Role of arterial stiffness and endothelial dysfunction on lower limb performance in older adults with type 2 diabetes: A cross-sectional study

AimTo verify whether arterial stiffness and endothelial dysfunction influence lower limb muscle strength and gait speed in older adults with type 2 diabetes mellitus (T2DM).MethodsCross-sectional study including seventy-eight older adults with T2DM (aged 67 ± 6 years and 42 % male). Arterial stiffness was assessed using pulse wave velocity (PWV), while endothelial function was measured by flow-mediated dilation (FMD). Lower limb muscle strength and gait speed were assessed using the 30-second chair stand test (30s-CST) and 10-Meter Walk Test, respectively.ResultsBoth PWV (m/s) and FMD (%) were univariately associated with number of repetitions in 30s-CST and gait speed (P < 0.05). After control for age, sex and body mass index, PWV remained associated with repetitions in 30s-CST (95 % CI: ?0.494 to ?0.054; P = 0.015) and gait speed (95 % CI: ?0.039 to ?0.002; P = 0.031). After adjustments for control variables, T2DM duration and glycemic control, FMD was associated with repetitions in 30s-CST (95 % CI: 0.008 to 0.324; P = 0.039) and gait speed (95 % CI: 0.011 to 0.038; P = 0.001).ConclusionIn older adults with T2DM, both arterial stiffness and endothelial dysfunction are associated with decreased leg muscle strength and slower gait speed.     

Prevention of alloimmune rejection using XBP1-deleted bone marrow-derived dendritic cells in heart transplantation

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治疗前外周血炎性标志物对EGFR突变阳性晚期非小细胞肺癌患者的预后价值研究

  目的  探讨治疗前外周血炎性标志物在表皮生长因子受体（epidermal growth factor receptor，EGFR）阳性晚期非小细胞肺癌（non-small cell lung cancer，NSCLC）患者中的预后作用。  方法  回顾性分析2015年1月至2018年10月中国人民解放军总医院第五医学中心142例EGFR突变阳性晚期NSCLC患者临床资料。通过受试者工作特征曲线（receiver operating characteristic curve，ROC）确定中性粒细胞与淋巴细胞计数比值（neutrophil-to-lymphocyte ratio，NLR）、血小板与淋巴细胞计数比值（platelet-to-lymphocyte ratio，PLR）、系统免疫炎症指数（systemic immune-inflammation index，SII）和淋巴细胞与单核细胞计数比值（lymphocyte-to-monocyte ratio，LMR）的最佳临界值，应用Kaplan-Meier方法进行生存分析。Cox比例风险模型评估各变量的预测价值。  结果  NLR、PLR、SII和LMR的最佳临界值分别为2.60、167.32、687.39和3.13。根据最佳临界值分别将研究对象分为高值组和低值组，高NLR、PLR和SII组的中位无进展生存期（median progression-free survival，mPFS）及中位总生存期（median overall survival，mOS）均显著低于低值组中相应值，高LMR组mPFS及mOS较低LMR组延长。  结论  治疗前升高的NLR、PLR、SII和降低的LMR可能与接受靶向治疗的EGFR突变阳性晚期NSCLC患者的不良预后相关。      

Prognosis Comparison Between Chronic Hepatitis B Patients Receiving a Finite Course of Tenofovir and Entecavir Treatment: A Nationwide Cohort Study in Taiwan

PurposeEntecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both recommended as first-line treatments for patients with chronic hepatitis B virus (CHB) infection according to international HBV treatment guidelines. However, recent studies reported conflicting results regarding the preferred antiviral in the prevention of hepatocellular carcinoma (HCC). This cohort study aimed to investigate this issue by using Taiwan's National Health Insurance Research Database, wherein a “finite” but not life-long treatment policy was applied.MethodsFrom January 2008 to December 2013, a total of 12,388 consecutive adult patients with CHB who received a finite course of TDF treatment (n = 1250) or ETV treatment (n = 11,138) were analyzed through screening for study eligibility followed by the 1:4 propensity score matching method.FindingsIn the entire cohort, the annual incidence and survival between the ETV and TDF groups were not significantly different regarding HCC occurrence (2.05 vs 2.74 per 100 patient-years [PY]; P = 0.055; hazard ratio [HR], 0.975; log-rank, P = 0.966), cirrhosis-related complications (1.9 vs 2.4 per 100 PY; P = 0.149; HR, 0.869; log-rank, P = 0.388), or all-cause mortality (2.16 vs 1.6 per 100 PY; P = 0.119; HR, 0.831; log-rank, P = 0.342), respectively. Propensity score matching analyses yielded similar results regarding HCC occurrence, cirrhosis-related complications, and all-cause mortality. In addition, these findings were consistently reproduced in the subgroups of patients with chronic hepatitis and cirrhosis that developed before antiviral treatment.ImplicationsETV and TDF did not significantly differ in prevention of HCC occurrence or reduction of cirrhosis-related complications and all-cause mortality in patients with CHB receiving a finite period of treatment.     

An Artificial Gut/Absorption Simulator: Simultaneous Evaluation of Desupersaturation and Absorption from Ketoconazole Supersaturated Solutions

For supersaturating formulations of BCS-II compounds, which by definition have high intestinal permeability, a closed USP apparatus does not provide the necessary absorptive conditions during dissolution. To address this, an artificial gut simulator (AGS) has been constructed consisting of a 2.5 mL donor compartment in which a hollow fiber-based absorption module is suspended. Drug from donor diffuses across the hollow fiber membrane to be absorbed by the continuously flowing intraluminal receiver fluid. The membrane surface area and intraluminal fluid flow rate are tuned to obtain the physiologically observed absorption rate constant for a weakly basic, poorly water-soluble model compound, ketoconazole (KTZ). Supersaturated solutions of KTZ were generated in the donor in pH 6.5 phosphate buffer by the pH-shift method in the absence (closed system, control) and presence (open system, biorelevant) of an optimally or suboptimally tuned absorption module. Drug concentrations in the donor and intraluminal fluids were determined by in-line UV spectroscopy. The presence of an absorptive sink reduced the supersaturated solution's crystallization propensity, more so in the case of the optimally tuned AGS. This study demonstrates the significance of simulating absorption of drug at a physiological rate during dissolution studies, especially to predict the performance of formulations of BCS-II drugs.     

携带同源重组修复相关基因突变的消化道肿瘤的临床特点

目的:探讨消化道肿瘤中同源重组修复相关基因(homologous recombination repair related gene，HRR)突变的发生情况及临床意义。方法:共92例消化道肿瘤患者，79例患者进行了血液标本HRR检测，53例患者进行了组织标本HRR检测，40例患者同时行血液和组织的HRR基因检测，收集患者基因检测结果及临床相关资料。结果:在79例患者血液标本检测中发现10例（12.6%）有临床意义HRR突变，在53例患者组织标本检测中发现9例（17.0%）有临床意义HRR突变。40例同时行血液和组织的HRR基因检测患者中常见的有临床意义HRR突变为CDK12突变4例（10.0%）、ATM突变3例（7.5%）、BRCA1突变2例（5.0%）。13例有临床意义HRR突变患者中常见共存突变为TP53突变10例（76.9%）、APC突变5例（38.5%）、PIK3CA突变4例（30.8%）。40例患者中13例患者血液和/或组织中有临床意义HRR突变，27例患者血液和组织中均无任何临床意义HRR突变且两组相比，有临床意义HRR突变组肿瘤突变负荷（tumor mutational burden，TMB）为6.17(2.24～11.52)，而未携带HRR突变组TMB为0.4(0～3.75)，差异有统计学意义（P＜0.05）。40例患者组织检测中7例HRR有临床意义的突变，33例无HRR突变，血液检测中10例HRR有临床意义的突变，30例无HRR突变，一致性检验的Kappa值为0.333（P=0.031）。结论:携带有临床意义HRR突变的消化道肿瘤患者TMB更高，血液和组织检测HRR突变有较好的一致性。     

Gender difference in association between diabetes mellitus and all-cause mortality in atrial fibrillation patients

ObjectiveThere may be gender difference in correlation of diabetes mellitus (DM) and cardiovascular events. We attempt to investigate whether there is gender-heterogeneity in one-year outcomes of atrial fibrillation (AF) patients with DM or not.MethodsPatients who were diagnosed with AF admitted to the emergency departments in the Chinese AF Multicenter Registry study were enrolled. Basic demographics information, initial Blood Pressure and heart rate, medical histories, and treatments of each patient were collected. Follow-up was carried out with a mean duration of one year. The primary endpoint was all-cause mortality and systemic embolism.ResultsA total of 2016 patients were selected from September 2008 and April 2011. All-cause mortality was significantly higher in male AF patients with DM than those without (21.8 % & 13.6 %, P = 0.014). Cox regression analysis showed that there was an interaction between gender and DM for one-year all-cause mortality (P = 0.049). DM was significantly associated with one-year all-cause mortality regardless of univariate analysis (HR = 1.436, 95%CI:1.079–1.911, P = 0.013) or multivariate analysis (HR = 1.418, 95%CI: 1.059–1.899, P = 0.019). For male patients with AF, DM was significantly associated with one-year all-cause mortality (P = 0.048), but not for female patients with AF (P = 0.362).ConclusionDM was independently associated with one-year all-cause mortality in the entire cohort of AF patients. This association was found mainly in male patients with AF, but not in female patients. DM management programs may need to reflect gender difference.     

Seronegative autoimmune diseases: A challenging diagnosis

Autoimmune diseases (AID) are increasingly prevalent conditions which comprise more than 100 distinct clinical entities that are responsible for a great disease burden worldwide. The early recognition of these diseases is key for preventing their complications and for tailoring proper management. In most cases, autoantibodies, regardless of their potential pathogenetic role, can be detected in the serum of patients with AID, helping clinicians in making a definitive diagnosis and allowing screening strategies for early -and sometimes pre-clinical- diagnosis. Despite their undoubted crucial role, in a minority of cases, patients with AID may not show any autoantibody, a condition that is referred to as seronegative AID. Suboptimal accuracy of the available laboratory tests, antibody absorption, immunosuppressive therapy, immunodeficiencies, antigen exhaustion, and immunosenescence are the main possible determinants of seronegative AID. Indeed, in seronegative AID, the diagnosis is more challenging and must rely on clinical features and on other available tests, often including histopathological evaluation and radiological diagnostic tests. In this review, we critically dissect, in a narrative fashion, the possible causes of seronegativity, as well as the diagnostic and management implications, in several AID including autoimmune gastritis, celiac disease, autoimmune liver disease, rheumatoid arthritis, autoimmune encephalitis, myasthenia gravis, Sjögren’s syndrome, antiphospholipid syndrome, and autoimmune thyroid diseases.