MedNexus
2023年 · 第136卷第19期
出版日期 2023-10-05电子版 ￥0.00元
MedNexus
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- Review Article
- Meta Analysis
- Original Article
- Clinical Observation
- Correspondence
Review Article
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心血管疾病中的肠道微生物群和微生物群衍生代谢物Xiaofeng Chen, Hua Zhang, Sichong Ren, Yangnan Ding, Naznin Sultana Remex, Md. Shenuarin Bhuiyan, Jiahua Qu, Xiaoqiang Tang
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002206
摘要
Cardiovascular diseases, including heart failure, coronary artery disease, atherosclerosis, aneurysm, thrombosis, and hypertension, are a great economic burden and threat to human health and are the major cause of death worldwide. Recently, researchers have begun to appreciate the role of microbial ecosystems within the human body in contributing to metabolic and cardiovascular disorders. Accumulating evidence has demonstrated that the gut microbiota is closely associated with the occurrence and development of cardiovascular diseases. The gut microbiota functions as an endocrine organ that secretes bioactive metabolites that participate in the maintenance of cardiovascular homeostasis, and their dysfunction can directly influence the progression of cardiovascular disease. This review summarizes the current literature demonstrating the role of the gut microbiota in the development of cardiovascular diseases. We also highlight the mechanism by which well-documented gut microbiota-derived metabolites, especially trimethylamine N-oxide, short-chain fatty acids, and phenylacetylglutamine, promote or inhibit the pathogenesis of cardiovascular diseases. We also discuss the therapeutic potential of altering the gut microbiota and microbiota-derived metabolites to improve or prevent cardiovascular diseases.
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嵌合抗原受体-T细胞治疗恶性血液病的临床进展Zhihuan Yang, Ying Wang
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002549
摘要
Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development. Chimeric antigen receptor (CAR)-T cell therapy is the most widely applied cellular therapy. Since the Food and Drug Administration approved two CD19-CAR-T products for clinical treatment of relapsed/refractory acute lymphoblastic leukemia and diffuse large B cell lymphoma in 2017, five more CAR-T cell products were subsequently approved for treating multiple myeloma or B cell malignancies. Moreover, clinical trials of CAR-T cell therapy for treating other hematological malignancies are ongoing. Both China and the United States have contributed significantly to the development of clinical trials. However, CAR-T cell therapy has many limitations such as a high relapse rate, adverse side effects, and restricted availability. Various methods are being implemented in clinical trials to address these issues, some of which have demonstrated promising breakthroughs. This review summarizes developments in CAR-T cell trials and advances in CAR-T cell therapy.
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JAK-STAT信号通路在原发性干燥综合征发病和治疗中的作用Mucong Li, Mengtao Li, Lin Qiao, Chanyuan Wu, Dong Xu, Yan Zhao, Xiaofeng Zeng
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002539
摘要
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with high prevalence and possible poor prognosis. Though the pathogenesis of pSS has not been fully elucidated, B cell hyperactivity is considered as one of the fundamental abnormalities in pSS patients. It has long been identified that Janus kinases-signal transducer and activator of transcription (JAK-STAT) signaling pathway contributes to rheumatoid arthritis and systemic lupus erythematosus. Recently, increasing numbers of studies have provided evidence that JAK-STAT pathway also has an important role in the pathogenesis of pSS via direct or indirect activation of B cells. Signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activated by various cytokines and ribonucleic acid contribute to pSS development, respectively or synergically. These results reveal the potential application of Janus kinase inhibitors for treatment of pSS, which may fundamentally improve the quality of life and prognosis of patients with pSS.
Meta Analysis
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妊娠期低环境温度与不良分娩结局的关系：一项系统综述和荟萃分析Tiechao Ruan, Yan Yue, Wenting Lu, Ruixi Zhou, Tao Xiong, Yin Jiang, Junjie Ying, Jun Tang, Jing Shi, Hua Wang 等
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002361
摘要
Background:
Extreme temperature events, including extreme cold, are becoming more frequent worldwide, which might be harmful to pregnant women and cause adverse birth outcomes. We aimed to investigate the association between exposure to low ambient temperature in pregnant women and adverse birth outcomes, such as preterm birth, low birth weight, and stillbirth, and to summarize the evidence herein.
Methods:
Relevant studies were searched in PubMed, Cochrane, and Embase electronic databases until November 2021. Studies involving low ambient temperature, preterm birth, birth weight, and stillbirth were included. The guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses were followed to conduct this study risk of bias and methods for data synthesis.
Results:
A total of 34 studies were included. First, pregnant women exposed to low ambient temperature had an increased risk of preterm birth (risk ratio [RR] 1.08; 95% confidence interval [CI] 1.04–1.13). Subgroup analyses revealed that exposure during late pregnancy was more likely to induce preterm birth. In addition, only pregnant women exposed to <1st percentile of the mean temperature suffered increased risk of preterm birth. Moreover, pregnant women living in medium or hot areas were more prone to have preterm births than those in cold areas when exposed to low ambient temperatures. Asians and Blacks were more susceptible to low ambient temperatures than Caucasians. Second, pregnant women exposed to low ambient temperature had an increased risk of low birth weight (RR 1.07; 95% CI 1.03–1.12). Third, pregnant women had an increased risk of stillbirth while exposed to low ambient temperature during the entire pregnancy (RR 4.63; 95% CI 3.99–5.38).
Conclusions:
Exposure to low ambient temperature during pregnancy increases the risk of adverse birth outcomes. Pregnant women should avoid exposure to extremely low ambient temperature (<1st percentile of the mean temperature), especially in their late pregnancy. This study could provide clues for preventing adverse outcomes from meteorological factors.
Registration:
No. CRD42021259776 at PROSPERO (https://www.crd.york.ac.uk/PROSPERO/).
Original Article
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中国成年人新鲜水果消费与慢性阻塞性肺疾病相关住院和死亡风险的关系：一项前瞻性队列研究Xin Huang, Jiachen Li, Weihua Cao, Jun Lyu, Yu Guo, Pei Pei, Qingmei Xia, Huaidong Du, Yiping Chen, Yang Ling 等
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002591
摘要
Background:
Existing evidence suggests that fruit consumption is a significant influencing factor for chronic obstructive pulmonary disease (COPD), but this is unclear in the Chinese population. We examined the association of fresh fruit consumption with the risk of COPD-related hospitalization and death in a nationwide, population-based prospective cohort from China.
Methods:
Between 2004 and 2008, the China Kadoorie Biobank recruited >0.5 million adults aged 30 to 79 years from ten diverse regions across China. After excluding individuals diagnosed with major chronic diseases and prevalent COPD, the prospective analysis included 421,428 participants. Cox regression was used to calculate the hazard ratios (HRs) for the association between fresh fruit consumption and risk of COPD-related hospitalization and death, with adjustment for established and potential confounders.
Results:
During a mean follow-up of 10.9 years, 11,292 COPD hospitalization events and deaths were documented, with an overall incidence rate of 2.47/1000 person-years. Participants who consumed fresh fruit daily had a 22% lower risk of COPD-related hospitalization and death compared with non-consumers (HR= 0.78, 95% confidence interval [CI]: 0.71–0.87). The inverse association between fresh fruit consumption and COPD-related hospitalization and death was stronger among non-current smokers and participants with normal body mass index (BMI) (18.5 kg/m2 ≤ BMI < 24.0 kg/m2); the corresponding HRs for daily fresh fruit consumption were 0.78 (95% CI: 0.68–0.89) and 0.69 (95% CI: 0.59–0.79) compared with their counterparts, respectively.
Conclusions:
High-frequency fruit consumption was associated with a lower risk of COPD in Chinese adults. Increasing fruit consumption, together with cigarette cessation and weight control, should be considered in the prevention and management of COPD.
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冠状病毒疾病2019疫苗接种后稳定型类风湿性关节炎患者的发作和疾病活动性变化：一项前瞻性中国队列研究Yan Geng, Yong Fan, Yu Wang, Xuerong Deng, Lanlan Ji, Xiaohui Zhang, Zhibo Song, Hong Huang, Yanni Gui, Haoze Zhang 等
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002562
摘要
Background:
Vaccination has been shown effective in controlling the global coronavirus disease 2019 (COVID-19) pandemic and reducing severe cases. This study was to assess the flare and change in disease activity after COVID-19 vaccination in patients with stable rheumatoid arthritis (RA).
Methods:
A prospective cohort of RA patients in remission or with low disease activity was divided into a vaccination group and a non-vaccination group based on their COVID-19 vaccination status. Each of them was examined every 3 to 6 months. In the vaccination group, disease activity was compared before and after vaccination. The rates of flare defined as disease activity scores based on 28-joint count (DAS28) >3.2 with ΔDAS28 ≥0.6 were compared between vaccination and non-vaccination groups.
Results:
A total of 202 eligible RA patients were enrolled. Of these, 98 patients received no vaccine shot (non-vaccination group), and 104 patients received two doses of vaccine (vaccination group). The median time interval from pre-vaccination visit to the first immunization and from the second dose of vaccine to post-vaccination visit was 67 days and 83 days, respectively. The disease activity scores at pre-vaccination and post-vaccination visits in the vaccination group patients were similar. At enrollment, gender, RA disease course, seropositivity, and disease activity were comparable across the two groups. Flare was observed in five (4.8%) of the vaccination group patients and nine (9.2%) of the non-vaccination group patients at post-vaccination assessment (P = 0.221). In terms of safety, 29 (27.9%) patients experienced adverse events (AEs) after vaccination. No serious AEs occurred.
Conclusions:
COVID-19 vaccinations had no significant effect on disease activity or risk of flare in RA patients in remission or with low disease activity. Patients with stable RA should be encouraged to receive the COVID-19 vaccination.
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老年非心脏手术后患者术中体温与出现谵妄：一项前瞻性观察性研究的二次分析Guojun Wang, Shuting He, Mengyao Yu, Yan Zhang, Dongliang Mu, Dongxin Wang
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002375
摘要
Background:
Emergence delirium (ED) is a kind of delirium that occured in the immediate post-anesthesia period. Lower body temperature on post-anesthesia care unit (PACU) admission was an independent risk factor of ED. The present study was designed to investigate the association between intraoperative body temperature and ED in elderly patients undergoing non-cardiac surgery.
Methods:
This study was a secondary analysis of a prospective observational study. Taking baseline body temperature as a reference, intraoperative absolute and relative temperature changes were calculated. The relative change was defined as the amplitude between intraoperative lowest/highest temperature and baseline reference. ED was assessed with the confusion assessment method for intensive care unit at 10 and 30 min after PACU admission and before PACU discharge.
Results:
A total of 874 patients were analyzed with a mean age of 71.8 ± 5.3 years. The incidence of ED was 38.4% (336/874). When taking 36.0°C, 35.5°C, and 35.0°C as thresholds, the incidences of absolute hypothermia were 76.7% (670/874), 38.4% (336/874), and 17.5% (153/874), respectively. In multivariable logistic regression analysis, absolute hypothermia (lowest value <35.5°C) and its cumulative duration were respectively associated with an increased risk of ED after adjusting for confounders including age, education, preoperative mild cognitive impairment, American Society of Anesthesiologists grade, duration of surgery, site of surgery, and pain intensity. Relative hypothermia (decrement >1.0°C from baseline) and its cumulative duration were also associated with an increased risk of ED, respectively. When taking the relative increment >0.5°C as a threshold, the incidence of relative hyperthermia was 21.7% (190/874) and it was associated with a decreased risk of ED after adjusting above confounders.
Conclusions:
In the present study, we found that intraoperative hypothermia, defined as either absolute or relative hypothermia, was associated with an increased risk of ED in elderly patients after non-cardiac surgery. Relative hyperthermia, but not absolute hyperthermia, was associated with a decreased risk of ED.
Registration:
Chinese Clinical Trial Registry (No. ChiCTR-OOC-17012734).
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lncRNA TUG1通过竞争性抑制miR-29b调节Smac/DIABLO表达并调节年龄相关性白内障晶状体上皮细胞凋亡Miaomiao Sun, Ke Li, Xiao Li, Huajun Wang, Li Li, Guangying Zheng
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002530
摘要
Background:
As one of the early discovered long non-coding RNAs (lncRNA), taurine upregulation gene 1 (TUG1) has been widely expressed in a variety of tumors. Moreover, it promotes cell proliferation, differentiation, apoptosis, and migration. However, our understanding of its importance in the pathogenesis of cataracts remains limited. This study aimed to explore the mechanism by which lncRNA TUG1 mediates lens epithelial cell apoptosis in age-related cataracts (ARC) by regulating the microRNAs (miR-29b)/second mitochondria-derived activator of caspases axis, and to identify more non-surgical strategies for cataract treatment.
Methods:
The messenger RNA expression levels of TUG1, miR-29b, and Smac were detected using quantitative real-time polymerase chain reaction in vivo and in vitro. The expression of the Smac protein was analyzed by Western blotting and immunofluorescence. Flow cytometry and cell counting kit-8 assays were used to detect the cell apoptosis and proliferation rates, respectively. The targeted regulatory relationship between lncRNA TUG1, miR-29b, and Smac was verified by viral vector construction, co-transfection, nuclear and cytoplasmic separation, luciferase reporter assays, and RNA immunoprecipitation.
Results:
TUG1 and Smac were expressed at high levels in ARC and HLE-B3 cells treated with 200 μmol/L H2O2, whereas miR-29b expression was decreased. In vitro cell experiments confirmed that down-regulation of TUG1 could inhibit the apoptosis of lens epithelial cells. Mechanistically, Smac expression was negatively regulated by miR-29b. TUG1 competitively inhibited miR-29b expression and caused greater release of Smac. In addition, miR-29b partially reversed the effects of TUG1 on human lens epithelial cell line cells.
Conclusions:
lncRNA TUG1 increases Smac expression and promotes apoptosis of lens epithelial cells in ARC by competitively inhibiting miR-29b. This mechanism is the cytological basis for ARC formation. Based on these results, the lncRNA TUG1/miR29b/Smac axis may be a new molecular pathway that regulates ARC development.
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长非编码RNA结肠癌相关转录物1-波形蛋白轴促进HeLa细胞的迁移和侵袭Zhangfu Li, Jiangbei Yuan, Qingen Da, Zilong Yan, Jianhua Qu, Dan Li, Xu Liu, Qimin Zhan, Jikui Liu
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002373
摘要
Background:
Long non-coding RNA colon cancer-associated transcript 1 (CCAT1) is involved in transforming multiple cancers into malignant cancer types. Previous studies underlining the mechanisms of the functions of CCAT1 primarily focused on its decoy for miRNAs (micro RNAs). However, the regulatory mechanism of CCAT1–protein interaction associated with tumor metastasis is still largely unknown. The present study aimed to identify proteome-wide CCAT1 partners and explored the CCAT1–protein interaction mediated tumor metastasis.
Methods:
CCAT1–proteins complexes were purified and identified using RNA antisense purification coupled with the mass spectrometry (RAP-MS) method. The database for annotation, visualization, and integrated discovery and database for eukaryotic RNA binding proteins (EuRBPDB) websites were used to bioinformatic analyzing CCAT1 binding proteins. RNA pull-down and RNA immunoprecipitation were used to validate CCAT1–Vimentin interaction. Transwell assay was used to evaluate the migration and invasion abilities of HeLa cells.
Results:
RAP-MS method worked well by culturing cells with nucleoside analog 4-thiouridine, and cross-linking was performed using 365 nm wavelength ultraviolet. There were 631 proteins identified, out of which about 60% were RNA binding proteins recorded by the EuRBPDB database. Vimentin was one of the CCAT1 binding proteins and participated in the tumor metastasis pathway. Knocked down vimetin (VIM) and rescued the downregulation by overexpressing CCAT1 demonstrated that CCAT1 could enhance tumor migration and invasion abilities by stabilizing Vimentin protein.
Conclusion:
CCAT1 may bind with and stabilize Vimentin protein, thus enhancing cancer cell migration and invasion abilities.
Clinical Observation
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病毒载量对替诺福韦的影响vs.恩替卡韦预防乙型肝炎病毒相关性肝细胞癌复发的疗效观察Weili Qi, Junyi Shen, Yu Zhang, Fengwei Gao, Chuan Li
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002433
摘要
血清乙型肝炎病毒脱氧核糖核酸（HBV-DNA）载量是用于反映肝细胞中病毒复制程度和评价宿主肝炎病毒状态的关键指标。肝细胞癌（HCC）发病率或复发的风险因HBV-DNA载量是高还是低而异。[
Correspondence
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中国白癜风患者负担的在线调查Abdulrahman Amer, Yan Wu, Chunying Li, Juan Du, Hong Jia, Shanshan Li, Caixia Tu, Qiang Li, Hongxia Liu, Junling Zhang 等
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002429
摘要
致编辑：白癜风是一种慢性疾病，影响患者生活的许多方面。白癜风的患病率一直在增加，目前涉及全球所有种族的0.5%至2%。[
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丁酸作为G蛋白偶联受体配体，通过蛋白激酶B/糖原合酶激酶-3 β途径阻止高糖诱导的N2a细胞淀粉样变性Yujie Xu, Shufang Shan, Xiaoyu Wang, Lingli Li, Liang Ma, Jingyuan Xiong, Ping Fu, Guo Cheng
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002541
摘要
致编辑：阿尔茨海默病（AD）和2型糖尿病（T2DM）是老年人发病和死亡的主要原因，它们的流行病学联系给这些毁灭性疾病的管理带来了巨大的挑战。糖代谢异常，伴随蛋白激酶B（Akt）/糖原合酶激酶-3 β（GSK-3 β）信号通路的抑制，是神经元细胞中淀粉样前体蛋白（APP）积累和淀粉样β（A β）形成的关键因素。[
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Expressman延长系统在复杂冠状动脉病变经皮冠状动脉介入治疗中的安全性和有效性Yanzhuo Ma, Xinxing Song, Zhiwen Li, Xiaojiang Zhang, Xiaoye Wang, Gang Wang, Yuhong Peng, Leisheng Ru
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002521
摘要
致编辑：复杂冠状动脉病变尤其是慢性完全闭塞（CTO）血运重建失败的主要原因是由于缺乏足够的引导支撑或导丝操作失败而无法输送器械，例如逆行导丝外部化失败和无法再进入真管腔。一些设备和技术已经被用于处理这些问题，导引导管延长系统（GCES）是有效的解决方案之一。目前，有五种GCES设备可商购，即Proxis、Heartrail II（Terumo，东京，日本）、GuideLiner（GL；血管解决方案，夏洛特，北卡罗来纳州，美国）、Guidezilla（GZ；波士顿科学，马尔伯勒，马萨诸塞州，美国）和Expressman扩展系统（EES；APT医疗公司，中国湖南）。据报道，GL和GZ不仅通过提供额外的备份支持，还通过容纳多种器械和促进器械交付来实现手术成功。[
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柴油机尾气颗粒促进哮喘的理论和观察机制Yuan Gao, Yan Zhou, Xinjia Zhou, Rui Zheng
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002592
摘要
致编辑：柴油机排气颗粒（DEPs）促进哮喘的气道炎症，但DEPs影响哮喘发作和恶化的机制是复杂的。标准DEP已用于许多关于DEP和哮喘的毒理学研究。然而，最近的研究表明，标准DEP不适合代表与交通相关的排放。再生DEPs和真实世界DEPs对哮喘的影响尚未得到充分研究，迫切需要更多的研究。
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放射性标记成纤维细胞活化蛋白抑制剂评价心肌纤维化Xiangyu Su, Yiheng Zhao, Xiang Zhou
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002590
摘要
致编辑：心肌纤维化是心力衰竭（HF）常见的病理过程。无创诊断心肌纤维化的方法有限。目前，作为确定纤维化病变的金标准的心脏磁共振（CMR）能够提供高空间分辨率并验证心肌纤维化。然而，用CMR测量的细胞外体积分数在其他病理如炎性水肿或蛋白质沉积中甚至可以增加；因此，需要一种新的补充成像方式来检测心脏纤维化。
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内脏脂肪面积与体脂质量之比(VBR)是冠心病的一个较好的预测指标Binbin Zhang, Jiangshan He, Pei Guo, Jianxiong Wang, Chunjun Li, Li Zhang, Congfang Guo, Yirui Guo, Fenghua Guo, Mianzhi Zhang 等
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002601
摘要
致编辑：心血管疾病（CVD）仍然是全球发病率和死亡率的主要原因，其中冠心病（CHD）的死亡率最高。肥胖是心脏代谢并发症和心血管疾病的重要危险因素。内脏脂肪（VA）和皮下脂肪（SA）组织对心脏代谢结果的影响不同且可能相反。[
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椎间盘生成组织工程治疗平台：明胶-甲基丙烯酰水凝胶复合体系Yicun Hu, Xiaopeng Wang, Meiling Zhao, Peng Wang, Xiaobo Zhang, Haiyu Zhou, Jintao Shi, Mengxue Cong
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002434
摘要
致编辑：在中老年个体中，椎间盘（IVD）变性（IVDD）通常会导致腰痛（LBP）。IVDD机制复杂，影响因素多。退行性IVD的生物学改变主要包括髓核（NP）、纤维环（AF）和软骨终板的结构异常，以及细胞外基质（ECM）组成和数量的改变。IVDD病先保守治疗，再手术，但这些都是对症治疗，并发症发生率高。[
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不同巨细胞病毒感染状态下自身免疫性疾病患者巨细胞病毒抗原特异性T细胞免疫反应Yuting Tan, Huimin Ma, Xiaoqing Liu, Xiaochun Shi, Wenjie Zheng, Jingtao Cui, Lifan Zhang, Yaling Dou, Baotong Zhou
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002452
摘要
致编辑：自身免疫性疾病患者由于免疫功能障碍或应用糖皮质激素和免疫抑制剂，活动性巨细胞病毒（CMV）感染的风险增加。[
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采血管理对减少极早产儿输血的影响Jingjun Pei, Jun Tang, Yanling Hu, Xingli Wan, Jing Shi, Hua Wang, Qiong Chen, Xiaowen Li, Jian Chen, Chao Chen 等
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002596
摘要
致编辑：不稳定的临床状况和并发症使得早产儿不可避免地需要多次实验室检查和采血，从而导致医源性失血。毫无疑问，医源性失血与红细胞输血（RBCT）高度相关。先前一项关于极低出生体重（BW）婴儿的研究报告称，出生后第一周内的采样失血量为30.0 mL/kg，导致98%的患者出现一次或多次RBCT。[
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右美托咪定对术后认知功能障碍的影响及可能机制Huijuan He, Manhua Zhu, Yupeng Lyu, Yuan Yuan, Yong Qi
中华医学杂志英文版2023年 136卷 19期
DOI: 10.1097/CM9.0000000000002372
摘要
致编辑：术后认知功能障碍（POCD）被描述为患者神经认知状况和行为的一系列改变，发生在麻醉和手术后的几周甚至几个月内。POCD发生在20%至50%的患者中，给患者带来负担，并产生显著的社会和经济影响。[
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