bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixed-dosing, long-term outcome of weight-based dosing
Authors: Rischin Danny , Migden Michael R , Lim Annette M , Schmults Chrysalyne D , Khushalani Nikhil I , Hughes Brett G M , Schadendorf Dirk , Dunn Lara A , Hernandez-Aya Leonel , Chang Anne Lynn S , Modi Badri , Hauschild Axel , Ulrich Claas , Eigentler Thomas , Stein Brian , Pavlick Anna C , Geiger Jessica L , Gutzmer Ralf , Alam Murad , Okoye Emmanuel , Mathias Melissa , Jankovic Vladimir , Stankevich Elizabeth , Booth Jocelyn , Li Siyu , Lowy Israel , Fury Matthew G , Guminski Alexander 
Published: June 2020

BackgroundCemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498).MethodsThe primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability.ResultsFor Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan–Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%).ConclusionIn patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses.Trial registration numberClinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498
Chronic immune checkpoint inhibitor pneumonitis
Authors: Naidoo Jarushka , Cottrell Tricia R , Lipson Evan J , Forde Patrick M , Illei Peter B , Yarmus Lonny B , Voong K Ranh , Feller-Kopman David , Lee Hans , Riemer Joanne , Wang Daphne , Taube Janis M , Brahmer Julie R , Lin Cheng Ting , Danoff Sonye K , D'Alessio Franco R , Suresh Karthik 
Published: June 2020

BackgroundPneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4–6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression.MethodsPatients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available.ResultsAmong 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0–50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3–12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16–43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper.ConclusionsA subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features.
Smouldering ashes: burning questions after the outbreak of electronic cigarette or vaping-associated lung injury (EVALI)
Authors: Xantus Gabor Zoltan , Gyarmathy Anna V , Johnson Carole Ann 
Published: June 2020

AbstractIn the summer of 2019, the Center for Disease Control and Prevention (CDC) declared an emergency of electronic cigarettes and/or vaping (vaping)-associated lung injury (EVALI) in the USA. The outbreak abated by January 2020, which the CDC attributed to heightened public awareness, ‘user actions to reduce risk’ and potentially the removal of vitamin E acetate (VEA) from vaping products (VEA is an oily chemical cutting agent, strongly associated with the disease). Even though the EVALI outbreak appears to be over, numerous epidemiological and medical questions are left still open. First, why were there practically no cases outside the USA, which represents nearly a quarter of the global vaping market? Comparative studies to map the differences in device/fluids/user habits between countries might be needed urgently. Second, what is the pathomechanism that sickens vapers irrespective of VEA exposure? VEA was only confirmed in about half of the cases and the presumed toxicity is yet to be determined. Aetiology/epidemiology focused research is needed to investigate/interpret the broader context to explain the outbreak. Third, could any socioeconomic/environmental factors have influenced the course of the outbreak? Finally, what should we expect in the years to come? Was EVALI a serious but reversible emergency medicine condition or is vaping as detrimental to long-term health as smoking? Besides the complex legislative, regulatory, ethical aspects of EVALI, biomedical research is also difficult: in-vitro experiments have limited inferential value to real real-life vaping due to its complexity; user habits are self-reported and under-researched; there is an active black market pouring unknown quality counterfeit products and, in the USA, federal restrictions limit cannabis research. Vaping is a toxicological, multidimensional conundrum; therefore, stringent quality control, transparent legal/ethical boundaries, meticulous international research and user education are paramount to prevent potential future outbreaks and determine the parameters safe vaping (if these exist).
Cosmological constant, Planck mass, Hubble mass, and axion: a relation through higher-order loops Coleman–Weinberg potential with Weinberg–Landau gauge
Authors: El-Nabulsi Rami Ahmad 
Published: June 2020

In this communication, a conformal coupling gravity is discussed in the presence of a complex Coleman–Weinberg potential, which is generated from the contributions from first-, second-, and all higher-order loops. A relation between the cosmological constant, the Hubble mass, and the Higgs vacuum energy is obtained in particular when Weinberg–Landau gauge is used. Moreover, it was observed that the removal of the logarithmic mass boosts the scalar mass from Hubble mass of order 10–33 eV to 2.47 × 10–3 eV, which is comparable to the mass of non-baryonic cold dark matter or axion based on recent observations and which constitutes about 84% of all matter in the Universe.
Differentiating the Differentiation Syndrome Associated with IDH Inhibitors in AML
Authors: Zeidner Joshua F. 
Published: June 2020

Abstract
Isocitrate dehydrogenase (IDH) inhibitors have clinical activity in acute myeloid leukemia, in part, by differentiating blasts to mature myeloid cells. In the largest systematic analysis to date, differentiation syndrome was seen in 19% of patients treated with IDH inhibitors. Early recognition with uniform diagnostic criteria, as utilized in acute promyelocytic leukemia, may reduce subsequent complications.
See related article by Norsworthy et al., p. 4280
Real power loss reduction by tundra wolf algorithm
Authors: Lenin Kanagasabai 
Published: June 2020

In this work Tundra wolf algorithm (TWA) is proposed to solve the optimal reactive power problem. In the projected Tundra wolf algorithm (TWA) in order to avoid the searching agents from trapping into the local optimal the converging towards global optimal is divided based on two different conditions. In the proposed Tundra wolf algorithm (TWA) omega tundra wolf has been taken as searching agent as an alternative of indebted to pursue the first three most excellent candidates. Escalating the searching agents numbers will perk up the exploration capability of the Tundra wolf wolves in an extensive range. Proposed Tundra wolf algorithm (TWA) has been tested in standard IEEE 14, 30 bus test systems and simulation results show the proposed algorithm reduced the real power loss effectively.
Using Salivary Cortisol as an Objective Measure of Physiological Stress in People With Dementia and Chronic Pain: A Pilot Feasibility Study
Authors: Pu Lihui , Todorovic Michael , Moyle Wendy , Jones Cindy 
Published: June 2020

Background: Pain can elevate stress in people with dementia. Although salivary cortisol is used as a biomarker of stress in people with dementia, few studies have reported the feasibility of collection methods to assess salivary cortisol in nursing home residents with both dementia and chronic pain. Objective: To explore the feasibility of collecting cortisol via salivary swab as an indicator of stress in people with dementia and chronic pain. Methods: Participants ( N = 43) aged ≥ 65 years and living with dementia and chronic pain were randomly assigned to the PARO (individual, nonfacilitated, 30-min sessions with the robotic seal PARO, 5 days per week for 6 weeks) or usual-care group using computer-generated random numbers. Salivary cortisol was collected in the early morning before the intervention (Week 0) and at the completion of the intervention (Week 6) for comparison. Results: There were multiple challenges associated with saliva collection and analysis, including cognitive impairment of participants, ability to obtain repeated samples with saliva volume adequate for assay, and overall cost. Ultimately, adequate saliva was collected from only 8 participants (both pre- and post-intervention) for assay and quantitative analysis. Conclusion: Considering the multiple challenges involved in obtaining valid saliva samples in this population, salivary cortisol may not be a feasible biomarker of physiological stress in people with dementia and chronic pain.
Construction and validation of a scale for assessing arteriovenous fistulas
Authors: Bulbul Elif , Enc Nuray 
Published: June 2020

Aim: This methodological study was conducted to develop a reliable instrument for the assessment of the arteriovenous fistula in patients under hemodialysis therapy. The purpose of the scale is to evaluate risk of developing arteriovenous fistula complications in patients receiving hemodialysis treatment. Methods: An item pool was created in accordance with data obtained from our literature review and expert opinions. Validity of the scale was evaluated using construct and content validity analyses. Cronbach’s alpha coefficient, test–retest, and split-half reliability were used to assess reliability. Results: The final 3-point Likert-type Arteriovenous Fistula Assessment Scale developed in this study consists of 18 items in three subdimensions: arteriovenous fistula flow, stenosis and ischemia, and needle entry site. The scale-level Content Validity Ratio was 0.90. Explanatory factor analysis revealed a three-factor structure with factor loadings of 0.622–0.800, 0.361–0.891, and 0.431–0.954, respectively, explaining 55.51% of the total variance. The Cronbach’s alpha values for the subdimensions were 0.72, 0.71, and 0.83, respectively, and 0.82 for the scale overall. Conclusion: The Arteriovenous Fistula Assessment Scale is a valid and reliable instrument that can be used to monitor arteriovenous fistulas in hemodialysis patients.
Combination therapy of gefitinib and miR-30a-5p may overcome acquired drug resistance through regulating the PI3K/AKT pathway in non-small cell lung cancer
Authors: Wang Fengfeng , Meng Fei , Wong Sze Chuen Cesar , Cho William C.S. , Yang Sijun , Chan Lawrence W.C. 
Published: June 2020

Background: Non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation often initially respond to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment but may acquire drug resistance due to multiple factors. MicroRNAs are a class of small noncoding and endogenous RNA molecules that may play a role in overcoming the resistance. Materials and methods: In this study, we explored and validated, through in vitro experiments and in vivo models, the ability of a combination treatment of EGFR-TKI, namely gefitinib, and a microRNA mimic, miR-30a-5p, to overcome drug resistance through regulation of the insulin-like growth factor receptor-1 (IGF1R) and hepatocyte growth factor receptor signaling pathways, which all converge on phosphatidylinositol 3 kinase (PI3K), in NSCLC. First, we examined the hypothesized mechanisms of drug resistance in H1650, H1650-acquired gefitinib-resistance (H1650GR), H1975, and H460 cell lines. Next, we investigated a potential combination treatment approach to overcome acquired drug resistance in the H1650GR cell line and an H1650GR cell implanted mouse model. Results: Dual inhibitors of EGFR and IGF1R significantly lowered the expression levels of phosphorylated protein kinase B (p-AKT) and phosphorylated mitogen-activated protein kinase (p-ERK) compared with the control group in all cell lines. With the ability to repress PI3K expression, miR-30a-5p mimics induced cell apoptosis, and inhibited cell invasion and migration in the treated H1650GR cell line. Conclusion: Gefitinib, combined with miR-30a-5p mimics, effectively suppressed the growth of H1650GR-induced tumor in xenografts. Hence, a combination therapy of gefitinib and miR-30a-5p may play a critical role in overcoming acquired resistance to EGFR-TKIs. The reviews of this paper are available via the supplemental material section.
Long-term oncological outcomes for radiofrequency ablation of small renal masses
Authors: Steen Benjamin , Curry David , Pahuja Ajay , Loan Willy , Thwaini Ali 
Published: June 2020

Objective: To describe oncology outcomes and complications with radiofrequency ablation (RFA) for T1 renal cell carcinoma in a centre with 14 years of experience. Method: Retrospective study of 95 consecutive patients from 2005 to 2013 who underwent RFA. Those with metastatic disease at time of treatment, incomplete follow up, proven benign pathology, genetic underlying genetic pre-disposition were excluded. 48 patients with 49 tumours met the inclusion criteria. Data was collected on demographics oncological outcomes and complications. Primary outcome measures were disease free survival and cancer specific survival at five and eight years. Results: Median follow up was 83 months. We demonstrate an 87% 5-year disease free survival (DFS) and 70% eight-year DFS. Mean time to progression was 45 months. Cancer specific survival was demonstrated as 97.9% at five years and 93.6% at eight years – all cancer-related deaths had an initial tumour of > 3 cm diameter. 42.9% of the recurrences occurred beyond five years The median time to progression for secondary failure was 50.7 months. One Clavien-Dindo Grade 2 complication was encountered in the series. Outcome: RFA produces comparable long-term oncological outcomes to other modalities for T1 tumours with a low complication rate. Follow up should be considered beyond five years as a significant proportion of the recurrences (42.9%) in this study occurred beyond this point. Level of evidence: 4
The standard for the management of male urethral strictures in the UK: a consensus document
Authors: Bugeja Simon , Payne Stephen R. , Eardley Ian , Mundy Anthony R. 
Published: June 2020

Objective: The aim of this study was to establish an evidence-based best clinical practice consensus for the management of urethral stricture disease in the UK. Methods: A systematic review of optimal management of urethral stricture generated a base document which was endorsed by the British Association of Urological Surgeons (BAUS) section of Andrology and Genito-Urinary Reconstructive Surgeons (AGUS). A two-round electronic mail modified Delphi survey of 43 consultant reconstructive urologists, members of the British Association of Genito-Urinary Reconstructive Surgeons (BAGURS), was then performed. The panel’s views about the base document was sought in seven domains: definition, diagnosis, investigation, conservative, endoscopic and reconstructive treatments, and follow up. Responses were collated and used to modify the base to achieve a consensus statement. Results: In round one of the Delphi process four panel members commented on the base document and seven in round two. Consensus was thereby reached on 38 statements regarding definition (one), diagnosis (three), investigation (two), conservative/endoscopic (five) and reconstructive (24) treatments and follow up (three) for the management of urethral stricture disease. Conclusion: This consensus statement will help standardise care, provide guidance on the management of urethral stricture disease, and assist in clinical decision-making for healthcare professionals of all grades.
Fulvic acid ameliorates drought stress-induced damage in tea plants by regulating the ascorbate metabolism and flavonoids biosynthesis
Authors: Sun Jianhao , Qiu Chen , Ding Yiqian , Wang Yu , Sun Litao , Fan Kai , Gai Zhongshuai , Dong Guoqiang , Wang Jiguo , Li Xinghui , Song Lubin , Ding Zhaotang 
Published: June 2020

Abstract
Background
Fulvic acid (FA) is a kind of plant growth regulator, which can promote plant growth, play an important role in fighting against drought, improve plant stress resistance, increase production and improve quality. However, the function of FA in tea plants during drought stress remain largely unknown.

Results
Here, we examined the effects of 0.1 g/L FA on genes and metabolites in tea plants at different periods of drought stress using transcriptomics and metabolomics profiles. Totally, 30,702 genes and 892 metabolites were identified. Compared with controlled groups, 604 and 3331 differentially expressed metabolite genes (DEGs) were found in FA-treated tea plants at 4 days and 8 days under drought stress, respectively; 54 and 125 differentially expressed metabolites (DEMs) were also found at two time points, respectively. Bioinformatics analysis showed that DEGs and DEMs participated in diverse biological processes such as ascorbate metabolism (GME, AO, ALDH and L-ascorbate), glutathione metabolism (GST, G6PDH, glutathione reduced form and CYS-GYL), and flavonoids biosynthesis (C4H, CHS, F3’5’H, F3H, kaempferol, quercetin and myricetin). Moreover, the results of co-expression analysis showed that the interactions of identified DEGs and DEMs diversely involved in ascorbate metabolism, glutathione metabolism, and flavonoids biosynthesis, indicating that FA may be involved in the regulation of these processes during drought stress.

Conclusion
The results indicated that FA enhanced the drought tolerance of tea plants by (i) enhancement of the ascorbate metabolism, (ii) improvement of the glutathione metabolism, as well as (iii) promotion of the flavonoids biosynthesis that significantly improved the antioxidant defense of tea plants during drought stress. This study not only confirmed the main strategies of FA to protect tea plants from drought stress, but also deepened the understanding of the complex molecular mechanism of FA to deal with tea plants to better avoid drought damage.
Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19
Authors: Farhadian Shelli , Glick Laura R. , Vogels Chantal B. F. , Thomas Jared , Chiarella Jennifer , Casanovas-Massana Arnau , Zhou Jing , Odio Camila , Vijayakumar Pavithra , Geng Bertie , Fournier John , Bermejo Santos , Fauver Joseph R. , Alpert Tara , Wyllie Anne L. , Turcotte Cynthia , Steinle Matthew , Paczkowski Patrick , Dela Cruz Charles , Wilen Craig , Ko Albert I. , MacKay Sean , Grubaugh Nathan D. , Spudich Serena , Barakat Lydia Aoun 
Published: June 2020

AbstractBackgroundCOVID-19 is caused by the severe acute respiratory syndrome virus SARS-CoV-2. It is widely recognized as a respiratory pathogen, but neurologic complications can be the presenting manifestation in a subset of infected patients.Case presentationWe describe a 78-year old immunocompromised woman who presented with altered mental status after witnessed seizure-like activity at home. She was found to have SARS-CoV-2 infection and associated neuroinflammation. In this case, we undertake the first detailed analysis of cerebrospinal fluid (CSF) cytokines during COVID-19 infection and find a unique pattern of inflammation in CSF, but no evidence of viral neuroinvasion.ConclusionOur findings suggest that neurologic symptoms such as encephalopathy and seizures may be the initial presentation of COVID-19. Central nervous system inflammation may associate with neurologic manifestations of disease.