bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamics of Pre-Operative PD1 checkpoint blockade and receptor activator of NFkB ligand (RANKL) inhibition in non-small cell lung cancer (NSCLC): study protocol for a multicentre, open-label, phase 1B/2, translational trial (POPCORN)
Authors: Ahern Elizabeth , Cubitt Annette , Ballard Emma , Teng Michele W. L. , Dougall William C. , Smyth Mark J. , Godbolt David , Naidoo Rishendran , Goldrick Amanda , Hughes Brett G. M. 
Published: December 2019

Abstract
Background
Neoadjuvant immunotherapy targeting immune checkpoint programmed death-1 (PD-1) is under investigation in various tumour settings including non-small-cell lung cancer (NSCLC). Preclinical models demonstrate the superior power of the immunotherapy provided in a neoadjuvant (pre-operative) compared with an adjuvant (post-operative) setting to eradicate metastatic disease and induce long-lasting antigen-specific immunity. Novel effective immunotherapy combinations are widely sought in the oncology field, targeting non-redundant mechanisms of immune evasion. A promising combination partner with anti-PD1 in NSCLC is denosumab, a monoclonal antibody blocking receptor activator of NF-κB ligand (RANKL). In preclinical cancer models and in a large retrospective case series in NSCLC, anti-cancer activity has been reported for the combination of immune checkpoint inhibition (ICI) and denosumab. Furthermore, clinical trials of ICI and denosumab are underway in advanced melanoma and clear-cell renal cell carcinoma. However, the mechanism of action of combination anti-PD1 and anti-RANKL is poorly defined.

Methods
This open-label multicentre trial will randomise by minimisation 30 patients with resectable stage IA (primary > 2 cm) to IIIA NSCLC to a neoadjuvant treatment regime of either two doses of nivolumab (3 mg/kg every 2 weeks) or two doses of nivolumab (same regimen) plus denosumab (120 mg every 2 weeks, following nivolumab). Each treatment arm is of equal size and will be approximately balanced with respect to histology (squamous vs. non-squamous) and clinical stage (I-II vs. IIIA). All patients will receive surgery for their tumour 2 weeks after the final dose of neoadjuvant therapy. The primary outcome will be translational research to define the tumour-immune correlates of combination therapy compared with monotherapy. Key secondary outcomes will include a comparison of rates of the following between each arm: toxicity, response (pathological and radiological), and microscopically complete resection.

Discussion
The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer.

Trial registration
Prospectively registered on Australian New Zealand Clinical Trials Registry (ACTRN12618001121257) on 06/07/2018.
Comparative Effectiveness of Local Application of Chlorhexidine Gluconate, Mupirocin Ointment, and Normal Saline for the Prevention of Peritoneal Dialysis-related Infections (COSMO-PD Trial): a multicenter randomized, double-blind, controlled protocol
Authors:   for the Thai Renal Outcomes Research (THOR) Investigators, Nochaiwong Surapon , Ruengorn Chidchanok , Noppakun Kajohnsak , Panyathong Setthapon , Dandecha Phongsak , Sood Manish M. , Saenjum Chalermpong , Awiphan Ratanaporn , Sirilun Sasithorn , Mongkhon Pajaree , Chongruksut Wilaiwan , Thavorn Kednapa 
Published: December 2019

Abstract
Background
Current international guidelines recommend the use of a daily topical exit-site antimicrobial to prevent peritoneal dialysis (PD)-related infections. Although nonantibiotic-based therapies are appealing because they may limit antimicrobial resistance, no controlled trials have been conducted to compare topical antimicrobial agents with usual exit-site care for the prevention of PD-related infections among the Thai PD population. We propose a controlled three-arm trial to examine the efficacy and safety of a daily chlorhexidine gluconate-impregnated patch versus mupirocin ointment versus usual exit-site care with normal saline for the prevention of PD-related infections.

Methods/Designs
This study is a randomized, double-blind, multicenter, active-controlled, clinical trial. Adult patients aged 18 years or older who have end-stage kidney disease and are undergoing PD will be enrolled at three PD Centers in Thailand. A total of 354 PD patients will be randomly assigned to either the 2% chlorhexidine gluconate-impregnated patch, mupirocin ointment, or usual exit-site care with normal saline dressing according to a computer-generated random allocation sequence. Participants will be followed until discontinuation of PD or completion of 24 months. The primary study outcomes are time to first PD-related infection (exit-site/tunnel infection or peritonitis) event and the overall difference in PD-related infection rates between study arms. Secondary study outcomes will include (i) the rate of infection-related catheter removal and PD technique failure, (ii) rate of nasal and exit-site Staphylococcus aureus colonization, (iii) healthcare costs, and (iv) skin reactions and adverse events. We plan to conduct a cost-utility analysis alongside the trial from the perspectives of patients and society. A Markov simulation model will be used to estimate the total cost and health outcome in terms of quality-adjusted life years (QALYs) over a 20-year time horizon. An incremental cost-effectiveness ratio in Thai Baht and U.S. dollars per QALYs gained will be illustrated. A series of probabilistic sensitivity analyses will be conducted to assess the robustness of the cost-utility analysis findings.

Discussion
The results from this study will provide new clinical and cost-effectiveness evidence to support the best strategy for the prevention of PD-related infections among the Thai PD population.

Trial registration
ClinicalTrials.gov, NCT02547103. Registered on September 11, 2015.
High genetic diversity but no geographical structure of Aedes albopictus populations in Réunion Island
Authors: Latreille Anne C. , Milesi Pascal , Magalon Hélène , Mavingui Patrick , Atyame Célestine M. 
Published: December 2019

AbstractBackgroundIn recent years, the Asian tiger mosquitoAedes albopictushas emerged as a species of major medical concern following its global expansion and involvement in many arbovirus outbreaks. On Réunion Island,Ae. albopictuswas responsible for a large chikungunya outbreak in 2005–2006 and more recently an epidemic of dengue which began at the end of 2017 and is still ongoing at the time of writing. This dengue epidemic has seen a high number of human cases in south and west coastal regions, while few cases have been reported in the north and east of the island. To better understand the role of mosquito populations in such spatial patterns of dengue virus transmission in Réunion Island, we examined the genetic diversity and population structure ofAe. albopictussampled across the island.ResultsBetween November 2016 and March 2017, a total of 564 mosquitoes were collected from 19 locations in three main climatic regions (West, East and Center) of Réunion Island and were genotyped using 16 microsatellite loci. A high genetic diversity was observed with 2–15 alleles per locus and the average number of alleles per population varying between 4.70–5.90. Almost allFISvalues were significantly positive and correlated to individual relatedness within populations using a hierarchical clustering approach based on principal components analyses (HCPC). However, the largest part of genetic variance was among individuals within populations (97%) while only 3% of genetic variance was observed among populations within regions. Therefore, no distinguishable population structure or isolation by distance was evidenced, suggesting high rates of gene flow at the island scale.ConclusionsOur results show high genetic diversity but no genetic structure ofAe. albopictuspopulations in Réunion Island thus reflecting frequent movements of mosquitoes between populations probably due to human activity. These data should help in the understanding ofAe. albopictusvector capacity and the design of effective mosquito control strategies.
Ubiquitin ligases HUWE1 and NEDD4 cooperatively control signal-dependent PRC2-Ezh1α/β-mediated adaptive stress response pathway in skeletal muscle cells
Authors: Liu Peng , Shuaib Muhammad , Zhang Huoming , Nadeef Seba , Orlando Valerio 
Published: December 2019

Abstract
Background
While the role of Polycomb group protein-mediated “cell memory” is well established in developmental contexts, little is known about their role in adult tissues and in particular in post-mitotic cells. Emerging evidence assigns a pivotal role in cell plasticity and adaptation. PRC2-Ezh1α/β signaling pathway from cytoplasm to chromatin protects skeletal muscle cells from oxidative stress. However, detailed mechanisms controlling degradation of cytoplasmic Ezh1β and assembly of canonical PRC2-Ezh1α repressive complex remain to be clarified.

Results
Here, we report NEDD4 ubiquitin E3 ligase, as key regulator of Ezh1β. In addition, we report that ubiquitination and degradation of Ezh1β is controlled by another layer of regulation, that is, one specific phosphorylation of serine 560 located at Ezh1β-specific C terminal. Finally, we demonstrate that also Ezh1α needs to be stabilized under stress condition and this stabilization process requires decreased association pattern between another E3 ubiquitin ligase HUWE1.

Conclusions
Together, these results shed light on key components that regulate PRC2-Ezh1α/β pathway to direct modulation of epigenome plasticity and transcriptional output in skeletal muscle cells.
Quantifying disease activity in rheumatoid arthritis with the TSPO PET ligand 18F-GE-180 and comparison with 18F-FDG and DCE-MRI
Authors: de Groot Marius , Patel Neel , Manavaki Roido , Janiczek Robert L. , Bergstrom Mats , Östör Andrew , Gerlag Danielle , Roberts Alexandra , Graves Martin J. , Karkera Yakshitha , Fernando Disala , Mistry Prafull , Walker Adam , Wisniacki Nicolas , Fryer Tim D. , Jimenez-Royo Pilar 
Published: December 2019

Abstract
Purpose
While the aetiology of rheumatoid arthritis (RA) remains unclear, many of the inflammatory components are well characterised. For diagnosis and therapy evaluation, in vivo insight into these processes would be valuable. Various imaging probes have shown value including dynamic contrast-enhanced (DCE) MRI and PET/CT using 18F-fluorodeoxyglucose (18F-FDG) or tracers targeting the translocator protein (TSPO). To evaluate 18F-GE-180, a novel TSPO PET tracer, for detecting and quantifying disease activity in RA, we compared 18F-GE-180 uptake with that of 18F-FDG and DCE-MRI measures of inflammation.

Methods
Eight RA patients with moderate-to-high, stable disease activity and active disease in at least one wrist were included in this study (NCT02350426). Participants underwent PET/CT examinations with 18F-GE-180 and 18F-FDG on separate visits, covering the shoulders and from the pelvis to the feet, including hands and wrists. DCE-MRI was performed on one affected hand. Uptake was compared visually between tracers as judged by an experienced radiologist and quantitatively using the maximum standardised uptake value (SUVmax). Uptake for both tracers was correlated with DCE-MRI parameters of inflammation, including the volume transfer coefficient Ktrans using Pearson correlation (r).

Results
PET/CT imaging with 18F-GE-180 in RA patients showed marked extra-synovial uptake around the affected joints. Overall sensitivity for detecting clinically affected joints was low (14%). 18F-GE-180 uptake did not or only weakly correlate with DCE-MRI parameters in the wrist (r = 0.09–0.31). 18F-FDG showed higher sensitivity for detecting symptomatic joints (34%), as well as strong positive correlation with DCE-MRI parameters (SUVmax vs. Ktrans: r = 0.92 for wrist; r = 0.68 for metacarpophalangeal joints).

Conclusions
The correlations between DCE-MRI parameters and 18F-FDG uptake support use of this PET tracer for quantification of inflammatory burden in RA. The TSPO tracer 18F-GE-180, however, has shown limited use for the investigation of RA due to its poor sensitivity and ability to quantify disease activity in RA.
Generalizations and refinements of three-tuple Diamond-Alpha integral Hölder’s inequality on time scales
Authors: Yan Fei , Wang Jianfeng 
Published: December 2019

AbstractIn this paper, based on the existing Hölder’s inequality, some new three-tuple diamond-alpha integral Hölder’s inequalities on time scales are proposed and the related theorems and corollaries are given. At the same time, we also give the relevant conclusions and proof ofn-tuple diamond-alpha integral Hölder’s inequalities on time scales.
Charting global position and vision of stakeholders towards sustainable bioenergy
Authors: Mai-Moulin T. , Fritsche U. R. , Junginger M. 
Published: December 2019

Abstract
Background
Stakeholder’s position of bioenergy sustainability is important for the deployment and contribution of bioenergy to sustainable development. Existing publications are usually limited to specific geographical contexts and focuses. This paper aims more broadly to examine the position and vision of a wider range of stakeholder groups towards bioenergy and its development at a global level.

Method
The applied methodology includes six steps: (1) identification of stakeholders as belonging to one of seven groups; (2) describing the role of each group in relation to bioenergy; (3) data collection via an online questionnaire, roundtable dialogues and interviews to examine their stated awareness and opinions of bioenergy development, driver and barriers to such development; (4) data analysis; (5) comparison of interests and influence as a basis for expressing position and vision; and (6) recommendations for gaining support for sustainable bioenergy development.

Results
The stakeholders state awareness of bioenergy development and have in general a positive view of the sector. They also inform that the general public is less aware of and not sufficiently involved in bioenergy development. Internet and social media are the most consulted sources of information but least trusted, while scientific information is most trusted but least used. Agricultural residues, energy crops cultivated on marginal or degraded land and forestry residues are widely accepted as feedstocks for bioenergy production, whereas use of agricultural land is viewed critically. The stakeholders generally support bioenergy development when jointly agreed sustainability requirements are met.

Conclusions
The stakeholders acknowledge the important role of effectively disseminating scientific information as an influencing factor on the position towards bioenergy. They also find that enhancing support for the bioenergy sector relies on mandatory sustainability requirements covering social, economic and environmental aspects, applied to all types of biomass regardless of end use. Some also emphasise that all relevant sectors should work on market conditions to create a level playing field and that this is crucial to change stakeholders’ position to gain more social acceptance of bioenergy. Transparency in demonstrating compliance with sustainability criteria is also an expected pre-condition to enhance support for bioenergy (and ultimately the bioeconomy) in the long term.
First report of Klebsiella quasipneumoniae harboring blaKPC-2 in Saudi Arabia
Authors: Hala Sharif , Antony Chakkiath Paul , Alshehri Mohammed , Althaqafi Abdulhakeem O. , Alsaedi Asim , Mufti Areej , Kaaki Mai , Alhaj-Hussein Baraa T. , Zowawi Hosam M. , Al-Amri Abdulfattah , Pain Arnab 
Published: December 2019

AbstractBackgroundNosocomial infections caused by multi-drug resistantEnterobacteriaceaeare a global public health threat that ought to be promptly identified, reported, and addressed accurately. Many carbapenem-resistantEnterobacteriaceae-associated genes have been identified in Saudi Arabia but not the endemicKlebsiella pneumoniaecarbapenemases (KPCs), which are encoded byblaKPC-typegenes. KPCs are known for their exceptional spreading potential.MethodsWe collectedn = 286 multi-drug resistant (MDR)Klebsiella spp.isolates as part of screening for resistant patterns from a tertiary hospital in Saudi Arabia between 2014 and 2018. Antimicrobial susceptibility testing was carried out using both VITEK II and the broth microdilution of all collected isolates. Detection of resistance-conferring genes was carried out using Illumina whole-genome shotgun sequencing and PacBio SMRT sequencing protocols.ResultsA Carbapenem-resistantEnterobacteriaceae(CRE)Klebsiella quasipneumoniaesubsp.similipneumoniaestrain was identified as a novel ST-3510 carrying ablaKPC-2carbapenemase encoding gene. The isolate, designated as NGKPC-421, was obtained from shotgun Whole Genome Sequencing (WGS) surveillance of 286 MDRKlebsiella spp. clinical isolates. The NGKPC-421 isolate was collected from a septic patient in late 2017 and was initially misidentified asK. pneumoniae. The sequencing and assembly of the NGKPC-421 genome resulted in the identification of a putative ~ 39.4 kb IncX6 plasmid harboring ablaKPC-2gene, flanked by transposable elements (ISKpn6-blaKPC-2–ISKpn27).ConclusionThis is the first identification of a KPC-2-producing CRE in the Gulf region. The impact on this finding is of major concern to the public health in Saudi Arabia, considering that it is the religious epicenter with a continuous mass influx of pilgrims from across the world. Our study strongly highlights the importance of implementing rapid sequencing-based technologies in clinical microbiology for precise taxonomic classification and monitoring of antimicrobial resistance patterns.
KEA-1010, a ketamine ester analogue, retains analgesic and sedative potency but is devoid of Psychomimetic effects
Authors: Harvey Martyn , Sleigh Jamie , Voss Logan , Bickerdike Mike , Dimitrov Ivaylo , Denny William 
Published: December 2019

Abstract
Background
Ketamine, a widely used anaesthetic and analgesic agent, is known to improve the analgesic efficacy of opioids and to attenuate central sensitisation and opioid-induced hyperalgesia. Clinical use is, however, curtailed by unwanted psychomimetic effects thought to be mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. KEA-1010, a ketamine ester-analogue designed for rapid offset of hypnosis through hydrolysis mediated break-down, has been shown to result in short duration sedation yet prolonged attenuation of nociceptive responses in animal models. Here we report on behavioural effects following KEA-1010 administration to rodents.

Methods
KEA-1010 was compared with racemic ketamine in its ability to produce loss of righting reflex following intravenous injection in rats. Analgesic activity was assessed in thermal tail flick latency (TFL) and paw incision models when injected acutely and when co-administered with fentanyl. Tail flick analgesic assessment was further undertaken in morphine tolerant rats. Behavioural aberration was assessed following intravenous injection in rats undergoing TFL assessment and in auditory pre-pulse inhibition models.

Results
KEA-1010 demonstrated an ED50 similar to ketamine for loss of righting reflex following bolus intravenous injection (KEA-1010 11.4 mg/kg [95% CI 10.6 to 12.3]; ketamine (racemic) 9.6 mg/kg [95% CI 8.5–10.9]). Duration of hypnosis was four-fold shorter in KEA-1010 treated animals. KEA-1010 prolonged thermal tail flick responses comparably with ketamine when administered de novo, and augmented morphine-induced prolongation of tail flick when administered acutely. The analgesic effect of KEA-1010 on thermal tail flick was preserved in opioid tolerant rats. KEA-1010 resulted in increased paw-withdrawal thresholds in a rat paw incision model, similar in magnitude yet more persistent than that seen with fentanyl injection, and additive when co-administered with fentanyl. In contrast to ketamine, behavioural aberration following KEA-1010 injection was largely absent and no pre-pulse inhibition to acoustic startle was observed following KEA-1010 administration in rats.

Conclusions
KEA-1010 provides antinociceptive efficacy in acute thermal and mechanical pain models that augments standard opioid analgesia and is preserved in opioid tolerant rodents. The NMDA channel affinity and psychomimetic signature of the parent compound ketamine is largely absent for KEA-1010.
Antidiabetic and antioxidant potentials of Vitellaria paradoxa barks in alloxan-induced diabetic rats
Authors: Miaffo David , Guessom Kamgue Oulianovie , Ledang Tebou Narcisse , Maa Maa Temhoul Clarice , Kamanyi Albert 
Published: December 2019

Abstract
Background
Vitellaria paradoxa (V. paradoxa) is a plant used in traditional medicine in the treatment of many diseases including diabetes mellitus. Although the different parts of this plant are used empirically as antidiabetic drug, no scientific work to our knowledge has yet been undertaken to evaluate its effects on blood glucose, and lipid and antioxidant parameters of diabetic animals. The objective of this study is therefore to evaluate the hypoglycaemic, hypolipidemic and antioxidant activities of the aqueous extract of V. paradoxa barks in diabetic rats.

Methods
Diabetes was induced by intraperitoneal injection of alloxan (120 mg/kg bw). Thirty male albino rats were divided into groups and orally treated for 14 days with distilled water, glibenclamide (2.5 mg/kg bw) and aqueous extract of V. paradoxa (125, 250 and 500 mg/kg bw). Glycaemia, insulin level, relative body weight, hepatic glycogen level, some liver enzymes, and lipid and antioxidant parameters were evaluated.

Results
The results showed that the extract caused a significant increase in relative body weight, insulin level, HDL-cholesterol, hepatic glycogen rate, and fructose-1,6-biphosphate and glucokinase activities. A significant decrease in glycaemia, glucose-6-phosphatase activity, total cholesterol, triglycerides and LDL-cholesterol were also observed after the administration of V. paradoxa. Glutathione level and the activities of catalase and superoxide dismutase increased significantly while the nitric oxide and malondialdehyde levels decreased significantly in the liver of animals treated with the extract of V. paradoxa.

Conclusion
These results justify the hypoglycaemic, hypolipidemic and antioxidant effects of aqueous extract of V. paradoxa barks, which can reduce the complications associated with diabetes.