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81.
Pawe Poznaski Hanna Augustyniak-Bartosik Anna Magiera-ak Karolina Skalec Katarzyna Jakuszko Oktawia Mazanowska Dariusz Janczak Magdalena Krajewska Dorota Kamiska 《Viruses》2022,14(10)
Background: Molnupiravir demonstrated an in vitro antiviral activity against positive-sense RNA viruses, including SARS-CoV-2. The study aimed to present the results of outpatient molnupiravir use in kidney transplant recipients and hemodialysis patients during the first months of 2022 in Poland. Methods: The retrospective observational cohort study at one kidney transplant center included 36 patients diagnosed with COVID-19 with an automated nucleic acid amplification test on nasopharyngeal swab specimens. All patients received molnupiravir for home-based therapy at a dose of 800 mg every 12 h orally for 5 days. Both kidney transplant recipients (n = 16) and hemodialysis patients (n = 20) presented a lot of comorbidities with a Charlson comorbidity index of 4.1 and 5.1, respectively. Results: Patients presented with fever, cough, and weakness followed by muscle and joint pain. Five kidney transplant recipients experienced acute kidney injury with a rise in serum creatinine level from 0.4 to 1.9 mg/dL. No serious side effects of molnupiravir therapy or interactions with immunosuppressive medications were observed. Symptoms of COVID-19 improved rapidly or resolved within 24–48 h of starting treatment. Conclusion: The study suggests the safety and efficacy of molnupiravir therapy alone early after the onset of SARS-CoV-2 infection, but further investigations should be performed to confirm our preliminary results. To the best of the authors’ knowledge, it is the first published report on molnupiravir use in end-stage kidney disease (ESKD) patients on hemodialysis and the third concerning kidney transplant recipients. 相似文献
82.
Trejeeve Martyn Andres Carmona Rubio Jerry D. Estep Mazen Hanna 《Methodist DeBakey Cardiovascular Journal》2022,18(5):27
Despite the rapid expansion of noninvasive (nonbiopsy) diagnosis, contemporary patients with cardiac amyloidosis too often present with advanced features of disease, such as diminished quality of life, elevated natriuretic peptides, and advanced heart failure. Therapeutics for transthyretin cardiomyopathy (ATTR-CM) are most effective when administered before significant symptoms of cardiac dysfunction manifest, making early identification of affected individuals of paramount importance. Community engagement and ensuring that a broad range of clinicians have working knowledge of how to screen for ATTR-CM in everyday practice will be an important step in moving disease identification further upstream. However, reliance on the appropriate and timely diagnosis by individual clinicians may continue to underperform. This review highlights how targeted screening of special populations may facilitate earlier diagnosis. Systems of care that operationalize screening of high-risk subpopulations and prospective validation of novel approaches to ATTR-CM identification are needed. 相似文献
83.
Neeltje Steeghs Aaron R. Hansen Glenn J. Hanna Elena Garralda Haeseong Park James Strauss Michael Adam Gossett Campbell Jennifer Carver Rachael Easton Katherine Mays Peter Skrdla Herbert Struemper Michael L. Washburn Christopher Matheny Sarina
A. PihaPaul 《CTS Clinical and Translational Science》2022,15(11):2625
A phase I trial (; 204686) evaluated the safety and efficacy of GSK1795091, a Toll‐like receptor 4 (TLR4) agonist, in combination with immunotherapy (GSK3174998 [anti‐OX40 monoclonal antibody], GSK3359609 [anti‐ICOS monoclonal antibody], or pembrolizumab) in patients with solid tumors. The primary endpoint was safety; other endpoints included efficacy, pharmacokinetics, and pharmacodynamics (PD). Manufacturing of GSK1795091 formulation was modified during the trial to streamline production and administration, resulting in reduced PD (cytokine) activity. Fifty‐four patients received GSK1795091 with a combination partner; 32 received only the modified GSK1795091 formulation, 15 received only the original formulation, and seven switched mid‐study from the original to the modified formulation. Despite the modified formulation demonstrating higher systemic GSK1795091 exposure compared with the original formulation, the transient, dose‐dependent elevations in cytokine and chemokine concentrations were no longer observed (e.g., IP‐10, IL10, IL1‐RA). Most patients (51/54; 94%) experienced ≥1 treatment‐emergent adverse event (TEAE) during the study. Safety profiles were similar between formulations, but a higher incidence of TEAEs associated with immune responses (chills, fatigue, pyrexia, nausea, and vomiting) were observed with the original formulation. No conclusions can be made regarding GSK1795091 anti‐tumor activity due to the limited data collected. Manufacturing changes were hypothesized to have caused the change in biological activity in this study. Structural characterization revealed GSK1795091 aggregate size in the modified formulation to be twice that in the original formulation, suggesting a negative correlation between GSK1795091 aggregate size and PD activity. This may have important clinical implications for future development of structurally similar compounds. Study Highlights NCT03447314
- WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
- WHAT QUESTION DID THIS STUDY ADDRESS?
- WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
- HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
84.
Gene therapy has progressed from early clinical trials to first commercial gene therapy drugs. While there is a long history with the side-effects and adverse effects of pharmaceutical drugs, drugs based on gene delivery have presented new challenges for researchers, clinicians and regulatory authorities. On the path from early pre-clinical research to final commercial products, gene therapy tools and production methods have undergone tremendous changes to improve safety and efficacy. Deletion of adenovirus replication genes E1 and E3 has progressed to gutless adenoviruses with all viral genes removed; similarly evolution of lentiviral vectors has progressed from first generation viruses to safer third generation self-inactivating vectors. Improved chromatographic methods have eased the purification of viruses and delivery reservoirs, such as collagen or silicon collars for cardiovascular gene transfer have decreased systemic leakage of viruses; together with tissue-specific promoters and imaging of the biodistribution of viral particles, gene therapy specificity and safety can be improved even further. This review will introduce gene delivery vectors used in gene therapy and highlight key approaches used to improve their safety. 相似文献
85.
p-Aminophenol (pAP, 225 mg/kg) administration to rats induced renal failure and has been associated with markers of endoplasmic reticulum (ER) stress, as well as calpain and caspase-12 activation in kidneys. To determine the importance of ER stress and calpain during pAP-induced nephrotoxicity, rats were pretreated with low, nontoxic, doses of ER stress inducers or with the selective calpain inhibitor PD150606 (3 mg/kg). Prior ER stress induced by tunicamycin and oxidized dithiothreitol did not result in protection against renal failure, but PD150606 administration was protective and decreased significantly the rise in creatinine and blood urea nitrogen observed after 24-h post-pAP administration. pAP-induced XBP1 upregulation was not modified by calpain inhibition, but a trend to lower GRP94 induction was determined, suggesting that pAP-induced ER stress was mostly calpain independent. In contrast, pAP-induced caspase-12 cleavage products were significantly decreased with PD150606 pretreatment, demonstrating that caspase-12 activation was calpain dependent. This study reveals the importance of calpain in pAP-induced renal failure. Further research with other nephrotoxicants needs to be performed to determine if calpain activation is a common feature of drug-induced renal failure. 相似文献
86.
Elia Wyverkens Hanna Van Parys Veerle Provoost Guido Pennings Petra De Sutter Ann Buysse 《Journal of reproductive and infant psychology》2016,34(3):314-323
Objective: This study aimed to gain an in-depth understanding of the experiences of genetic ties in intrafamily oocyte donation families. Background: Previous research has shown that most mothers have a good and stable relationship with their donor. Little is known about the meaning of the difference in genetic ties for parents who conceived through sister-to-sister oocyte donation. Methods: An Interpretative Phenomenological Analysis was performed and focused on both individual experiences and couple experiences with regard to genetic ties. Ten participants were recruited via an infertility clinic and took part in semistructured couple interviews. Results: Our analysis revealed that the donation was seen as a way to equal genetic parenthood. Participants struggled with this prevailing ideal of genetic parenthood and questioned the legitimacy of their motherhood. Several dynamics were identified when couples tried to deal with the imbalance in genetic ties: they acknowledged each other, convinced one another, or pushed away the difference in genetic ties. Couples also managed the presence of a genetic tie with the donor by negotiating the closeness in their family relationships. Conclusion: The lack of a full genetic tie remained a meaningful absence for some mothers and the way couples dealt with this varied. We plead that the option of post-donation care should be offered to support couples with the complexities they try to deal with. 相似文献
87.
88.
Malgorzata Harasymczuk William Gooding Aleksandra Kruk-Zagajewska Jerzy Wojtowicz Grzegorz Dworacki Hanna Tomczak Witold Szyfter Theresa L. Whiteside 《European archives of oto-rhino-laryngology》2013,270(3):1105-1114
Head and neck squamous cell carcinomas (HNSCC) are characterized by exophytic or endophytic growth. We hypothesized that the growth pattern predicts outcome and associates with distinct clinical and immunological profiles. Tumors obtained from 60 HNSCC patients treated with surgery and adjuvant radiotherapy were identified as exophytic or endophytic. Recurrence-free survival (RFS) at 42 months was determined. In a subsets of 30 patients (22 exophytic and 8 endophytic) tumor stroma and parenchyma were evaluated for infiltrating CD4+ and CD8+ T, dendritic, myeloid and FOXP3+ regulatory T cells (Treg) and expression of immunosuppressive cytokines by immunohistochemistry. The localization and frequency of positive cells were determined microscopically and analyzed by hierarchical clustering to distinguish exophytic versus endophytic tumors. 34/60 patients had exophytic and 26/60 endophytic tumors. No differences in clinicopathologic data, disease progression or RFS were seen between the two cohorts. Infiltrates of CD3+CD8+ T cells were larger in endophytic than exophytic tumors, while FOXP3+ Treg, TGF-β+, IL-10+, Arg-1+, CD11b+ cells were equally prominent in both. FOXP3+ Treg accumulated in endophytic tumor nests, while the exophytic tumor stroma was enriched in IL-10+ cells (both at p < 0.05). Hierarchical clustering based on immunophenotyping failed to identify different clusters in these two tumor types. However, CD68+ macrophages and FOXP3+ Treg showed a distinct distribution. The HNSCC growth pattern did not predict RFS. Although higher numbers and differences in localization of immunosuppressive cells in endophytic versus exophytic tumors were observed, no significant relationship was established between the growth pattern and the immune profile of infiltrating lymphocytes. 相似文献
89.
90.