bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of the dual sodium–glucose linked transporter inhibitor, licogliflozin vs placebo or empagliflozin in patients with type 2 diabetes and heart failure
Authors: de Boer Rudolf A. , Núñez Julio , Kozlovski Plamen , Wang Yi , Proot Pieter , Keefe Deborah
Published: February 2020

Aims

Explore the efficacy, safety and tolerability of the dual sodium–glucose cotransporter (SGLT) 1 and 2 inhibitor, licogliflozin in patients with type‐2 diabetes mellitus (T2DM) and heart failure.

Methods

This multicentre, parallel‐group phase IIA study randomized 125 patients with T2DM and heart failure (New York Heart Association II–IV; plasma N‐terminal pro b‐type natriuretic peptide [NT‐proBNP] >300 pg/mL) to licogliflozin (2.5 mg, 10 mg, 50 mg) taken at bedtime, empagliflozin (25 mg) or placebo (44 patients completed the study). The primary endpoint was change from baseline in NT‐proBNP after 12 weeks. Secondary endpoints included change from baseline in glycated haemoglobin, fasting plasma glucose, weight, blood pressure, fasting lipid profile, high‐sensitivity c‐reactive protein, and safety and tolerability.

Results

Licogliflozin 10 mg for 12 weeks significantly reduced NT‐proBNP vs placebo (Geometric mean ratio 0.56 [95% confidence interval: 0.33, 0.95], P = .033). A trend was observed with 50 mg licogliflozin (0.64 [95% confidence interval: 0.40, 1.03], P = .064), with no difference between licogliflozin and empagliflozin. The largest numerical decreases in glycated haemoglobin were with licogliflozin 50 mg (−0.58 ± 0.34%) and empagliflozin (−0.44 ± 1.18%) vs placebo (−0.04 ± 0.91%). The reduction in body weight was similar with licogliflozin 50 mg (−2.15 ± 2.40 kg) and empagliflozin (−2.25 ± 1.89 kg). A numerical reduction in systolic blood pressure was seen with licogliflozin 50 mg (−9.54 ± 16.88 mmHg) and empagliflozin (−6.98 ± 15.03 mmHg) vs placebo (−2.85 ± 11.97 mmHg). Adverse events (AEs) were mild, including hypotension (6.5%), hypoglycaemia (8.1%) and inadequate diabetes control (1.6%). The incidence of diarrhoea (4.9%) was lower than previously reported.

Conclusion

The reduction in NT‐proBNP with licogliflozin suggests a potential benefit of SGLT1 and 2 inhibition in patients with T2DM and heart failure.
First‐in‐human study with ACT‐539313, a novel selective orexin‐1 receptor antagonist
Authors: Kaufmann Priska , Anliker‐Ort Marion , Golor Georg , Kornberger Rüdiger , Dingemanse Jasper
Published: February 2020

Aims

The orexin system is involved in anxiety behaviour and corresponding physiological reactions and constitutes a target for treatment of anxiety disorders. ACT‐539313 is a potent, selective orexin‐1 receptor antagonist being developed for the treatment of anxiety disorders. This first‐in‐human study investigated its single‐dose pharmacokinetics (PK) including food effect, pharmacodynamics (PD), safety and tolerability.

Methods

This double‐blind, placebo‐controlled, randomized study included 40 healthy male subjects. Ascending oral doses of 10–400 mg ACT‐539313 were investigated in 5 dose groups of 8 subjects (of whom 2 received placebo per dose group). At 100 mg, subjects received ACT‐539313 in fasted and fed conditions in a fixed sequential design. PK, PD (objective and subjective measures of sedation and effects on central nervous system), safety and tolerability were assessed.

Results

In fasted conditions, ACT‐539313 was rapidly absorbed (median time to maximum plasma concentration [Cmax] 0.7–3.5 h) and cleared from plasma with a mean terminal half‐life of 3.3–5.7 h across dose levels. A 1.63‐fold (90% confidence interval: 1.26–2.11) increase in Cmax and no change in area under the concentration–time curve extrapolated to infinity was observed under fed compared to fasted conditions. No relevant PD signals were detected except for a trend of reduced saccadic peak velocity around time to Cmax. The most commonly reported adverse events were somnolence and headache. All adverse events were transient and of mild or moderate intensity. No treatment‐related effects on vital signs, clinical laboratory or 12‐lead electrocardiogram were observed.

Conclusions

ACT‐539313 exhibits good safety and tolerability at single doses of up to and including 400 mg that warrant further investigations.
Effect of ciclosporin on safety, lymphocyte kinetics and left ventricular remodelling in acute myocardial infarction
Authors: Cormack Suzanne , Mohammed Ashfaq , Panahi Pedram , Das Rajiv , Steel Alison J. , Chadwick Thomas , Bryant Andrew , Egred Mohaned , Stellos Konstantinos , Spyridopoulos Ioakim ,   the CAPRI investigators
Published: February 2020

Aims

Following a favourable pilot trial using a single bolus of ciclosporin, it has been unclear why 2 large studies (CYCLE and CIRCUS) failed to prevent reperfusion injury and reduce infarct size in STEMI (ST elevation myocardial infarction). The purpose of this study was to assess the effect of ciclosporin on myocardial injury, left ventricular remodelling and lymphocyte kinetics in patients with acute STEMI undergoing primary percutaneous coronary intervention.

Methods

In this double‐blind, single centre trial, we randomly assigned 52 acute STEMI patients with an onset of pain of <6 hours and blocked culprit artery to a single bolus of ciclosporin (n = 26) or placebo (n = 26, control group) prior to reperfusion by stent percutaneous coronary intervention. The primary endpoint was infarct size at 12 weeks.

Results

Mean infarct size at 12 weeks was identical in both groups (9.1% [standard deviation= 7.0] vs 9.1% [standard deviation = 7.0], P = .99; 95% confidence interval for difference: −4.0 to 4.1). CD3 T‐lymphocytes dropped to similar levels at 90 minutes (867 vs 852 cells/μL, control vs ciclosporin) and increased to 1454 vs 1650 cells/μL at 24 hours.

Conclusion

In our pilot trial, a single ciclosporin bolus did not affect infarct size or left ventricular remodelling, matching the results from CYCLE and CIRCUS. Our study suggests that ciclosporin does either not reach ischaemic cardiomyocytes, or requires earlier application during first medical contact. Finally, 1 bolus of ciclosporin is not sufficient to inhibit CD4 T‐lymphocyte proliferation during remodelling. We therefore believe that further studies are warranted.

(Evaluating the effectiveness of intravenous Ciclosporin on reducing reperfusion injury in pAtients undergoing PRImary percutaneous coronary intervention [CAPRI]; NCT02390674)
A semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance
Authors: Langenhorst Jurgen B. , Boss Jill , van Kesteren Charlotte , Lalmohamed Arief , Kuball Jürgen , Egberts Antoine C. G. , Boelens Jaap Jan , Huitema Alwin D. R. , van Maarseveen Erik M.
Published: February 2020

Aim

To develop a semi‐mechanistic model, based on glutathione depletion and predict a previously identified intra‐individual reduction in busulfan clearance to aid in more precise dosing.

Methods

Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semi‐mechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi‐mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi‐mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment.

Results

In both models, a similar clearance decrease of 7% (range −82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6–8%, P = 0.009), causing the effect to increase more than a 2‐fold over the observed age‐range (0–73 years). Compared to the empirical model, the final semi‐mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients.

Conclusion

These results suggest that the time‐dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi‐mechanistic model could be used to further improve TDM‐guided exposure target attainment of busulfan in patients undergoing HCT.
Effect of postdose fasting duration on hetrombopag olamine pharmacokinetics and pharmacodynamics in healthy volunteers
Authors: Yang Guoping , Huang Ranglang , Yang Shuang , Zhang Xingfei , Yang Xiaoyan , Chen Honghui , Huang Zhijun , Guo Chengxian , Pei Qi , Tai Yanfei , Shen Yancong , Huang Jie , Zou Chan
Published: February 2020

Aims

Hetrombopag olamine is a novel small‐molecule, nonpeptide thrombopoietin receptor agonist developed for immune thrombocytopenia treatment. This study aims to determine the safety and the effect of fasting duration after administration of hetrombopag on pharmacokinetics and pharmacodynamics in Chinese healthy subjects.

Methods

A randomized, open‐label, single‐dose, 3‐period crossover, self‐control trial was conducted. 15 eligible subjects were enrolled and received hetrombopag 7.5 mg at day 1 of each period followed by a standard meal 4 hours postdose (treatment A/fasting condition), or a high‐calorie, high‐fat meal 1 hour postdose (treatment B), or a high‐calorie, high‐fat meal 2 hours postdose (treatment C). The plasma concentrations of hetrombopag were determined by validated liquid chromatography–tandem mass spectrometry, platelet counts were quantified by blood test. Analysis was performed using a mixed model, including treatment, period as fixed effects and participant as a random effect.

Results

Compared with treatment A, peak concentration and area under concentration–time curve extrapolated to infinity decreased by 56 and 74.6%, and 44 and 61% in treatments B and C, respectively. The mean platelet number on day 6 increased by 15.8, 6.96 and 10.26%, respectively, in treatments A, B and C in comparison with baseline platelet level. No severe adverse events happened in any of the 3 treatments.

Conclusion

Hetrombopag was well tolerated in healthy male subjects under fasted/fed conditions. The shorter fasting duration resulted in lower hetrombopag exposure, corresponding to a lower level of platelet elevation. Therefore, we recommended oral administration of hetrombopag on an empty stomach (fasting condition) or at least 2 hours before a meal to achieve maximum bioavailability.
Comparison of efficacy from two different dosing regimens of bortezomib: an exposure–response analysis
Authors: Parasrampuria Dolly A. , He Jianming , Zhang Liping , Muresan Bogdan , Hu Peter , Nemat Sepideh , Hashim Mahmoud , Lam Annette , Appiani Carlos , Cavo Michele , Dimopoulos Meletios A. , San‐Miguel Jesus , Mateos Maria‐Victoria
Published: February 2020

Bortezomib is a first‐in‐class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib’s benefit–risk profile. Here, we performed exposure–response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6‐week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42·2 vs. 38·5 mg/m2) and ALCYONE patients stayed on treatment longer (mean: 7·2 vs. 5·8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with ≥ 39·0 versus < 39·0 mg/m2 cumulative dose (hazard ratio, 0·119; P < 0·0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions.
DPEP1 expression promotes proliferation and survival of leukaemia cells and correlates with relapse in adults with common B cell acute lymphoblastic leukaemia
Authors: Zhang Jia‐Min , Xu Yan , Gale Robert P. , Wu Li‐Xin , Zhang Jing , Feng Yong‐Huai , Qin Ya‐Zhen , Jiang Hao , Jiang Qian , Jiang Bin , Liu Yan‐Rong , Chen Yu‐Hong , Wang Yu , Zhang Xiao‐Hui , Xu Lan‐Ping , Huang Xiao‐Jun , Liu Kai‐Yan , Ruan Guo‐Rui
Published: February 2020

Dehydropeptidase‐1 (DPEP1) is a zinc‐dependent metalloproteinase abnormally expressed in many cancers. However, its potential role in adults with B cell acute lymphoblastic leukaemia (ALL) is unknown. We found that in adults with common B cell ALL high DPEP1, transcript levels at diagnosis were independently associated with an increased cumulative incidence of relapse (CIR) and worse relapse‐free survival (RFS) compared with subjects with low transcript levels. We show an increased proliferation and prosurvival role of DPEP1 in B cell ALL cells via regulation of phosphCREB and p53, which may be the biological basis of the clinical correlation we report. Our data implicate DPEP1 expression in the biology of common B cell ALL in adults. We report clinical correlates and provide a potential biological basis for these correlations. If confirmed, analysing DPEP1 transcript levels at diagnosis could help predict therapy outcomes. Moreover, regulation of DPEP1 expression could be a therapy target in B cell ALL.
Novel phenotype of syndromic premature ovarian insufficiency associated with TP63 molecular defect
Authors: Mathorne Stine W. , Ravn Pernille , Hansen Dorte , Beck‐Nielsen Signe S. , Gjørup Hans , Sørensen Kristina P. , Fagerberg Christina R.
Published: February 2020

There is growing evidence that TP63 is associated with isolated as well as syndromic premature ovarian insufficiency (POI). We report two adolescent sisters diagnosed with undetectable ovaries, uterine hypoplasia, and mammary gland hypoplasia. A novel paternally inherited nonsense variant in TP63 [NM_003722.4 c.1927C > T,p.(Arg643*)] in exon 14 was identified by exome sequencing. One of the syndromes linked to TP63 is limb mammary syndrome (LMS), an autosomal dominant inherited disorder characterized by ectrodactyly, hypoplasia of mammary‐gland and nipple, lacrimal duct stenosis, nail dysplasia, dental anomalies, cleft palate and/or cleft lip and absence of skin and hair defects. The TP63 variant segregated with symptoms of LMS in the family, however, no affected individual had limb defects. The phenotype reported here represents a novel syndromic phenotype associated with TP63. Reported cases with TP63 associated POI are reviewed.
Drinking contexts and their association with acute alcohol‐related harm: A systematic review of event‐level studies on adults' drinking occasions
Authors: Stevely Abigail K. , Holmes John , McNamara Simon , Meier Petra S.
Published: February 2020

Issues

Event‐level alcohol research can inform prevention efforts by determining whether drinking contexts—such as people or places—are associated with harmful outcomes. This review synthesises evidence on associations between characteristics of adults' drinking occasions and acute alcohol‐related harm.

Approach

We systematically searched Ovid MEDLINE, Ovid PsycInfo and the Web of Science Social Sciences Citation Index. Eligible papers used quantitative designs and event‐level data collection methods. They linked one or more drinking contexts to acute alcohol‐related harm. Following extraction of study characteristics, methods and findings, we assessed study quality and narratively synthesised the findings. PROSPERO ID: CRD42018119701.

Key Findings

Searches identified 95 eligible papers, 65 (68%) of which study young adults and 62 (65%) of which are set in the United States, which limits generalisability to other populations. These papers studied a range of harms from assault to drink driving. Study quality is good overall although measures often lack validation. We found substantial evidence for direct effects of drinking context on harms. All of the contextual characteristics types studied (e.g. people, place, timing, psychological states, drink type) were consistently associated with harms. Certain contexts were frequently studied and associated with harms, in particular, weekend drinking, drinking in licensed premises and concurrent illicit drug use.

Implications

The findings of our review indicate target drinking contexts for prevention efforts that are consistently associated with increased acute alcohol‐related harm.

Conclusion

A large range of contextual characteristics of drinking occasions are directly associated with acute alcohol‐related harm, over and above levels of consumption.
Completeness of reporting of case reports in high‐impact medical journals
Authors: Calvache José A. , Vera‐Montoya Maira , Ordoñez Darío , Hernandez Adrian V. , Altman Douglas , Moher David
Published: February 2020

Introduction

Case reports represent a relevant, timely and important study design in advancing medical scientific knowledge. They allow integration between clinical practice and clinical epidemiology. We aimed to assess the completeness of reporting (COR) of case reports published in high‐impact journals. We assessed the COR of case reports using the CARE guidelines.

Materials and methods

We selected three high‐impact journals and one journal specialized in publishing case reports, in which we included all published case reports from July to December 2017. Median COR score was calculated per study, and CORs were compared between journals with and without endorsement of CARE guidelines.

Results

One hundred and fourteen case reports were included. Overall median COR was 81%, IQR [63%‐96%]. Sections with the highest COR (84%‐100%) were patient information, clinical findings, therapeutic intervention, follow‐up and outcomes, discussion and informed consent. Sections with the lowest COR were title, keywords, timeline and patient perspective (2%‐34%). COR was higher in journals endorsing in comparison to those not endorsing CARE guidelines (77% vs 65%), respectively, median difference = −12% 95% CI [−16% to −7%].

Discussion

Overall completeness of case reports in included journals is high especially for CARE endorsing and dedicated journals but reporting of some items could be improved. Ongoing and future evaluations of endorsement status of reporting guidelines in medical journals should be assessed to improve completeness and reduce waste of clinical research, including case reports.
Quality–quantity trade‐offs drive functional trait evolution in a model microalgal ‘climate change winner’
Authors: Lindberg Rasmus T. , Collins Sinéad
Published: February 2020

Phytoplankton are the unicellular photosynthetic microbes that form the base of aquatic ecosystems, and their responses to global change will impact everything from food web dynamics to global nutrient cycles. Some taxa respond to environmental change by increasing population growth rates in the short‐term and are projected to increase in frequency over decades. To gain insight into how these projected ‘climate change winners’ evolve, we grew populations of microalgae in ameliorated environments for several hundred generations. Most populations evolved to allocate a smaller proportion of carbon to growth while increasing their ability to tolerate and metabolise reactive oxygen species (ROS). This trade‐off drives the evolution of traits that underlie the ecological and biogeochemical roles of phytoplankton. This offers evolutionary and a metabolic frameworks for understanding trait evolution in projected ‘climate change winners’ and suggests that short‐term population booms have the potential to be dampened or reversed when environmental amelioration persists.
Clinical characteristics of fibroblast growth factor receptor 3 antibody‐related polyneuropathy: a retrospective study
Authors: Kovvuru S. , Cardenas Y. C. , Huttner A. , Nowak R. J. , Roy B.
Published: February 2020

Background and purpose

Autoantibodies are increasingly being used as a diagnostic biomarker of chronic inflammatory neuropathies. However, their role and associated clinical syndrome are not well defined.

Methods

This retrospective chart review evaluated the clinical presentation, diagnostic workup and therapeutic responses in fibroblast growth factor receptor 3 (FGFR3) antibody‐associated neuropathy.

Results

A total of 27 patients [14 men, aged 29–87 (65 ± 14) years] with positive FGFR3 antibody were included. Distal lower‐extremity paresthesia (66%), unsteady gait (26%) and foot drop (11%) were common presenting symptoms. Symptom onset was acute in four (15%) cases. Distal lower‐extremity weakness (mild in eight and severe in three patients) was the most frequent motor finding. Decreased distal sensation to pinprick (59%) and loss of vibration sensation (37%) were observed. Titer of FGFR3 ranged between 3100 and 30 000 (normal < 3000) with a mean of 10 688 ± 7284. Apart from the occasional association of other neuropathy‐related autoantibodies, comprehensive neuropathy workup was otherwise unrevealing. Six patients had other autoimmune disease and seven patients had a history of cancer. Electromyography reflected sensorimotor neuropathy with mixed axonal and demyelinating features in 11 cases. Pure sensory neuropathy was noted in three patients. Demyelination was found in five of six nerve biopsies. Intravenous immunoglobulin response was observed in 8/10 treated patients.

Conclusions

The FGFR3 antibody appears not to be restricted to sensory neuropathy only. Its role in the pathogenicity of chronic inflammatory neuropathies is not yet well established and, although there may be a role for immunotherapy, larger studies are warranted.
Finding weaknesses in networks using Greedy Randomized Adaptive Search Procedure and Path Relinking
Authors: Pérez‐Peló Sergio , Sánchez‐Oro Jesús , Duarte Abraham
Published: February 2020

In recent years, the relevance of cybersecurity has been increasingly evident to companies and institutions, as well as to final users. Because of that, it is important to ensure the robustness of a network. With the aim of improving the security of the network, it is desirable to find out which are the most critical nodes in order to protect them from external attackers. This work tackles this problem, named the α‐separator problem, from a heuristic perspective, proposing an algorithm based on the Greedy Randomized Adaptive Search Procedure (GRASP). In particular, a novel approach for the constructive procedure is proposed, where centrality metrics derived from social network analysis are used as a greedy criterion. Furthermore, the quality of the provided solutions is improved by means of a combination method based on Path Relinking (PR). This work explores different variants of PR, also adapting the most recent one, Exterior PR, for the problem under consideration. The combination of GRASP + PR allows the algorithm to obtain high‐quality solutions within a reasonable computing time. The proposal is supported by a set of intensive computational experiments that show the quality of the proposal, comparing it with the most competitive algorithm found in the state of art.
Large herbivore conservation in a changing world: Surface water provision and adaptability allow wildebeest to persist after collapse of long‐range movements
Authors: Weeber Joshua , Hempson Gareth P. , February Edmund C.
Published: February 2020

Large herbivores, particularly wide‐ranging species, are extensively impacted by land use transformation and other anthropogenic barriers to movement. The adaptability of a species is, therefore, crucial to determining whether populations can persist in ever smaller subsets of their historical home ranges. Access to water, by drinking or from forage moisture, is an essential requirement, and surface water provision is thus a long‐established, although controversial, conservation practice. In the arid Kgalagadi Transfrontier Park (KTP), South Africa, surface water provision in the 1930s facilitated the establishment of a sedentary wildebeest (Connochaetes taurinus) population in a region historically accessed only in the wet season, via now collapsed long‐distance movements. Here, we investigate the behaviour and diet of this wildebeest population, and how these relate to water in the landscape, to better understand the process of transitioning from a mobile to sedentary population. Data from 26 monthly surveys reveal that wildebeest distributions are shaped by water availability and salinity, shade, forage, season and possibly predator detectability. Areas with saline or no water are used predominantly in the wet season when forage moisture is high. Wet season movements beyond the study area mean the timing of wildebeest grazing in these regions matches historical timing. Grass utilization field data suggest that the KTP grazer population experiences forage deficits during the dry season, when ~80% of grass tufts are grazed and C:N and crude protein levels decline. Nonetheless, dung isotope data show that wildebeest meet their crude protein intake requirements during the dry season, likely by consuming unprecedentedly high levels of browse (>33%). While restoring the full historical range and movements of most large herbivore populations is not possible, these findings highlight that understanding the behavioural and dietary adaptability of a species can augment ‘next best’ efforts to conserve viable populations while home ranges contract.
Voters' wrath? Policy change and government popularity
Authors: Arndt Christoph , Jensen Carsten , Wenzelburger Georg
Published: February 2020

Recent research suggests that voters are bad at responding in a meaningful way to policy events when deciding for whom to vote. Voters rely on so‐called “blind retrospection”, punishing governments for events outside politicians' control. However, another core aspect of the blind retrospection perspective has not been put to the test: are voters unable to respond to policy decisions that clearly are under the politicians' control? We construct a unique large‐N dataset on legislative changes in German old age pensions and unemployment protection to see if cutbacks and expansions lead to lower/higher support for the government. Our data are exceptionally fine‐grained and allow us to track the policy‐vote link for 416 months from 1977 to 2013 with a total of 329,167 respondents. We find substantial support for the notion that voters react in a meaningful way to policy changes, but also that they can be distracted by high‐profile, extreme events.
Complexity of best‐evidenced practice in periodontal therapy: Views of Swedish Dental Hygienists
Authors: Liss Anna , Nilsson Kerstin , Wennström Jan L. , Abrahamsson Kajsa H.
Published: February 2020

Objectives

Dental hygienists (DHs) have an important role in the treatment of patients with periodontitis. The objective of the current qualitative interview study was to gain understanding about personal and organizational factors that influence best‐evidenced DH practice in the treatment of periodontitis.

Methods

Data were obtained by interviewing Swedish DHs, who had been engaged in a preceding clinical field study on evidence‐based periodontal therapy. Qualitative content analysis was used for analysis. Data sampling was terminated after 18 interviews, when deemed that sufficient amount of information had been gained.

Results

In the analysis of the interview data, a main theme was identified as “I know what to do, but I do as I usually do; DHs' ambivalence between theory and practice in the treatment of patients with periodontitis.” The results elucidated that the DHs were well aware of “what to do” in order to offer their patients adequate periodontal care, but this knowledge was not congruent with how they usually worked. Established routines and culture at the clinic, DHs' predetermined beliefs about lack of motivation and ability to cooperate among patients, lack of time and reflection, economic demands in care and lack of interest and support by co‐working dentists were barriers to best‐evidenced DH practice in periodontal care.

Conclusions

The results elucidate the complexity of best‐evidenced DH practice in the treatment of periodontal patients and indicate needs for quality improvement of the periodontal care provided in general dental practice, by actions taken on both individual/professional and organizational levels.
A web‐based therapeutic patient education intervention for pain and sleep for women with fibromyalgia: A sequential exploratory mixed‐methods research protocol
Authors: Climent‐Sanz Carolina , Gea‐Sánchez Montserrat , Moreno‐Casbas María T. , Blanco‐Blanco Joan , García‐Martínez Ester , Valenzuela‐Pascual Fran
Published: February 2020

Aims

To evaluate cognitive and behavioural factors related to pain and poor sleep quality in women diagnosed with fibromyalgia and to develop and test the effects of a web‐based therapeutic education intervention on pain intensity, pain catastrophizing, chronic pain self‐efficacy, sleep quality, dysfunctional beliefs and attitudes about sleep and quality of life and health status related to fibromyalgia.

Design

The project will employ a sequential exploratory mixed methods research design.

Methods

For the qualitative phase, a theoretical sample living in the community will be recruited to participate in personal, semi‐structured interviews. For the quantitative phase, a sample of adult women with fibromyalgia will be recruited from secondary care centres and randomly allocated an intervention or a control group. The study protocol was approved in 2019.

Discussion

Fibromyalgia is the most common central sensitivity syndrome and one of the principal worldwide causes of chronic widespread pain among the adult population. Poor sleep quality is a highly prevalent and troublesome symptom for people with fibromyalgia. Psychosocial and behavioural factors have been shown to relate intimately with the symptom experiences of people with fibromyalgia; pain catastrophizing and dysfunctional beliefs and attitudes about sleep can perpetuate those and other fibromyalgia symptoms.

Conclusion

It is imperative to reflect people's actual symptom experiences to develop effective symptom management strategies. In the Internet era, this project's proposed web‐based therapeutic education intervention could offer women with fibromyalgia a new avenue for treatment as part of standard fibromyalgia management programs in primary and secondary healthcare services.

Impact

Pain and poor sleep quality are highly prevalent and troublesome symptoms for people with fibromyalgia. The web‐based therapeutic education intervention proposed in this project could provide women with fibromyalgia a new avenue for treatment in primary and secondary healthcare services.

Protocol registration: ClinicalTrials.gov Identifier: NCT03686410.
Experiences of an adolescent inpatient model of care: Adolescent and caregiver perspectives
Authors: Hayes Claire , Simmons Magenta , Palmer Victoria J. , Hamilton Bridget , Simons Christine , Hopwood Malcolm
Published: February 2020

Problem

Adolescent inpatient units have been studied regarding their effectiveness, yet little is known about the experiences of young people who are admitted and their caregivers. It is important to address this gap to understand adolescent inpatient models of care and therapeutic outcomes to maximize the benefit. Our aim was to explore adolescent and caregivers' experiences of an inpatient model of care (MoC) and perceived helpfulness.

Methods

A longitudinal prospective qualitative design was utilized. Semistructured interviews were conducted with 16 adolescents and 12 caregivers at T1 (admission), T2 (discharge), and T3 (6 months postdischarge). Data were analysed first thematically and then using trajectory analysis. Themes from the three time‐points are presented from the combined perspectives of adolescents and caregivers.

Findings

Experiences described followed a recovery narrative consisting of three key phases which included, “waiting for help” (T1), “help arrived” (T2), and having “returned to regular life” (T3). The overarching trajectory theme was a “winding road to recovery.”

Conclusion

Findings provide insights into the lived experiences from adolescents who have had an inpatient stay and their caregivers of an adolescent‐specific inpatient MoC. These findings can help conceptualize quality adolescent models of care for young people and their families.
Journeying with fear: Young people's experiences of cannabis use, crime and violence before treatment entry
Authors: Comiskey Catherine , James Philip , Smyth Bobby
Published: February 2020

Problem

The experiences of crime and policing from the perspective of adolescent cannabis users before treatment entry are not often understood by practitioners.

Methods

A qualitative design within an interpretivist paradigm was used. Data were collected using one‐to‐one semi‐structured interviews. A convenience sample was recruited through two treatment centers in Dublin, Ireland in 2015. A deductive thematic analysis was used.

Findings

In‐depth interviews with eight young people were conducted. At the individual level, there was a common theme of naïve crimes with the introduction of debt and developing violence. Young people often stole from their families and obtained credit from dealers. Policing was initially viewed as benign. Families suffered as a result of the drug debts but young people also spoke of intergenerational drug use. As the young person's use progressed, the oppressed became the oppressor, young people were entrapped, violence escalated and real fear of incarceration and remorse was expressed.

Conclusion

Findings highlight the commonality of fear and the seriousness of personal and familial violent harms. The need for targeted developmental preventions in vulnerable settings is proposed. Parents and professionals need to have an awareness of money in the home and the role of intergenerational substance use.
Pingyangmycin inhibits glycosaminoglycan sulphation in both cancer cells and tumour tissues
Authors: Lan Ying , Li Xiulian , Liu Yong , He Yanli , Hao Cui , Wang Hua , Jin Liying , Zhang Guoqing , Zhang Shufeng , Zhou Aimin , Zhang Lijuan
Published: February 2020

Pingyangmycin is a clinically used anticancer drug and induces lung fibrosis in certain cancer patients. We previously reported that the negatively charged cell surface glycosaminoglycans are involved in the cellular uptake of the positively charged pingyangmycin. However, it is unknown if pingyangmycin affects glycosaminoglycan structures. Seven cell lines and a Lewis lung carcinoma‐injected C57BL/6 mouse model were used to understand the cytotoxicity of pingyangmycin and its effect on glycosaminoglycan biosynthesis. Stable isotope labelling coupled with LC/MS method was used to quantify glycosaminoglycan disaccharide compositions from pingyangmycin‐treated and untreated cell and tumour samples. Pingyangmycin reduced both chondroitin sulphate and heparan sulphate sulphation in cancer cells and in tumours. The effect was persistent at different pingyangmycin concentrations and at different exposure times. Moreover, the cytotoxicity of pingyangmycin was decreased in the presence of soluble glycosaminoglycans, in the glycosaminoglycan‐deficient cell line CHO745, and in the presence of chlorate. A flow cytometry‐based cell surface FGF/FGFR/glycosaminoglycan binding assay also showed that pingyangmycin changed cell surface glycosaminoglycan structures. Changes in the structures of glycosaminoglycans may be related to fibrosis induced by pingyangmycin in certain cancer patients.
Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression
Authors: Li Hai‐ru , Wang Chao , Sun Ping , Liu Dan‐dan , Du Guo‐qing , Tian Jia‐wei
Published: February 2020

There are increasing concerns related to the cardiotoxicity of doxorubicin in the clinical setting. Recently, melatonin has been shown to exert a cardioprotective effect in various cardiovascular diseases, including cardiotoxic conditions. In this study, we examined the possible protective effects of melatonin on doxorubicin‐induced cardiotoxicity and explored the underlying mechanisms related to this process. We found that in vitro doxorubicin treatment significantly decreased H9c2 cell viability and induced apoptosis as manifested by increased TUNEL‐positive cells, down‐regulation of anti‐apoptotic protein Bcl‐2, as well as up‐regulation of pro‐apoptotic protein Bax. This was associated with increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potentials (MMP). In vivo, five weeks of doxorubicin treatment significantly decreased cardiac function, as evaluated by echocardiography. TUNEL staining results confirmed the increased apoptosis caused by doxorubicin. On the other hand, combinational treatment of doxorubicin with melatonin decreased cardiomyocyte ROS and apoptosis levels, along with increasing MMP. Such doxorubicin‐melatonin co‐treatment alleviated in vivo doxorubicin‐induced cardiac injury. Western Blots, along with in vitro immunofluorescence and in vivo immunohistochemical staining confirmed that doxorubicin treatment significantly down‐regulated Yes‐associated protein (YAP) expression, while YAP levels were maintained under co‐treatment of doxorubicin and melatonin. YAP inhibition by siRNA abolished the protective effects of melatonin on doxorubicin‐treated cardiomyocytes, with reversed ROS level and apoptosis. Our findings suggested that melatonin treatment attenuated doxorubicin‐induced cardiotoxicity through preserving YAP levels, which in turn decreases oxidative stress and apoptosis.
Let Us Europeans Move: How Collective Identities Drive Public Support for Border Regimes inside the EU
Authors: Karstens Felix
Published: February 2020

After three decades of European integration, during which border controls seemed like a relic from the past, the refugee crisis and Brexit have brought the issue to the centre of public debate. Existing research points towards the relevance of collective identity for attitude formation in the field of high politics, but has so far not answered the question of how far collective identities explain support for different intra‐EU border regimes. My article closes this gap. It is based on an original representative EU‐wide survey from 2017 (N = 10,827), which analyses the nexus between border regime support, identity and migration experience, as well as contextual factors like immigration rates. Support for Schengen membership is significantly stronger among respondents with a European identity than those identifying exclusively with their nation‐state. These findings suggest that the endorsement of open borders and further integration in this policy area is strongly dependent on an inclusive European collective identity.
Mind the Gap: Southern Exit, Northern Voice and Changing Loyalties since the Euro Crisis
Authors: Matthijs Matthias , Merler Silvia
Published: February 2020

In this article, we examine whether the EU's unequal encroachment on its northern and southern members' core state powers since the Euro crisis – manifested in highly uneven burdens of economic adjustment and the reversal of intra‐EU migration dynamics – has in turn affected individual European identity. Using individual‐level data from Eurobarometer pooled over time, we investigate the micro‐foundations of EU citizens' continued sense of belonging, be it shared (national or EU) or exclusive (national). Though a steady majority of EU citizens continues to identify at least partially as European, we observe a rather puzzling North–South divergence in identity among the young and a widening skills gap overall. We argue that the Euro crisis triggered dynamics of southern exit (through surging South–North migration), northern voice (based on EU adoption of policies preferred in the North) and shifting national versus European loyalties, which may have consequences for the changing nature of European identity research.
Extra‐pair paternity as a strategy to reduce the costs of heterospecific reproduction? Insights from the crow hybrid zone
Authors: Knief Ulrich , Bossu Christen M. , Wolf Jochen B.W.
Published: February 2020

Within hybrid zones of socially monogamous species, the number of mating opportunities with a conspecific can be limited. As a consequence, individuals may mate with a heterospecific (social) partner despite possible fitness costs to their hybrid offspring. Extra‐pair copulations with a conspecific may thus arise as a possible post hoc strategy to reduce the costs of hybridization. We here assessed the rate of extra‐pair paternity in the hybrid zone between all‐black carrion crows (Corvus (corone) corone) and grey hooded crows (C. (c.) cornix) and tested whether extra‐pair paternity (EPP) was more likely in broods where parents differed in plumage colour. The proportion of broods with at least one extra‐pair offspring and the proportion of extra‐pair offspring were low overall (6.98% and 2.90%, respectively) with no evidence of hybrid broods having higher EPP rates than purebred nests.
Radio frequency‐assisted extraction of pectin from jackfruit (Artocarpus heterophyllus) peel and its characterization
Authors: Naik Mohan , Rawson Ashish , Rangarajan Jagan Mohan
Published: February 2020

Emerging technologies for extraction of valuable components from food by‐products is the need of the hour as they are classified as green technology. Radio‐frequency assisted extraction (RFAE) is one such novel technology. The present study focused on the extraction of pectin from Jackfruit waste (peel) using RFAE. The optimum RFAE conditions found were RF time of 61.50 min, the ratio of liquid to solid 20.63:1 (ml/g), and pH 2.61. Under these conditions, the yield and degree of esterification (DE) of pectin was 29.40% and 65.07%, respectively. The value of DE suggests that Jackfruit pectin is categorized as high methoxyl pectin. Compared to the conventional method of extraction (12.37%) the yield of pectin was much higher in RFAE (29.40%). The study of viscosity measurement revealed that the solutions of pectin showed nearly pseudoplastic flow behavior. Hence, RFAE was found to be an effective, time saving, and eco‐friendly method for extraction of pectin from Jackfruit peel.

Practical applications

Jackfruit peels are the major by‐product of Jackfruit processing industries and contribute to the waste disposal problem. Peels are a potential source of pectin, fiber, and starch. Recovery of these compounds from the peel is the biggest challenge. Conventional boiling is the traditional method used for extraction of pectin, which considerably takes more time and yields less pectin. Radio frequency‐assisted extraction of pectin under acidic conditions is an efficient, quick, and environmentally friendly method. This study demonstrated that radio frequency heating enhances the yield of pectin and reduces the extraction time. The extracted pectin has the potential to be used as a jellying, stabilizing, emulsifying, and thickening agent in food processing industries. Hence, radio frequency heating has a potential application as an efficient extraction technology, thus enhancing the yield of pectin.
Virtues as Qualities of Character
Authors: Darr Ryan
Published: February 2020

Over the last two decades, a growing philosophical literature has subjected virtue ethics to empirical evaluation. Drawing on results in social psychology, a number of critics have argued that virtue ethics depends upon false presuppositions about the cross‐situational consistency of psychological traits. Alasdair MacIntyre’s After Virtue has been a prime target for the situationist critics. This essay assesses the situationist critique of MacIntyre’s account of virtue. It argues that MacIntyre’s social teleological account of virtue is not what his situationist critics take it to be. Virtues, for MacIntyre, are not reducible to psychological traits. They are qualities of one’s socially constituted character, and their intelligibility as virtues derives from their role in the narrative of one’s life. Recognizing this both clarifies and complicates debates about the implication of situationist social psychology for virtue ethics. It also grants a new significance to MacIntyre’s attention to the socio‐historical context of virtue, a significance that should be especially interesting to religious ethicists.
The Phenomenology of Democracy
Authors: Davis G. Scott
Published: February 2020

Molly Farneth’s Hegel’s Social Ethics hearkens back to the tradition of Josiah Royce, which has continued in the work of Richard Bernstein and Jeffrey Stout. At the same time, it reflects the impact of three decades of interpretive work which has offered an alternative to the 19th and early 20th century reading of Hegel as a metaphysical systematizer. In this new reading he was from the beginning a social critic and political theorist who looked to lay the groundwork for post‐Enlightenment vision of the social world as evolving toward one of social cooperation based on mutual recognition. Farneth has developed this reading of Hegel into one of powerful resources for democratic pluralism.
Canon, Repetition, and the Opponent
Authors: Levene Nancy
Published: February 2020

This essay considers two concepts of repetition in thinking about canon, the history of ideas, and the work of an opponent, both real and fantastical. I take up these motifs in a variety of figures and cases, but principally in Søren Kierkegaard’s reading of the biblical Abraham in Fear and Trembling, a text rich in interpretive challenges. How might readers in the humanities contend with interpretive rivals while investing in the power of diverse readings? The argument turns on the relationship between the struggle for self‐consciousness, understood through Hegel and Freud as an appointment with otherness, and the work of interpretation, understood as the endeavor to understand others, including other texts, other minds, and one’s own mind. What is the aim of interpretation? How does interpretation fail? To which history of ideas is a reader responsible?
Venetoclax, bortezomib and S63845, an MCL1 inhibitor, in multiple myeloma
Authors: Wong Kwan Yeung , Chim Chor Sang
Published: February 2020

Objectives

Venetoclax, an orally available BCL2-selective inhibitor, has demonstrated promising single-agent anti-tumour activity in myeloma especially patients with t(11;14). Herein, whether venetoclax sensitivity could be enhanced or restored in combination with bortezomib or S63845, a novel MCL1-selective inhibitor, was examined in human myeloma cell lines (HMCLs), including bortezomib-resistant HMCLs.

Methods

By MTS assay, half-maximal inhibitory concentration (IC50) and hence sensitivity/resistance to venetoclax, bortezomib and S63845 were determined.

Key findings

Venetoclax (IC50 ≥100 nm), bortezomib (IC50 ≥50 nm) and S63845 (IC50 ≥100 nm) resistance was observed in nine (75%), three (25%) and six (50%) HMCLs, respectively. Moreover, venetoclax sensitivity was independent of bortezomib (R2 = 0.1107) or S63845 (R2 = 0.0213) sensitivity. Venetoclax sensitivity correlated with high mRNA ratio of BCL2/MCL1 (P = 0.0091), BCL2/BCL2L1 (P = 0.0182) and low MCL1 expression (P = 0.0091). In HMCLs sensitive to both venetoclax and bortezomib/S63845, venetoclax combined with S63845 showed stronger synergistic effect than combined with bortezomib. Moreover, in venetoclax-resistant HMCLs, S63845, but not bortezomib, significantly restored venetoclax sensitivity. Conversely, bortezomib combined with S63845 did not result in augmented bortezomib sensitivity or abolishment of bortezomib resistance.

Conclusions

Regardless of t(11;14), combination of venetoclax with S63845 is a promising strategy in enhancing venetoclax sensitivity or overcoming venetoclax resistance in myeloma therapy, hence warrant future clinical studies.