bluuebunny/crossref_metadata_2025_split huggingface dataset:
KEYNOTE-630: Phase 3 study of adjuvant pembrolizumab versus placebo in patients with high-risk, locally advanced cutaneous squamous cell carcinoma.
Authors: Geiger Jessica Lyn , Daniels Gregory A. , Cohen Ezra E.W. , Ge Joy Yang , Gumuscu Burak , Swaby Ramona F. , Chang Anne Lynn S. 
Published: May 2019

TPS9597 Background: Among patients with high-risk, locally advanced (LA) cutaneous squamous cell carcinoma (cSCC) who receive current standard-of-care surgical resection and adjuvant radiotherapy, ~40-50% develop local recurrence and regional metastasis ( J Clin Oncol. 2018;36:1275-1283). Recent data suggest that programmed death 1 inhibitors such as pembrolizumab may provide a well-tolerated, effective, and durable response in patients with LA or metastatic cSCC. To evaluate the efficacy and safety of adjuvant pembrolizumab in patients with high-risk LA cSCC, the randomized, double-blind, placebo-controlled phase 3 KEYNOTE-630 trial (NCT03833167) will be conducted. Methods: After surgical resection and radiotherapy for high-risk LA cSCC, eligible patients will be randomly assigned 1:1 to intravenous pembrolizumab (400 mg Q6W) or placebo for up to 9 cycles (~1 year), with radiographic imaging at least every 12 weeks until year 2 and then every 6 months until the end of year 5 to assess treatment response. Eligibility criteria will include age ≥18 years, histologically confirmed LA cSCC with ≥1 high-risk feature at the primary site of malignancy, macroscopic resection with or without microscopic positive margins, completed adjuvant radiotherapy, disease free ≤28 days from randomization, and ECOG performance status 0-1. Treatment will be discontinued at disease recurrence, start of new anticancer treatment, unacceptable toxicity, intercurrent illness that prevents treatment, pregnancy, investigator or patient decision to withdraw, or administrative reasons that require treatment cessation. After the first disease recurrence, all patients who meet crossover or retreatment criteria may receive pembrolizumab 400 mg Q6W for up to 18 cycles. Adverse events will be monitored throughout the study and graded according to the NCI CTCAE, version 4.0. The primary efficacy end point will be investigator-assessed and biopsy-confirmed recurrence-free survival. Secondary end points will be overall survival, health-related quality of life, and safety. Recruitment is ongoing in 19 countries and will continue until approximately 570 patients are enrolled. Clinical trial information: NCT03833167.
CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL).
Authors: Khushalani Nikhil I. , Diab Adi , Ascierto Paolo Antonio , Larkin James M.G. , Sandhu Shahneen Kaur , Sznol Mario , Koon Henry B. , Jarkowski Anthony , Zhou Ming , Wang Rui , Bajaj Gaurav , Long Georgina V. 
Published: May 2019

TPS9601 Background: Standard of care for pts with previously untreated, unresectable or metastatic MEL includes checkpoint inhibitors. Bempegaldesleukin is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor to activate and proliferate effector CD8+ T and NK cells over T-regulatory cells in the tumor (Hurwitz ME et al. ASCO GU 2017). In the dose-expansion phase of the phase 1/2 PIVOT-02 trial, bempegaldesleukin + NIVO was well tolerated at the recommended phase 2 dose (RP2D; bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W), and previously untreated pts with MEL receiving the RP2D achieved an objective response rate (ORR) of 20/38 (53%) and a complete response of 9/38 (24%) by independent radiology review (Diab A et al. SITC 2018). Presented is the design of the first phase 3 trial in the bempegaldesleukin + NIVO development program in pts with previously untreated, unresectable or metastatic MEL. Methods: This phase 3, randomized, open-label study aims to evaluate the effectiveness, safety, and tolerability of bempegaldesleukin + NIVO (NCT03635983). Eligible pts are ≥12 y with histologically confirmed stage III (unresectable) or stage IV MEL and ECOG PS ≤1 or Lansky PS ≥80% (minors 12-17 y). Pts are ineligible if they have active brain or leptomeningeal metastases, uveal MEL, or a recurrence within 6 mo of completing adjuvant treatment with any approved agent. Pts will be stratified by PD-L1 status (measured using PD-L1 IHC 28-8 pharmDx), BRAF mutation status, and lactate dehydrogenase level, and will be randomized to receive bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W or NIVO 360 mg IV Q3W up to 24 mo, or until progression or unacceptable toxicity (N ~ 764). Primary endpoints are ORR and progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints include ORR and PFS by investigator, ORR and PFS by BICR in biomarker population, OS in biomarker population, and safety. Additional endpoints include pharmacokinetics and quality-of-life assessment. Clinical trial information: NCT03635983.
Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling
Authors: Lippincott Margaret F , León Silvia , Chan Yee-Ming , Fergani Chrysanthi , Talbi Rajae , Farooqi I Sadaf , Jones Christopher M , Arlt Wiebke , Stewart Susan E , Cole Trevor R , Terasawa Ei , Hall Janet E , Shaw Natalie D , Navarro Victor M , Seminara Stephanie Beth 
Published: May 2019

Abstract

Context
Kisspeptin–neurokinin B (NKB)–dynorphin neurons are critical regulators of the hypothalamic–pituitary–gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear.

Objective
To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB.

Design
Case/control.

Setting
Academic medical center.

Participants
Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice.

Interventions
Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin.

Main Outcome Measures
LH pulse characteristics.

Results
Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin.

Conclusion
The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.
Human-Specific Function of IL-10 in Adipose Tissue Linked to Insulin Resistance
Authors: Acosta Juan R , Tavira Beatriz , Douagi Iyadh , Kulyté Agné , Arner Peter , Rydén Mikael , Laurencikiene Jurga 
Published: May 2019

Abstract

Objective
Although IL-10 is generally considered as an anti-inflammatory cytokine, it was recently shown to have detrimental effects on insulin sensitivity and fat cell metabolism in rodents. Whether this also pertains to human white adipose tissue (hWAT) is unclear. We therefore determined the main cellular source and effects of IL-10 on human adipocytes and hWAT-resident immune cells and its link to insulin resistance.

Methods
Associations between hWAT IL-10 production and metabolic parameters were investigated in 216 participants with large interindividual variations in body mass index and insulin sensitivity. Adipose cells expressing or secreting IL-10 and the cognate IL-10 receptor α (IL10RA) were identified by flow cytometry sorting. Effects on adipogenesis, lipolysis, and inflammatory/metabolic gene expression were measured in two human primary adipocyte models. Secretion of inflammatory cytokines was investigated in cultures of IL-10–treated hWAT macrophages and leukocytes by Luminex analysis (Luminex Corp.).

Results
IL-10 gene expression and protein secretion in hWAT correlated positively with body mass index (BMI) and homeostasis model assessment-insulin resistance (HOMA-IR). Gene expression analyses in mature fat cells and flow cytometry–sorted hWAT-resident adipocyte progenitors, macrophages, and leukocytes demonstrated that the expression of IL-10 and the IL10RA were significantly enriched in proinflammatory M1 macrophages. In contrast to murine data, functional studies showed that recombinant IL-10 had no effect on adipocyte phenotype. In hWAT-derived macrophages and leukocytes, it induced an anti-inflammatory profile.

Conclusion
In hWAT, IL-10 is upregulated in proinflammatory macrophages of obese and insulin-resistant persons. However, in contrast to findings in mice, IL-10 does not directly affect human adipocyte function.
Bilateral Thoracic Paravertebral Blocks Compared to Thoracic Epidural Analgesia After Midline Laparotomy: A Pragmatic Noninferiority Clinical Trial
Authors: Sondekoppam Rakesh V. , Uppal Vishal , Brookes Jonathan , Ganapathy Sugantha 
Published: May 2019

BACKGROUND:
Bilateral paravertebral block (PVB) is a suitable alternative to thoracic epidural analgesia (TEA) for abdominal surgeries. This randomized clinical trial aims to determine if PVB is noninferior to TEA in terms of analgesia after midline laparotomy.

METHODS:
Seventy American Society of Anesthesiologists (ASA) class I–III patients undergoing a laparotomy through a midline incision were randomized to receive either TEA (TEA group) or continuous bilateral PVB (PVB group) as a part of a multimodal analgesia regimen in an open-label design. Noninferiority was to be concluded if the mean between-group difference in pain on movement at the 24 postoperative hours was within a margin of 2 points on a 0–10 numerical rating scale (NRS). Pain score at rest and on movement, analgesic consumption, hemodynamics, and adverse events during the first 72 postoperative hours were the secondary outcome measures assessed for superiority. Postblock and steady-state plasma concentrations of ropivacaine and pattern of dye spread were also recorded in the PVB group.

RESULTS:
The primary outcome of pain scores on movement at 24 postoperative hours was noninferior in PVB group in comparison to TEA group (mean difference [95% confidence interval {CI}], 0.43 [−0.72–1.58]). The pain scores at rest and on movement at other time points of assessment were within clinically acceptable limits in both groups with no significant differences between the groups over time. Arterial plasma ropivacaine levels were within safe limits, while steady-state venous level was higher than an acceptable threshold in 9 of 34 cases.

CONCLUSIONS:
As a component of multimodal analgesia, bilateral PVB provides noninferior analgesia compared to TEA for midline laparotomy.
A revisão judicial das decisões proferidas pelo Conselho Administrativo de Defesa Econômica
Authors: Burg Amanda Karolini , Gonçalves Everton das Neves , Stelzer Joana 
Published: May 2019

The judicial review of decisions rendered by the Brazilian Administrative Council of Economic Defense Neste trabalho busca-se verificar se, e em que medida, as decisões proferidas pelo Conselho Administrativo de Defesa Econômica (Cade) no controle estrutural e de condutas podem ser revisadas pelo Poder Judiciário. A metodologia de abordagem é indutiva; quanto ao método de procedimento, tem-se o monográfico; a técnica de pesquisa é documental e bibliográfica. Não há consenso acerca da natureza, discricionária ou não, das decisões proferidas pelo Cade. Mesmo assim, por meio de dados quantitativos e qualitativos, decorrentes de pesquisas empíricas elaboradas pela Sociedade Brasileira de Direito Público (SBDP) e por pesquisadores vinculados ao Conselho Nacional de Justiça (CNJ), é possível concluir que as decisões do Cade são objeto de revisão, inclusive de mérito, perante o Poder Judiciário. This paper aims to verify if, and to what extent, the decisions of the Brazilian Administrative Council of Economic Defense (Cade) can be reviewed by the Judiciary. The investigate methodology is inductive, the procedure method is monographic; and research technic is documental e bibliographical. There is no consensus if the decisions of the Cade are discretionary. Nevertheless, through quantitative and qualitative data, derived from empirical researches by the Brazilian Society of Public Law (SBDP) and by researchers of the Justice National Council (CNJ), it is possible to conclude that the decisions of the Brazilian Administrative Council of Economic Defense are subject to judicial review, even by merit.
Reviews
Authors: Sporton Gregory , Sporton Gregory , Sporton Gregory 
Published: May 2019

Life and Fate, adapted for the stage and directed by Lev Dodin, Maly Drama Theatre Company, Theatre Royal, Haymarket, 12 May 2018
Life is a Dream, by Kim Brandstrup, Rambert Dance Company, Sadler's Wells Theatre, London, 26 May 2018
New Work/New Music, The Royal Ballet, Royal Opera House, Linbury Theatre, 8 February 2019
Syphilis, The Great Mimicker, Presents As a Rare Case of Concurrent Hepatitis and Gastroparesis
Authors: Shinn Brianna , Kistler Charles , Dhanekula Raja Koteswar , Civan Jesse 
Published: May 2019

ABSTRACT
Syphilis has been called “the great mimicker” given its ability to affect a wide variety of organs and subsequently present with a vast array of symptoms. The variability in clinical presentation seen in syphilis can make the diagnosis challenging. We describe a unique presentation of syphilis manifesting as hepatitis and gastroparesis. To our knowledge, this is the first case report with simultaneous hepatic and gastric involvement.
Impact of Preoperative Nutritional Status on the Incidence Rate of Surgical Complications in Patients With Inflammatory Bowel Disease With Vs Without Preoperative Biologic Therapy: A Case-Control Study
Authors: Yamamoto Takayuki , Shimoyama Takahiro , Umegae Satoru , Kotze Paulo Gustavo 
Published: May 2019

OBJECTIVES:
A case-control study was undertaken to assess the impact of preoperative nutrition on surgical outcomes in patients with inflammatory bowel disease with vs without preoperative biologic therapy.

METHODS:
Seventy patients who had received biologic therapy within 8 weeks before undergoing resection for active ulcerative colitis (n = 34) or Crohn's disease (n = 36) were included (BIO group). The control group comprised 70 patients without exposure to biologics, selected based on 5 matching criteria: inflammatory bowel disease subtype (ulcerative colitis/Crohn's disease), age (≤ or >40 years), disease severity (moderate/severe), surgical approach (open/laparoscopic), and main surgical procedure. Poor nutrition was defined as the presence of at least one of the following criteria: weight loss >10%–15% within 6 months, body mass index <18.5 kg/m2, Subjective Global Assessment Grade C, or serum albumin <30 g/L.

RESULTS:
The proportion of patients with preoperative poor nutrition was 43% in the BIO and 33% in the control groups (P = 0.22). The incidence of postoperative infectious complications (anastomotic leak, intra-abdominal abscess, enterocutaneous fistula, or wound infection) was 16% in the BIO and 14% in the control groups (P = 0.81). In the BIO group, poor nutrition significantly increased the risk of infectious complications (27% vs 8% without poor nutrition, P = 0.03). In addition, in the control group, the incidence of infectious complications was higher in patients with poor nutrition, but not significantly (22% vs 11%, P = 0.21).

DISCUSSION:
Poor nutrition increases the risk of infectious complications after surgery. The detrimental effects of poor nutrition on postsurgical infection may be enhanced in patients who have received biologic therapy preoperatively.
CO2 sequestration by carbonation of olivine: a new process for optimal separation of the solids produced
Authors: Turri Laura , Gérardin Karine , Muhr Hervé , Lapicque François , Saravia Alvaro , Szenknect Stéphanie , Mesbah Adel , Mastretta Régis , Dacheux Nicolas , Meyer Daniel , Cloteaux Anaëlle , Gérard Antoine , Bertucci Salvatore 
Published: May 2019

Abstract
CO2 sequestration by reaction with abundant, reactive minerals such as olivine has often been considered. The most straightforward, direct process consists in performing the reaction at high temperature and CO2 pressure, in view to producing silica, magnesium and iron carbonates and recovering the traces of nickel and chromite contained in the feedstock mineral. Most of direct processes were found to have an overall cost far larger than the CO2 removal tax, because of incomplete carbonation and insufficient properties of the reaction products. Similar conclusions could be drawn in a previous investigation with a tubular autoclave. An indirect process has been designed for high conversion of olivine and the production of separate, profitable products e.g. silica, carbonates, nickel salts, so that the overall process could be economically viable: the various steps of the process are described in the paper. Olivine particles (120 μm) can be converted at 81% with a low excess of acid within 3 h at 95°C. The silica quantitatively recovered exhibits a BET area over 400 m2 g-1, allowing valuable applications to be considered. Besides, the low contents of nickel cations could be separated from the magnesium-rich solution by ion exchange with a very high selectivity.
Multiculturalism, (Im)Migration, Theatre: The National Arts Centre, Ottawa, a Case of Staging Canadian Nationalism
Authors: Meerzon Yana 
Published: May 2019

Abstract
On October 22, 2015, two days after the Liberal Party of Canada came to power, The Globe and Mail published an editorial entitled “Canada to the World: Xenophobia Doesn’t Play Here.” The article suggested that, in these times of migration crises, a rising xenophobic discourse and neo-nationalism, it is essential for the European countries to start taking lessons in navigating cultural diversity from Canada, the first country in the world that institutionalized principles of multiculturalism. This view is clearly reflected in the repertoire politics of Canadian theatre institutions, specifically the National Arts Centre (NAC) Ottawa, the only theatre company in Canada directly subsidized by its government. Mandated to support artistic excellence through arts, the NAC acts as a pulpit of official ideology. It presents diversity on stage as the leading Canadian value, and thus fulfills its symbolic function to serve as a mirror to its nation.However, this paper argues that, by offering an image of Canada, constructed by our government and tourist agencies, as an idyllic place to negotiate our similarities and differences, the NAC fosters what Loren Kruger calls a theatrical nationhood (4–16). A closer look at the 2014 NAC English theatre co-production of Kim’s Convenience will help illustrate how the politics of mimicry can become a leading device in the aesthetics of national mimesis – a cultural activity of “representing the nation as well as the result of it (an image of the nation)” (Hurley 24); and how the artistry of a multicultural kitchen-sink can turn a subject of diversity into that of affirmation and sentimentalism.
The State We’re in: Violence and Working-Class Women on and off the Contemporary Irish Stage
Authors: Maguire Tom 
Published: May 2019

Abstract
This essay examines the ways in which women in the lowest socio-economic class are represented on the contemporary Irish stage. Its central concern is with the ways in which the Naturalistic dramatic representation of the home as a domestic sphere for poor women may confound nationalist discourses of the country as home, yet may fail to resist the systemic violence of the state against its most precarious citizens. To do so I set the actual economic conditions of these precarious women alongside social attitudes to poverty and the poor to demonstrate the systemic violence enacted on the most vulnerable. Turning then to dominant media representations, the essay questions the interaction between representation and reality more generally, whereby Ireland’s poorest are demonised and disenfranchised as figures of fun or fear in forms of representational violence. Against this broader backdrop, the paper identifies recurrent forms of and tropes in stage representations to raise questions about both the form and function of theatre for contemporary spectators, focusing on two contemporary plays Waiting on Ikea and Pineapple. For some, this promotes pleasures of recognition; for others the frisson of class voyeurism. The central argument is that little has changed since O'Casey put Juno Boyle and Bessie Burgess onstage – in either the precarious lives led by poor women, their representation on stage or the failures of the audiences or the state to accept responsibility for the unequal lives of Irish citizens.
Resource limitations and competitive interactions affect carnivore community composition at different ecological scales in a temperate island system
Authors: Allen Maximilian L. , Harris Rachel E. , Olson Lucas O. , Olson Erik R. , Van Stappen Julie , Van Deelen Timothy R. 
Published: May 2019

AbstractSelective pressures (i.e. resource limitation and competitive interaction) that drive the composition of ecological communities vary, and often operate on different ecological scales (ecological variables across varying spatial scales) than observed patterns. We studied the drivers of distribution and abundance of the American marten (Martes americana) and the carnivore community at three ecological scales on a Great Lakes island archipelago using camera traps. We found different drivers appeared important at each ecological scale and studying any of the three scales alone would give a biased understanding of the process driving the system. Island biogeography (resource limitation) was most important for carnivore richness, with higher richness on larger islands and lower richness as distance from the mainland increased. Marten presence on individual islands appeared to be driven by island size (resource limitation) and human avoidance (competitive interaction). Marten abundance at camera trap sites was driven by the cascading effect of coyotes (Canis latrans) on fishers (Pekania pennanti) (competitive interaction). Incorporating three ecological scales gave novel insights into the varying effects of resource limitation and competitive interaction processes. Our data suggests that ecological communities are structured through multiple competing ecological forces, and effective management and conservation relies on our ability to understand ecological forces operating at multiple ecological scales.