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

九二一集集大地震前後集水區泥砂量推估之探討-以烏溪支流北港溪集水區為例

There caused a large landslide after the CHI-CHI earthquake in Wu-Chi watershed, the central area of Taiwan, at 1999 year. After that the sediment yield has been increasing obviously for being washed off by the peak flow caused by Typhoon and Storm. How to estimate the quantity of sediment yield reasonably is becoming to be a very important work for watershed management. In this study we selected the Peikang creek watershed as a sample for researching. We estimated the sediment yield by using the Universal Soil Loss Equation(USLE), Watershed Information System WinGrid and Soil Erosion Index Model(SEIM) to estimate the sediment yield of the watershed and then to compare with the observed data. The sediment yield was defined to equal “slopeland Soil Erosion” and “sediment transport of stream bed in mountain area”. After we compared the result with the observed suspended yield at the hydrological station of the downstream, we found it that the transported sediment from landslide is about 76% of the total estimated quantity, and to be the main quantity, and it will take 33 years to transport it up. On the other hand, to compare the estimated yield with the suspensing yield in the bower stream hydrologic station, it was a reasonable approach. It can be used as important reference for a watershed manager to make program for controlling and preventing flood disaster.1999年9月21日之集集大地震引起台灣中部地區上游集水區大規模崩塌，其後經過颱風豪雨之沖洗，其泥砂生產量明顯增加，如何合理評估其泥砂之生產量對集水區之經營管理相當重要，此亦為集水區治理或河道治理工作者極需掌握的工作重點。 本研究旨在利用『通用土壤流失公式（USLE）』、『集水區資訊系統 （WinGrid）』及『土壤沖蝕指標模式（SEIM）』等三種泥砂推估模式，推估集水區泥沙之產量，並將推估之結果與實測值進行探討與比較。經選定烏溪流域內面積最大，於桃芝颱風時崩塌最嚴重的北港溪集水區為研究範圍，就九二一地震前後對該集水區之泥砂生產評量採用『坡地土壤沖蝕量』及『山區河道土砂輸送量』兩項相加。結果顯示，崩塌土方輸移泥砂量佔總推估量之76 ﹪，為集水區泥砂主要來源，子集水區崩塌地泥砂需約33年始可輸移完畢。另外，再将推估之結果與下游水文流量站之懸浮載輸砂量實測值進行比較，結果推估量與實測值相當。應可作為地震前後北港溪集水區出口泥砂生產量估算作業之參考及擬訂集水區水土防災治理計畫時之空間決策的重要參考資料。中文摘要………….. ………….. ………….. I ABSTRACT………….. ………….. ………….. Ⅱ 目錄………….. ………….. ………….. …..Ⅲ 表目錄………….. ………….. ………….. …Ⅵ 圖目錄………….. ………….. ………….. …Ⅶ 附錄………….. ………….. ………….. ……Ⅷ 第一章 前言………….. ………….. …………1 第二章 文獻回顧………….. ………….. ……2 第三章 研究材料與方法……..…………..……5 一、 試區簡介………….. ………….. ………5 (一) 流域位置及行政區域………..……… ….5 (二) 地理位置……………………………………6 (三) 地質.. ………….. ………….. ……….6 (四) 地形與氣候….. …..……….. …………8 (五) 氣象……..…………..…………..…....9 (六) 土地利用………….. …………..……….9 二、資料蒐集……………………………………10 (一) 水文分析………….. ………….. …….10 (二)集水區地文分布……………………………11 (三)崩塌地分布……………………………….11 三、 研究流程……..…………..…………...12 四、 研究方法…….. ………….. ………….13 (一) 推估模式…….. ………….. ………….13 (二) 坡地土壤沖蝕量估算……..…………...13 (三) 遞移率（SDR）……..…………..…….23 (四) 崩塌土方生成量推估……..…………...25 (五) 山區河道泥砂輸移量……..…………..25 (六) 集水區出口泥砂總生產量……..……….27 (七) 輸砂量實測演算結果……..…………...27 第四章 結果分析與討論……..…………..….28 一、 集水區特性之分析……..…………..….28 (一) 北港溪集水區地文分析結果……..…….28 (二) 北港溪各子集水區地文分析結果……...28 二、 土壤沖蝕流失量之推估模式……..…….30 (一) 『通用土壤流失公式』模式…… ..……30 (二) 集水區資訊系統（WinGrid）模式……..32 (三) 土壤沖蝕指標模式（SEIM）……..…….32 三、 遞移率（Sediment Dilivery Rate）之推估結果…….….….….35 四、 輸砂量實測演算結果……..…………..…………. …….. ….…35 五、 以水文統計抽樣理論F檢定法檢定相關水文站流量-懸浮質含砂量 回歸關係式……..…………..…………. …….. ….………… ………37 六、 演算步驟……..…………..…………..… … …….. ……… …47 七、 結果比較與討論……..…………..…………..…… ……..…….50 八、 綜合討論……..…………..…………..…………..…………..…51 第五章 結論與建議…….. …………..…… …….. ………… ..……54 參考文獻……..…………..…………..………..……… .. ……….. 5

Therapeutic Efficacy Evaluation of Pegylated Liposome Encapsulated With Vinorelbine Plus 111In Repeated Treatments in Human Colorectal Carcinoma With Multimodalities of Molecular Imaging

[[abstract]]Background/Aim: In precision therapy, liposomal encapsulated chemotherapeutic drugs have been developed to treat cancers by achieving higher drug accumulation in the tumor compared to normal tissues/organs. Materials and Methods: We developed a novel chemoradiotherapeutic approach via nanoliposomes conjugated with vinorelbine (VNB) and 111In (111In-VNB-liposome) and examined their pharmacokinetics, biodistribution, maximum tolerance dose, and toxicity in a NOD/SCID mouse model. Results: Pharmacokinetic results showed that the area under the curve (AUC) of PEGylated liposomes was about 17-fold higher than that of the free radioisotope. Tumor growth inhibition by 111In-VNB-liposome was significantly higher than that of the control (p<0.05). Conclusion: The tumors in NOD/SCID mice bearing HT-29/tk-luc xenografts were significantly suppressed by 111In-VNB-liposomes. The study proposed repeated treatments with a novel liposome-mediated radiochemotherapy and validation of therapeutic efficacy via imaging

36-month clinical outcomes of patients with venous thromboembolism: GARFIELD-VTE

Background: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide.Methods: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries.Findings: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE +/- DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %).Interpretation: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population

Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI) : a phase 3, placebo-controlled, randomised trial

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p interaction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, p interaction=0·012. Benefit was present irrespective of time from most recent PCI. Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk