The comprehensive analysis of clinical trials registration for IgA nephropathy therapy on ClinicalTrials.gov

ObjectivesIgA Nephropathy (IgAN) is common chronic kidney disease with a high incidence. This study aims to analyze comprehensively therapeutic clinical trials for IgAN registered on ClinicalTrials.gov.MethodsTherapeutic trials for IgAN registered on ClinicalTrials.gov. up to 15 August 2021 were obtained. The general characteristics, features of experimental design, treatment strategies, and some main inclusion criteria and outcome measures were accessed.ResultsA total of 104 therapeutic clinical trials for IgAN were extracted on ClinicalTrials.gov up to 15 August 2021. Most of these trials explored the treatment for primary IgAN confirmed by renal biopsy in adults. Only 9% of all selected trials had results. Forty-five percent of trials recruited 50 or fewer participants, and 73% were adults or older adults. 99% of trials were interventional studies, and of all the interventional trials, 70% of trials were randomized, and 68% exercised a parallel assignment of intervention model. Immunosuppression was the most studied for the treatment of IgAN. Moreover, many novel agents had been increasingly studied in recent years. Furthermore, the inclusion criteria and primary outcome measures in these trials were diverse, and the level of proteinuria and change of proteinuria levels were the most used as inclusion criteria and primary outcome, respectively.ConclusionsThe majority of therapeutic trials for IgAN were randomized, none masking and parallel-assignment interventional studies, primarily recruiting adult patients as research subjects. These trials had relatively small sample sizes and short observation. Thus, more large-scale, multicenter, and randomized controlled trials are still needed to improve the management for IgAN.     

Dynamic single-molecule sensing by actively tuning binding kinetics for ultrasensitive biomarker detection

The ability to measure many single molecules simultaneously in large and complex samples is critical to the translation of single-molecule sensors for practical applications in biomarker detection. The challenges lie in the limits imposed by mass transportation and thermodynamics, resulting in long assay time and/or insufficient sensitivity. Here, we report an approach called Sensing Single Molecule under MicroManipulation (SSM³) to circumvent the above limits. In SSM³, single-molecule binding processes were dynamically recorded by surface plasmon resonance microscopy in a nanoparticle-mediated sandwich scheme. The binding kinetics between analyte and probes are fine-tuned by nanoparticle micromanipulations to promote the repetitive binding and dissociation. Quantifying the heterogeneous lifetime of each molecular complex allows the discrimination of specific binding from nonspecific background noise. By digitally counting the number of repetitive specific binding events, we demonstrate the direct detection of microRNAs and amyloid-β proteins with the limit of detection at the subfemtomolar level in buffer and spiked human serum. Together with the nanoparticle micromanipulation to promote the transportation rate of analyte molecules, the assay could be performed within as short as 15 min without the need for preincubation. The advantages over other single-molecule sensors include short assay time, compatible with common probes and ultrasensitive detection. With further improvement on the throughput and automation, we anticipate the proposed approach could find wide applications in fundamental biological research and clinical testing of disease-related biomarkers.

The analytical methods have converged from ensemble measurements of numerous entities to quantized measurements at the single-molecule level. Single-molecule measurements could reveal heterogeneities and stochastic processes within biological systems (1, 2) and set the ultimate detection limit of chemical and biological sensors. By reducing the measurement volume to a few femtoliters, the detection of a single molecule has been realized in various forms [i.e., single-molecule fluorescence (3, 4), nanopores (5, 6), localized surface plasmon resonance (7, 8), and surface-enhanced Raman scattering (9, 10)]. These measurements typically require quantifying many single-molecule events to gain new molecular and mechanistic insights or to achieve better analytical performance. However, it has been difficult to perform quantitative analysis with sufficient efficiency and statistical accuracy because of the concentration limit from mass transportation (11, 12) and the thermodynamic limit from probe affinity (13). For quantification of biomarkers in biological media, in which the required concentrations are usually at the femtomolar level or even lower (14), the single-molecule measurements could take inordinately long, and the nonspecific binding of unwanted species degrades the accuracy.In the past two decades, several single-molecule approaches for biomarker detection have been developed to surpass the above limits by biasing the equilibrium and driving binding reactions (15, 16). A typical scheme involves the usage of nanoparticles to collect the analyte followed by a digital measurement of single molecules at a confined space (17), such as the commercialized, single-molecule enzyme-linked immunosorbent analysis (digital ELISA) (18). The digital ELISA uses the antibody-modified magnetic beads to capture the analyte in solution and loads them into femtoliter-sized reaction chambers termed single-molecule arrays. It effectively improves the sensitivity of conventional ELISA by three orders with a limit of detection (LoD) at the subfemtomolar level but requires sophisticated devices and excessive operation to remove free analyte molecules. Besides, the performance is still limited by the probe affinity and false positive arising from detection antibodies that bind nonspecifically to assay surface.A distinct yet effective strategy is to explore the in-depth heterogeneous information of single-molecule interaction (19). Walter et al. first demonstrated a kinetic fingerprinting approach to perform highly specific and sensitive detection of biomarkers via single-molecule fluorescence microscopy (20–22). This single-molecule recognition through equilibrium Poisson sampling technique surpasses the thermodynamic limit by exploiting the repetitive binding of fluorescently labeled, low-affinity probes to the analyte (23) and discriminating specific binding from background noise by a kinetic signature. The detection limits of microRNAs (miRNAs) and proteins also reach the subfemtomolar level, but screening probes with unique kinetic property is not compatible with current pipelines, and the concentration limit implies long incubation time before detection.Herein, we present the integration of single-molecule manipulation and dynamic sensing to allow rapid and ultrasensitive detection of biomarkers beyond the concentration and thermodynamic limits. In this Sensing Single Molecule under MicroManipulation (SSM³) approach, an external force is applied on the molecular bound between analyte and probes through tethered nanoparticles to actively tune the binding kinetics. This strategy, together with a dynamic sensing approach to exploit the heterogeneity at the single-molecule level, is able to beat the limits in both assay time and sensitivity. We show the principle and realization of the SSM³ technique and demonstrate 15-min assays to directly measure miRNAs and proteins at the subfemtomolar concentration.     

Effects of Inorganic Metabolites of Sulphate-Reducing Bacteria on the Corrosion of AZ31B and AZ63B Magnesium Alloy in 3.5 wt.% NaCl Solution

This study seeks prevent and alleviate the failure of magnesium alloy anodes in pipelines, which we suspect is a problem related to SRB. The electrochemical corrosion behaviour of two kinds of magnesium alloys, AZ31B and AZ63B, in 3.5 wt.% NaCl solution with sulphide or phosphide—the two main inorganic metabolites of sulphate-reducing bacteria—were studied by electrochemical tests combined with other characterisation methods such as scanning electron microscopy and X-ray diffraction. The results show that the corrosion film formed by inorganic metabolites of SRB’s initial stage of corrosion (1–3 d) can lead to the corrosion of magnesium alloys. However, the loose and porous corrosion product film cannot protect the substrate effectively. The inorganic metabolites in the solution can accelerate the corrosion of the surface of magnesium alloy after the corrosion products have fallen off. This study provides a theoretical basis for alleviating the premature failure of magnesium alloy anodes and for corrosion protection in the future.     

Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1

The calcium activated K⁺ channel KCa3.1 plays an important role in T lymphocyte Ca²⁺ signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca²⁺ influx. We previously showed that nucleoside diphosphate kinase beta (NDPK-B), a mammalian histidine kinase, is required for KCa3.1 channel activation in human CD4 T lymphocytes. We now show that the mammalian protein histidine phosphatase (PHPT-1) directly binds and inhibits KCa3.1 by dephosphorylating histidine 358 on KCa3.1. Overexpression of wild-type, but not a phosphatase dead, PHPT-1 inhibited KCa3.1 channel activity. Decreased expression of PHPT-1 by siRNA in human CD4 T cells resulted in an increase in KCa3.1 channel activity and increased Ca²⁺ influx and proliferation after T cell receptor (TCR) activation, indicating that endogenous PHPT-1 functions to negatively regulate CD4 T cells. Our findings provide a previously unrecognized example of a mammalian histidine phosphatase negatively regulating TCR signaling and are one of the few examples of histidine phosphorylation/dephosphorylation influencing a biological process in mammals.     

Effectiveness of E-SBIRT intervention in community healthcare institution in China: study proposal for a randomised controlled trial

BackgroundMany studies have demonstrated the effectiveness of Screening, Brief Intervention and Referral to Treatment (SBIRT) in addressing substance use problem. However, owing to the shortage of counsellors, it has not been widely used in China. With the development of smart medicine, we developed a web-based electronic SBIRT (E-SBIRT) program and explored the effectiveness of E-SBIRT in reducing substance use in China.MethodsA randomised controlled trial will be conducted in primary healthcare institutions. Four primary healthcare institutions will be selected and randomly divided into an intervention group and a control group (each institution will recruit 60 participants, and in total, 240 participants will be recruited). The control group will get a pamphlet of drug abuse prevention, and the intervention group will get the E-SBIRT intervention and the pamphlet. Both groups will receive baseline and follow-up assessment at 1 and 3 months after the intervention. The primary outcome is the change in scores on the Alcohol, Smoking and Substance Use Involvement Screening Test, and the secondary outcomes include changes in motivation, depression, anxiety, positive/negative emotion, self-esteem, addiction knowledge and addiction severity index.ConclusionsIf the ‘E-SBIRT’ program is found to be effective, it will be an accessible, affordable and widely implementable intervention to help participants at moderate risk of substance use to reduce their consumption. The potential benefit is to provide early intervention to high-risk patients in time and reduce the harmful consequences to individuals and society.Trial registration number{"type":"clinical-trial","attrs":{"text":"NCT03452241","term_id":"NCT03452241"}}NCT03452241.     

针刺,中药对胆道“T”字管外引流胆汁量的影响

对９０例阻塞性黄疸患者作胆囊切除、胆总管切开取石及Ｔ字管外引流手术，术后随机分３组，分别予以耳针、中药及自然对照，结果针刺组和中药组在胆汁量、肝功能恢复及肛门排气恢复均优于对照组，说明针刺、中药结合手术治疗阻塞性黄疸效果优于单纯手术治疗。     

中性粒细胞与淋巴细胞比值对急性脑梗死患者预后的预测价值

目的探讨中性粒细胞与淋巴细胞比值(NLR)对急性脑梗死患者预后的预测价值。方法回顾性连续纳入2014年1月至2015年12月郑州大学第五附属医院神经内科住院的急性脑梗死患者307例,其中女80例,男227例。根据改良Rankin量表评分标准,分为预后良好组(195例)和预后不良组(112例)。记录入院时年龄、性别、既往病史、美国国立卫生研究院卒中量表(NIHSS)评分等资料,根据入院中性粒细胞计数与淋巴细胞计数计算出NLR值。采用Logistics回归分析急性脑梗死预后不良的影响因素,采用受试者工作特征(ROC)曲线评价入院时NLR水平对急性脑梗死患者预后不良的预测作用。结果 (1)与预后良好组比较,预后不良组患者年龄、复发性脑梗死发生率、入院时NIHSS评分、入院NLR水平均较高,组间差异均有统计学意义[(69±12)岁比(62±14)岁,25.0%(28/112)比14.4%(28/195),5.00(3.00,9.00)分比3.00(1.75,5.00)分,3.66(2.62,7.91)比2.47(1.94,3.40),均P0.05],其余基线资料和临床特征的组间差异均无统计学意义(均P0.05)。(2)多因素Logistics回归分析结果显示,年龄、入院NIHSS评分及入院时NLR水平的升高,是预后不良的独立危险因素(OR值分别为1.030,1.148,1.427,95%CI分别为1.007~1.053,1.059~1.246,1.247~1.634,均P0.05)。(3)入院时NLR水平对急性脑梗死患者预后不良的诊断界值为2.84,其敏感度为69.6%,特异度为64.6%。结论入院时NLR水平增高对评估急性脑梗死患者预后不良具有一定的参考价值。     

Pancreatic mucinous lesions: a retrospective analysis with cytohistological correlation

The diagnosis of mucinous pancreatic lesions, which include mucinous noncystic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), and mucinous metaplasia, is critical, given different clinical management and prognosis. This retrospective study is done to assess the cytological features and pitfalls associated with these entities in cytological samples.A search for pancreatic cytology specimens with histological confirmation of the various pancreatic mucinous lesions was done from 1988 to 2005: 9 mucinous adenocarcinoma, 14 IPMN, 11 MCN, and 3 mucinous metaplasia. The majority (35/37) had been endoscopic ultrasound-guided fine-needle aspirations. The cellularity, background extracellular mucin, epithelial architecture, mucinous nature of the epithelium, cell shape, and nuclear features were evaluated on the cytology material. Of the 22 cytological features evaluated, the presence of three-dimensional clusters, micropapillary structures, and nuclear atypia, which includes nuclear crowding, increased N/C ratio, anisonucleosis, nuclear membrane contour irregularity, clumpy chromatin, and prominent nucleoli, was found to be consistently associated with mucinous adenocarcinoma. There were no statistically significant cytological features, which helped in differentiating IPMN, MCN, and mucinous metaplasia. There was a relatively high false-positive rate in the IPMN group (5/14, 36%). Review of the histological specimen showed severe dysplastic epithelial change in these cases. One false-positive case of mucinous metaplasia (1/3, 33%) showed marked intraepithelial acute inflammation.The cytological diagnosis of mucinous pancreatic lesions remains challenging, except for mucinous noncystic adenocarcinoma. The findings were largely nonspecific in the differentiation between IPMN, MCN, mucinous metaplasia, and incidentally sampled gastrointestinal epithelium. False-positive diagnosis of adenocarcinoma occurs not infrequently in the setting of IPMN with severe dysplastic epithelial change and in lesions with associated acute inflammation, and can be a pitfall in the diagnosis of these lesions.