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51.
Stefan Willmann Kirstin Thelen Dagmar Kubitza Anthonie W. A. Lensing Matthias Frede Katrin Coboeken Jan Stampfuss Rolf Burghaus Wolfgang Mück Jörg Lippert 《Thrombosis journal》2018,16(1):32
Background
The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed.Methods
We quantitatively assessed the pharmacokinetics (PK) of a single rivaroxaban dose in children using population pharmacokinetic (PopPK) modelling and assessed the applicability of the PBPK model. Plasma concentration–time data from the EINSTEIN-Jr phase I study were analysed by non-compartmental and PopPK analyses and compared with the predictions of the PBPK model. Two rivaroxaban dose levels, equivalent to adult doses of rivaroxaban 10 mg and 20 mg, and two different formulations (tablet and oral suspension) were tested in children aged 0.5–18 years who had completed treatment for VTE.Results
PK data from 59 children were obtained. The observed plasma concentration–time profiles in all subjects were mostly within the 90% prediction interval, irrespective of dose or formulation. The PopPK estimates and non-compartmental analysis-derived PK parameters (in children aged ≥6 years) were in good agreement with the PBPK model predictions.Conclusions
These results confirmed the applicability of the rivaroxaban pediatric PBPK model in the pediatric population aged 0.5–18 years, which in combination with the PopPK model, will be further used to guide dose selection for the treatment of VTE with rivaroxaban in EINSTEIN-Jr phase II and III studies.52.
Dagmar Kubitza Stefan Willmann Michael Becka Kirstin Thelen Guy Young Leonardo R. Brandão Paul Monagle Christoph Male Anthony Chan Gili Kennet Ida Martinelli Paola Saracco Anthonie W. A. Lensing 《Thrombosis journal》2018,16(1):31
Background
The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.Methods
This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5–18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5–2 years, 2–6 years, 6–12 years and 12–18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.Results
Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.Conclusions
Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.Trial registration
ClinicalTrials.gov number, NCT01145859.53.
Hans-Ulrich Siegmund Rolf Burghaus Dagmar Kubitza Katrin Coboeken 《British journal of clinical pharmacology》2015,79(6):959-966
Aim
This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin.Methods
We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6 h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR.Results
The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0–3.0, the INR contribution of rivaroxaban with Neoplastin Plus® was 0.5–1.2, decreasing to 0.3–0.6 with Innovin® at median trough rivaroxaban plasma concentrations (38 μg l−1).Conclusions
The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24 h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin® is preferable to Neoplastin Plus® because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR. 相似文献54.
55.
Limperger Verena Kenet Gili Kiesau Bettina Köther Max Schmeiser Malin Langer Florian Juhl David Shneyder Maria Franke Andre Klostermeier Ulrich K. Mesters Rolf Rühle Frank Stoll Monika Steppat Dagmar Kowalski Dorothee Rocke Angela Kuta Piotr Bajorat Tido Torge Antje Neuner Bruno Junker Ralf Nowak-Göttl Ulrike 《Journal of thrombosis and thrombolysis》2021,51(2):494-501
Journal of Thrombosis and Thrombolysis - The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism... 相似文献
56.
Alber DG Vallance P Powell KL 《Arteriosclerosis, thrombosis, and vascular biology》2002,22(5):793-798
Viral and bacterial infectious agents have been implicated in the etiology of atherosclerosis. We have previously shown that a gamma-herpesvirus can accelerate atherosclerosis in the apolipoprotein E-deficient (apoE-/-) mouse. To address whether a virally induced systemic immune response is sufficient to trigger enhanced atheroma formation, we infected apoE-/- mice with murine gamma-herpesvirus-68 (MHV-68) or herpes simplex virus-1 (HSV-1). In this study, we show that both viruses were able to induce a cell-mediated and humoral immune response in the apoE-/- mouse, which was sustained over a period of 24 weeks. Although intranasal or intraperitoneal infection with MHV-68 induced similar levels of virus-specific IgG1 and IgG2a antibodies in the serum of apoE-/- mice, those infected with HSV-1 showed higher anti-HSV-1 IgG2a compared with IgG1 antibody levels. In addition, viral message was not detected in the aortas of HSV-1-infected animals, whereas we have shown previously that MHV-68 mRNA can be detected in the aortas of infected mice as early as 5 days after infection. Compared with control mice, apoE-/- mice infected with MHV-68 showed accelerated atherosclerosis, whereas mice infected with HSV-1 did not. These data indicate that a systemic immune response to any particular infectious agent is insufficient to induce enhanced atherosclerosis in the apoE-/- mouse and point to specific infections or immune mechanisms that might be essential for virally enhanced atherogenesis. 相似文献
57.
Marka van Blitterswijk Michael A. van Es Dagmar Verbaan Jacobus J. van Hilten Hans Scheffer Bart P. van de Warrenburg Jan H. Veldink Leonard H. van den Berg 《Neurobiology of aging》2013,34(5):1517.e1-1517.e3
Mutations in TAR DNA-binding protein (TARDBP) are associated with heterogenic phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease. In this study, we investigated the presence of TARDBP mutations in a cohort of 429 Dutch patients with Parkinson's disease. Though we detected 1 silent mutation, p.S332S, no missense mutations were present in our cohort. Our findings, therefore, demonstrate that TARDBP mutations do not appear to contribute to the pathogenesis of Parkinson's disease in The Netherlands. 相似文献
58.
59.
Robin K?ck Lea C. Ei?ing Matthias G. Boschin Bj?rn Ellger Dagmar Horn Evgeny A. Idelevich Karsten Becker 《Journal of clinical microbiology》2013,51(11):3683-3687
Clinical practice guidelines recommend performing follow-up cultures for patients with candidemia in order to determine the time when Candida is cleared from the bloodstream. Since this requires culturing blood samples from patients undergoing antifungal treatment, we evaluated two blood culture bottles (the Bactec Mycosis IC/F [MICF], specifically adapted to the growth of fungi, and the Bactec Plus Aerobic/F [PAF], containing resins to inactivate anti-infective agents) for their effectiveness in detecting Candida albicans and Candida glabrata when seeded in concentrations of 1 CFU/ml and 10 CFU/ml, respectively, together with human whole blood and various antifungal agents in therapeutic peak serum concentrations (Cmax). Significant differences between the MICF and PAF vials for the detection of Candida spp. were found when inoculated with caspofungin (0/12 versus 8/12) (P < 0.001) or amphotericin B (3/12 versus 12/12) (P < 0.001). Inoculation of fluconazole or voriconazole did not influence the effectiveness of detection in the MICF and PAF bottles (P = 1.0). Neither the MICF nor the PAF bottles detected Candida spp. reliably when seeded together with anidulafungin (1/12 versus 1/12) (P = 1.0) or micafungin (0/12 versus 1/12) (P = 1.0). The times to positivity of both bottles were significantly prolonged when antifungal agents were added compared to those of controls without antimycotic drugs (P < 0.001). Overall, the results of this in vitro study indicate that the PAF bottles detected Candida spp. more reliably than the MICF bottles when supplemented with certain antifungal agents. Consequently, clinical studies should evaluate whether this holds true when blood cultures from patients undergoing antifungal treatment are performed. 相似文献
60.
Melanie Fhrenbach Rami Abou Jamra Arndt Borkhardt Triantafyllia Brozou Petra Muschke Bernt Popp Linda K. Rey Jrg Schaper Harald Surowy Martin Zenker Christiane Zweier Dagmar Wieczorek Silke Redler 《Clinical genetics》2021,99(1):199-207
Ververi‐Brady syndrome (VBS, # 617982) is a rare developmental disorder, and loss‐of‐function variants in QRICH1 were implicated in its etiology. Furthermore, a recognizable phenotype was proposed comprising delayed speech, learning difficulties and dysmorphic signs. Here, we present four unrelated individuals with one known nonsense variant (c.1954C > T; p.[Arg652*]) and three novel de novo QRICH1 variants, respectively. These included two frameshift mutations (c.832_833del; p.(Ser278Leufs*25), c.1812_1813delTG; p.(Glu605Glyfs*25)) and interestingly one missense mutation (c.2207G > A; p.[Ser736Asn]), expanding the mutational spectrum. Enlargement of the cohort by these four individuals contributes to the delineation of the VBS phenotype and suggests expressive speech delay, moderate motor delay, learning difficulties/mild ID, mild microcephaly, short stature and notable social behavior deficits as clinical hallmarks. In addition, one patient presented with nephroblastoma. The possible involvement of QRICH1 in pediatric cancer assumes careful surveillance a key priority for outcome of these patients. Further research and enlargement of cohorts are warranted to learn about the genetic architecture and the phenotypic spectrum in more detail. 相似文献