Discussion Law & Society Review at Fifty: A Debate on the Future of Publishing by the Law & Society Association

This contribution presents a series of statements on the future of publishing by the Law & Society Review and the Law & Society Association generally. Framed by the first author's introductory and concluding comments are contributions by Halliday, Liu, Morrill, Seron, and Silbey. This debate, based on a LSR 50th anniversary panel held at the 2016 Annual Meeting of the LSA, is intended to open up a broader conversation among members of the Association. Positions by individual contributors can only be linked to them and not to the group of contributors

Measurements and analysis of microwave nonlinearities in ferroelectric thin film transmission lines

This work evaluates the microwave nonlinear properties of ferroelectric BaSrTiO thin films by measuring the frequency response of several coplanar transmission lines and interdigital capacitor structures as a function of the applied electric field from 150 Hz to 40 GHz. From these measurements, we obtain the distributed nonlinear capacitance C(Vdc) as a function of dc bias. We also measure the harmonic generation at microwave frequencies in ferroelectric transmission lines, and use an accurate circuit model to obtain C(Vrf), the nonlinear capacitance as a function of RF bias. Information about the tuning speed of the film is obtained from a comparison between the two nonlinear capacitances. Characterization of this mechanism is also required to assess the spurious signal generation in ferroelectric-based devicesPeer Reviewe

Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation

The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability-and ambiguity-in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation.Copyright © 2022 Seron, Rabant, Becker, Roufosse, Bellini, Böhmig, Budde, Diekmann, Glotz, Hilbrands, Loupy, Oberbauer, Pengel, Schneeberger and Naesens

Proposed Definitions of Antibody-Mediated Rejection for Use as a Clinical Trial Endpoint in Kidney Transplantation

Antibody-mediated rejection (AMR) is caused by antibodies that recognize donor human leukocyte antigen (HLA) or other targets. As knowledge of AMR pathophysiology has increased, a combination of factors is necessary to confirm the diagnosis and phenotype. However, frequent modifications to the AMR definition have made it difficult to compare data and evaluate associations between AMR and graft outcome. The present paper was developed following a Broad Scientific Advice request from the European Society for Organ Transplantation (ESOT) to the European Medicines Agency (EMA), which explored whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research. ESOT considers that an AMR diagnosis must be based on a combination of histopathological factors and presence of donor-specific HLA antibodies in the recipient. Evidence for associations between individual features of AMR and impaired graft outcome is noted for microvascular inflammation scores ≥2 and glomerular basement membrane splitting of >10% of the entire tuft in the most severely affected glomerulus. Together, these should form the basis for AMR-related endpoints in clinical trials of kidney transplantation, although modifications and restrictions to the Banff diagnostic definition of AMR are proposed for this purpose. The EMA provided recommendations based on this Broad Scientific Advice request in December 2020; further discussion, and consensus on the restricted definition of the AMR endpoint, is required.Copyright © 2022 Roufosse, Becker, Rabant, Seron, Bellini, Böhmig, Budde, Diekmann, Glotz, Hilbrands, Loupy, Oberbauer, Pengel, Schneeberger and Naesens

Cellular Immunity to Predict the Risk of Cytomegalovirus Infection in Kidney Transplantation: A Prospective, Interventional, Multicenter Clinical Trial

Background: Improving cytomegalovirus (CMV) immune-risk stratification in kidney transplantation is highly needed to establish guided preventive strategies. Methods: This prospective, interventional, multicenter clinical trial assessed the value of monitoring pretransplant CMV-specific cell-mediated immunity (CMI) using an interferon-γrelease assay to predict CMV infection in kidney transplantation. One hundred sixty donor/recipient CMV-seropositive (D+/R+) patients, stratified by their baseline CMV (immediate-early protein 1)-specific CMI risk, were randomized to receive either preemptive or 3-month antiviral prophylaxis. Also, 15-day posttransplant CMI risk stratification and CMI specific to the 65 kDa phosphoprotein (pp65) CMV antigen were investigated. Immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids in 80% of patients, whereas 20% received thymoglobulin induction therapy. Results: Patients at high risk for CMV based on pretransplant CMI developed significantly higher CMV infection rates than those deemed to be at low risk with both preemptive (73.3% vs 44.4%; odds ratio [OR], 3.44 [95% confidence interval {CI}, 1.30-9.08]) and prophylaxis (33.3% vs 4.1%; OR, 11.75 [95% CI, 2.31-59.71]) approaches. The predictive capacity for CMV-specific CMI was only found in basiliximab-treated patients for both preemptive and prophylaxis therapy. Fifteen-day CMI risk stratification better predicted CMV infection (81.3% vs 9.1%; OR, 43.33 [95% CI, 7.89-237.96]). Conclusions: Pretransplant CMV-specific CMI identifies D+/R+ kidney recipients at high risk of developing CMV infection if not receiving T-cell-depleting antibodies. Monitoring CMV-specific CMI soon after transplantation further defines the CMV infection prediction risk. Monitoring CMV-specific CMI may guide decision making regarding the type of CMV preventive strategy in kidney transplantation. Clinical Trials Registration: NCT02550639

Efficacy of Metreleptin in Obese Patients With Type 2 Diabetes: Cellular and Molecular Pathways Underlying Leptin Tolerance

Objective: Metreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes. Research Design and Methods: We studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo–controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro. Results: In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA$_{1c}$ marginally (8.01 $\pm$ 0.93–7.96 $\pm$ 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of $\sim$50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at $\sim$50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling. Conclusions: In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA$_{1c}$ marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes

Carnegie Supernova Project: The First Homogeneous Sample of Super-Chandrasekhar-mass/2003fg-like Type Ia Supernovae

We present a multiwavelength photometric and spectroscopic analysis of 13 super-Chandrasekhar-mass/2003fg-like Type Ia supernovae (SNe Ia). Nine of these objects were observed by the Carnegie Supernova Project. The 2003fg-like SNe have slowly declining light curves (Δm 15(B) < 1.3 mag), and peak absolute B-band magnitudes of -19 < M B < -21 mag. Many of the 2003fg-like SNe are located in the same part of the luminosity-width relation as normal SNe Ia. In the optical B and V bands, the 2003fg-like SNe look like normal SNe Ia, but at redder wavelengths they diverge. Unlike other luminous SNe Ia, the 2003fg-like SNe generally have only one i-band maximum, which peaks after the epoch of the B-band maximum, while their near-IR (NIR) light-curve rise times can be ⪆40 days longer than those of normal SNe Ia. They are also at least 1 mag brighter in the NIR bands than normal SNe Ia, peaking above M H = -19 mag, and generally have negative Hubble residuals, which may be the cause of some systematics in dark-energy experiments. Spectroscopically, the 2003fg-like SNe exhibit peculiarities such as unburnt carbon well past maximum light, a large spread (8000-12,000 km s-1) in Si ii λ6355 velocities at maximum light with no rapid early velocity decline, and no clear H-band break at +10 days. We find that SNe with a larger pseudo-equivalent width of C ii at maximum light have lower Si ii λ6355 velocities and more slowly declining light curves. There are also multiple factors that contribute to the peak luminosity of 2003fg-like SNe. The explosion of a C-O degenerate core inside a carbon-rich envelope is consistent with these observations. Such a configuration may come from the core-degenerate scenario.Fil: Ashall, C.. University Hawaii Institute For Astronomy; Estados UnidosFil: Lu, J.. Florida State University; Estados UnidosFil: Hsiao, E. Y.. Florida State University; Estados UnidosFil: Hoeflich, P.. Florida State University; Estados UnidosFil: Phillips, M. M.. Las Campanas Observatory; ChileFil: Galbany, Lluís. Instituto de Ciencias del Espacio; EspañaFil: Burns, C. R.. Las Campanas Observatory; ChileFil: Contreras, C.. Las Campanas Observatory; ChileFil: Krisciunas, K.. Texas A&M University; Estados UnidosFil: Morrell, Nidia Irene. Las Campanas Observatory; ChileFil: Stritzinger, M. D.. University Aarhus; DinamarcaFil: Suntzeff, Nicholas B.. Texas A&M University; Estados UnidosFil: Taddia, F.. University Aarhus; DinamarcaFil: Anais, J.. Las Campanas Observatory; ChileFil: Baron, E.. Oklahoma State University; Estados Unidos. Universitat Hamburg; AlemaniaFil: Brown, P. J.. Texas A&M University; Estados UnidosFil: Busta, L.. Las Campanas Observatory; ChileFil: Campillay, A.. Universidad de La Serena; ChileFil: Castellón, S.. Las Campanas Observatory; ChileFil: Corco, C.. Las Campanas Observatory; Chile. Soar Telescope; ChileFil: Davis, S.. University of California at Davis; Estados UnidosFil: Folatelli, Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Förster, F.. Universidad de Chile; Chile. Instituto Milenio de Astrofísica; ChileFil: Freedman, W. L.. University of Chicago; Estados UnidosFil: Gonzaléz, C.. Las Campanas Observatory; ChileFil: Hamuy, M.. Universidad de Chile; ChileFil: Holmbo, S.. University Aarhus; DinamarcaFil: Kirshner, R. P.. Harvard-Smithsonian Center for Astrophysics; Estados UnidosFil: Kumar, S.. Florida State University; Estados UnidosFil: Marion, G. H.. University of Texas at Austin; Estados UnidosFil: Mazzali, P.. Liverpool John Moores University; Reino UnidoFil: Morokuma, T.. The University Of Tokyo; JapónFil: Nugent, P. E.. Lawrence Berkeley National Laboratory; Estados Unidos. University of California at Berkeley; Estados UnidosFil: Persson, S. E.. Las Campanas Observatory; ChileFil: Piro, A. L.. Las Campanas Observatory; ChileFil: Roth, M.. Las Campanas Observatory; ChileFil: Salgado, F.. Las Campanas Observatory; ChileFil: Sand, D.J.. University of Arizona; Estados UnidosFil: Seron, J.. Las Campanas Observatory; ChileFil: Shahbandeh, M.. Florida State University; Estados UnidosFil: Shappee, B. J.. University Hawaii Institute For Astronomy; Estados Unido

Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation : The 2019 Expert Consensus From the Transplantion Society Working Group

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes