later and conscious processing. From the results of diminished differences between ERN/Ne and CRN amplitudes, we conclude a general predictive deficit in early aspects of self‐monitoring associated with positive symptoms in patients with schizophrenia.  相似文献   
8.
9.
10.
Volunteer infection studies using the induced blood stage malaria (IBSM) model have been shown to facilitate antimalarial drug development. Such studies have traditionally been undertaken in single‐dose cohorts, as many as necessary to obtain the dose‐response relationship. To enhance ethical and logistic aspects of such studies, and to reduce the number of cohorts needed to establish the dose‐response relationship, we undertook a retrospective in silico analysis of previously accrued data to improve study design. A pharmacokinetic (PK)/pharmacodynamic (PD) model was developed from initial fictive‐cohort data for OZ439 (mixing the data of the three single‐dose cohorts as: n = 2 on 100 mg, 2 on 200 mg, and 4 on 500 mg). A three‐compartment model described OZ439 PKs. Net growth of parasites was modeled using a Gompertz function and drug‐induced parasite death using a Hill function. Parameter estimates for the PK and PD models were comparable for the multidose single‐cohort vs. the pooled analysis of all cohorts. Simulations based on the multidose single‐cohort design described the complete data from the original IBSM study. The novel design allows for the ascertainment of the PK/PD relationship early in the study, providing a basis for rational dose selection for subsequent cohorts and studies.

Study Highlights
  • WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
☑ Volunteer infection studies are routinely used in antimalarial drug development to generate early pharmacokinetic/pharmacodynamic data for compounds.
  • WHAT QUESTION DID THIS STUDY ADDRESS?
☑ Can in silico analyses be used to suggest improvements to volunteer infection study designs?
  • WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
☑ Multiple dose adaptive trial designs can potentially reduce the number of cohorts needed to establish the dose‐response relationship in volunteer infection studies.
  • HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
☑ Real time data analyses can be used to recommend doses for adaptive volunteer infection studies.

Volunteer infection studies using the induced blood stage malaria (IBSM) model have been recognized as a valuable system for defining the key pharmacokinetic (PK) and pharmacodynamic (PD) relationships for dose selection in antimalarial drug development. 1 , 2 , 3 , 4 , 5 , 6 , 7 In such studies, healthy volunteers are inoculated intravenously with a given quantity (with small variability) of Plasmodium‐infected red cells. Parasitemia is then followed by quantitative polymerase chain reaction until a prespecified treatment threshold is reached when the test drug is administered. Parasite and drug concentrations are then measured. These studies are conducted prior to phase II dose‐response (D‐R) trials and can be included in an integrated first‐in‐human study protocol, or after completion of the first‐in‐human PK and safety study. IBSM studies have been typically designed as flexible multiple cohort studies where each volunteer of one cohort receives a single dose of the same amount of drug (“single dose per cohort”). 2 , 3 , 4 , 5 After each cohort, a decision is made to stop or to add a cohort to test a lower or higher dose based on the response observed in the previous cohorts.For the multiple single‐dose‐per‐cohort design, the starting dose is typically selected based on safety and PK information from a phase I single ascending dose (SAD) study and, more recently, on preclinical data from a severe combined immunodeficient mouse model, with the dose selected on the basis of being best able to inform the D‐R relationship, rather than aiming for cure. This approach, where a single dose is tested in all subjects of the initial cohort, risks missing the dose likely to be most informative for defining the PK/PD relationship.An alternative approach is to spread a range of doses across a smaller number of subjects within the initial cohort and use PK/PD models developed based on data from this cohort to support dose selections of subsequent cohorts and studies. Using data from a previous study, 2 we undertook an in silico investigation of such an adaptive study design, aiming to reduce the number of subjects exposed to inefficacious doses, and to establish a D‐R relationship. This multiple‐dose‐groups‐per‐cohort design, referred to as the “2‐2‐4” design, is contrasted with the already implemented study design depicted in Figure  1 .Open in a separate windowFigure 1Comparison of standard and adaptive designs of IBSM studies. A/B/C, dose levels to be selected during the progress of the study based on pharmacokinetic/pharmacodynamic results of the initial cohort; CHMI, controlled human malaria infection; D‐R, dose‐response; IBSM, induced blood stage malaria infection; n, number of subjects at each dose.The objectives of this retrospective analysis were to: (i) compare PK/PD parameter estimates from the initial cohort of the 2‐2‐4 study design with the prior results from the data of the full study and (ii) propose a preliminary workflow to establish D‐R early in an IBSM study, and use modeling and simulation (M&S) to support dose selections for subsequent cohorts and later phase clinical trials.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号