Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Research and Design of a Routing Protocol in Large-Scale Wireless Sensor Networks

无线传感器网络，作为全球未来十大技术之一，集成了传感器技术、嵌入式计算技术、分布式信息处理和自组织网技术，可实时感知、采集、处理、传输网络分布区域内的各种信息数据，在军事国防、生物医疗、环境监测、抢险救灾、防恐反恐、危险区域远程控制等领域具有十分广阔的应用前景。 本文研究分析了无线传感器网络的已有路由协议，并针对大规模的无线传感器网络设计了一种树状路由协议，它根据节点地址信息来形成路由，从而简化了复杂繁冗的路由表查找和维护，节省了不必要的开销，提高了路由效率，实现了快速有效的数据传输。 为支持此路由协议本文提出了一种自适应动态地址分配算——ADAR（AdaptiveDynamicAddre...As one of the ten high technologies in the future, wireless sensor network, which is the integration of micro-sensors, embedded computing, modern network and Ad Hoc technologies, can apperceive, collect, process and transmit various information data within the region. It can be used in military defense, biomedical, environmental monitoring, disaster relief, counter-terrorism, remote control of haz...学位：工学硕士院系专业：信息科学与技术学院通信工程系_通信与信息系统学号：2332007115216

The Transformer Bridge Principle Circuit Using RF Admittance Technology

To investigate the problem of the lag stability of the capacitance value during the level drop of the dirty U-shaped liquid level sensor, the equivalent circuit of the dirty U-shaped liquid level sensor was analyzed, and the transformer bridge’s principle circuit that uses RF admittance technology was designed accordingly. Using the method of controlling a single variable, the measurement accuracy of the circuit was simulated when the dividing capacitance and the regulating capacitance had different values. Then, the right parameter values for the dividing capacitance and the regulating capacitance were found. On this basis, the change of the sensor output capacitance and the change of the length of the attached seawater mixture were controlled separately under the condition of removing the seawater mixture. The simulation outcomes showed that the measurement accuracy was excellent under various situations, validating the transformer principle bridge circuit’s efficacy in minimizing the influence of the output capacitance value’s lag stability

Cichorium intybus L. Extract Suppresses Experimental Gout by Inhibiting the NF-κB and NLRP3 Signaling Pathways

Background: The production and maturation of interleukin (IL)-1&beta;, regulated by the NF-&kappa;B and NLRP3 signaling pathways, lie at the core of gout. This study aimed to evaluate the antigout effect of Cichorium intybus L. (also known as chicory) in vivo and in vitro. Methods: A gout animal model was established with monosodium urate (MSU) crystal injections. Rats were orally administered with chicory extract or colchicine. Levels of ankle edema, inflammatory activity, and IL-1&beta; release were observed. Several essential targets of the NF-&kappa;B and NLRP3 signaling pathways were detected. Primary macrophages were isolated to verify the antigout mechanism of chicory extract as well as chicoric acid in vitro. Results: Improvements of swelling degree, inflammatory activity, and histopathological lesion in MSU-injected ankles were observed in the treatment with chicory extract. Further, the chicory extract significantly decreased IL-1&beta; release by suppressing the NF-&kappa;B and NLRP3 signaling pathways in gout rats. Similar to the in vivo results, IL-1&beta; release was also inhibited by chicory extract and chicoric acid, a specific effective compound in chicory, through the NF-&kappa;B and NLRP3 signaling pathways. Conclusion: This study suggests that chicory extract and chicoric acid may be used as promising therapeutic agents against gout by inhibiting the NF-&kappa;B and NLRP3 signaling pathways

Quantitative analysis of global terrorist attacks based on the global terrorism database

Terrorist attacks have become a serious source of risk affecting the security of the international community. Using the Global Terrorism Database (GTD), in order to quantitatively study past terrorist attacks and their temporal and spatial evolution the analytic hierarchy process (AHP) was used to classify the degree of damage from terrorist attacks. The various factors influencing terrorist attacks were extracted and represented in three dimensions. Subsequently, using MATLAB for analysis and processing, the grading standards for terrorist attacks were classified into five levels according to the degree of hazard. Based on this grading standard, the top ten terrorist attacks with the highest degree of hazard in the past two decades were listed. Because the characteristics and habits of a terrorist or group exhibit a certain consistency, the K-means cluster analysis method was used to classify terrorists according to region, type of attack, type of target and type of weapon used by the terrorists. Several attacks that might have been committed by the same terrorist organization or individual at different times and in different locations were classified into one category, and the top five categories were selected according to the degree of sabotage inflicted by the organization or individual. Finally, the spatiotemporal evolution of terrorist attacks in the past three years was analyzed, considering the terrorist attack targets and key areas of terrorist attacks. The Middle East, Southeast Asia, Central Asia, and Africa were predicted to be the regions that will be most seriously affected by future global terrorist events. The terrorist attacks in Southeast Asia are expected to become more severe, and the scope of terrorist attacks in Africa is expected to widen. Civilians are the targets most at risk for terrorist attacks, and the corresponding risk index is considerably higher than it is for other targets. The results of this research can help individuals and the government to enable a better understanding of terrorism, improve awareness to prevent terrorism and enhance emergency management and rescue, and provide a solid and reliable basis and reference for joint counterterrorism in various countries and regions

mitoSomatic: a tool for accurate identification of mitochondrial DNA somatic mutations without paired controls

Mitochondrial DNA (mtDNA) somatic mutations play important roles in the initiation and progression of cancer. Although next‐generation sequencing (NGS) of paired tumor and control samples has become a common practice to identify tumor‐specific mtDNA mutations, the unique nature of mtDNA and NGS‐associated sequencing bias could cause false‐positive/‐negative somatic mutation calling. Additionally, there are clinical scenarios where matched control tissues are unavailable for comparison. Therefore, a novel approach for accurately identifying somatic mtDNA variants is greatly needed, particularly in the absence of matched controls. In this study, the ground truth mtDNA variants orthogonally validated by triple‐paired tumor, adjacent nontumor, and blood samples were used to develop mitoSomatic, a random forest‐based machine learning tool. We demonstrated that mitoSomatic achieved area under the curve (AUC) values over 0.99 for identifying somatic mtDNA variants without paired control in three tumor types. In addition, mitoSomatic was also applicable in nontumor tissues such as adjacent nontumor and blood samples, suggesting the flexibility of mitoSomatic's classification capability. Furthermore, analysis of triple‐paired samples identified a small group of variants with uncertain somatic/germline origin, whereas application of mitoSomatic significantly facilitated the prediction of their possible source. Finally, a control‐free evaluation of the public pan‐cancer NGS dataset with mitoSomatic revealed a substantial number of variants that were probably misclassified by conventional tumor‐control comparison, further emphasizing the usefulness of mitoSomatic in application. Taken together, our study demonstrates that mitoSomatic is valuable for accurately identifying somatic mtDNA variants in mtDNA NGS data without paired controls, applicable for both tumor and nontumor tissues

Effect of Sea-Level Change on Deep-Sea Sedimentary Records in the Northeastern South China Sea over the past 42 kyr

We integrated multiple geochemical analysis of a 13.75 m-long core 973-4 recovered from the northeastern South China Sea (SCS) to detect the response of deep-sea sediment archives to sea-level change spanning the last 42 kyr. The age-depth model based on AMS 14C dating, together with the sediment grain size, shows an occurrence of turbidity current at around 14 kyr, which was associated with submarine landslides caused by gas hydrate dissociation. A dominantly terrigenous sediment input was supplied from southwestern Taiwan rivers. By synthesizing environment-sensitive indexes, four distinct stages of paleoenvironmental evolutions were recognized throughout the studied interval. Well-oxygenated condition occurred during the stage I (42.4-31.8 kyr) with low sea-level stand below -80 m, accompanied by flat terrigenous input. The largest amounts of terrigenous sediment input occurred during the late phase of stage II (31.8-20.4 kyr) with the lowest sea-level stand below -120 m because of a short distance from paleo-Taiwan river estuaries to the core location. An occurrence of Ca-enriched turbidity current disturbed the original sediments during the stage III (20.4-13.9 kyr). The stepwise elevated sea-level stand resulted in an enclosed (semi-enclosed) system and contributed to a relatively low-oxygen environment in deep ocean during the stage IV (13.9 kyr—present). Temporal variations of TOC and CaCO3 display contrary pattern synchronously, indicating a decoupled relationship between organic carbon burial and carbonate productivity. Our results highlight that these sedimentary records as reflected in the paleoenvironmental changes in the northeastern SCS were mainly driven by sea-level fluctuations and later, since the mid-Holocene, the strengthening East Asian summer monsoon (EASM) overwhelmed the stable sea level in dominating the environmental changes

Treatment of Large and Complicated Scalp Defects with Free Flap Transfer

Background. Large scalp defects, especially those complicated by calvarial defects, titanium mesh exposure, or cerebrospinal fluid (CSF) leak, pose a challenge for the neurosurgeon and plastic surgeon. Here, we describe our experience of reconstructing the complex scalp defect with free flap transfer. Methods. From October 2012 to September 2017, 8 patients underwent free flap transfer for the reconstruction of the scalp or complicated scalp and calvarial defects. Five patients presented with scalp tumor and the other 3 patients with scalp necrosis or ulceration (2 patients with titanium plate exposure). Seven anterolateral thigh flaps and one radial forearm flap were harvested and employed. The clinical data, including defect characteristics, flap type, complications, and outcomes, were recorded and analyzed. Results. Five patients were pathologically diagnosed with malignant tumor, and 3 of them were given further radiotherapy. For the 2 patients with exposure of titanium plate, no titanium plate was removed. For the patient with scalp necrosis after decompressive craniectomy accompanied by CSF leakage, the CSF leak was stopped after reconstruction. The size of the flaps ranged from 3 to 14 cm in width and 4 to 18 cm in length. No flap failure occurred in these cases. From follow-up to the present, no ulceration or necrosis occurred. Conclusions. Free flap transfer is an ideal method for the reconstruction of large, complicated scalp defects with a one-stage operation. The anterolateral thigh flap is favored because of its durability, adjustability, water tightness, and infection prevention

Effects of Pre-Injection Strategy on Combustion Characteristics of Ammonia/Diesel Dual-Fuel Compression Ignition Mode

As a zero-carbon clean fuel, the use of ammonia in internal combustion engines is of great significance to achieve the “two-carbon” goal. This paper investigates the effect of the ammonia energy ratio and diesel injection timing on combustion and emissions. Based on Computational fluid dynamics (CFD) and the simulation analysis software, Converge, three-dimensional modeling is carried out for a direct injection diesel engine with a Compression Ignition (CI) mode. Under the initial full-load conditions of 1200 r/min, the engine simulation was calculated. The results show that the peak cylinder pressure increases and then decreases as the ammonia energy ratio increases, the ignition delay time increases, and the CO2 and N2O emissions decrease. With pre-injection, the peak cylinder pressure increases at the same energy ratio and the combustion stage advances, resulting in improved indicated thermal efficiency. In comparison to the pure diesel mode, the pre-injection strategy shows an obvious reduction in greenhouse gas (GHG) emissions with a decrease of 40.9% by adjusting the injection timing, while the single injection strategy shows a reduction of 36.5%. The soot emission peak occurs in the diesel-only mode with 98.13% and 99.6% reductions in emissions under single and pre-injection, respectively. The ammonia–diesel dual-fuel (ADDF) engine with an ammonia-to-energy ratio of 70% and optimized ammonia and diesel injection timing significantly reduces the NH3 emissions and GHG emissions by 69.34%

Dual-targeting inhibition of TNFR1 for alleviating rheumatoid arthritis by a novel composite nucleic acid nanodrug

Selective suppression of tumor necrosis factor (TNF) α-TNF receptor 1 (TNFR1) signaling is a potent solution for rheumatoid arthritis (RA). Herein, novel composite nucleic acid nanodrugs that simultaneously restrain TNF α binding and TNFR1 multimerization were designed to reinforce inhibition of TNF α-TNFR1 signaling for RA therapy. Towards this end, a novel peptide Pep4‐19 that suppresses TNFR1 clustering was extracted from TNFR1. The resulting peptide and a DNA aptamer Apt2‐55, which inhibits TNF α binding, were integrally or separately anchored on DNA tetrahedron (TD) to obtain nanodrugs with different spatial distribution of Apt2‐55 and Pep4‐19 (TD-3A-3P and TD-3(A-P)). Our results showed that Pep4‐19 enhanced the viability of inflammatory L929 cells. Both TD-3A-3P and TD-3(A-P) suppressed caspase 3, reduced cell apoptosis, and inhibited FLS-RA migration. Compared to TD-3(A-P), TD-3A-3P supplied sufficient flexibility for Apt2‐55 and Pep4‐19, and showed better anti-inflammation properties. Furthermore, TD-3A-3P significantly relieved symptoms in collagen-induced arthritis (CIA) mice, and the anti-RA efficacy through intravenous injection was comparable to transdermal administration via microneedles. Overall, the work provides an effective strategy for RA treatment by dual-targeting TNFR1, and demonstrates that microneedles are promising approach to drug administration in the treatment of RA