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Antibody-directed chemotherapy (ADC) offers an advantage over conventional chemotherapy because it provides antibody-directed targeting, with resultant improvement in therapeutic efficacy and reduced toxicity. Despite extensive research, with notable exceptions, broad clinical application of ADC remains elusive; major hurdles include the instability of antibody–chemotherapy linkers and reduced tumor toxicity of the chemotherapy when bound to the antibody. To address these challenges, we have developed a platform technology that utilizes the nab-paclitaxel formulation of paclitaxel, Abraxane, in which hydrophobic paclitaxel is suspended in 130-nm albumin nanoparticles and thus made water-soluble. We have developed a method to noncovalently coat the Abraxane nanoparticle with recombinant mAbs (anti-VEGF, bevacizumab) and guide Abraxane delivery into tumors in a preclinical model of human A375 melanoma. Here, we define the binding characteristics of bevacizumab and Abraxane, demonstrate that the chemotherapy agent retains its cytotoxic effect, while the antibody maintains the ability to bind its ligand when the two are present in a single nanoparticle (AB160), and show that the nanoparticle yields improved antitumor efficacy in a preclinical human melanoma xenograft model. Further data suggest that numerous therapeutic monoclonal IgG1 antibodies may be utilized in this platform, which has implications for many solid and hematologic malignancies. Cancer Res; 76(13); 3954–64. ©2016 AACR.

Mouse toxicity study of organs from 3 mice in each treatment group.

Background Survivors of acute COVID-19 often suffer prolonged, diffuse symptoms post-infection, referred to as “Long-COVID”. A lack of Long-COVID biomarkers and pathophysiological mechanisms limits effective diagnosis, treatment and disease surveillance. We performed targeted proteomics and machine learning analyses to identify novel blood biomarkers of Long-COVID. Methods A case–control study comparing the expression of 2925 unique blood proteins in Long-COVID outpatients versus COVID-19 inpatients and healthy control subjects. Targeted proteomics was accomplished with proximity extension assays, and machine learning was used to identify the most important proteins for identifying Long-COVID patients. Organ system and cell type expression patterns were identified with Natural Language Processing (NLP) of the UniProt Knowledgebase. Results Machine learning analysis identified 119 relevant proteins for differentiating Long-COVID outpatients (Bonferonni corrected P Conclusions Proteomic analysis of plasma from Long-COVID patients identified 119 highly relevant proteins and two optimal models with nine and five proteins, respectively. The identified proteins reflected widespread organ and cell type expression. Optimal protein models, as well as individual proteins, hold the potential for accurate diagnosis of Long-COVID and targeted therapeutics.

Aims Long-COVID occurs after SARS-CoV-2 infection and results in diverse, prolonged symptoms. The present study aims to determine the underlying mechanisms, and to inform prognosis and treatment. Methods Plasma proteome from Long-COVID outpatients was analyzed in comparison to acutely ill COVID-19 (mild and severe) inpatients and healthy control subjects. The expression of approximately 3000 protein biomarkers was determined with proximity extension assays and then deconvoluted with multiple bioinformatics tools into both cell types and signaling mechanisms, as well as organ specificity. Results Compared to age- and sex-matched acutely ill COVID-19 inpatients and healthy control subjects, Long-COVID outpatients showed natural killer cells with a resting phenotype, as opposed to active, and neutrophils that formed extracellular traps. This resetting of cell phenotypes was reflected in vascular events mediated by both angiopoietin-1 (ANGPT1) and vascular-endothelial growth factor-A (VEGFA). Levels of ANGPT1 and VEGFA were validated by serological methods in different patient cohorts. Silent signaling of transforming growth factor-β1 with elevated EP300 favored not only vascular inflammation, but also tumor necrosis factor-α driven pathways. In addition, a vascular proliferative state associated with hypoxia inducible factor 1 pathway was predicted that progressed from COVID-19 to Long-COVID. The vasculo-proliferative process identified in Long-COVID was associated with significant changes in the organ-specific proteome reflective of neurological and cardiometabolic dysfunction. Conclusions Taken together, our study uncovered a vasculo-proliferative process in Long-COVID initiated by prior hypoxia, and identified potential organ-specific prognostic biomarkers and therapeutic targets.

In this study, we present the assimilation of data from the Orbiting Carbon Observatory-2 (OCO-2) (land nadir and glint data, version 9) to estimate the Australian carbon surface fluxes for the year 2015. To perform this estimation, we used both a regional-scale atmospheric transport–dispersion model and a four-dimensional variational assimilation scheme. Our results suggest that Australia was a carbon sink of −0.41 ± 0.08 PgC yr−1 compared to the prior estimate 0.09 ± 0.20 PgC yr−1 (excluding fossil fuel emissions). Most of the carbon uptake occurred in northern Australia over the savanna ecotype and in the western region over areas with sparse vegetation. Analysis of the enhanced vegetation index (EVI) suggests that the majority of the carbon uptake over the savanna ecosystem was due to an increase of vegetation productivity (positive EVI anomalies) amplified by an anomalous increase of rainfall in summer. Further from this, a slight increase of carbon uptake in Western Australia over areas with sparse vegetation (the largest ecosystem in Australia) was noted due to increased land productivity in the area caused by positive rainfall anomalies. The stronger carbon uptake estimate in this ecosystem was partially due to the land surface model (CABLE-BIOS3) underestimating the gross primary productivity of the ecosystem. To evaluate the accuracy of our carbon flux estimates from OCO-2 retrievals, we compare our posterior concentration fields against the column-averaged carbon retrievals from the Total Carbon Column Observing Network (TCCON) and ground-based in situ monitoring sites located around our domain. The validation analysis against TCCON shows that our system is able to reduce bias mainly in the summer season. Comparison with surface in situ observations was less successful, particularly over oceanic monitoring sites that are strongly affected by oceanic fluxes and subject to less freedom by the inversion. For stations located far from the coast, the comparison with in situ data was more variable, suggesting difficulties matching the column-integrated and surface data by the inversion, most likely linked to model vertical transport. Comparison of our fluxes against the OCO-2 model intercomparison (MIP) was encouraging. The annual carbon uptake estimated by our inversion falls within the ensemble of the OCO-2 MIP global inversions and presents a similar seasonal pattern.

Point of Care Testing (POCT) refers to clinical laboratory testing performed outside the central laboratory, nearer to the patient and sometimes at the patient bedside. The testing is usually performed by clinical staff, such as physicians or nurses, who are not laboratory trained. This document was developed by the POCT Interest group of the Canadian Society of Clinical Chemists (CSCC) as practical guidance for quality assurance practices related to POCT performed in hospital and outside hospital environments. The aspects of quality assurance addressed in this document include: (1) device selection, (2) initial device verification, (3) ongoing device verification, (4) ongoing quality assurance including reagent and quality control (QC) lot changes, and (5) quality management including operator and document management.

Objective To compare transperineal (TP-TBx) and transrectal (TR-TBx) targeted prostate biopsy in a prospective non randomized single surgeon series of MR/US fusion-guided targeted biopsy performed using an electromagnetic tracking platform (NCT04026763). Materials and Methods In this single-institution prospective study, 168 patients who underwent transperineal systematic 12-core biopsy and TP-TBx with electromagnetic tracking (UroNav, Invivo, Gainesville, FL) were compared to 211 patients who underwent a similar procedure by a transrectal approach. Univariate and multivariate analyses were used to assess if biopsy technique impacted all cancer detection rates or clinically significant (Gleason score >3+4) cancer detection rates. Results Patients who underwent TP-TBx were older (68 vs 65 y, P = .014), with a slightly higher rate of PI-RADSv2.0 score (39% vs 28%, P = .039) and higher lesion volume on mpMRI (0.54 vs 0.41 cc, P = .039). The rates of CS disease detection by TP-TBx and TR-TBx were 59% and 54%, respectively. In a multivariate analysis adjusting for PSA, previous biopsy status, prostate volume, PI-RADS score, lesion volume, and lesion location, there was no statistically significant difference in likelihood to detect any PCa (OR, 0.98; 95% CI, 0.56-1.71; P = .940) or CS PCa (OR, 0.94, 95% CI, 0.58-1.51; P = .791). Conclusion Transperineal targeted biopsy with electromagnetic-tracking is comparable to the transrectal fusion-guided approach in the detection of any PCa and csPCa cancer.

We present recent highlights from the most recent operation phases of Wendelstein 7-X, the most advanced stellarator in the world. Stable detachment with good particle exhaust, low impurity content, and energy confinement times exceeding 100 ms, have been maintained for tens of seconds. Pellet fueling allows for plasma phases with reduced ion-temperature-gradient turbulence, and during such phases, the overall confinement is so good (energy confinement times often exceeding 200 ms) that the attained density and temperature profiles would not have been possible in less optimized devices, since they would have had neoclassical transport losses exceeding the heating applied in W7-X. This provides proof that the reduction of neoclassical transport through magnetic field optimization is successful. W7-X plasmas generally show good impurity screening and high plasma purity, but there is evidence of longer impurity confinement times during turbulence-suppressed phases. This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014-2018 and 2019-2020 under Grant Agreement No. 633053. Peer Reviewed Article signat per 497 autors/es: Thomas Sunn Pedersen1,2,∗ , I. Abramovic3, P. Agostinetti4, M. Agredano Torres1, S. Äkäslompolo1, J. Alcuson Belloso1, P. Aleynikov1, K. Aleynikova1, M. Alhashimi1, A. Ali1, N. Allen5, A. Alonso6, G. Anda7, T. Andreeva1, C. Angioni8, A. Arkhipov8, A. Arnold1, W. Asad8, E. Ascasibar6, M.-H. Aumeunier9, K. Avramidis10, E. Aymerich11, S.-G. Baek3, J. Bähner1, A. Baillod12, M. Balden1, M. Balden8, J. Baldzuhn1, S. Ballinger3, M. Banduch1, S. Bannmann1, A. Banon Navarro8, A. Bañon Navarro ´ 1, T. Barbui13, C. Beidler1, C. Belafdil9, A. Bencze7, A. Benndorf1, M. Beurskens1, C. Biedermann1, O. Biletskyi14, B. Blackwell15, M. Blatzheim1, T. Bluhm1, D. Böckenhoff1, G. Bongiovi16, M. Borchardt1, D. Borodin17, J. Boscary8, H. Bosch1,18, T. Bosmann19, B. Böswirth8, L. Böttger1, A. Bottino8, S. Bozhenkov1, R. Brakel1, C. Brandt1, T. Bräuer1, H. Braune1, S. Brezinsek17, K. Brunner1, S. Buller1, R. Burhenn1, R. Bussiahn1, B. Buttenschön1, A. Buzás7, V. Bykov1, I. Calvo6, K. Camacho Mata1, I. Caminal20, B. Cannas11, A. Cappa6, A. Carls1, F. Carovani1, M. Carr21, D. Carralero6, B. Carvalho22, J. Casas20, D. Castano-Bardawil17, F. Castejon6, N. Chaudhary1, I. Chelis23, A. Chomiczewska24, J.W. Coenen13,17, M. Cole1, F. Cordella25, Y. Corre9, K. Crombe26, G. Cseh7, B. Csillag7, H. Damm1, C. Day10, M. de Baar27, E. De la Cal6, S. Degenkolbe1, A. Demby13, S. Denk3, C. Dhard1, A. Di Siena8,28, A. Dinklage12, T. Dittmar17, M. Dreval14, M. Drevlak1, P. Drewelow1, P. Drews17, D. Dunai7, E. Edlund3, F. Effenberg29, G. Ehrke1, M. Endler1, D.A. Ennis5, F.J. Escoto6, T. Estrada6, E. Fable8, N. Fahrenkamp1, A. Fanni11, J. Faustin1, J. Fellinger1, Y. Feng1, W. Figacz4, E. Flom13, O. Ford1, T. Fornal24, H. Frerichs13, S. Freundt1, G. Fuchert1, M. Fukuyama30, F. Füllenbach1, G. Gantenbein10, Y. Gao1, K. Garcia13, J.M. García Regaña6, I. García-Cortés6, J. Gaspar31, D.A. Gates29, J. Geiger1, B. Geiger13, L. Giudicotti32, A. González6, A. Goriaev26,33, D. Gradic1, M. Grahl1, J.P. Graves12, J. Green13, E. Grelier9, H. Greuner8, S. Groß1, H. Grote1, M. Groth34, M. Gruca24, O. Grulke1,35, M. Grün1, J. Guerrero Arnaiz1, S. Günter8, V. Haak1, M. Haas1, P. Hacker1, A. Hakola36, A. Hallenbert1, K. Hammond29, X. Han17,37, S.K. Hansen3, J.H. Harris38, H. Hartfuß1, D. Hartmann1, D. Hathiramani1, R. Hatzky8, J. Hawke39, S. Hegedus7, B. Hein8, B. Heinemann8, P. Helander12, S. Henneberg1, U. Hergenhahn8,40, C. Hidalgo6, F. Hindenlang8, M. Hirsch1, U. Höfel1, K.P. Hollfeld17, A. Holtz1, D. Hopf8, D. Höschen17, M. Houry9, J. Howard19, X. Huang41, M. Hubeny17, S. Hudson29, K. Ida9, Y. Igitkhanov10, V. Igochine8, S. Illy10, C. Ionita-Schrittwieser42, M. Isobe39, M. Jabłczynska ´ 24, S. Jablonski24, B. Jagielski1, M. Jakubowski1, A. Jansen van Vuuren1, J. Jelonnek10, F. Jenko8, F. Jenko8, T. Jensen35, H. Jenzsch1, P. Junghanns8, J. Kaczmarczyk24, J. Kallmeyer1, U. Kamionka1, M. Kandler8, S. Kasilov43, Y. Kazakov26, D. Kennedy1, A. Kharwandikar1, M. Khokhlov1, C. Kiefer8, C. Killer1, A. Kirschner17, R. Kleiber1, T. Klinger12, S. Klose1, J. Knauer1, A. Knieps17, F. Köchl44, G. Kocsis7, Ya.I. Kolesnichenko45, A. Könies1, R. König1, J. Kontula34, P. Kornejew1, J. Koschinsky, M.M. Kozulia14, A. Krämer-Flecken17, R. Krampitz1, M. Krause1, N. Krawczyk24, T. Kremeyer1, L. Krier10, D.M. Kriete5, M. Krychowiak1, I. Ksiazek46, M. Kubkowska24, M. Kuczynski1, G. Kühner1, A. Kumar15, T. Kurki-Suonio34, S. Kwak1, M. Landreman47, P.T. Lang8, A. Langenberg1, H.P. Laqua12, H. Laqua1, R. Laube1, S. Lazerson1, M. Lewerentz1, C. Li17, Y. Liang17, Ch. Linsmeier17, J. Lion1, A. Litnovsky17,48, S. Liu37, J. Lobsien1, J. Loizu12, J. Lore38, A. Lorenz1, U. Losada6, F. Louche26, R. Lunsford29, V. Lutsenko45, M. Machielsen12, F. Mackel8, J. Maisano-Brown3, O. Maj8, D. Makowski49, G. Manduchi50, E. Maragkoudakis6, O. Marchuk17, S. Marsen1, E. Martines4, J. Martinez-Fernandez6, M. Marushchenko1, S. Masuzaki41, D. Maurer5, M. Mayer8, K.J. McCarthy6, O. Mccormack4, P. McNeely1, H. Meister8, B. Mendelevitch8, S. Mendes1, A. Merlo1, A. Messian26, A. Mielczarek49, O. Mishchenko1, B. Missal1, R. Mitteau9, V.E. Moiseenko14, A. Mollen1, V. Moncada9, T. Mönnich1, T. Morisaki41, D. Moseev1, G. Motojima41, S. Mulas6, M. Mulsow1, M. Nagel1, D. Naujoks1, V. Naulin35, T. Neelis19, H. Neilson29, R. Neu8, O. Neubauer17, U. Neuner1, D. Nicolai17, S.K. Nielsen35, H. Niemann1, T. Nishiza1, T. Nishizawa1, T. Nishizawa8, C. Nührenberg1, R. Ochoukov8, J. Oelmann17, G. Offermanns17 K. Ogawa41, S. Okamura41, J. Ölmanns17, J. Ongena26, J. Oosterbeek1, M. Otte1, N. Pablant29, N. Panadero Alvarez6, N. Panadero Alvarez6, A. Pandey1, E. Pasch1, R. Pavlichenko14, A. Pavone1, E. Pawelec46, G. Pechstein1, G. Pelka24, V. Perseo1, B. Peterson41, D. Pilopp1, S. Pingel1, F. Pisano11, B. Plöckl8, G. Plunk1, P. Pölöskei1, B. Pompe2, A. Popov51, M. Porkolab3, J. Proll19, M.J. Pueschel19,27, M.-E. Puiatti52, A. Puig Sitjes1, F. Purps1, K. Rahbarnia1, M. Rasinski ´ 17, J. Rasmussen35, A. Reiman29, F. Reimold1, M. Reisner8, D. Reiter17, M. Richou9, R. Riedl8, J. Riemann1, K. Riße1, G. Roberg-Clark1, V. Rohde8, J. Romazanov17, D. Rondeshagen1, P. Rong1, L. Rudischhauser1, T. Rummel1, K. Rummel1, A. Runov1, N. Rust1, L. Ryc24, P. Salembier20, M. Salewski35, E. Sanchez6, S. Satake41, G. Satheeswaran17, J. Schacht1, E. Scharff1, F. Schauer8, J. Schilling1, G. Schlisio1, K. Schmid8, J. Schmitt5, O. Schmitz13, W. Schneider1, M. Schneider1, P. Schneider8, R. Schrittwieser42, T. Schröder1, M. Schröder1, R. Schroeder1, B. Schweer26, D. Schwörer1, E. Scott1, E. Scott8, B. Shanahan1, G. Sias11, P. Sichta29, M. Singer1, P. Sinha29, S. Sipliä34, C. Slaby1, M. Sleczka53, H. Smith1, J. Smoniewski54, E. Sonnendrücker8, M. Spolaore4, A. Spring1, R. Stadler8, D. Stanczak24, T. Stange1, I. Stepanov26, L. Stephey13, J. Stober8, U. Stroth8,55, E. Strumberger8, C. Suzuki41, Y. Suzuki41, J. Svensson1, T. Szabolics7, T. Szepesi7, M. Szücs7, F.L. Tabares6, N. Tamura41, A. Tancetti35, C. Tantos10, J. Terry3, H. Thienpondt6, H. Thomsen1, M. Thumm10, J.M. Travere9, P. Traverso5, J. Tretter8, E. Trier8, H. Trimino Mora1, T. Tsujimura41, Y. Turkin1, A. Tykhyi45, B. Unterberg17, P. van Eeten1, B.Ph. van Milligen6, M. van Schoor26, L. Vano1, S. Varoutis10, M. Vecsei7, L. Vela56, J.L. Velasco6, M. Vervier17, N. Vianello50, H. Viebke1, R. Vilbrandt1, G. Vogel8, N. Vogt1, C. Volkhausen1, A. von Stechow1, F. Wagner1, E. Wang17, H. Wang57, F. Warmer1, T. Wauters26, L. Wegener1, T. Wegner1, G. Weir1, U. Wenzel1, A. White3, F. Wilde1, F. Wilms1, T. Windisch1, M. Winkler1, A. Winter1, V. Winters1, R. Wolf118, A.M. Wright29, G.A. Wurden39, P. Xanthopoulos1, S. Xu17, H. Yamada58, H. Yamaguchi41, M. Yokoyama41, M. Yoshinuma41, Q. Yu8, M. Zamanov14, M. Zanini1, M. Zarnstorff29, D. Zhang1, S. Zhou17, J. Zhu1, C. Zhu29, M. Zilker8, A. Zocco1, H. Zohm8, S. Zoletnik7 and L. Zsuga7 // 1 Max Planck Institute for Plasma Physics, Garching and Greifswald, Germany: 2 University of Greifswald, Greifswald, Germany; 3 Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA 02139, United States of America; 4 Consorzio RFX, Corso Stati Uniti, 4-35127 Padova, Italy; 5 Auburn University, Auburn, AL 36849, United States of America; 6 CIEMAT, Avenida Complutense, 40, 28040 Madrid, Spain; 7 Center for Energy Research, Konkoly-Thegeut 29-33, 1121 Budapest, Hungary; 8 Max-Planck-Institute for Plasma Physics, Boltzmannstraße 2, 85748 Garching bei München, Germany; 9 CEA Cadarache, 13115 Saint-Paul-lez-Durance, France; 10 Karlsruhe Institute of Technology, Kaiserstr. 12, 76131 Karlsruhe, Germany; 11 University of Cagliari, Via Universita, 40, 09124 Cagliari, Italy; 12 École Polytechnique Fédérale de Lausanne, Swiss Plasma Center, CH-1015 Lausanne, Switzerland; 13 University of Wisconsin–Madison, Engineering Drive, Madison, WI 53706, United States of America; 14 Institute of Plasma Physics, National Science Center ‘Kharkiv Institute of Physics and Technology’, Kharkiv, Ukraine; 15 The Australian National University, Acton ACT 2601, Canberra, Australia; 16 Department of Engineering, University of Palermo, Viale delle Scienze, Edificio 6, Palermo, 90128, Italy; 17 Forschungszentrum Jülich GmbH, Institut für Energie-und Klimaforschung—Plasmaphysik, 52425 Jülich, Germany; 18 Technical University of Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany; 19 Eindhoven University of Technology, 5600 MB Eindhoven, Netherlands; 20 Universitat Politècnica de Catalunya. BarcelonaTech, C. Jordi Girona, 31, 08034 Barcelona, Spain; 21 Culham Center for Fusion Energy, Abingdon OX14 3EB, United Kingdom; 22 Instituto de Plasmas e Fusao Nuclear, Av. Rovisco Pais, 1049-001 Lisboa, Portugal; 23 Department of Physics, National and Kapodistrian University of Athens, 15784 Athens, Greece; 24 Institute of Plasma Physics and Laser Microfusion, 23 Hery Str., 01-497 Warsaw, Poland; 25 ENEA—Centro Ricerche Frascati, Via Enrico Fermi, 45, 00044 Frascati RM, Italy; 26 Laboratory for Plasma Physics, LPP-ERM/KMS, TEC Partner, B-1000 Brussels, Belgium; 27 Dutch Institute for Fundamental Energy Research, PO Box 6336, 5600 HH Eindhoven, Netherlands; 28 University of Texas, Austin, TX, United States of America; 29 Princeton Plasma Physics Laboratory, Princeton, NJ 08543, United States of America; 30 Kyushu University, 744 Motooka Nishi-ku, Fukuoka 819-0395, Japan; 31 Aix-Marseille University, Jardin du Pharo, 58 Boulevard Charles Livon, 13007, Marseille, France; 32 Department of Physics and Astronomy, Padova University, Via Marzolo 8, 35131 Padova, Italy; 33 Department of Applied Physics, Ghent University, Sint-Pietersnieuwstraat 41 B4, 9000 Ghent, Belgium; 34 Aalto University, 02150 Espoo, Finland; 35 Department of Physics, Technical University of Denmark, Anker Engelunds Vej, 2800 Kgs Lyngby, Denmark; 36 VTT Technical Research Center of Finland Ltd., PO Box 1000, FI-02044 VTT, Finland; 37 Institute of Plasma Physics, Chinese Academy of Sciences, 230031 Hefei, Anhui, China; 38 Oak Ridge National Laboratory, 1 Bethel Valley Rd, Oak Ridge, TN 37830, United States of America; 39 Los Alamos National Laboratory, NM 87545, United States of America; 40 Fritz-Haber-Institut der Max-Planck-Gesellschaft, 14195 Berlin, Germany; 41 National Institute for Fusion Science, National Institutes of Natural Sciences, 322-6 Oroshi-cho, Toki, Gifu Prefecture 509-5292, Japan; 42 Institute for Ion Physics and Applied Physics, University of Innsbruck, Innsbruck, Austria; 43 Graz University of Technology, Rechbauerstraße 12, 8010 GRAZ, Austria; 44 Austrian Academy of Science, Doktor-Ignaz-Seipel-Platz 2, 1010 Wien, Austria; 45 Institute for Nuclear Research, prospekt Nauky 47, Kyiv 03028, Ukraine; 46 University of Opole, plac Kopernika 11a, 45-001 Opole, Poland; 47 University of Maryland, Paint Branch Drive, College Park, MA 20742, United States of America; 48 National Research Nuclear University MEPhI, 115409 Moscow, Russian Federation; 49 Department of Microelectronics and Computer Science, Lodz University of Technology, Wolczanska 221/223, 90-924 Lodz, Poland; 50 Consiglio Nazionale delle Ricerche, Piazzale Aldo Moro, 7, 00185 Roma, Italy; 51 Ioffe Physical-Technical Institute of the Russian Academy of Sciences, 26 Politekhnicheskaya, St Petersburg 194021, Russian Federation; 52 Istituto di Fisica del Plasma Piero Caldirola, Via Roberto Cozzi, 53, 20125 Milano, Italy; 53 University of Szczecin, 70-453, aleja Papieza Jana Pawła II 22A, Szczecin, Poland; 54 Lawrence University, 711 E Boldt Way, Appleton, WI 54911, United States of America; 55 Physik-Department E28, Technische Universität München, 85747 Garching, Germany; 56 Universidad Carlos III de Madrid, Av. de la Universidad, 30 Madrid, Spain; 57 Yale University, New Haven, CT 06520, United States of America; 58 University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chhiab 277-0882, Japan Objectius de Desenvolupament Sostenible::7 - Energia Assequible i No Contaminant Objectius de Desenvolupament Sostenible::7 - Energia Assequible i No Contaminant::7.a - Per a 2030, augmentar la cooperació internacional per tal de facilitar l’accés a la investigació i a les tecnolo­gies energètiques no contaminants, incloses les fonts d’energia renovables, l’eficiència energètica i les tecnologies de combustibles fòssils avançades i menys contaminants, i promoure la inversió en infraestructures energètiques i tecnologies d’energia no contaminant

Objective To evaluate the ability to detect clinically significant prostate cancer (PCa) using a novel electromagnetically (EM) tracked transperineal magnetic resonance imaging (MRI)/ultrasonography (US) fusion-guided targeted biopsy (transperineal TBx) platform and the impact of inter-reader variability on cancer detection. Materials and methods A total of 176 patients with suspicious lesions detected on multiparametric MRI (mpMRI) underwent a systematic modified Barzel template biopsy (12-core) transperineal biopsy (transperineal SBx) and transperineal TBx with EM tracking (UroNav; Philips Healthcare, Best, the Netherlands) in the same setting. Cancer detection rates (CDRs) were stratified by Prostate Imaging Reporting and Data System (PI-RADS) v2 scores and compared with Fisher's exact test. Area under the curve (AUC) was calculated for prostate-specific antigen (PSA), PSA density (PSAD), PI-RADS score, and subgroup analysis of individual readers' PI-RADS scores with respect to overall CDR and clinically significant CDR. Results The overall CDR was 76.7% (135/176), of which 76.3% (103/135) was clinically significant PCa. Among the 135 patients with PCa, transperineal TBx detected 90.4% of cases (122/135), either alone or in combination with transperineal SBx. The remaining 9.6% of cases (13/135) missed by transperineal TBx were diagnosed by transperineal SBx alone, of which three were clinically significant. Conversely, transperineal SBx missed 14% of cases (19/135), 14 of which were clinically significant PCa. Sensitivities for transperineal TBx and transperineal SBx were 90.4% and 85.9%, respectively. On a per-lesion basis, PI-RADS score (AUC 0.74) outperformed both PSA (AUC 0.59) and PSAD (AUC 0.63) in discriminating clinically significant from non-clinically significant PCa on transperineal TBx. Although not formally statistically tested, AUCs amongst different mpMRI readers appeared to display considerable variability. There were no adverse events, including sepsis. Conclusions Electromagnetically tracked transperineal TBx of MRI-visible lesions enhanced the ability of transperineal SBx to detect PCa, with greater sensitivity for clinically significant disease. These findings suggest transperineal TBx is a safe, alternative fusion platform for patients with a suspicious lesion on prostate MRI. The assessment of inter-reader variability, in conjunction with prediction of clinically significant PCa and CDR, is an important first step for quality control in implementing an MRI-based screening programme.

BackgroundDetection of viral RNA by nucleic acid amplification testing (NAAT) remains the gold standard for diagnosis of SARS-CoV-2 infection but is limited by high cost and other factors. Whether serology-based assays can be effectively incorporated into a diagnostic algorithm remains to be determined. Herein we describe the development of a serology-based testing algorithm for SARS-CoV-2 infection.Patients and MethodsBetween July 2020 and February 2021, we included symptomatic unvaccinated patients evaluated in the Emergency Department of our institution for suspected SARS-CoV-2. All patients had testing by real-time Reverse Transcription Polymerase Chain Reaction. The performance characteristics of five commercial enzymatic serology assays testing for different antibody isotypes were evaluated in a derivation cohort and the assay with the best performance was further tested on a validation cohort. Optimal cut-off points were determined using receiver operating characteristic (ROC) curves and further tested using logistic regression.ResultsThe derivation and validations cohorts included 72 and 319 patients, respectively. Based on its initial performance, the Elecsys Anti-SARS-CoV-2 assay (Roche Diagnostics) was further tested in the validation cohort. Using ROC curve analysis, we estimated the diagnostic performance for different cut-off points assuming a prevalence of positive tests of 5%. At any given cut-off point the NPV was over 97%.DiscussionThis study suggests that an initial diagnostic strategy using the Elecsys Anti-SARS-CoV-2 serology test in symptomatic unvaccinated patients could help to rule out an acute SARS-CoV2 infection and potentially lead to appropriately tailored infection control measures or rational guidance for further testing with a potential cost reduction and increased availability.

Electron-temperature (T e) measurements in implosions provide valuable diagnostic information, as T e is negligibly affected by residual flows and other non-thermal effects unlike ion-temperature inferred from a fusion product spectrum. In OMEGA cryogenic implosions, measurement of T e(t) can be used to investigate effects related to time-resolved hot-spot energy balance. The newly implemented phase-2 Particle X-ray Temporal Diagnostic (PXTD) utilizes four fast-rise (∼15 ps) scintillator-channels with distinct x-ray filtering. Titanium and stepped aluminum filtering were chosen to maximize detector sensitivity in the 10–20 keV range, as it has been shown that these x rays have similar density and temperature weighting to the emitted deuterium–tritium fusion neutrons (DTn) from OMEGA Cryo-DT implosions. High quality data have been collected from warm implosions at OMEGA. These data have been used to infer spatially integrated T e(t) with 3Hep). A future upgrade to the system will enable spatially integrated T e(t) with 40 ps time-resolution from cryogenic DT implosions.

In nuclear fusion research, the effective ion charge Z

BACKGROUND. The role of humoral immunity in COVID-19 is not fully understood, owing, in large part, to the complexity of antibodies produced in response to the SARS-CoV-2 infection. There is a pressing need for serology tests to assess patient-specific antibody response and predict clinical outcome. METHODS. Using SARS-CoV-2 proteome and peptide microarrays, we screened 146 COVID-19 patients’ plasma samples to identify antigens and epitopes. This enabled us to develop a master epitope array and an epitope-specific agglutination assay to gauge antibody responses systematically and with high resolution. RESULTS. We identified linear epitopes from the spike (S) and nucleocapsid (N) proteins and showed that the epitopes enabled higher resolution antibody profiling than the S or N protein antigen. Specifically, we found that antibody responses to the S-811–825, S-881–895, and N-156–170 epitopes negatively or positively correlated with clinical severity or patient survival. Moreover, we found that the P681H and S235F mutations associated with the coronavirus variant of concern B.1.1.7 altered the specificity of the corresponding epitopes. CONCLUSION. Epitope-resolved antibody testing not only affords a high-resolution alternative to conventional immunoassays to delineate the complex humoral immunity to SARS-CoV-2 and differentiate between neutralizing and non-neutralizing antibodies, but it also may potentially be used to predict clinical outcome. The epitope peptides can be readily modified to detect antibodies against variants of concern in both the peptide array and latex agglutination formats. FUNDING. Ontario Research Fund (ORF) COVID-19 Rapid Research Fund, Toronto COVID-19 Action Fund, Western University, Lawson Health Research Institute, London Health Sciences Foundation, and Academic Medical Organization of Southwestern Ontario (AMOSO) Innovation Fund.

We have developed a rapid, accurate, and cost-effective serologic test for SARS-CoV-2 virus, which caused the COVID-19 pandemic, on the basis of antibody-dependent agglutination of antigen-coated latex particles. When validated using plasma samples that are positive or negative for SARS-CoV-2, the agglutination assay detected antibodies against the receptor-binding domain of the spike (S-RBD) or the nucleocapsid protein of SARS-CoV-2 with 100% specificity and ∼98% sensitivity. Furthermore, we found that the strength of the S-RBD antibody response measured by the agglutination assay correlated with the efficiency of the plasma in blocking RBD binding to the angiotensin-converting enzyme 2 in a surrogate neutralization assay, suggesting that the agglutination assay might be used to identify individuals with virus-neutralizing antibodies. Intriguingly, we found that >92% of patients had detectable antibodies on the day of a positive viral RNA test, suggesting that the agglutination antibody test might complement RNA testing for the diagnosis of SARS-CoV-2 infection., Graphical abstract, Motivation As COVID-19 continues to spread around the world, there is urgent need for a rapid yet accurate antibody test to detect individuals' humoral immune responses to the SARS-CoV-2 virus and emerging variants of concern. A simple and reliable antibody test would also allow longitudinal analysis of antibody responses to inform vaccination strategies. We addressed this pressing need by developing a simple, quick, and sensitive antibody test based on latex particle agglutination., Esmail et al. develop and validate a rapid and cost-effective antibody-dependent agglutination (aggregation) test by using SARS-CoV-2 antigen-coated latex particles. The agglutination assay detects SARS-CoV-2 antibodies with 100% specificity and ∼98% sensitivity. They further show that the agglutination assay might be used to identify neutralizing antibodies and monitor dynamic changes in antibody responses over time.

Objectives A consensus guidance is provided for testing, utility and verification of SARS-CoV-2 point-of-care test (POCT) performance and implementation of a quality management program, focusing on nucleic acid and antigen targeted technologies. Design and Methods The recommendations are based on current literature and expert opinion from the members of Canadian Society of Clinical Chemists (CSCC), and are intended for use inside or outside of healthcare settings that have varied levels of expertise and experience with POCT. Results and Conclusions Here we discuss sampling requirements, biosafety, SARS-CoV-2 point-of-care testing methodologies (with focus on Health Canada approved tests), test performance and limitations, test selection, testing utility, development and implementation of quality management systems, quality improvement, and medical and scientific oversight.

We calibrated the JSBACH model with six different stomatal conductance formulations using measurements from 10 FLUXNET coniferous evergreen sites in the boreal zone. The parameter posterior distributions were generated by the adaptive population importance sampler (APIS); then the optimal values were estimated by a simple stochastic optimisation algorithm. The model was constrained with in situ observations of evapotranspiration (ET) and gross primary production (GPP). We identified the key parameters in the calibration process. These parameters control the soil moisture stress function and the overall rate of carbon fixation. The JSBACH model was also modified to use a delayed effect of temperature for photosynthetic activity in spring. This modification enabled the model to correctly reproduce the springtime increase in GPP for all conifer sites used in this study. Overall, the calibration and model modifications improved the coefficient of determination and the model bias for GPP with all stomatal conductance formulations. However, only the coefficient of determination was clearly improved for ET. The optimisation resulted in best performance by the Bethy, Ball–Berry, and the Friend and Kiang stomatal conductance models. We also optimised the model during a drought event at a Finnish Scots pine forest site. This optimisation improved the model behaviour but resulted in significant changes to the parameter values except for the unified stomatal optimisation model (USO). Interestingly, the USO demonstrated the best performance during this event.

Significance Prostate cancer is the most common nonskin cancer in the United States, where approximately 1 in 9 men will be diagnosed in their lifetime. The prostate is near several vital structures, such as the urethra and neurovascular bundle, and whole gland treatments for prostate cancer can disrupt normal urinary, bowel, and sexual functioning. Here we report the initial results of a clinical trial for nanoparticle-based photothermal cancer therapy. The trial was designed to perform ultrafocal photothermal ablation of cancerous tumors within the prostate. Gold-silica nanoparticles designed to absorb near-infrared light at wavelengths of high tissue transparency provide a highly localized light-based strategy for the treatment of prostate cancer, with substantially reduced risks for deleterious treatment-related side effects., Biocompatible gold nanoparticles designed to absorb light at wavelengths of high tissue transparency have been of particular interest for biomedical applications. The ability of such nanoparticles to convert absorbed near-infrared light to heat and induce highly localized hyperthermia has been shown to be highly effective for photothermal cancer therapy, resulting in cell death and tumor remission in a multitude of preclinical animal models. Here we report the initial results of a clinical trial in which laser-excited gold-silica nanoshells (GSNs) were used in combination with magnetic resonance–ultrasound fusion imaging to focally ablate low-intermediate-grade tumors within the prostate. The overall goal is to provide highly localized regional control of prostate cancer that also results in greatly reduced patient morbidity and improved functional outcomes. This pilot device study reports feasibility and safety data from 16 cases of patients diagnosed with low- or intermediate-risk localized prostate cancer. After GSN infusion and high-precision laser ablation, patients underwent multiparametric MRI of the prostate at 48 to 72 h, followed by postprocedure mpMRI/ultrasound targeted fusion biopsies at 3 and 12 mo, as well as a standard 12-core systematic biopsy at 12 mo. GSN-mediated focal laser ablation was successfully achieved in 94% (15/16) of patients, with no significant difference in International Prostate Symptom Score or Sexual Health Inventory for Men observed after treatment. This treatment protocol appears to be feasible and safe in men with low- or intermediate-risk localized prostate cancer without serious complications or deleterious changes in genitourinary function.

e18780 Background: Patients with hematologic malignancies have a lower vaccine response and higher rates for SARS CoV-2 morbidity and mortality. We present preliminary data focusing on humoral vaccine responses and correlates with disease subtype and treatment exposure. Methods: We analyzed data from 332 patients with a hematologic malignancy from May 1, 2021 – Jan 31, 2022 who received SARS-CoV-2 vaccination and performed a prospective cohort serologic study with the Elecsys® Anti-SARS-CoV-2-S test. Patients received homologous or heterologous vaccine combination of BNT162b2, mRNA1273, ChAdOx1 nCoV-19, and/or Ad26.COV2.S. Blood samples were obtained before any vaccination, 2-6 weeks after the second vaccine (2V), before third vaccine (3V), and 2-6 weeks after 3V. Results: The median age was 67 years (range 18-91years) with 41.9% female. At 2V, 11.5% and at 3V, 23.8% received heterologous vaccines. Treatment status at first vaccine dose significantly affected peak 2V antibody response (p < 0.05). Seropositive rate and median antibody titer after 2V for previously untreated patients were higher compared to patients on active therapy or had previously been treated. Treatment naïve (n = 60; seropositivity 85.1%; median titer 1306 U/mL; [Q1-Q3:11.4- > 2499]); first-line (1L) active therapy (n = 127;65.4%; 41.25 U/mL; [ < 0.8-592.5]); second-line and beyond (2L+) active therapy (n = 56; 60.7%; 2.6U/mL; [ < 0.8-154]); previous treatment with 1L (n = 66;64.8%; 118 U/mL; [ < 0.8- > 2499]); previous treatment with 2L+ (n = 23; 59.1%; 4U/mL; [ < 0.8-229.5]). Of 61 patients that were seronegative at 2V, 17 (27.9%) seroconverted after 3V. Anti-CD20 monoclonal antibody (mAb) containing therapy as the most recent treatment from 2V had the greatest impact on humoral response. Exposure to anti-CD20 mAb based regimens or as monotherapy revealed low antibody responses (n = 84; seropositivity 22.6%; median titer < 0.8 U/mL; Q1-Q3 [ < 0.8- < 0.8]). On analysis of indolent B-cell Non-Hodgkin Lymphomas whereby antiCD-20 mAb are often incorporated, treatment proximity to 2V impacted responses: < 3 months (n = 33; 22%; < 0.8 U/mL; [ < 0.8- < 0.8]) vs. 12-24 months (n = 4; 60%; 228 U/mL; [ < 0.8-232]). In contrast, tyrosine kinase inhibitor (n = 38; 100%; 858 U/mL; [221- > 2499]), proteosome inhibitor monotherapy (n = 4;100%; median titer 1520 U/mL; [462- > 2499]) were among the subgroups with the highest numerical responses, however, the addition of corticosteroids impacted vaccine response as seen in proteosome inhibitor with corticosteroids (n = 7; 85.7%; 6.6 U/mL; [1.8-115.2]). Conclusions: The humoral response from our single institution cohort identifies diminished responses depending on treatment status and the type of treatment including the proximity of treatment exposure to receipt of vaccination. Furthermore, vaccine boosters can induce antibody responses in patients who were previously seronegative.

BACKGROUNDThe role of humoral immunity in the coronavirus disease 2019 (COVID-19) is not fully understood owing, in large part, to the complexity of antibodies produced in response to the SARS-CoV-2 infection. There is a pressing need for serology tests to assess patient-specific antibody response and predict clinical outcome.METHODSUsing SARS-CoV-2 proteome and peptide microarrays, we screened 146 COVID-19 patients plasma samples to identify antigens and epitopes. This enabled us to develop a master epitope array and an epitope-specific agglutination assay to gauge antibody responses systematically and with high resolution.RESULTSWe identified 54 linear epitopes from the Spike (S) and Nucleocapsid (N) protein and showed that epitopes enabled higher resolution antibody profiling than protein antigens. Specifically, we found that antibody responses to the S(811-825), S(881-895) and N(156-170) epitopes negatively or positively correlated with clinical severity or patient survival. Moreover, we found that the P681H and S235F mutations associated with the coronavirus variant B.1.1.7 altered the specificity of the corresponding epitopes.CONCLUSIONSEpitope-resolved antibody testing not only offers a high-resolution alternative to conventional immunoassays to delineate the complex humoral immunity to SARS-CoV-2 and differentiate between neutralizing and non-neutralizing antibodies, it may also be used as predictor of clinical outcome. The epitope peptides can be readily modified to detect antibodies against variants in both the peptide array and latex agglutination formats.FUNDINGOntario Research Fund (ORF)-COVID-19 Rapid Research Fund, the Toronto COVID-19 Action Fund, Western University, the Lawson Health Research Institute, the London Health Sciences Foundation, and the AMOSO Innovation Fund.

Key Messages • Consider safety precautions and infection control processes, particularly in remote testing locations when using rapid SARS-CoV-2 devices. • Seek oversight and partnership with an accredited clinical laboratory for guidance on setting up a quality assurance framework. • Rapid-testing for SARS-CoV-2 requires method verification prior to clinical implementation.

The second operation phase of W7-X (OP1.2) showed the potential of exclusively electron cyclotron resonance heating (ECRH)-sustained plasma operations in stellarators. Employing multi-pass ECRH scenario in the second harmonic O-mode (O2-ECRH), stationary densities of up to 1.4 × 1020 m−3 could be achieved. This scenario also made stationary divertor detachment possible, which is a reactor-relevant scenario for power and particle exhaust. At high densities and with sufficiently high density gradients for an improved ion confinement, the coupling between the electrons and ions was strong enough to bring the ion temperature to values above 3 keV and to the neoclassical limit for some magnetic configurations, thus enabling to test the W7-X neoclassical optimization. The planned enhancement of the ECRH performance will enable to advance towards reactor-relevant beta values and to investigate their stability and confinement of fast particles, which is a priority goal of W7-X.

When the first suspected human-to-human transmission of the novel coronavirus was reported in January 2020, the United States had in place an elaborate set of pandemic disaster and response plans that spanned hundreds of pages. The George W. Bush administration spearheaded national pandemic planning in 2005 as part of the post-September 11 efforts to modernize the country’s disaster response capabilities. Subsequent administrations revisited and revised the various pandemic plans, including the Trump administration as recently as 2017 and 2018. Despite these detailed plans, the Trump administration was slow to respond to the emerging public health crisis or implement any of the prescribed protocols. Federal officials lost valuable time as they downplayed the risk posed by COVID-19 and repeatedly assured the American people that the virus would simply “go away.” By March 2020, a frightening spike in cases in the Northeast made the pandemic impossible to ignore. President Trump and other administration officials shifted tactics and began to characterize COVID-19 as the quintessential “black swan” – a threat that no one could have foreseen. President Trump repeatedly told the American people that “no one could have predicted something like this” even though official federal policy suggested a very different story. Far from being a black swan, the COVID-19 pandemic was widely anticipated and, according to many epidemiologists, inevitable. This article argues that our botched federal response was not so much a failure of policy per se, but rather a failure of political will. The federal government had a robust pandemic policy in place; it simply chose not to follow it. This failure of political will illustrates the dangers that arise when public health measures are politicized and weaponized for partisan advantage and demands strong interventions to ensure federal accountability and transparency. The first section of this article outlines the evolution of our national pandemic plans within the broader context of disaster and response planning. The second section explains the pandemic staging framework that is used to organize and coordinate decision making within a pandemic. The third section charts the federal response during the crucial first three months of the public health crisis, specifically identifying instances where the federal government failed to follow its own clearly articulated pandemic policy. The final section outlines some lessons learned from the pandemic and proposes reforms to insulate public health measures from partisan wrangling and keep our federal government faithful to its foremost obligation, namely to promote the general welfare

The investigation of fuel retention in fusion experiments is important in view of plasma density control as well as tritium inventory for future fusion reactors. We present a first gas balance of the stellarator Wendelstein 7-X with its inertially cooled graphite divertor. The gas balance is used to estimate the wall inventory and it is found that the wall plays an important and dynamic role, absorbing or releasing particles depending on the plasma conditions. Several different scenarios are presented and the effect of fueling and heating on the wall inventory is assessed. We find that the record duration plasma experiment of 100 s required previous shorter plasmas to be successfully conducted.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has grown into worst public health crisis since the 1918 influenza pandemic. As COVID-19 continues to spread around the world, there is urgent need for a rapid, yet accurate antibody test to identify infected individuals in populations to inform health decisions. We have developed a rapid, accurate and cost-effective serologic test based on antibody-dependent agglutination of antigen-coated latex particles, which uses ∼5 µl plasma and takes 92% of patients had detectable antibodies on the day of positive viral RNA test, suggesting that seroconversion may occur earlier than previously thought and that the agglutination antibody test may complement RNA testing for POC diagnosis of SARS-CoV-2 infection.

A single-reservoir particle balance for the main plasma species hydrogen has been established for W7-X. This has enabled the quantitative characterization of the particle sources in the standard island divertor configuration for the first time. Findings from attached scenarios with two different island sizes with a boronized wall and turbo molecular pumping are presented. Fueling efficiencies, particle flows and source locations were measured and used to infer the total particle confinement time τ p. Perturbative gas injection experiments served to measure the effective particle confinement time τ p * . Combining both confinement times provides access to the global recycling coefficient R ¯ . Hydrogen particle inventories have been addressed and the knowledge of particle sources and sinks reveals the core fueling distribution and provides insight into the capability of the magnetic islands to control exhaust features. Measurements of hydrogen fueling efficiencies were sensitive to the precise fueling location and measured between 12% and 31% with the recycling fueling at the strike line modeled at only 6%, due to much higher densities. 15% of the total 5.2 × 1022 a/s recycling flow ionizes far away from the recycling surfaces in the main chamber. It was shown that 60% of recycled particles ionize above the horizontal and 18% above the vertical divertor target, while the remainder of the recycling flow ionizes above the baffle (7%). Combining these source terms with their individual fueling efficiencies resolves the core fueling distribution. Due to the higher fueling efficiency in the main chamber, up to 51% of the total 5.1 × 1021 s−1 core fueling particles are entering the confined plasma from the main chamber. τ p values in the range of 260 ms were extracted for these discharges. Together with τ p, the global recycling coefficient R ¯ was resolved for every τ p * measurement and a typical value close to unity was obtained. An increase of the island size, resulted in no change of τ p, but doubled τ p * , indicating the feasibility of the control coils as an actuator to control exhaust features without affecting core confinement properties.

In Europe, three widespread extreme summer drought and heat (DH) events have occurred in 2003, 2010 and 2018. These events were comparable in magnitude but varied in their geographical distribution and biomes affected. In this study, we perform a comparative analysis of the impact of the DH events on ecosystem CO2 fluxes over Europe based on an ensemble of 11 dynamic global vegetation models (DGVMs), and the observation-based FLUXCOM product. We find that all DH events were associated with decreases in net ecosystem productivity (NEP), but the gross summer flux anomalies differ between DGVMs and FLUXCOM. At the annual scale, FLUXCOM and DGVMs indicate close to neutral or above-average land CO2 uptake in DH2003 and DH2018, due to increased productivity in spring and reduced respiration in autumn and winter compensating for less photosynthetic uptake in summer. Most DGVMs estimate lower GPP sensitivity to soil moisture during extreme summers than FLUXCOM. Finally, we show that the different impacts of the DH events at continental-scale GPP are in part related to differences in vegetation composition of the regions affected and to regional compensating or offsetting effects from climate anomalies beyond the DH centres.This article is part of the theme issue ‘Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale’.

The COVID-19 pandemic is an unprecedented public health crisis that has prompted an unprecedented response Drastic and previously unthinkable steps have been t

The dynamic global vegetation model LPJmL4 is a process-based model that simulates climate and land use change impacts on the terrestrial biosphere, agricultural production, and the water and carbon cycle. Different versions of the model have been developed and applied to evaluate the role of natural and managed ecosystems in the Earth system and the potential impacts of global environmental change. A comprehensive model description of the new model version, LPJmL4, is provided in a companion paper (Schaphoff et al., 2018c). Here, we provide a full picture of the model performance, going beyond standard benchmark procedures and give hints on the strengths and shortcomings of the model to identify the need for further model improvement. Specifically, we evaluate LPJmL4 against various datasets from in situ measurement sites, satellite observations, and agricultural yield statistics. We apply a range of metrics to evaluate the quality of the model to simulate stocks and flows of carbon and water in natural and managed ecosystems at different temporal and spatial scales. We show that an advanced phenology scheme improves the simulation of seasonal fluctuations in the atmospheric CO2 concentration, while the permafrost scheme improves estimates of carbon stocks. The full LPJmL4 code including the new developments will be supplied open source through https://gitlab.pik-potsdam.de/lpjml/LPJmL. We hope that this will lead to new model developments and applications that improve the model performance and possibly build up a new understanding of the terrestrial biosphere.

This paper provides a comprehensive description of the newest version of the Dynamic Global Vegetation Model with managed Land, LPJmL4. This model simulates – internally consistently – the growth and productivity of both natural and agricultural vegetation as coherently linked through their water, carbon, and energy fluxes. These features render LPJmL4 suitable for assessing a broad range of feedbacks within and impacts upon the terrestrial biosphere as increasingly shaped by human activities such as climate change and land use change. Here we describe the core model structure, including recently developed modules now unified in LPJmL4. Thereby, we also review LPJmL model developments and evaluations in the field of permafrost, human and ecological water demand, and improved representation of crop types. We summarize and discuss LPJmL model applications dealing with the impacts of historical and future environmental change on the terrestrial biosphere at regional and global scale and provide a comprehensive overview of LPJmL publications since the first model description in 2007. To demonstrate the main features of the LPJmL4 model, we display reference simulation results for key processes such as the current global distribution of natural and managed ecosystems, their productivities, and associated water fluxes. A thorough evaluation of the model is provided in a companion paper. By making the model source code freely available at https://gitlab.pik-potsdam.de/lpjml/LPJmL, we hope to stimulate the application and further development of LPJmL4 across scientific communities in support of major activities such as the IPCC and SDG process.

In the original version of [this article][1] ([1][2]), the test groups in Fig. 3B were incorrectly listed. The error has been corrected in the latest online HTML and PDF versions of the article. The authors regret this error. 1. 1.[↵][3]1. Nevala WK, 2. Buhrow SA, 3. Knauer DJ

INTRODUCTION AND OBJECTIVES:The rationale behind focal therapy (FT) for prostate cancer (PCA) is to achieve cancer control while minimizing side effects associated with whole gland treatment. Multi...

Organic anion transporting polypeptide 2B1 (OATP2B1) is a widely expressed membrane transporter with diverse substrate specificity. In vitro and clinical studies suggest a role for intestinal OATP2B1 in the oral absorption of medications. Moreover, OATP2B1 is highly expressed in hepatocytes where it is thought to promote liver drug clearance. But until now, a shortcoming of studies implicating OATP2B1 in drug disposition has been a lack of in vivo models. Here, we report the development of a mouse model with targeted, global disruption of the Slco2b1 gene (KO) for examining the disposition of two confirmed mOATP2B1 substrates, namely fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wildtype (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-last) than WT mice, respectively. In WT mice, co-administration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced Cmax by 80% and 88%, respectively, while the AUC0-last was lower by 35% and 70%, respectively. In KO mice, AJ co-administration reduced oral fexofenadine Cmax and AUC0-last by 67% and 59%, respectively, while GFJ had no effects. Intravenous and oral rosuvastatin pharmacokinetics were similar among WT and KO mice. We conclude that intestinal OATP2B1 is a determinant of oral fexofenadine absorption, as well as a target for fruit juice interactions. OATP2B1 does not significantly influence rosuvastatin disposition in mice. SIGNIFICANCE STATEMENT A novel mouse model with targeted disruption of the Slco2b1 gene revealed that OATP2B1 is a determinant of the oral absorption but not systemic disposition of fexofenadine, as well as a target of fruit juice interactions. Rosuvastatin oral and intravenous pharmacokinetics were not dependent on OATP2B1. These findings support the utility of the Slco2b1 knockout mice model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology.

This chapter examines the implications of the landmark US Supreme Court decision Obergefell v. Hodges for same-sex marriage, divorce, and parental rights. Heralded as one of the most significant civil rights victories in recent memory, Obergefell had an immediate impact on the lives of same-sex couples by providing uniform and nationwide access to both marriage and divorce. It ended a confusing patchwork of state laws, some of which recognized same-sex marriage and some of which prohibited not only same-sex marriage but also domestic partnerships and civil unions. Obergefell also ensured that all same-sex married couples would be eligible for federal benefits regardless of where they lived. The longer-term effects and applications of Obergefell remain unclear, especially with respect to parental rights. In addition, Obergefell has ignited a backlash of religious exemptions law and concern remains that marriage equality may further marginalize nontraditional families and those who choose not to marry.

In the United States, informal elder care is principally the responsibility of younger relatives. Adult children perform the majority of elder care and non-relatives perform only 14 percent of care. Caregiving in the lesbian, gay, bisexual, and transgender, or LGBT, community follows a very different pattern that reflects the importance of “chosen family” in the lives of LGBT older adults. Instead of relying on relatives, LGBT older adults largely care for each other. Relatives provide only 11 percent of all elder care. This article explores the high level of caregiving by non-relatives in the LGBT community. It asks what motivates friends, neighbors, and community members to provide care for someone whom the law considers a legal stranger. It also asks what steps policy makers can take to facilitate and encourage this type of caregiving. Finally, it asks what lessons can be learned from LGBT older adults about the nature of both caregiving and community. As the aging population becomes more diverse, aging policies will have to become more inclusive to address the differing needs of various communities, including LGBT older adults. The potential lessons learned from the pattern of elder care in the LGBT community, however, extend far beyond a simple commitment to diversity.

Dual antiplatelet therapy with clopidogrel and aspirin has become the mainstay of therapy for patients with acute coronary syndrome (ACS)6 undergoing percutaneous coronary interventions (PCI). Many pharmacokinetic and pharmacodynamic studies have demonstrated substantial interindividual variation in antiplatelet response with clopidogrel, a significant proportion of which is explained by the variation in plasma concentrations of the clopidogrel active metabolite. Clopidogrel is a prodrug that requires bioactivation by the highly polymorphic enzyme CYP2C19 to form the active metabolite. The growing body of literature has implicated the loss-of-function cytochrome P450, family 2, subfamily C, polypeptide 19 variant ( CYP2C19 * 2 )7 variant with an increased risk of major cardiovascular events. This evidence prompted the US Food and Drug Administration (FDA) to implement a boxed warning on the clopidogrel label describing the relationship between CYP2C19 pharmacogenetics and drug response, emphasizing the diminished effectiveness in CYP2C19 poor metabolizers. CYP2C19 pharmacogenetic testing is currently available to guide antiplatelet therapy; however, there are challenges with implementing pharmacogenetic-guided therapy in clinical practice. In this Q&A, 3 experts discuss the current state, challenges, and future direction of CYP2C19 pharmacogenetic testing for clopidogrel therapy. Can you briefly summarize the latest developments and evidence for pharmacogenetic testing in patients on clopidogrel therapy? Jean Hulot: Clopidogrel is a prodrug that requires hepatic bioactivation to generate an active metabolite with antiplatelet properties. The CYP2C19 enzyme is directly involved in this bioactivation process but its activity is genetically determined. A common loss-of-function genetic variant (named CYP2C19 * 2 ; c.681G>A; rs4244285) is associated with reduced formation of the clopidogrel active metabolite and reduced pharmacodynamic response to the drug, thus resulting in high on-treatment platelet reactivity and more frequent adverse cardiovascular events. This effect is particularly observed in homozygous carriers of the mutated allele (so-called poor metabolizers), who represent 3%–4% of Caucasian patients. …

With the eddy covariance (EC) technique, net fluxes of carbon dioxide (CO2) and other trace gases as well as water and energy fluxes can be measured at the ecosystem level. These flux measurements are a main source for understanding biosphere–atmosphere interactions and feedbacks through cross-site analysis, model–data integration, and upscaling. The raw fluxes measured with the EC technique require extensive and laborious data processing. While there are standard tools1 available in an open-source environment for processing high-frequency (10 or 20 Hz) data into half-hourly quality-checked fluxes, there is a need for more usable and extensible tools for the subsequent post-processing steps. We tackled this need by developing the REddyProc package in the cross-platform language R that provides standard CO2-focused post-processing routines for reading (half-)hourly data from different formats, estimating the u* threshold, as well as gap-filling, flux-partitioning, and visualizing the results. In addition to basic processing, the functions are extensible and allow easier integration in extended analysis than current tools. New features include cross-year processing and a better treatment of uncertainties. A comparison of REddyProc routines with other state-of-the-art tools resulted in no significant differences in monthly and annual fluxes across sites. Lower uncertainty estimates of both u* and resulting gap-filled fluxes by 50 % with the presented tool were achieved by an improved treatment of seasons during the bootstrap analysis. Higher estimates of uncertainty in daytime partitioning (about twice as high) resulted from a better accounting for the uncertainty in estimates of temperature sensitivity of respiration. The provided routines can be easily installed, configured, and used. Hence, the eddy covariance community will benefit from the REddyProc package, allowing easier integration of standard post-processing with extended analysis. 1http://fluxnet.fluxdata.org/2017/10/10/toolbox-a-rolling-list-of-softwarepackages-for-flux-related-data-processing/, last access: 17 August 2018

Introduction We assessed the pharmacokinetic and pharmacodynamic impact of converting stable simultaneous pancreas-kidney (SPK) recipients from standard tacrolimus (Prograf) to long-acting tacrolimus (Advagraf). Methods In a randomized prospective crossover study, stable SPK recipients on Prograf were assigned to Prograf with 1:1 conversion to Advagraf or vice versa. Demographics, tacrolimus, mycophenolic acid levels, and Cylex CD4 + ATP levels were taken at specified intervals in addition to standard blood work. Results Twenty-one patients, who were a minimum of 1 year post-transplant, were entered into the study. No difference in tacrolimus or mycophenolic acid levels was noted between patients who were first assigned to Prograf or Advagraf. Additionally, Cylex levels as well as serum creatinine, lipase, and blood sugar levels were unchanged. There were no episodes of rejection during the 6-month study. Conclusions It is safe to convert between Prograf and Advagraf 1:1, without major impact on pharmacokinetics or pharmacodynamics in SPK recipients.