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1. Unique continuation property of solutions to general second order elliptic systems

Author

Honda, N., Lin, C. -L., Nakamura, G., and Sasayama, S.

Subjects
Mathematics - Analysis of PDEs, Applied Mathematics, FOS: Mathematics, Analysis of PDEs (math.AP)
Abstract

This paper concerns the weak unique continuation property of solutions of a general system of differential equation/inequality with a second order strongly elliptic system as its leading part. We put not only some natural assumptions which we call basic assumptions, but also some technical assumptions which we call further assumptions. It is shown as usual by first applying the Holmgren transform to this equation/inequality and then establishing a Carleman estimate for the leading part of the transformed inequality. The Carleman estimate is given via a partition of unity and the Carleman estimate for the operator with constant coefficients obtained by freezing the coefficients of the transformed leading part at a point. A little more details about this are as follows. Factorize this operator with constant coefficients into two first order differential operators. Conjugate each factor by a Carleman weight, and derive an estimate which is uniform with respect to the point at which we froze the coefficients for each conjugated factor by constructing a parametrix for its adjoint operator.

Published
2021
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2. A multistep conditionally P-stable method with phase properties of high order for problems in quantum chemistry

Author

Lin, C.-L. Simos, T.E.

Abstract

A new two-step method, for the numerical solution of problems in quantum chemistry, is introduced in the present paper. The new algorithm is conditionally P-Stable and an economical scheme. It has vanished phase–lag and it’s first to fourth derivatives. We use for the new scheme the symbol LOWPF4DECN2ST. We apply the newly introduced method to problems in Quantum Chemistry. The new scheme is defined as economical since it uses 4 function evaluations per step in order to achieve an algebraic order (AOR) of 10. © 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Published
2022

3. Runge–kutta pairs of orders 6(5) with coefficients trained to perform best on classical orbits

Author

Shen, Y.-C. Lin, C.-L. Simos, T.E. Tsitouras, C.

Subjects
Astrophysics::Earth and Planetary Astrophysics
Abstract

We consider a family of explicit Runge–Kutta pairs of orders six and five without any additional property (reduced truncation errors, Hamiltonian preservation, symplecticness, etc.). This family offers five parameters that someone chooses freely. Then, we train them in order for the presented method to furnish the best results on a couple of Kepler orbits, a certain interval and tolerance. Consequently, we observe an efficient performance on a wide range of orbital problems (i.e., Kepler for a variety of eccentricities, perturbed Kepler with various disturbances, Arenstorf and Pleiades). About 1.8 digits of accuracy is gained on average over conventional pairs, which is truly remarkable for methods coming from the same family and order. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Published
2021

4. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial

Author

Petrylak, D.P. de Wit, R. Chi, K.N. Drakaki, A. Sternberg, C.N. Nishiyama, H. Castellano, D. Hussain, S.A. Fléchon, A. Bamias, A. Yu, E.Y. van der Heijden, M.S. Matsubara, N. Alekseev, B. Necchi, A. Géczi, L. Ou, Y.-C. Coskun, H.S. Su, W.-P. Bedke, J. Gakis, G. Percent, I.J. Lee, J.-L. Tucci, M. Semenov, A. Laestadius, F. Peer, A. Tortora, G. Safina, S. Garcia del Muro, X. Rodriguez-Vida, A. Cicin, I. Harputluoglu, H. Tagawa, S.T. Vaishampayan, U. Aragon-Ching, J.B. Hamid, O. Liepa, A.M. Wijayawardana, S. Russo, F. Walgren, R.A. Zimmermann, A.H. Hozak, R.R. Bell-McGuinn, K.M. Powles, T. Wong, S.-L.S. Tan, T.H. Hovey, E.J. Clay, T.D. Wan Ng, S.S. Rutten, A. Machiels, J.-P. Dumez, H. Cheng, S.Y.-S. Ferrario, C. Sengeloev, L. Jensen, N.V. Thibault, C. Laguerre, B. Joly, F. Culine, S. Becht, C. Niegisch, G. Stöckle, M. Grimm, M.-O. Schwentner, C.A. Schultze-Seemann, W. Kalofonos, H. Mavroudis, D. Papandreou, C. Karavasilis, V. Révész, J. Rosenbaum, E. Leibowitz-Amit, R. Kejzman, D. Sarid, D. Scagliotti, G.V. Bracarda, S. Massari, F. Osawa, T. Miyajima, N. Shinohara, N. Fukuta, F. Ohyama, C. Obara, W. Yamashita, S. Tomita, Y. Kawai, K. Fukasawa, S. Oyama, M. Yonese, J. Nagata, M. Uemura, M. Nishimura, K. Kawakita, M. Tsunemori, H. Hashine, K. Inokuchi, J. Yokomizo, A. Nagamori, S. Lee, H.J. Park, S.H. Rha, S.Y. Kim, Y.J. Lee, Y.-G. Vazquez Cortés, L. Lorena Urzua Flores, C. Blaisse, R.J.B. Erdkamp, F.L.G. Aarts, M.J.B. Wojcik-Tomaszewska, J. Tomczak, P. Sikora-Kupis, B. Schenker, M. Herzal, A.A. Udrea, A.A. Karlov, P. Fomkin, R. Gajate Borau, P. Grande, E. Delgado Mignorance, J.I. Su, Y.-L. Li, J.-R. Lin, C.-L. Lin, C.-C. Yeh, S.-P. Erman, M. Urun, Y. Golovko, Y. Bondarenko, I. Sinielnikov, I. Crabb, S.J. Syndikus, I. Huddart, R. Sundar, S. Chowdhury, S. Sarwar, N. Flaig, T.W. Pan, C.X. Schwarz, J.K. Cultrera, J.L. Acs, P.I. Hainsworth, J.D. Herms, B.T. Lawler, W.E. Lowe, T.E.

Abstract

Background: Ramucirumab—an IgG1 vascular endothelial growth factor receptor 2 antagonist—plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5–13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3–4·8] vs 2·8 months [2·6–2·9]; HR 0·696 [95% CI 0·573–0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9–11·4) in the ramucirumab group versus 7·9 months (7·0–9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724–1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Funding: Eli Lilly and Company. © 2020 Elsevier Ltd

Published
2020

5. Spectral density, Levinson's theorem, and the extra term in the second virial coefficient for 1D delta-function potential

Author

Camblong, H. E., Chakraborty, A., Daza, W. S., Drut, J. E., Lin, C. L., and Ordóñez, C. R.

Subjects
Quantum Gases (cond-mat.quant-gas), FOS: Physical sciences, Condensed Matter - Quantum Gases
Abstract

In contrast with the 3D result, the Beth-Uhlenbeck (BU) formula in 1D contains an extra -1/2 term. The origin of this -1/2 term is explained using a spectral density approach. To be explicit, a delta-function potential is used to show that the correction term arises from a pole of the density of states at zero energy. The spectral density method shows that this term is actually an artifact of the non-normalizability of the scattering states and an infrared cutoff regularization scheme has to be used to get the correct result in 1D. The formal derivation of the BU formula would miss this term since it ignores the effects of the boundary terms. While the result is shown for the delta-function potential, the method and result are valid for more general potentials. Additionally, the 1D Levinson's theorem can be extracted from the spectral density method using the asymptotic form of general potentials. The importance of the result lies in the fact that all these correction terms in 1D have a universal source: a pole at zero energy. Similar calculations using quantum field theoretical approaches (without explicit infrared cutoff regularization schemes) also show the same subtleties with the correction term originating from the zero energy scattering states (appendix A)., Comment: 12 pages, 3 figures

Published
2019
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6. Imaging-based clusters in current smokers of the COPD cohort associate with clinical characteristics: The SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology

Author

Hansel, N.N., Kanner, R.E., Choi, J., Bleecker, E., Martinez, F.J., O'Neal, W., Comellas, A.P., Lin, C.-L., Han, M.L., Graham Barr, R., Hoffman, E.A., Haghighi, B., Couper, D., Kleerup, E.A.C., Newell, J.D., Jr., Cooper, C.B., Rennard, S.I., Woodruff, P.G., Choi, S., and Kazerooni, E.A.

Subjects
respiratory system, respiratory tract diseases
Abstract

Background: Classification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD. Methods: Among the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering. Results: Four clusters were identified. Cluster 1 had relatively normal airway structures; Cluster 2 had an increase of fSAD% and wall thickness; Cluster 3 exhibited a further increase of fSAD% but a decrease of wall thickness and airway diameter; Cluster 4 had a significant increase of fSAD% and emphysema. Clinically, Cluster 1 showed normal FEV1/FVC and low exacerbations. Cluster 4 showed relatively low FEV1/FVC and high exacerbations. While Cluster 2 and Cluster 3 showed similar exacerbations, Cluster 2 had the highest BMI among all clusters. Conclusions: Association of imaging-based clusters with existing clinical metrics suggests the sensitivity of MICA in differentiating subpopulations.

Published
2018
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7. N-Type Monolike Silicon Bifacial Solar Cell: An Alternative Way of High Efficiency and Low Cost

Author

Lin, C.-L., Cheng, Y.-T., Huang, Y.-H., Wang, C.-C., and Chien, J.-W.

Subjects
Homojunction Solar Cells, Silicon Photovoltaics
Abstract

33rd European Photovoltaic Solar Energy Conference and Exhibition; 595-599, China “Top Runner Program” leads to huge demand of high efficient solar cells in 2016. Every company is enthusiastic to develop their own high efficient solar cell technologies and products to keep competence in this field. Mono and multi PERC cells are the most popular among high efficient solar cells, however, the shortage of p-type mono wafer, Al2O3 and LIR tools hinder the cost and development of mono PERC. Besides, extra black silicon texturing and severe LID are still the issues for multi PERC. To solve the difficulties of mono and multi PERC, ntype monolike silicon bifacial solar cell is developed and presented in this article. The front cell efficiency up to 20.8% in average was realized by industrial-available process and facilities. Zero LID because of the intrinsic characteristic of n-type silicon wafers was proven without LIR process. Module power of 295Wp was achieved with 60 pcs cells and white backsheet. With the development and commercialization of double glass module, it is expected that low cost and high efficient bifacial solar cells will get more and more attention.

Published
2017
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8. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Author

Petrylak, D.P. de Wit, R. Chi, K.N. Drakaki, A. Sternberg, C.N. Nishiyama, H. Castellano, D. Hussain, S. Fléchon, A. Bamias, A. Yu, E.Y. van der Heijden, M.S. Matsubara, N. Alekseev, B. Necchi, A. Géczi, L. Ou, Y.-C. Coskun, H.S. Su, W.-P. Hegemann, M. Percent, I.J. Lee, J.-L. Tucci, M. Semenov, A. Laestadius, F. Peer, A. Tortora, G. Safina, S. del Muro, X.G. Rodriguez-Vida, A. Cicin, I. Harputluoglu, H. Widau, R.C. Liepa, A.M. Walgren, R.A. Hamid, O. Zimmermann, A.H. Bell-McGuinn, K.M. Powles, T. Wong, S.-L.S. Tan, T.H. Hovey, E.J. Clay, T.D. Ng, S.S.W. Rutten, A. Machiels, J.-P. Dumez, H. Cheng, S.Y.-S. Ferrario, C. Sengeloev, L. Jensen, N.V. Thibault, C. Laguerre, B. Joly, F. Flechon, A. Culine, S. Becht, C. Niegisch, G. Stöckle, M. Grimm, M.-O. Gakis, G. Schultze-Seemann, W. Kalofonos, H. Mavroudis, D. Papandreou, C. Karavasilis, V. Révész, J. Geczi, L. Rosenbaum, E. Leibowitz-Amit, R. Kejzman, D. Sarid, D. Scagliotti, G.V. Bracarda, S. Massari, F. Osawa, T. Miyajima, N. Shinohara, N. Fukuta, F. Ohyama, C. Obara, W. Yamashita, S. Tomita, Y. Kawai, K. Fukasawa, S. Oyama, M. Yonese, J. Nagata, M. Uemura, M. Nishimura, K. Kawakita, M. Tsunemori, H. Hashine, K. Inokuchi, J. Yokomizo, A. Nagamori, S. Lee, H.J. Park, S.H. Rha, S.Y. Kim, Y.J. Lee, Y.-G. Cortés, L.V. Flores, C.L.U. Blaisse, R.J.B. Erdkamp, F.L.G. Aarts, M.J.B. Wojcik-Tomaszewska, J. Tomczak, P. Sikora-Kupis, B. Schenker, M. Herzal, A.A. Udrea, A.A. Karlov, P. Fomkin, R. Pulido, E.G. Mignorance, J.I.D. Gauna, D.C. Rodríguez-Vida, A. Su, Y.-L. Lin, C.-L. Lin, C.-C. Yeh, S.-P. Çiçin, I. Erman, M. Urun, Y. Golovko, Y. Bondarenko, I. Sinielnikov, I. Crabb, S. Syndikus, I. Huddart, R. Sundar, S. Chowdhury, S. Sarwar, N. Flaig, T. Pan, C.X. Schwarz, J. Cultrera, J. Hainsworth, J. Herms, B. Lawler, W. Lowe, T. Tagawa, S. Aragon-Ching, J. Vaishampayan, U.

Abstract

Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company. © 2017 Elsevier Ltd

Published
2017

9. Reversible devitrification in amorphous A s2 S e3 under pressure

Author

Cui, S., Bureau, B., Zhang, D.-X., Wang, X.-D., Cao, Q.-P., Greer, A.L., Jiang, J.-Z., Ahmad, A.S., Lou, H.-B., Lin, C.-L., Li, A.-G., Yang, K., Glazyrin, K., Liermann, H.P., Franz, H., Ståhl, K., Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Department of Materials Science and Engineering, Zhejiang University, Univ. Cambridge, Dept. Mat. Sci. & Met., University of Cambridge [UK] (CAM), 51371157, National Natural Science Foundation of China, Engineering and Physical Sciences Research Council, Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[CHIM]Chemical Sciences
Abstract

International audience; In pressure-induced reversible structural transitions, the term "reversible" refers to the recovery of the virgin structure in a material upon complete decompression. Pressure-induced amorphous-to-crystalline transitions have been claimed to be reversible, but evidence that amorphous material recovers its virgin amorphous structure upon complete depressurization has been lacking. In amorphous As2Se3 (a-As2Se3) chalcogenide, however, we report a novel reversible amorphous-to-crystalline transition that provides compelling experimental evidence that upon complete decompression, the recovered amorphous phase is structurally the same as that of the virgin (as-cast) amorphous phase. Combining the experimental results with ab initio molecular dynamics simulations, we elucidate that the amorphization is mediated by a surplus of total free energy in the high-pressure face-centered cubic phase as compared to the virgin amorphous phase and that the structural recovery to the virgin amorphous phase is a consequence of an enhancement in covalent bonding character over interlayer forces upon complete decompression. Furthermore, we observed a two-dimensional to three-dimensional network transition under compression and its reversibility upon decompression. © 2016 American Physical Society.

Published
2016
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10. High Efficient n-Type and p-Type PERT Solar Cells by Industrially Feasible Processes

Author

Wang, C.-C., Lin, C.-L., Cheng, Y.-T., Huang, Y.-H., Tsao, C.-P., Chien, J.-W., Chen, I.-L., Chen, C.-H., and Wang, C.-L.

Subjects
Silicon Solar Cells Improvements and Innovation, Wafer-Based Silicon Solar Cells and Materials Technology
Abstract

32nd European Photovoltaic Solar Energy Conference and Exhibition; 602-605, PERT crystalline silicon solar cell is getting popular in recent years due to its bifacial property which collects sunlight more effectively than monofacial solar cells. Inventec started to develop n-type PERT from 2012Q1 and published cell efficiency up to 19.7% in 2013 EUPVSEC. Mass production of n-PERT was started from 2014H2 with 40MW capacity and expanded to 80MW in 2015H2. Through continuous improvement, the average and champion efficiency of Gen1 bifacial solar cells with 3busbar are 20.12% and 20.56% in 2015Q3. Meanwhile, n-type PERT, ptype PERT and p-type PERT+ on 6” commercially available mono-Si wafers were also be studied. The cell structure, IV performance and bifaciality were compared. Surprisingly, the champion efficiency of p-PERT+ is 20.30% and average efficiency is only 0.15% lower than that of n-PERT. However, n-PERT is still the highest among these cell type in terms of both front and rear side cell efficiency. In 2016Q1, 4 busbar design and optimized process were developed and adopted to Inventec Gen2 n-PERT solar cells and the cell efficiency successfully achieved 21.15% of champion and 21.02% in average. Finally, high performance of n-PERT monofacial module achieved 300.7W by using 60 pieces of Inventec Gen2 n-PERT bifacial solar cells and Winaico advanced module technologies.

Published
2016
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11. Computational fluid dynamics (CFD) Simulations of aerosol deposition in the lungs

Author

Koullapis, P. G., Kassinos, Stavros C., Lin, C.-L., and Kassinos, Stavros C. [0000-0002-3501-3851]

Subjects
Aerosols, Mean flow structures, Electrostatic charges, Chronic obstructive pulmonary disease, Large eddy simulation, Computational fluid dynamics, Turbulent intensities, Respiratory system, Reynolds number, Shear flow, Turbulence, Computational fluid dynamics simulations, Electrostatics, Particle transport and depositions, Pulmonary diseases, Aerosol deposition, Deposition, Atmospheric movements, Deposition efficiencies
Abstract

In the current study, Large Eddy Simulations (LES) are used to investigate the transport and deposition of inhaled aerosol particles (dp = 0.1, 0.5, 1, 2.5, 5, 10 μm) in a realistic geometry of the human airways under steady inhalation. The effects of electrostatic charge and lower generation airway narrowing caused by Chronic Obstructive Pulmonary Disease (COPD) on particle transport and deposition are examined for various flowrates (sedentary - 15.2 lt/min, light - 30 lt/min and heavy activity - 60 lt/min). Results show that the mean flow structures at the three flowrates are qualitatively similar regardless of Reynolds number. Similar swirling motions are generated from the impingement of the laryngeal jet on the tracheal front wall. However, higher turbulent intensities that persist further downstream in the trachea and the main bronchi are observed as the flowrate is increased. The Deposition Efficiency (DE) of particles is increased with the flowrate due to greater inertial impaction. The majority of the larger particles are filtered in the mouththroat region, while 0.1, 0.5 and 1μm diameter particles have similar DE at a given flowrate. The effect of charge on DE of particles is more pronounced for smaller particles 1000 elementary charge units on 0.1, 0.5,1 and 2.5 μm diameter particles results in approximately 7, 3, 2.5 and 1.5 times greater overall DE than that with no charge, respectively. Obstructed lower generation airways result in enhanced deposition due to impaction caused by higher velocities in these airways. 2

Published
2015

12. Large Area High Efficient Back-Junction Back-Contact Silicon Solar Cells with Industrial Process

Author

Lin, C.-L., Chen, C.C., Cheng, Y.-T., Huang, Y.-H., Tsao, C.-P., and Chien, J.-W.

Subjects
WAFER-BASED SILICON SOLAR CELLS AND MATERIALS TECHNOLOGY, Silicon Solar Cell Improvements
Abstract

29th European Photovoltaic Solar Energy Conference and Exhibition; 816-820, High efficiency back-junction back-contact silicon solar cells using 6” n-type Cz material and an industrial feasible process flow based on hybrid junction formations and all screen printed metallization are presented. The boron emitter and FSF/BSF were formed by diffusion technique with BCl3 precursor and PH3 ion-implantation respectively. The interdigitated pattern was formed by single dielectric masking and opening for ion-implantation. Both of front and rear sides were passivated by silicon oxide and nitride stack. Excellent current collection was achieved due to an optimized FSF and reduced electrical shading effect. Also, the FF had been improved by the study of the metal contact ratio and pitch effect. The large area cell efficiency up to 21.6% was realized and zero LID had been proved.

Published
2014
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14. Binding of HIV-1 gp120 to DC-SIGN Promotes ASK-1-Dependent Activation-Induced Apoptosis of Human Dendritic Cells

Author

Chen, Y, Hwang, S-L, Chan, VSF, Chung, NPY, Wang, S-R, Li, Z, Ma, J, Lin, C-W, Hsieh, Y-J, Chang, K-P, Kung, S-S, Wu, Y-C, Chu, C-W, Tai, H-T, Gao, GF, Zheng, B, Yokoyama, KK, Austyn, JM, Lin, C-L, Ross, SR, and Ross, SR

Subjects
CD4-Positive T-Lymphocytes, Lipopolysaccharides, lcsh:Immunologic diseases. Allergy, Lipopolysaccharide, Immunology, Apoptosis, HIV Infections, Receptors, Cell Surface, HIV Envelope Protein gp120, MAP Kinase Kinase Kinase 5, Transfection, Microbiology, Pathogenesis, chemistry.chemical_compound, Immune system, Viral envelope, Virology, Molecular Cell Biology, Genetics, Humans, Lectins, C-Type, Gene Silencing, CD40 Antigens, RNA, Small Interfering, Biology, lcsh:QH301-705.5, Molecular Biology, Cells, Cultured, biology, virus diseases, Dendritic Cells, Hematology, DC-SIGN, Infectious Diseases, chemistry, lcsh:Biology (General), Host-Pathogen Interactions, biology.protein, Medicine, Clinical Immunology, Tumor necrosis factor alpha, Parasitology, lcsh:RC581-607, Cell Adhesion Molecules, Protein Binding, Research Article
Abstract

During disease progression to AIDS, HIV-1 infected individuals become increasingly immunosuppressed and susceptible to opportunistic infections. It has also been demonstrated that multiple subsets of dendritic cells (DC), including DC-SIGN(+) cells, become significantly depleted in the blood and lymphoid tissues of AIDS patients, which may contribute to the failure in initiating effective host immune responses. The mechanism for DC depletion, however, is unclear. It is also known that vast quantities of viral envelope protein gp120 are shed from maturing HIV-1 virions and form circulating immune complexes in the serum of HIV-1-infected individuals, but the pathological role of gp120 in HIV-1 pathogenesis remains elusive. Here we describe a previously unrecognized mechanism of DC death in chronic HIV-1 infection, in which ligation of DC-SIGN by gp120 sensitizes DC to undergo accelerated apoptosis in response to a variety of activation stimuli. The cultured monocyte-derived DC and also freshly-isolated DC-SIGN(+) blood DC that were exposed to either cross-linked recombinant gp120 or immune-complex gp120 in HIV(+) serum underwent considerable apoptosis after CD40 ligation or exposure to bacterial lipopolysaccharide (LPS) or pro-inflammatory cytokines such as TNFα and IL-1β. Furthermore, circulating DC-SIGN(+) DC that were isolated directly from HIV-1(+) individuals had actually been pre-sensitized by serum gp120 for activation-induced exorbitant apoptosis. In all cases the DC apoptosis was substantially inhibited by DC-SIGN blockade. Finally, we showed that accelerated DC apoptosis was a direct consequence of excessive activation of the pro-apoptotic molecule ASK-1 and transfection of siRNA against ASK-1 significantly prevented the activation-induced excessive DC death. Our study discloses a previously unknown mechanism of immune modulation by envelope protein gp120, provides new insights into HIV immunopathogenesis, and suggests potential therapeutic approaches to prevent DC depletion in chronic HIV infection., Author Summary HIV-1 infected individuals become increasingly immunocompromised and susceptible to opportunistic infection during disease progression, which is associated with significant reduction of the dendritic cell number in the peripheral blood or secondary lymphoid tissues. Because dendritic cells are the most powerful antigen-presenting cells, their survival is critical for host defence and inadequate dendritic cell number will fail to induce effective host immune responses. Here we describe a mechanism that may at least partly explain why dendritic cells become significantly depleted in chronic HIV-1 infection. We found that after binding of the HIV-1 envelope protein gp120 to the dendritic cell surface protein DC-SIGN, the subsequent activation by CD40 ligation, or by exposure to bacterial product lipopolysaccharide or pro-inflammatory cytokines such as TNF-α and IL-1β, will lead to overexpression of pro-apoptotic molecule ASK-1, resulting in excessive dendritic cell death. We also confirmed that DC-SIGN(+) dendritic cells in the blood of HIV-1 infected individuals have actually been pre-sensitized by viral gp120, which exists in vast amount in the blood, for activation-induced exorbitant death. Our study thus reveals a previously unknown pathway for dendritic cell depletion and provides clues for potential therapeutic approaches to prevent DC depletion in chronic HIV infection.

Published
2013
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15. High Efficiency N-Type Silicon Bifacial Solar Cells with Novel Industrial Process

Author

Chen, C.-C., Lin, C.-L., Cheng, Y.-T., Huang, Y.-H., and Chien, J.-W.

Subjects
WAFER-BASED SILICON SOLAR CELLS AND MATERIALS TECHNOLOGY, Silicon Solar Cell Improvements
Abstract

28th European Photovoltaic Solar Energy Conference and Exhibition; 1053-1056, In this article, a large area bifacial solar cell on n-type silicon substrates using novel process and only industrial facilities is introduced. The boron emitter is formed by BCl3 precursor and the phosphorus BSF is made by ionimplantation followed by in-situ front and rear side passivation with silicon oxide. Meanwhile, the wafer source and cell series resistance affiliated to process control variability are analyzed. The resulting cell efficiency achieved 19.7% on 156 PSQ n-type Cz wafers. Moreover, such process was adopted on 156 inch n-type mono-like wafers and achieved cell efficiency up to 18.9%.

Published
2013
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16. A Rule-based Forecasting System Integrating combining and Single Forecast for Decision Making

Author

Lin, C-L, Lin, C-C, Z. Shyu, J, and Lin, C-T

Subjects
Networking & Telecommunications
Abstract

Many studies demonstrated that combining forecasts produces consistent but modest gains in accuracy. However, little researches define well the conditions under neither which combining is most effective nor how methods should be combined in each situation. In this paper, a rule-based forecasting system industry is proposed in order to compare forecast performance between combining forecasts and single forecasts, then define these conditions and to specify more effective combinations, finally suggest the best methods. Two comparative case studies for the telecommunications and TFT-LCD industry are proposed to examine the performance of the proposed system. Results from this study indicate that combining forecasts outperform single forecasts only when data set is data have various nonlinear characteristics. In this research, empirical evidence shows that rules based on causal forces improved the selection of forecasting methods, the structuring of time series, and the assessment of prediction intervals.

Published
2012

17. Effect of respiratory modulation on relationship between heart rate variability and motion sickness

Author

Lin, C. T., Lin, C. L., Chiu, T. W., Duann, J. R., and Jung, T. P.

Subjects
Adult, Male, Motion Sickness, Heart Rate, Statistics as Topic, Respiratory Mechanics, Humans, Female
Abstract

This study investigates the interplay among heart rate variability (HRV), respiration, and the severity of motion sickness (MS) in a realistic passive driving task. Although HRV is a commonly used metrically in physiological research or even believed to be a direct measure of sympathovagal activities, the results of MS-effected HRV remain mixed across studies. The goal of this study is to find the source of these contradicting results of HRV associated with MS. Experimental results of this study showed that the group trend of the low-frequency (LF) component and the LF/HF ratio increased and high-frequency (HF) component decreased significantly as self-reported MS level increased (p0.001), consistent with a perception-driven autonomic response of the cardiovascular system. However, in one of the subjects, the relationship was reversed when individuals intentionally adjust themselves (deep breathing) to relieve the discomfort of MS during the experiments. It appears that the correlations between HRV and MS level were higher when individuals made fewer adjustments (the number of deep breathing) during the passive driving experiments. © 2011 IEEE.

Published
2011

18. Quantitative strong unique continuation for the Lam\'e system with less regular coefficients

Author

Lin, C. -L., Nakamura, G., Uhlmann, G., and Wang, J. -N.

Subjects
Mathematics - Analysis of PDEs, Mathematics::Analysis of PDEs
Abstract

In this paper we prove a quantitative form of the strong unique continuation property for the Lam\'e system when the Lam\'e coefficients $\mu$ is Lipschitz and $\lambda$ is essentially bounded in dimension $n\ge 2$. This result is an improvement of our earlier result \cite{lin5} in which both $\mu$ and $\lambda$ were assumed to be Lipschitz., Comment: 10 pages

Published
2010

19. Advances in Two-Photon Microstructuration of Polymers, Proteins and Metallic Materials with Q-switched Microlasers

Author

Scheul, T., Bosson, J., Losin, M., Lin, C.-L., Vitrant, G., Stephan, O., Institut de Microélectronique, Electromagnétisme et Photonique - Laboratoire d'Hyperfréquences et Caractérisation (IMEP-LAHC), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), and Domenget, Chahla

Subjects
[SPI.OPTI] Engineering Sciences [physics]/Optics / Photonic, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2010

20. Quantitative strong unique continuation for the Lam�� system with less regular coefficients

Author

Lin, C. -L., Nakamura, G., Uhlmann, G., and Wang, J. -N.

Subjects
Nonlinear Sciences::Exactly Solvable and Integrable Systems, Mathematics::Analysis of PDEs, FOS: Mathematics, Mathematics::Representation Theory, Analysis of PDEs (math.AP)
Abstract

In this paper we prove a quantitative form of the strong unique continuation property for the Lam�� system when the Lam�� coefficients $��$ is Lipschitz and $��$ is essentially bounded in dimension $n\ge 2$. This result is an improvement of our earlier result \cite{lin5} in which both $��$ and $��$ were assumed to be Lipschitz., 10 pages

Published
2010
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21. A revision of the family Dissonidae Kurtz, 1924 (Copepoda : Siphonostomatoida)

Author

Boxshall, G. A., Lin, C. L., Ho, J. S., Ohtsuka, S., Maran, B. A. V., and Justine, Jean-Lou

Abstract

Two new species of the parasitic copepod genus Dissonus Wilson, 1906 are described: D. excavatus n. sp. from the gills of a labrid, Bodianus perditio, and a lutjanid, Macolor niger, collected off New Caledonia and Taiwan, and D. inaequalis n. sp. from a hemiscylliid elasmobranch, Chiloscyllium punctatum, collected off Sarawak (Malaysia) and the Philippines. Material of D. heronensis Kabata, 1966 is described from a balistid host, Pseudobalistes fuscus, off New Caledonia, and this constitutes a new host record for this parasite. D. manteri Kabata, 1966 was collected from four serranid host species off New Caledonia and from one of the same hosts off Taiwan. Two of the hosts from New Caledonia, Plectropomus laevis and Epinephelus cyanopodus, represent new host records. D. pastinum Deets and Dojiri, 1990 was recognised as a new synonym of D. nudiventris Kabata, 1966, so the total number of valid species is now twelve. Material from museum collections of D. nudiventris, D. similis Kabata, 1966 and D. spinifer Wilson, 1906 was re-examined and provided new information which is utilised in a key to all valid species of Dissonus.

Published
2008

36. Advances in two-photon microstructuration of polymers, proteins and metallic materials with Q-switched microlasers

Author

patrice baldeck, Scheul, T., Bosson, J., Iosin, M., Lin, C. -L, Vitrant, G., Stephan, O., Institut de Microélectronique, Electromagnétisme et Photonique - Laboratoire d'Hyperfréquences et Caractérisation (IMEP-LAHC), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique des Solides (LPS), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), and Michelin, Isabelle

Subjects
[PHYS.PHYS.PHYS-OPTICS] Physics [physics]/Physics [physics]/Optics [physics.optics], [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

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

Author

Hiddo J L Heerspink, Hans-Henrik Parving, Dennis L Andress, George Bakris, Ricardo Correa-Rotter, Fan-Fan Hou, Dalane W Kitzman, Donald Kohan, Hirofumi Makino, John J V McMurray, Joel Z Melnick, Michael G Miller, Pablo E Pergola, Vlado Perkovic, Sheldon Tobe, Tingting Yi, Melissa Wigderson, Dick de Zeeuw, Alicia Elbert, Augusto Vallejos, Andres Alvarisqueta, Laura Maffei, Luis Juncos, Javier de Arteaga, Gustavo Greloni, Eduardo Farias, Alfredo Zucchini, Daniel Vogel, Ana Cusumano, Juan Santos, Margaret Fraenkel, Martin Gallagher, Tim Davis, Shamasunder Acharya, Duncan Cooke, Michael Suranyi, Simon Roger, Nigel Toussaint, Carol Pollock, Doris Chan, Stephen Stranks, Richard MacIsaac, Zoltan Endre, Alice Schmidt, Rudolf Prager, Gert Mayer, Xavier Warling, Michel Jadoul, Jean Hougardy, Chris Vercammen, Bruno Van Vlem, Pieter Gillard, Adriana Costa e Forti, Joao Lindolfo Borges, Luis Santos Canani, Freddy Eliaschewitz, Silmara Leite, Fadlo Fraige Filho, Raphael Paschoalin, Jose Andrade Moura Neto, Luciane Deboni, Irene de Lourdes Noronha, Cintia Cercato, Carlos Alberto Prompt, Maria Zanella, Nelson Rassi, Domingos D'Avila, Rosangela Milagres, Joao Felicio, Roberto Pecoits Filho, Miguel Carlos Riella, Joao Salles, Elizete Keitel, Sergio Draibe, Celso Amodeo, Joseph Youmbissi, Louise Roy, Serge Cournoyer, Shivinder Jolly, Vincent Pichette, Gihad Nesrallah, Harpreet Singh Bajaj, Hasnain Khandwala, Ronnie Aronson, Richard Goluch, Paul Tam, Christian Rabbat, Gordon Bailey, Stephen Chow, Alvaro Castillo, Alfredo Danin Vargas, Fernando Gonzalez, Rodrigo Munoz, Vicente Gutierrez, Gonzalo Godoy, Hongwen Zhao, Zhangsuo Liu, Minghui Zhao, Xiaohui Guo, Benli Su, Shuxia Fu, Yan Xu, Jinkui Yang, Bingyin Shi, Guanqing Xiao, Wei Shi, Chuanming Hao, Changying Xing, Fanfan Hou, Qun Luo, Yuxiu Li, Linong Ji, Li Zuo, Song Wang, Zhaohui Ni, Guohua Ding, Nan Chen, Jiajun Zhao, Weiping Jia, Shengqiang Yu, Jian Weng, Gang Xu, Ping Fu, Shiren Sun, Bicheng Liu, Xiaoqiang Ding, Ivan Rychlik, Alexandra Oplustilova, Dagmar Bartaskova, Vaclava Honova, Hana Chmelickova, Martin Petr, Petr Bucek, Vladimir Tesar, Emil Zahumensky, Johan Povlsen, Kenneth Egstrup, Anna Oczachowska-Kulik, Peter Rossing, Jorma Lahtela, Jorma Strand, Ilkka Kantola, Catherine Petit, Christian Combe, Philippe Zaoui, Vincent Esnault, Pablo Urena Torres, Jean-Michel Halimi, Bertrand Dussol, Tasso Bieler, Klemens Budde, Frank Dellanna, Thomas Segiet, Christine Kosch, Hans Schmidt-Guertler, Isabelle Schenkenberger, Volker Vielhauer, Frank Pistrosch, Mark Alscher, Christoph Hasslacher, Christian Hugo, Anja Muehlfeld, Christoph Wanner, Ploumis Passadakis, Theofanis Apostolou, Nikolaos Tentolouris, Ioannis Stefanidis, Konstantinos Mavromatidis, Vasilios Liakopoulos, Dimitrios Goumenos, Konstantinos Siamopoulos, Vincent Yeung, Risa Ozaki, Samuel Fung, Kathryn Tan, Sydney Tang, Sing Leung Lui, Siu Fai Cheung, Seamus Sreenan, Joseph Eustace, Donal O'Shea, Peter Lavin, Austin Stack, Yoram Yagil, Julio Wainstein, Hilla Knobler, Josef Cohen, Irina Kenis, Deeb Daoud, Yosefa Bar-Dayan, Victor Frajewicki, Faiad Adawi, Loreto Gesualdo, Domenico Santoro, Francesco Marino, Andrea Galfre, Chiara Brunati, Piero Ruggenenti, Giuseppe Rombola, Giuseppe Pugliese, Maura Ravera, Fabio Malberti, Giuseppe Pontoriero, Teresa Rampino, Salvatore De Cosmo, Ciro Esposito, Felice Nappi, Cataldo Abaterusso, Giuseppe Conte, Vincenzo Panichi, Davide Lauro, Giovambattista Capasso, Domenico Russo, Jiichi Anzai, Motoji Naka, Keita Ato, Tetsuro Tsujimoto, Toshinori Nimura, Eitaro Nakashima, Tetsuro Takeda, Shinya Fujii, Kunihisa Kobayashi, Hideaki Iwaoka, Koji Nagayama, Hiroyuki Harada, Hajime Maeda, Rui Kishimoto, Tadashi Iitsuka, Naoki Itabashi, Ryuichi Furuya, Yoshitaka Maeda, Daishiro Yamada, Nobuhiro Sasaki, Hiromitsu Sasaki, Shinichiro Ueda, Naoki Kashihara, Shuichi Watanabe, Takehiro Nakamura, Hidetoshi Kanai, Yuichiro Makita, Keiko Ono, Noriyuki Iehara, Daisuke Goto, Keiichiro Kosuge, Kenichi Tsuchida, Toshiaki Sato, Takashi Sekikawa, Hideki Okamoto, Tsuyoshi Tanaka, Naoko Ikeda, Takenobu Tadika, Koji Mukasa, Takeshi Osonoi, Fuminori Hirano, Motonobu Nishimura, Yuko Yambe, Yukio Tanaka, Makoto Ujihara, Takashi Sakai, Mitsuo Imura, Yutaka Umayahara, Shinya Makino, Jun Nakazawa, Yukinari Yamaguchi, Susumu Kashine, Hiroaki Miyaoka, Katsunori Suzuki, Toshihiko Inoue, Sou Nagai, Nobuyuki Sato, Masahiro Yamamoto, Noriyasu Taya, Akira Fujita, Akira Matsutani, Yugo Shibagaki, Yuichi Sato, Akira Yamauchi, Masahiro Tsutsui, Tamayo Ishiko, Shizuka Kaneko, Nobuyuki Azuma, Hirofumi Matsuda, Yasuhiro Hashiguchi, Yukiko Onishi, Mikiya Tokui, Munehide Matsuhisa, Arihiro Kiyosue, Junji Shinoda, Kazuo Ishikawa, Ghazali Ahmad, Shalini Vijayasingham, Nor Azizah Aziz, Zanariah Hussein, Yin Khet Fung, Wan Hasnul Halimi Wan Hassan, Hin Seng Wong, Bak Leong Goh, Norhaliza Mohd Ali, Nor Shaffinaz Yusuf Azmi Merican, Indralingam Vaithilingam, Nik Nur Fatnoon Nik Ahmad, Noor Adam, Norlela Sukor, V Paranthaman P Vengadasalam, Khalid Abdul Kadir, Mafauzy Mohamed, Karina Renoirte Lopez, Aniceto Leguizamo-Dimas, Alfredo Chew Wong, Jose Chevaile-Ramos, Jose Gonzalez Gonzalez, Raul Rico Hernandez, Jose Nino-Cruz, Leobardo Sauque Reyna, Guillermo Gonzalez-Galvez, Magdalena Madero Rovalo, Tomasso Bochicchio-Ricardelli, Jorge Aldrete, Jaime Carranza-Madrigal, Liffert Vogt, Peter Smak Gregoor, JNM Barendregt, Peter Luik, Ronald Gansevoort, Gozewijn Laverman, Helen Pilmore, Helen Lunt, John Baker, Steven Miller, Kannaiyan Rabindranath, Luis Zapata-Rincon, Rolando Vargas-Gonzales, Jorge Calderon Ticona, Augusto Dextre Espinoza, Jose Burga Nunez, Carlos Antonio Zea-Nunez, Benjamin Herrada Orue, Boris Medina-Santander, Cesar Delgado-Butron, Julio Farfan-Aspilcueta, Stanislaw Mazur, Miroslaw Necki, Michal Wruk, Katarzyna Klodawska, Grazyna Popenda, Ewa Skokowska, Malgorzata Arciszewska, Andrzej Wiecek, Kazimierz Ciechanowski, Michal Nowicki, Rita Birne, Antonio Cabrita, Aura Ramos, Manuel Anibal Antunes Ferreira, Evelyn Matta Fontanet, Altagracia Aurora Alcantara-Gonzalez, Angel Comulada-Rivera, Eugenia Galindo Ramos, Jose Cangiano, Luis Quesada-Suarez, Ricardo Calderon Ortiz, Jose Vazquez-Tanus, Rafael Burgos-Calderon, Carlos Rosado, Nicolae Hancu, Ella Pintilei, Cristina Mistodie, Gabriel Bako, Lavinia Ionutiu, Ligia Petrica, Romulus Timar, Liliana Tuta, Livia Duma, Adriana Tutescu, Svetlana Ivanova, Ashot Essaian, Konstantin Zrazhevskiy, Natalia Tomilina, Elena Smolyarchuk, Anatoly Kuzin, Olga Lantseva, Irina Karpova, Minara Shamkhalova, Natalia Liberanskaya, Andrey Yavdosyuk, Yuri Shvarts, Tatiana Bardymova, Olga Blagoveshchenskaya, Oleg Solovev, Elena Rechkova, Natalia Pikalova, Maria Pavlova, Elena Kolmakova, Rustam Sayfutdinov, Svetlana Villevalde, Natalya Koziolova, Vladimir Martynenko, Vyacheslav Marasaev, Adelya Maksudova, Olga Sigitova, Viktor Mordovin, Vadim Klimontov, Yulia Samoylova, Tatiana Karonova, Lee Ying Yeoh, Boon Wee Teo, Marjorie Wai Yin Foo, Adrian Liew, Ivan Tkac, Aniko Oroszova, Jozef Fekete, Jaroslav Rosenberger, Ida Obetkova, Alla Fulopova, Eva Kolesarova, Katarina Raslova, Peter Smolko, Adrian Oksa, Larry Distiller, Julien Trokis, Luthando Adams, Hemant Makan, Padaruth Ramlachan, Essack Mitha, Kathleen Coetzee, Zelda Punt, Qasim Bhorat, Puvenesvari Naiker, Graham Ellis, Louis Van Zyl, Kwan Woo Lee, Min Seon Kim, Soon-Jib Yoo, Kun Ho Yoon, Yong-Wook Cho, Tae-Sun Park, Sang Yong Kim, Moon-Gi Choi, Tae Keun Oh, Kang-Wook Lee, Ho Sang Shon, Sung Hwan Suh, Byung-Joon Kim, Kim Doo-Man, Joo Hark Yi, Sang Ah Lee, Ho Chan Cho, Sin-Gon Kim, Dae-Ryong Cha, Ji A Seo, Kyung Mook Choi, Jeong-Taek Woo, Kyu Jeung Ahn, Jae Hyuk Lee, In-Joo Kim, Moon-Kyu Lee, Hak Chul Jang, Kyong-Soo Park, Beom Seok Kim, Ji Oh Mok, Mijung Shin, Sun Ae Yoon, Il-Seong Nam-Goong, Choon Hee Chung, Tae Yang Yu, Hyoung Woo Lee, Alfonso Soto Gonzalez, Jaume Almirall, Jesus Egido, Francesca Calero Gonzalez, Gema Fernandez Fresnedo, Ildefonso Valera Cortes, Manuel Praga Terente, Isabel Garcia Mendez, Juan Navarro Gonzalez, Jose Herrero Calvo, Secundino Cigarran Guldris, Mario Prieto Velasco, Jose Ignacio Minguela Pesquera, Antonio Galan, Julio Pascual, Maria Marques Vidas, Judith Martins Munoz, Jose Rodriguez-Perez, Cristina Castro-Alonso, Josep Bonet Sol, Daniel Seron, Elvira Fernandez Giraldez, Javier Arrieta Lezama, Nuria Montero, Julio Hernandez-Jaras, Rafael Santamaria Olmo, Jose Ramon Molas Coten, Olof Hellberg, Bengt Fellstrom, Andreas Bock, Dee Pei, Ching-Ling Lin, Kai-Jen Tien, Ching-Chu Chen, Chien-Ning Huang, Ju-Ying Jiang, Du-An Wu, Chih-Hsun Chu, Shih-Ting Tseng, Jung-Fu Chen, Cho-Tsan Bau, Wayne Sheu, Mai-Szu Wu, Ramazan Sari, Siren Sezer, Alaattin Yildiz, Ilhan Satman, Betul Kalender, Borys Mankovskyy, Ivan Fushtey, Mykola Stanislavchuk, Mykola Kolenyk, Iryna Dudar, Viktoriia Zolotaikina, Orest Abrahamovych, Tetyana Kostynenko, Olena Petrosyan, Petro Kuskalo, Olga Galushchak, Oleg Legun, Ivan Topchii, Liliya Martynyuk, Vasyl Stryzhak, Svitlana Panina, Sergii Tkach, Vadym Korpachev, Peter Maxwell, Luigi Gnudi, Sui Phin Kon, Hilary Tindall, Phillip Kalra, Patrick Mark, Dipesh Patel, Mohamed El-Shahawy, Liqun Bai, Romanita Nica, Yeong-Hau Lien, Judson Menefee, Robert Busch, Alan Miller, Azazuddin Ahmed, Ahmed Arif, Joseph Lee, Sachin Desai, Shweta Bansal, Marie Bentsianov, Mario Belledonne, Charles Jere, Raul Gaona, Gregory Greenwood, Osvaldo Brusco, Mark Boiskin, Diogo Belo, Raffi Minasian, Naveen Atray, Mary Lawrence, John Taliercio, Pablo Pergola, David Scott, German Alvarez, Bradley Marder, Thomas Powell, Wa'el Bakdash, George Stoica, Christopher McFadden, Marc Rendell, Jonathan Wise, Audrey Jones, Michael Jardula, Ivy-Joan Madu, Freemu Varghese, Brian Tulloch, Ziauddin Ahmed, Melanie Hames, Imran Nazeer, Newman Shahid, Rekha John, Manuel Montero, David Fitz-Patrick, Lawrence Phillips, Antonio Guasch, Elena Christofides, Aijaz Gundroo, Mohammad Amin, Cynthia Bowman-Stroud, Michael Link, Laura Mulloy, Michael Nammour, Tarik Lalwani, Lenita Hanson, Adam Whaley-Connell, Lee Herman, Rupi Chatha, Sayed Osama, Kenneth Liss, Zeid Kayali, Anuj Bhargava, Ezra Israel, Alfredo Peguero-Rivera, Michael Fang, Judith Slover, Elena Barengolts, Jose Flores, Rosemary Muoneke, Virginia Savin, Stella Awua-Larbi, Andrew Levine, George Newman, Laden Golestaneh, Guillermo Bohm, Efrain Reisin, Lucita Cruz, Robert Weiss, Franklin Zieve, Edward Horwitz, Peale Chuang, James Mersey, John Manley, Ronald Graf, Fadi Bedros, Sudhir Joshi, Juan Frias, Ali Assefi, Andrew O'Shaughnessy, Roman Brantley, Todd Minga, David Tietjen, Samuel Kantor, Aamir Jamal, Ramon Guadiz, Kenneth Hershon, Peter Bressler, Nelson Kopyt, Harold Cathcart, Scott Bloom, Ronald Reichel, Samer Nakhle, Emily Dulude, Joshua Tarkan, Penelope Baker, Steven Zeig, Jaynier Moya Hechevarria, Armando Ropero-Cartier, Gilda De la Calle, Ankur Doshi, Fadi Saba, Teresa Sligh, Sylvia Shaw, Jayant Kumar, Harold Szerlip, George Bayliss, Alan Perlman, Lakhi Sakhrani, Steven Gouge, Georges Argoud, Idalia Acosta, John Elder, Sucharit Joshi, John Sensenbrenner, Steven Vicks, Roberto Mangoo-Karim, Claude Galphin, Carlos Leon-Forero, John Gilbert, Eric Brown, Adeel Ijaz, Salman Butt, Mariana Markell, Carlos Arauz-Pacheco, Lance Sloan, Odilon Alvarado, Serge Jabbour, Eric Simon, Anjay Rastogi, Sam James, Karen Hall, John Melish, Brad Dixon, Allen Adolphe, Csaba Kovesdy, Srinivasan Beddhu, Richard Solomon, Ronald Fernando, Ellis Levin, Charuhas Thakar, Brooks Robey, David Goldfarb, Linda Fried, Geetha Maddukuri, Stephen Thomson, Andrew Annand, Saeed Kronfli, Paramjit Kalirao, Rebecca Schmidt, Neera Dahl, Samuel Blumenthal, Debra Weinstein, Ove Ostergaard, Talia Weinstein, Yasuhiro Ono, Murat Yalcin, Shahana Karim, APH - Health Behaviors & Chronic Diseases, Nephrology, ACS - Amsterdam Cardiovascular Sciences, ACS - Microcirculation, Biomedical Signals and Systems, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Groningen Kidney Center (GKC), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Heerspink, H. J. L., Parving, H. -H., Andress, D. L., Bakris, G., Correa-Rotter, R., Hou, F. -F., Kitzman, D. W., Kohan, D., Makino, H., Mcmurray, J. J. V., Melnick, J. Z., Miller, M. G., Pergola, P. E., Perkovic, V., Tobe, S., Yi, T., Wigderson, M., de Zeeuw, D., Elbert, A., Vallejos, A., Alvarisqueta, A., Maffei, L., Juncos, L., de Arteaga, J., Greloni, G., Farias, E., Zucchini, A., Vogel, D., Cusumano, A., Santos, J., Fraenkel, M., Gallagher, M., Davis, T., Acharya, S., Cooke, D., Suranyi, M., Roger, S., Toussaint, N., Pollock, C., Chan, D., Stranks, S., Macisaac, R., Endre, Z., Schmidt, A., Prager, R., Mayer, G., Warling, X., Jadoul, M., Hougardy, J., Vercammen, C., Van Vlem, B., Gillard, P., Costa e Forti, A., Borges, J. L., Santos Canani, L., Eliaschewitz, F., Leite, S., Fraige Filho, F., Paschoalin, R., Moura Neto, J. A., Deboni, L., de Lourdes Noronha, I., Cercato, C., Prompt, C. A., Zanella, M., Rassi, N., D'Avila, D., Milagres, R., Felicio, J., Pecoits Filho, R., Riella, M. C., Salles, J., Keitel, E., Draibe, S., Amodeo, C., Youmbissi, J., Roy, L., Cournoyer, S., Jolly, S., Pichette, V., Nesrallah, G., Bajaj, H. 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Subjects
Male, endothelin, albuminuria, nephropathy, inhibition, Diabetes Mellitus, Type 2/drug therapy, Endocrinology, Diabetes and Metabolism, Placebo-controlled study, Administration, Oral, 030204 cardiovascular system & hematology, Settore MED/13 - Endocrinologia, chemistry.chemical_compound, 0302 clinical medicine, ENDOTHELIN, 80 and over, Diabetic Nephropathies, 030212 general & internal medicine, Renal Insufficiency, Chronic, Aged, 80 and over, Diabetic Nephropathies/blood, General Medicine, Middle Aged, Atrasentan/administration & dosage, Editorial Commentary, Treatment Outcome, Nephrology, Creatinine, Administration, young adult, Female, medicine.symptom, Glomerular filtration rate, Type 2, Endothelin A Receptor Antagonists/administration & dosage, medicine.drug, Glomerular Filtration Rate, Human, Oral, Adult, medicine.medical_specialty, ALBUMINURIA, Endothelin A Receptor Antagonists, NEPHROPATHY, Urology, INHIBITION, Renal function, Serum Albumin, Human, Placebo, Nephropathy, 03 medical and health sciences, Young Adult, Double-Blind Method, Atresentan, diabetes, chronic kidney disease, medicine, Diabetes Mellitus, Aged, Atrasentan, Diabetes Mellitus, Type 2, Humans, Renal Insufficiency, Chronic, Serum Albumin, business.industry, Creatinine/blood, medicine.disease, Serum Albumin, Human/urine, n/a OA procedure, chemistry, Albuminuria, Renal Insufficiency, Chronic/blood, business, aged, 80 and over, Kidney disease
Abstract

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 = 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. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Published
2019
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