替考拉宁在中国成人患者中的群体药动学研究

目的建立中国成年患者的替考拉宁(teicoplanin,TEC)群体药动学(population pharmacokinetics,PPK)模型,考察TEC药动学参数的影响因素。方法前瞻性收集139例革兰阳性球菌感染患者静脉注射TEC后的222份常规监测血药浓度和相关信息,采用一级消除的一室模型进行数据拟合,并应用非线性混合效应模型(nonlinear mixed effect model,NONMEM)程序建立PPK模型。采用Bootstrap、正态预测分布误差法(normalized predictive distribution error,NPDE)进行最终模型评价。利用蒙特卡洛模拟法对给药方案进行优化。结果确定了肌酐清除率(creatinine clearance,CLcr)、白蛋白(albumin,ALB)为影响TEC清除率的主要因素。最终模型为:CL(L·h^-1)=1.24×(CLcr/77)0.564×31/ALB;V(L)=69.2。验证表明,模型稳定、有效,且有较好的预测效能。对于不同ALB和CLcr的多数患者起始负荷剂量400 mg/q12h,iv,3次,维持剂量400~800 mg·d^-1的给药方案可达有效治疗谷浓度。严重感染者需调整负荷剂量至800 mg/q12h,iv,3次,维持剂量400~800 mg·d^-1的给药方案来确保血药浓度达到15 mg·L^-1以上。结论本实验报道了CLcr、ALB对TEC清除率有显著影响,所建模型对TEC在中国成人患者中实现个体化给药具有重要应用价值。     

REFUGE Challenge: A unified framework for evaluating automated methods for glaucoma assessment from fundus photographs

Glaucoma is one of the leading causes of irreversible but preventable blindness in working age populations. Color fundus photography (CFP) is the most cost-effective imaging modality to screen for retinal disorders. However, its application to glaucoma has been limited to the computation of a few related biomarkers such as the vertical cup-to-disc ratio. Deep learning approaches, although widely applied for medical image analysis, have not been extensively used for glaucoma assessment due to the limited size of the available data sets. Furthermore, the lack of a standardize benchmark strategy makes difficult to compare existing methods in a uniform way. In order to overcome these issues we set up the Retinal Fundus Glaucoma Challenge, REFUGE (https://refuge.grand-challenge.org), held in conjunction with MICCAI 2018. The challenge consisted of two primary tasks, namely optic disc/cup segmentation and glaucoma classification. As part of REFUGE, we have publicly released a data set of 1200 fundus images with ground truth segmentations and clinical glaucoma labels, currently the largest existing one. We have also built an evaluation framework to ease and ensure fairness in the comparison of different models, encouraging the development of novel techniques in the field. 12 teams qualified and participated in the online challenge. This paper summarizes their methods and analyzes their corresponding results. In particular, we observed that two of the top-ranked teams outperformed two human experts in the glaucoma classification task. Furthermore, the segmentation results were in general consistent with the ground truth annotations, with complementary outcomes that can be further exploited by ensembling the results.     

Multiple pipeline embolization devices improves aneurysm occlusion without increasing morbidity: A single center experience of 140 cases

IntroductionRates of aneurysm occlusion with the pipeline embolization device (PED) has varied widely in the literature from 55.7% to 93.3% at 6 months, which may reflect a difference in technique including sizing and number of devices used.Methods140 cases at our institution were retrospectively reviewed, and aneurysms treated with a single PED vs. multiple were compared.ResultsComplete aneurysm occlusion was achieved in 86.9% at 6 months, 91.8% at 1 year, and 97.6% at longest follow-up. Retreatment with an additional device was required in 7 (5.1%). Major and minor complication rate within 30 days was 1.4% and 5.0%, and at greater than 30 days was 0.8% and 3.1%.Patients treated with multiple PEDs had significantly higher rates of aneurysm occlusion at 6 months (92.9% vs. 75.6%, p = 0.017) and 12 months (98.4% vs. 81.1%, p = 0.014), with no difference in complications. The two groups were similar aside from a higher number of ophthalmic and paraophthalmic aneurysms treated with multiple PEDs (23.4% vs. 6.5%, p = 0.004; and 35.1% vs. 17.4%, p = 0.020), and more posterior communicating artery and recurrent aneurysms treated with a single PED (28.3% vs. 3.2%, p = 0.001; 23.9% vs. 8.5%, p = 0.031). The use of multiple PEDs was found to be an independent predictor of aneurysm occlusion in a multivariate analysis (p = 0.015).ConclusionsThe use of multiple PEDs for intracranial aneurysms leads to significantly higher occlusion rates without added morbidity. This benefit is particularly appropriate for ophthalmic segment aneurysms, while more distal segments with eloquent perforating branches should be managed with caution.     

个体化假体复合组织工程技术修复兔下颌骨缺损

目的研究快速成型（RP）技术辅助下制作的个体化假体复合珊瑚羟基磷灰石（CHA）、重组人骨形成蛋白2（rhBMP-2）修复兔下颌骨缺损的成骨效果。 方法以27只新西兰大白兔为实验对象，随机数字表法平均分成3组（每组9只），全部建立下颌骨连续性缺损模型，并在兔下颌骨缺损区分别植入个体化假体+自体骨（A组）、个体化假体+CHA（B组）、个体化假体+CHA+rhBMP-2（C组）。分别于术后4、12、24周3个时间点处死动物取材，进行大体标本观察，以及骨钙素（OC）、Ⅰ型胶原（COL-1）的免疫组化观察，分别比较各组修复骨缺损的能力，并对实验数据进行重复测量设计资料的单因素方差分析。 结果术后24周各组实验兔外形均对称，通过OC及COL-1的吸光度检测，骨缺损区均有大量新骨形成，A组（0.537 ± 0.010）、C组（0.530 ± 0.010）可见大量骨小梁及编织骨结构，缺损区的新骨OC、COL-1的免疫组化观察基本一致，差异无统计学意义（t = 0.007，P>0.05）；但A组强于B组（0.415 ± 0.009，t = 0.122，P<0.001）；C组也强于B组（t = 0.121，P<0.001），差异均有统计学意义。 结论在兔下颌骨缺损修复中，通过RP技术和组织工程技术相结合，CHA复合rhBMP-2后成骨能力明显增强，成骨效能肯定，为后期的临床应用提供可靠的实验基础。     

自发性高血压大鼠永久性脑缺血模型建立的研究

目的在比较自发性高血压大鼠(SHR)与同龄无高血压Wistar大鼠永久性大脑中动脉阻塞(pMCAO)后脑缺血损伤情况并初步分析其可能机制。方法雄性SHR和Wistar大鼠各30只分别随机分为:pMCAO模型6 h组、假手术6 h组、pMCAO模型24 h组、假手术24 h组和正常组(均n=6)。采用线栓法制作pMCAO模型,术后6、24 h对大鼠进行神经功能学评分后处死,制作脑冠状切片。术后6 h处死大鼠脑部切片行尼氏染色后在组织学层面上观察神经元损伤情况;术后24 h处死大鼠脑部切片行尼氏染色后计算脑梗死体积和水肿程度百分比。正常组脑部切片经苏木精-伊红染色后计算脑部小血管壁/腔比。结果术后6和24 h,不同品系大鼠神经功能学评分差异无统计学意义(P0.05);术后6 h尼氏染色示SHR神经元损伤重于Wistar大鼠。术后24 h SHR脑梗死体积百分比[(28.05±2.38)%]大于Wistar大鼠[(25.23±1.33)%],差异有统计学意义(P0.05)。两品系大鼠之间脑水肿程度差异无显著性。脑部小血管壁/腔比SHR[(11.46±3.74)%]较Wistar大鼠[(8.73±1.73)%]增大(P0.05)。结论 pMCAO术后SHR的脑缺血损伤程度重于Wistar大鼠,可能与高血压引起的脑侧支循环血管壁增厚、僵硬,自我调节能力降低有关。     

Celastrol inhibits microglial pyroptosis and attenuates inflammatory reaction in acute spinal cord injury rats

Pyroptosis pathway is closely related to inflammation. However, Celastrol effect on pyroptosis pathway after spinal cord injury (SCI) are poorly understood. We studied the anti-inflammatory and neuroprotective effects of Celastrol on acute spinal cord injury in rats, and its anti-inflammatory effects on lipopolysaccharide (LPS)/ATP-induced microgliosis. Our results show that Celastrol can improve the recovery of hindlimb motor function after SCI in Sprague-Dawley (SD) rats, and reduce the cavity area of spinal cord injury along with the neuronal loss. Celastrol simultaneously reduced the activation of microglia (especially M1 microglia) in the spinal cord, inhibited the pyroptosis-related proteins (NLRP3 ASC Caspase-1 GSDMD), reduced the release of TNF-α IL-1β and IL-18 inflammatory factors, and increased the release of IL10 cytokines. In vitro studies showed that Celastrol reduced the toxicity resulting from the administration of LPS with ATP to BV-2 cells, inhibited the pyroptosis-related proteins (NLRP3 Caspase-1 GSDMD), and inhibited the release of corresponding inflammatory factors. Finally, Celastrol can inhibit the expression of NFκB/p-p65 in vitro and in vivo. Our results show that Celastrol can attenuate the inflammatory response of the spinal cord after SCI, which is associated with inhibition of microglial activation and pyroptosis pathway. Further study to explore the use of Celastrol to treat SCI is warranted.     

Effect of corneal stromal pocket irrigation in small-incision lenticule extraction

ObjectivesTo investigate the effect of corneal stromal pocket irrigation after small-incision lenticule extraction (SMILE) on visual acuity, intraocular pressure (IOP), corneal parameters and complications after surgery.MethodsA total of 242 eyes of 121 patients undergoing SMILE were enrolled in this prospective controlled study, and it was designed for one eye to randomly undergo SMILE with balanced salt solution irrigation of the corneal stromal pocket, while the other eye was not. The uncorrected distance visual acuity (UDVA) and slit lamp examination were recorded at 1 hour, 1 day, 1 week, and 1 month. Postoperative corneal density, corneal biomechanical, corneal endothelial cell number, and anterior OCT images were compared at 1 day, 1 week, and 1 month.ResultsCompared with the nonirrigation group, the irrigation group showed significantly higher UDVA at 1 day postoperatively (P < 0.05), but there was no significant difference during the rest of the postoperative period (1 hour, 1 week, and 1 month). In addition, no significant differences were found in IOP, corneal density, corneal biomechanics, corneal endothelial cells, and corneal morphology. No visual decline or severe postoperative complications were found in the patients in this study.ConclusionsInterlamellar irrigation did not affect IOP, corneal parameters, morphology, complications, or UDVA at 1 hour, 1 week, and 1 month after the operation, but it may promote UDVA 1 day after the operation.Subject terms: Refractive errors, Outcomes research, Surgery     

Factors Affecting Recurrent Deep Vein Thrombosis after Pharmacomechanical Thrombolysis and Left Iliac Vein Stent Placement in Patients with Iliac Vein Compression Syndrome

PurposeThis study evaluated the factors affecting contralateral and ipsilateral recurrent deep vein thrombosis (DVT) after iliac vein stent placement in patients with iliac vein compression syndrome (IVCS).Materials and MethodsData from 130 patients (95 female patients) who underwent catheter-directed thrombolysis and stent placement for IVCS with left lower leg thrombosis at a single institution were retrospectively analyzed. Mean patient age was 69.0 ± 14.0 years old. Median follow-up was 14 months (range, 3–164 months). Anticoagulation therapy was prescribed for 6 months, followed by lifelong antiplatelet therapy. Multivariate logistic regression analysis was performed to evaluate the factors affecting the development of contralateral and ipsilateral recurrent DVT.ResultsSeven patients (5.4%) developed contralateral DVT (median, 26 months; range, 2–61 months), and 11 patients (8.5%) developed ipsilateral DVT (median, 1 month; range, 0–53 months). Stent location (odds ratio [OR], 11.564; 95% confidence interval [CI], 1.159–115.417) and in-stent thrombosis during follow-up (OR, 15.142; 95% CI, 1.406–163.119) were predictors of recurrent contralateral DVT. Thrombophilia (OR, 47.560; 95% CI, 2.369–954.711), remaining inferior vena cava filter (OR, 30.552; 95% CI, 3.495–267.122), and in-stent thrombosis during follow-up (OR, 82.057; 95% CI, 2.915–2309.848) were predictors of ipsilateral DVT.ConclusionsContralateral DVT occurs late and is associated with extension of the iliac vein stent to the inferior vena cava and in-stent thrombosis. Ipsilateral DVT occurs relatively early and is associated with thrombophilia, remaining inferior vena cava filter, and in-stent thrombosis.     

Poor clinical outcomes and immunoevasive contexture in SIRPα+ tumor-associated macrophages enriched muscle-invasive bladder cancer patients

ObjectivesIn tumor immune microenvironment, the functions of tumor-associated macrophages (TAMs), including phagocytosis and immunomodulatory, have attracted increasing attention recently. With the discovery of CD47–signal regulatory protein-α (SIRPα) as “don't eat me” signaling pathway, the role of novel subpopulation of TAMs expressing SIRPα has not been fully elucidated in a wide spectrum of solid tumors including bladder cancer. In this study, we investigated the prognostic and predictive implication of SIRPα⁺ TAMs regarding clinical outcomes and adjuvant chemotherapeutic benefit in muscle-invasive bladder cancer (MIBC), and preliminarily characterized the phenotypic features of SIRPα⁺ TAMs and its relationship with immune contexture.Materials and methodsA total of 141 histochemical MIBC samples from Zhongshan Hospital (ZS), 45 fresh tissue samples, and 391 MIBC patients from TCGA database were enrolled in this study. SIRPα⁺ TAMs was evaluated by immunohistochemical staining of CD68 and SIRPα, and flow cytometry fluorescence staining.ResultsOur results illustrated that SIRPα⁺ TAMs were enriched in MIBC specimens. Patients with high SIRPα⁺ TAMs infiltration suffered significant poor overall survival and recurrence-free survival (P = 0.0030 and P = 0.0282). SIRPα⁺ TAMs infiltration was an independent prognosticator in multivariate Cox model. Moreover, adjuvant chemotherapy (ACT) application showed significantly survival benefit in patients with low SIRPα⁺ TAMs infiltration (P = 0.0135). SIRPα⁺ TAMs with suppressive phenotype exhibited a positive correlation with immune tolerance and dysfunctional CD8⁺ T cells in MIBC.ConclusionsSIRPα⁺ TAMs infiltration indicated poor prognosis and ACT resistance in MIBC. Immunosuppressive SIRPα⁺ TAMs is closely related to immune evasion with exhausted T cells states, suggesting the prospect of SIRPα⁺ TAMs as a potential therapeutic target in MIBC.