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《Saudi Pharmaceutical Journal》2022,30(5):595-604
Anthrax is a zoonotic infection caused by the gram-positive, aerobic, spore-forming bacterium Bacillus anthracis. Depending on the origin of the infection, serious health problems or mortality is possible. The virulence of B. anthracis is reliant on three pathogenic factors, which are secreted upon infection: protective antigen (PA), lethal factor (LF), and edema factor (EF). Systemic illness results from LF and EF entering cells through the formation of a complex with the heptameric form of PA, bound to the membrane of infected cells through its receptor. The currently available anthrax vaccines have multiple drawbacks, and recombinant PA is considered a promising second-generation vaccine candidate. However, the inherent chemical instability of PA through Asn deamidation at multiple sites prevents its use after long-term storage owing to loss of potency. Moreover, there is a distinct possibility of B. anthracis being used as a bioweapon; thus, the developed vaccine should remain efficacious and stable over the long-term. Second-generation anthrax vaccines with appropriate adjuvant formulations for enhanced immunogenicity and safety are desired. In this article, using protein engineering approaches, we have reviewed the stabilization of anthrax vaccine candidates that are currently licensed or under preclinical and clinical trials. We have also proposed a formulation to enhance recombinant PA vaccine potency via adjuvant formulation. 相似文献
3.
《Journal of infection and chemotherapy》2022,28(9):1235-1241
IntroductionThe results from the phase 3 study that evaluated the efficacy and safety of tedizolid phosphate, an oxazolidinone drug, for the treatment of gram-positive ventilated hospital-acquired bacterial pneumonia (vHABP)/ventilator-associated bacterial pneumonia (VABP) compared with linezolid (VITAL study), have been previously reported. We conducted a subgroup analysis to report the data obtained from Japanese patients enrolled in this study.MethodsPatients aged ≥18 years with vHABP/VABP likely to be caused by gram-positive cocci were randomized 1:1 to tedizolid phosphate 200 mg once daily for 7 days or linezolid 600 mg twice daily for 10 days. In both treatment groups, patients with concurrent gram-positive bacteremia were treated for 14 days. Primary efficacy endpoints were day 28 all-cause mortality (ACM) and investigator-assessed clinical response at test-of-cure (TOC) in the intention-to-treat population. Safety outcomes included assessment of treatment-emergent adverse events.ResultsFifty-three Japanese patients were randomized at received study drug (tedizolid, n = 28; linezolid, n = 25). Demographics and characteristics were generally similar between treatment groups. Rates of day 28 ACM were 10.7% and 20.0% with tedizolid and linezolid, respectively (difference, 9.3%; 95% CI, ?10.1 to 28.7). Rates of investigator-assessed clinical cure at TOC were 78.6% and 72.0% with tedizolid and linezolid, respectively (difference, 6.6%; 95% CI, ?16.7 to 29.8). Tedizolid phosphate was generally well tolerated and no new safety concerns were observed in the Japanese subgroup.ConclusionThe results from this subgroup analysis suggest generally favorable efficacy and safety of tedizolid in adult Japanese patients with vHABP/VABP. (ClinicalTrials.gov identifier: NCT02019420). 相似文献
4.
目的:探讨小儿宝泰康颗粒联合磷酸奥司他韦治疗风热犯卫证甲型流行性感冒的临床疗效及作用机制。方法:选取2021年10月至2022年7月武汉市中医医院儿科门诊收治的甲型流行性感冒风热犯卫证患儿70例作为研究对象,采用随机数字表法分为观察组和对照组,每组35例。对照组给予基础治疗,以退热、补液为主,口服磷酸奥司他韦颗粒;观察组在对照组基础上加口服小儿宝泰康颗粒治疗,疗程5 d。观察记录患儿完全热退时间、卡他症状消退时间、咳嗽消退时间,并对其进行评分判断疗效,同时在入组第1天、第5天采血化验炎症介质超敏C反应蛋白(hs-CRP)、降钙素原(PCT)及白细胞介素-6(IL-6)含量,观察2组不良反应的发生情况,采用SPSS 26.0统计软件进行数据分析。结果:观察组总有效率97.14%,对照组总有效率85.71%,观察组优于对照组(P<0.01);与对照组比较,观察组完全热退时间、卡他症状消退时间、咳嗽消退时间短,差异有统计学意义(均P<0.05);治疗后,2组hs-CRP、PCT及IL-6水平与治疗前相较均有降低,且观察组hs-CRP、PCT及IL-6均明显低于对照组(均P<0.05)。结论:小儿宝泰康颗粒联合磷酸奥司他韦可以明显加快风热犯卫证甲流患儿完全退热时间,缩短病程,改善发热、咳嗽、腹胀等症状,降低炎症介质水平,对于治疗以风热犯卫证甲型流行性感冒具有较好的临床疗效,无明显不良反应,其作用机制可能与调节内致热原,抑制炎症介质分泌有关。 相似文献
5.
目的:探究舒血宁联合磷酸肌酸钠对心肌梗死大鼠的心肌保护作用及对血管再生的影响。方法:将60只建模成功的心肌梗死大鼠随机分为模型组、磷酸肌酸钠及联合组,每组20只,另选20只SD大鼠仅于左冠状动脉前降支穿线而不结扎作为假手术组。磷酸肌酸钠及联合组分别腹腔注射磷酸肌酸钠[0.2 g/(kg·d)]、磷酸肌酸钠[0.2 g/(kg·d)]+舒血宁[10 mL/(kg·d)],模型组及假手术组则注射等体积生理盐水,各组均连续干预4周。检测并比较各组大鼠心功能指标;观察各组大鼠心肌组织病理学形态变化;比较各组大鼠心肌组织微血管密度及血管内皮生长因子(VEGF)表达情况。结果:模型组大鼠左心室舒张末期内径(LVEDd)、左心室收缩末期内径(LVESd)较假手术组升高,而磷酸肌酸钠组及联合组较模型组降低,且联合组显著低于磷酸肌酸钠组,差异有统计学意义(P<0.05);模型组大鼠左心室短轴收缩率(FS)及左心室射血分数(LVEF),心肌组织CD31、VEGF蛋白A值及MVD较假手术组降低,而磷酸肌酸钠组及联合组较模型组升高,且联合组显著高于磷酸肌酸钠组,差异有统计学意义(P<0.05)。结论:舒血宁联合磷酸肌酸钠有效促进心肌组织缺血区域血管新生,改善心肌梗死大鼠心肌病理损伤,恢复其心功能,疗效显著优于单用磷酸肌酸钠。 相似文献
6.
Jingran Ji Woo Ram Park Soojeong Cho Yihe Yang Weiguo Li Kathleen Harris Xiaoke Huang Shangzhi Gu Dong-Hyun Kim Zhuoli Zhang Andrew C. Larson 《Journal of vascular and interventional radiology : JVIR》2019,30(7):1106-1115.e1
PurposeTo label Clostridium novyi-NT spores (C. novyi-NT) with iron oxide nanoclusters and track distribution of bacteria during magnetic resonance (MR) imaging-monitored locoregional delivery to liver tumors using intratumoral injection or intra-arterial transcatheter infusion.Materials and MethodsVegetative state C. novyi-NT were labeled with iron oxide particles followed by induction of sporulation. Labeling was confirmed with fluorescence microscopy and transmission electron microscopy (TEM). T2 and T2* relaxation times for magnetic clusters and magnetic microspheres were determined using 7T and 1.5T MR imaging scanners. In vitro assays compared labeled bacteria viability and oncolytic potential to unlabeled controls. Labeled spores were either directly injected into N1-S1 rodent liver tumors (n = 24) or selectively infused via the hepatic artery in rabbits with VX2 liver tumors (n = 3). Hematoxylin-eosin, Prussian blue, and gram staining were performed. Statistical comparison methods included paired t-test and ANOVA.ResultsBoth fluorescence microscopy and TEM studies confirmed presence of iron oxide labels within the bacterial spores. Phantom studies demonstrated that the synthesized nanoclusters produce R2 relaxivities comparable to clinical agents. Labeling had no significant impact on overall growth or oncolytic properties (P >.05). Tumor signal-to-noise ratio (SNR) decreased significantly following intratumoral injection and intra-arterial infusion of labeled spores (P <.05). Prussian blue and gram staining confirmed spore delivery.ConclusionsC. novyi-NT spores can be internally labeled with iron oxide nanoparticles to visualize distribution with MR imaging during locoregional bacteriolytic therapy involving direct injection or intra-arterial transcatheter infusion. 相似文献
7.
《Vaccine》2019,37(31):4302-4309
Influenza A virus (IAV) vaccines in pigs generally provide homosubtypic protection but fail to prevent heterologous infections. In this pilot study, the efficacy of an intradermal pDNA vaccine composed of conserved SLA class I and class II T cell epitopes (EPITOPE) against a homosubtypic challenge was compared to an intramuscular commercial inactivated whole virus vaccine (INACT) and a heterologous prime boost approach using both vaccines. Thirty-nine IAV-free, 3-week-old pigs were randomly assigned to one of five groups including NEG-CONTROL (unvaccinated, sham-challenged), INACT-INACT-IAV (vaccinated with FluSure XP® at 4 and 7 weeks, pH1N1 challenged), EPITOPE-INACT-IAV (vaccinated with PigMatrix EDV at 4 and FluSure XP® at 7 weeks, pH1N1 challenged), EPITOPE-EPITOPE-IAV (vaccinated with PigMatrix EDV at 4 and 7 weeks, pH1N1 challenged), and a POS-CONTROL group (unvaccinated, pH1N1 challenged). The challenge was done at 9 weeks of age and pigs were necropsied at day post challenge (dpc) 5. At the time of challenge, all INACT-INACT-IAV pigs, and by dpc 5 all EPITOPE-INACT-IAV pigs were IAV seropositive. IFNγ secreting cells, recognizing vaccine epitope-specific peptides and pH1N1 challenge virus were highest in the EPITOPE-INACT-IAV pigs at challenge. Macroscopic lung lesion scores were reduced in all EPITOPE-INACT-IAV pigs while INACT-INACT-IAV pigs exhibited a bimodal distribution of low and high scores akin to naïve challenged animals. No IAV antigen in lung tissues was detected at necropsy in the EPITOPE-INACT-IAV group, which was similar to naïve unchallenged pigs and different from all other challenged groups. Results suggest that the heterologous prime boost approach using an epitope-driven DNA vaccine followed by an inactivated vaccine was effective against a homosubtypic challenge, and further exploration of this vaccine approach as a practical control measure against heterosubtypic IAV infections is warranted. 相似文献
8.
《Vaccine》2019,37(44):6696-6706
Live attenuated viral vaccine/vector candidates are inherently unstable and infectivity titer losses can readily occur without defining appropriate formulations, storage conditions and clinical handling practices. During initial process development of a candidate vaccine against HIV-1 using a recombinant Human Cytomegalovirus vector (rHCMV-1), large vector titer losses were observed after storage at 4 °C and after undergoing freeze-thaw. Thus, the goal of this work was to develop candidate frozen liquid formulations of rHCMV-1 with improved freeze-thaw and short-term liquid stability for potential use in early clinical trials. To this end, a virus stability screening protocol was developed including use of a rapid, in vitro cell-based immunofluorescence focus assay to quantitate viral titers. A library of ∼50 pharmaceutical excipients (from various known classes of additives) were evaluated for their effect on vector stability after freeze-thaw cycling or incubation at 4 °C for several days. Certain additives including sugars and polymers (e.g., trehalose, sucrose, sorbitol, hydrolyzed gelatin, dextran 40) as well as removal of NaCl (lower ionic strength) protected rHCMV-1 against freeze-thaw mediated losses in viral titers. Optimized solution conditions (e.g., solution pH, buffers and sugar type) slowed the rate of rHCMV-1 titer losses in the liquid state at 4 °C. After evaluating various excipient combinations, three new candidate formulations were designed and rHCMV-1 stability was benchmarked against both the currently-used and a previously reported formulation. The new candidate formulations were significantly more stable in terms of reducing rHCMV-1 titer losses after 5 freeze-thaw cycles or incubation at 4 °C for 30 days. This case study highlights the utility of semi-empirical design of frozen liquid formulations of a live viral vaccine candidate, where protection against infectivity titer losses due to freeze-thaw and short-term liquid storage are sufficient to enable more rapid initiation of early clinical trials. 相似文献
9.
Iren Yeeling Wu Trygg Einar Nikolaisen Nataša Škalko-Basnet Massimiliano Pio di Cagno 《Journal of pharmaceutical sciences》2019,108(8):2570-2579
Systemic administration of drugs is ineffective in the treatment of central nervous system disorders because of the blood-brain barrier. Nasal administration has been suggested as an alternative administration route as drugs absorbed in the olfactory epithelium bypass the blood-brain barrier and reach the brain within minutes. However, the nasal mucosa properties (e.g., tonicity, pH) are not constant because of physiological and environmental factors, and this might limit the therapeutic outcome of nanocarrier-based formulations. To shine light on the impact of environmental ionic strength on nanocarrier-based formulations, we have studied how liposomal formulations respond to the change of tonicity of the external environment. Large unilamellar vesicles loaded with 6 different drugs were exposed to different hypotonic environments, creating an osmotic gradient within the inner core and external environment of the liposomes up to 650 mOsm/kg. Both size and polydispersity of liposomes were significantly affected by tonicity changes. Moreover, the release kinetics of hydrophilic and lipophilic drugs were largely enhanced by hypotonic environments. These results clearly demonstrate that the environmental ionic strength has an impact on liposomal formulation stability and drug release kinetics and it should be considered when liposomal formulations for nose-to-brain targeted drug delivery are designed. 相似文献
10.
目的:探讨不同剂量磷酸肌酸钠对儿童病毒性心肌炎T淋巴细胞亚群及血清炎症因子的影响。方法:选取我院2016年5月至2017年4月收治的90例病毒性心肌炎患儿,随机分为高剂量组、中剂量组和低剂量组各30例;选取30例同期在我院体检健康儿童作为对照组。高剂量组、中剂量组和低剂量组分别采用1.5 g、1.3 g和1.0 g磷酸肌酸钠静脉滴注,每日1次,疗程2~3周,治疗14 d后比较三组患儿的临床疗效、T淋巴细胞亚群及血清炎症因子水平。结果:高剂量组总有效率为96.67%,中剂量组的总有效率为90.00%,高于低剂量组的76.67%(P<0.05);高、中、低三个剂量组患儿治疗后的T淋巴细胞亚群及血清炎症因子水平改善情况均高于治疗前(P<0.05)。治疗后,三组患儿CD4+、CD8+、IL-6、IL-8、TNF-α水平比较差异有统计学意义(P均<0.05)。高剂量组、中剂量组患儿的T淋巴细胞亚群水平高于低剂量组(P<0.05);高剂量组、中剂量组患儿的IL-6、IL-8和TNF-α等血清炎症因子水平高于低剂量组(P<0.05)。结论:磷酸肌酸钠对病毒性心肌炎患儿T淋巴细胞亚群及血清炎症因子水平的影响与治疗剂量呈正相关关系且具有良好的安全性。 相似文献