bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous quantification of cyclosporin, tacrolimus, sirolimus and everolimus in whole blood by UHPLC–MS/MS for therapeutic drug monitoring
Authors: Antunes Natalicia J. , Kipper Karin , Couchman Lewis , Duncan Marie‐Anne , Holt David W. , De Nucci Gilberto , Johnston Atholl
Published: January 2021

The aim of this study was to develop and validate a UHPLC–MS/MS assay to quantify cyclosporin (CYC), tacrolimus (TAC), sirolimus (SIR) and everolimus (EVE) in human whole blood for therapeutic drug monitoring. Analytes were extracted from 50 μL human whole blood by protein precipitation. The separation of the drugs was performed on an Acquity UPLC BEH C18 column. Analytes were eluted with a mobile phase consisting of 2 mM ammonium acetate with 0.1% formic acid (v/v) in deionised water and 2 mM ammonium acetate with 0.1% formic acid (v/v) in methanol at a flow rate of 300 μL/min in gradient elution. The method performance was evaluated by analysing patient blood samples and/or external quality control samples [proficiency testing (PT) scheme]. The method was linear from 23.75 to 1094.0, 1.3 to 42.4, 1.3 to 47.0 and 1.2–41.6 μg/mL for CYC, TAC, SIR and EVE, respectively. The within‐ and between‐assay reproducibility results were ˂ 11%. Results from PT and patient sample quantification were comparable to those obtained previously by an in‐house validated method using protein precipitation and liquid–liquid extraction. This method showed good analytical performance for quantifying CYC, TAC, SIR and EVE in whole blood over their respective calibration ranges.
Some higher ed staff must grapple with conflicting mandatory reporting requirements
Authors: Taylor Z.W. , Barrera Myra C.
Published: January 2021

College campuses have faced a heightened sense of activism regarding sexual harassment and sexual violence during the past decade. Students, faculty, and staff members have brought a litany of lawsuits against colleges and universities alleging sexual assault on or near campus. These lawsuits often claim that the institutions failed to fulfill their Title IX reporting responsibilities. And others assert that their institution abused their authority by falsely accusing and punishing individuals under Title IX.
Qualitatively driven mixed‐methods approaches to counselling and psychotherapy research
Authors: Bailey‐Rodriguez Deborah
Published: January 2021

Many researchers and clinicians take an ‘either, or’ position regarding factors responsible for change when conducting research. Qualitatively driven mixed methods privilege the qualitative approach and offer the opportunity to generate multi‐dimensional material, permitting a more holistic insight into experiences that can be understood from a combination of epistemological and ontological stances. A qualitatively driven mixed‐methods approach apply a ‘both, and’ position when exploring the elements that produce change or that are under investigation, which can be of particular value to counselling and psychotherapy research. There are various ways of engaging with qualitatively driven mixed methods. Some designs include both qualitative and quantitative components, where the former is the core element. The secondary component may also be qualitative, known as a multimethod design. Yet, other designs mix different qualitative approaches, through the application of different qualitative analyses to the same data (pluralistic qualitative research). This paper discusses the application and value of qualitatively driven mixed methods in counselling and psychotherapy research through the presentation of two research case studies; one which mixes both qualitative and quantitative components to investigate the experiences of pain alleviation following a CBT pain management programme; and one which applies a pluralistic approach to a counselling psychology doctorate exploring the experiences and meanings attached to self‐harming. Through illustration and discussion of the case studies’ mixed‐methods approaches, this paper demonstrates that qualitatively driven mixed methods produce a more enhanced and holistic understanding into phenomena, and therefore a more balanced perspective to counselling and psychotherapy research.
Leaders pay it forward by becoming mentors
Authors: Hodges Dawn Z.
Published: January 2021

“Paying it forward” is not a new concept. It's probably as old as time. But in the past few years, the phrase has gained popularity.
Did court find coach endured hostile environment?
Authors: Lyerly Eric
Published: January 2021

The plaintiff was a prominent collegiate women's cross‐country and track‐and‐field coach at the University of Minnesota.
In vitro Antioxidant and Cytotoxic Activities of Extracts of Endemic Tanacetum erzincanense Together with Phenolic Content by LC‐ESI‐QTOF‐MS
Authors: Yapıcı İsmail , Altay Ahmet , Öztürk Sarıkaya Beyza , Korkmaz Mustafa , Atila Alptuğ , Gülçin İlhami , Köksal Ekrem
Published: January 2021

In this study, phenolic composition, and in vitro biological activities of ethyl acetate (EAE) and methanol (ME) extracts obtained from the aerial parts of endemic Tanacetum erzincanense were investigated. Total phenolic and flavonoid content of the extracts were determined by Folin‐Ciocalteu and aluminum chloride colorimetric methods, respectively. Antioxidant capacity of the extracts was evaluated over radical scavenging (DPPH and ABTS) and metal ion reducing power (FRAP and CUPRAC) tests. Individual phenolic compounds in ME was analyzed by high‐performance liquid chromatography coupled to electrospray ionization quadrupole time‐of‐flight mass spectrometry (LC‐ESI‐QTOF/MS). Cell inhibitory potential of the extracts was tested against colorectal adenocarcinoma (HT‐29), breast adenocarcinoma (MCF‐7), and hepatocarcinoma (HepG2) cells by 2,3‐bis(2‐methoxy‐4‐nitro‐5‐sulfophenyl)‐2H‐tetrazolium‐5‐carboxanilide (XTT) assay. The results showed that ME contains higher TPC (64.4 mg GAE/g) and TFC (62.2 mg QE/g) than those of EAE (41.5 mg GAE/g and 40.0 mg QE/g). LC‐ESI‐QTOF/MS analysis revealed that ME is rich in phenolic compounds, namely, chlorogenic acid, apigenin, quercetin, luteolin, and diosmetin. Antioxidant assay results indicated that ME possess stronger activity than EAE and a power that competes with synthetic antioxidants. XTT assay results demonstrated that although both extracts displayed a considerable cytotoxicity against the tested cancer cell lines in a time and dose‐dependent manner, ME expressed its selective inhibitory action towards MCF‐7 cells with an IC50 value of 20.4 μg/mL for 72 h. These results may serve as a basis for further in vivo studies to examine the potential applications of T. erzincanense in food and pharmaceutical industries.
Platelet function and microvesicle generation in patients with hemophilia A
Authors: Melero‐Amor Antonia , Romecín Paola , Iyú David , García‐Bernal David , García‐Navaro Esther , Moraleda José M. , García‐Estañ Joaquín , García‐Candel Faustino , Atucha Noemí M.
Published: January 2021

Our results do not support any effect of FVIII on platelet function in patients with severe HA treated under the regime of prophylaxis.
Histoplasma stomatitis unveiled: Not all opportunistic infections get better after initiation of antiretroviral therapy
Authors: Bansal Saurabh , Singhania Namrata , Nukala Chandra Mouli , Singh Anil Kumar , Al‐Rabadi Laith
Published: January 2021

Immune reconstitution inflammatory syndrome in AIDS patients can lead to an initial worsening of underlying diseases due to body's ability to mount a strong immune response after recovery of CD4 counts.
A laceration of a wired silastic tracheostomy tube: A case report and review of the literature
Authors: Noda Kotaro , Nosaka Nobuyuki , Sai Youshun , Nagaoka Eiki , Nagashima Michio , Arai Hirokuni , Shigemitsu Hidenobu
Published: January 2021

Fractured tracheostomy tube is a rare, late complication. It typically occurs at the junction of metallic tube. We report an atypical case with laceration of the main trunk of a silastic tube after short period of use (10 days).
MODs vs. NPs: Vying for the Future of Printed Electronics
Authors: Douglas Samuel P. , Mrig Shreya , Knapp Caroline E.
Published: January 2021

This Minireview compares two distinct ink types, namely metal‐organic decomposition (MOD) and nanoparticle (NP) formulations, for use in the printing of some of the most conductive elements: silver, copper and aluminium. Printing of highly conductive features has found purpose across a broad array of electronics and as processing times and temperatures reduce, the avenues of application expand to low‐cost flexible substrates, materials for wearable devices and beyond. Printing techniques such as screen, aerosol jet and inkjet printing are scalable, solution‐based processes that historically have employed NP formulations to achieve low resistivity coatings printed at high resolution. Since the turn of the century, the rise in MOD inks has vastly extended the range of potentially applicable compounds that can be printed, whilst simultaneously addressing shelf life and sintering issues. A brief introduction to the field and requirements of an ink will be presented followed by a detailed discussion of a wide array of synthetic routes to both MOD and NP inks. Unindustrialized materials will be discussed, with the challenges and outlook considered for the market leaders: silver and copper, in comparison with the emerging field of aluminium inks.
Approaches to the Synthesis of Perfluoroalkyl‐Modified Carbohydrates and Derivatives: Thiosugars, Iminosugars, and Tetrahydro(thio)pyrans
Authors: Uhrig María Laura , Mora Flores Erwin W. , Postigo Al
Published: January 2021

Fluoroalkyl‐substituted carbohydrates play relevant roles in diverse areas such as supramolecular chemistry, glycoconjugation, liquid crystals, and surfactants, with direct applications as wetting, antifreeze, and coating agents. In light of these promising applications, new methodologies for the late‐stage incorporation of fluoroalkyl RF groups into carbohydrates and derivatives are herein presented as they are relevant to the synthetic carbohydrate community. Previously reviewed protocols for the installation of RF groups onto carbohydrates and derivatives will be succinctly summarized in the light of the new achievements. Fluoroalkyl‐substituted iminosugars, on the other hand, are also interesting glycomimetic derivatives with prominent roles as glycosidases and glycosyltransferases inhibitors, as has recently been demonstrated. Also, they positively contribute to the study of sugar–protein interactions and enzyme mechanisms. New advances in the syntheses of fluoroalkyl‐substituted iminosugars will also be presented here.
Diagnostic mesothelioma biomarkers in effusion cytology
Authors: Eccher Albino , Girolami Ilaria , Lucenteforte Ersilia , Troncone Giancarlo , Scarpa Aldo , Pantanowitz Liron
Published: January 2021

Malignant mesothelioma is a rare malignancy with a poor prognosis whose development is related to asbestos fiber exposure. An increasing role of genetic predisposition has been recognized recently. Pleural biopsy is the gold standard for diagnosis, in which the identification of pleural invasion by atypical mesothelial cell is a major criterion. Pleural effusion is usually the first sign of disease; therefore, a cytological specimen is often the initial or the only specimen available for diagnosis. Given that reactive mesothelial cells may show marked atypia, the diagnosis of mesothelioma on cytomorphology alone is challenging. Accordingly, cell block preparation is encouraged, as it permits immunohistochemical staining. Traditional markers of mesothelioma such as glucose transporter 1 (GLUT1) and insulin‐like growth factor 2 mRNA‐binding protein 3 (IMP3) are informative, but difficult to interpret when reactive proliferations aberrantly stain positive. BRCA1‐associated protein 1 (BAP1) nuclear staining loss is highly specific for mesothelioma, but sensitivity is low in sarcomatoid tumors. Cyclin‐dependent kinase inhibitor 2A (CDKN2A)/p16 homozygous deletion, assessed by fluorescence in situ hybridization, is more specific for mesothelioma with better sensitivity, even in the sarcomatoid variant. The surrogate marker methylthioadenosine phosphorylase (MTAP) has been found to demonstrate excellent diagnostic correlation with p16. The purpose of this review is to provide an essential appraisal of the literature regarding the diagnostic value of many of these emerging biomarkers for malignant mesothelioma in effusion cytology.
Safety, Tolerability, and Pharmacokinetics of Multiple Repeated Oral Doses of the α2/3/5‐Subtype Selective GABAA‐Positive Allosteric Modulator PF‐06372865 in Healthy Volunteers
Authors: Gurrell Rachel , Whitlock Mark , Wei Hua , Shen Zhongzhou , Ogden Adam
Published: January 2021

Multiple‐dose pharmacokinetics (PK) and safety were investigated in this phase 1 study of PF‐06372865, a positive allosteric modulator of α2/3/5 subunit‐containing γ‐aminobutyric acid A receptors (NCT03351751). In 2 cohorts (7‐8 PF‐06372865 and 2 placebo in each cohort), healthy adult subjects received twice‐daily oral doses of PF‐06372865 for 21 days, which included titration in the first 7 days, followed by a maintenance dose of 25 mg twice daily (Cohort 1) and 42.5 mg twice daily (Cohort 2) for 14 days. Serial PK samples were collected on days 1 and 21. Nineteen subjects were assigned to study treatments; 18 completed the study. Approximate dose‐proportional increases in maximum plasma concentratin and area under the plasma concentration–time curve over the dosing interval were observed. PF‐06372865 was rapidly absorbed with a median time to maximum concentration of 1 to 2 hours following both single‐ and multiple‐dose administration. Mean terminal elimination half‐life on day 21 was approximately 11 hours in both cohorts. All adverse events were mild; the most frequently reported was dizziness. After titration, there were no reports of somnolence. There were no clinically significant safety findings, including a lack of withdrawal symptoms on discontinuation of treatment. These results demonstrate that PF‐06372865 is safe and well tolerated at doses estimated to achieve high receptor occupancy (>80%), a profile differentiated from nonselective benzodiazepines.
An Unsual Cys‐Glu‐Lys Catalytic Triad is Responsible for the Catalytic Mechanism of the Nitrilase Superfamily: A QM/MM Study on Nit2
Authors: Silva Teixeira Carla S. , Sousa Sérgio F. , Cerqueira Nuno M. F. S. A.
Published: January 2021

Nitrilase 2 (Nit2) is a representative member of the nitrilase superfamily that catalyzes the hydrolysis of α‐ketosuccinamate into oxaloacetate. It has been associated with the metabolism of rapidly dividing cells like cancer cells. The catalytic mechanism of Nit2 employs a catalytic triad formed by Cys191, Glu81 and Lys150. The Cys191 and Glu81 play an active role during the catalytic process while the Lys150 is shown to play only a secondary role. The results demonstrate that the catalytic mechanism of Nit2 involves four steps. The nucleophilic attack of Cys191 to the α‐ketosuccinamate, the formation of two tetrahedral enzyme adducts and the hydrolysis of a thioacyl‐enzyme intermediate, from which results the formation of oxaloacetate and enzymatic turnover. The rate limiting step of the catalytic process is the formation of the first tetrahedral intermediate with a calculated activation free energy of 18.4 kcal/mol, which agrees very well with the experimental kcat (17.67 kcal/mol).
Recycling of Primary Lithium Batteries Production Residues
Authors: Kahl M. , Pavón S. , Bertau M.
Published: January 2021

Production waste of primary lithium batteries constitutes a considerable secondary lithium feedstock. Although the recycling of lithium batteries is a widely studied field of research, the metallic residues of non‐rechargeable lithium battery production are disposed of as waste without further recycling. The risks of handling metallic Li on a large scale typically prevent the metal from being recycled. A way out of this situation is to handle Li in an aqueous solution, from where it can be isolated as Li2CO3. However, the challenge in hydrometallurgical treatment lies in the high energy release during dissolution and generation of H2. To reduce these process‐related risks, the Li sheet metal punching residues underwent oxidative thermal treatment from 300 to 400 °C prior to dissolution in water. Converting Li metal to Li2O in this initial process step results in an energy release reduction of ∼70 %. The optimal oxidation conditions have been determined by experimental design varying three factors: temperature, Li metal sheet thickness, and residence time. With 96.9±2.6 % almost the entire Li amount is converted to Li2O, after 2.5 h treatment at 400 °C for a Li sheet thickness of 1.99 mm. Final precipitation with CO2 yields 85.5±3.0 % Li2CO3. Using pure Li sheets, the product Li2CO3 is obtained in battery‐grade quality (>99.5 %). Non‐precipitated Li is recirculated into the process on the stage of dissolving Li2O, thus avoiding loss of material.
Spin‐projected QM/MM Free Energy Simulations for Oxidation Reaction of Guanine in B−DNA by Singlet Oxygen
Authors: Saito Toru , Takano Yu
Published: January 2021

Guanine is the most susceptible base to oxidation damage induced by reactive oxygen species including singlet oxygen (1O2, 1Δg). We clarify whether the first step of guanine oxidation in B−DNA proceeds via either a zwitterionic or a diradical intermediate. The free energy profiles are calculated by means of a combined quantum mechanical and molecular mechanical (QM/MM) method coupled with the adaptive biasing force (ABF) method. To describe the open‐shell electronic structure of 1O2 correctly, the broken‐symmetry spin‐unrestricted density functional theory (BS−UDFT) with an approximate spin projection (AP) correction is applied to the QM region. We find that the effect of spin contamination on the activation and reaction free energies is up to ∼8 kcal mol−1, which is too large to be neglected. The QM(AP−ULC−BLYP)/MM‐based free energy calculations also reveal that the reaction proceeds through a diradical transition state, followed by a conversion to a zwitterionic intermediate. Our computed activation energy of 5.2 kcal mol−1 matches experimentally observed range (0∼6 kcal mol−1).
Direct Deoxydehydration of Cyclic trans‐Diol Substrates: An Experimental and Computational Study of the Reaction Mechanism of Vanadium(V)‐based Catalysis**
Authors: Aksanoglu Ebru , Lim Yee Hwee , Bryce Richard A.
Published: January 2021

The deoxydehydration of carbohydrates represents a key target to leverage renewable biomass resources chemically. Using a vanadium(V)‐based catalyst, it was possible to directly deoxydehydrate cyclic trans‐diol substrates. Accompanying mechanistic characterisation of this process by density functional calculations pointed to an energetically tractable route for deoxydehydration of cyclic trans‐diol substrates involving stepwise cleavage of the diol C−O bonds via the triplet state; experimentally, this was supported by light dependence of the reaction. Calculations also indicated that cyclic cis‐diols and a linear diol substrate could additionally proceed by a concerted singlet DODH mechanism. This work potentially opens a new and cost‐effective way to efficiently convert carbohydrates of trans‐diol stereochemistry into alkenes.
A transnational perspective on the evolution of the synthetic cannabinoid receptor agonists market: Comparing prison and general populations
Authors: Norman Caitlyn , Halter Sebastian , Haschimi Belal , Acreman Dean , Smith Josie , Krotulski Alex J. , Mohr Amanda L.A. , Logan Barry K. , NicDaéid Niamh , Auwärter Volker , McKenzie Craig
Published: January 2021

The synthetic cannabinoid receptor agonist (SCRA) market is transnational, and the availability of individual SCRAs changes regularly in response to national and international legislative controls. This generates a cyclic pattern and near constant evolution of SCRA compounds. This study reports toxicology‐based and/or seized sample‐based prevalence data relating to SCRA use in prisons from Germany, the United Kingdom (UK; Scotland and Wales), and the United States (US), representing 4427 individual test results. The study examines SCRA detections in prisons from July 2018 to September 2020, and where possible, prison‐based data are compared with SCRA prevalence data in the wider population. The relative influence of Chinese, other international, and national drug legislation on the prevalence of individual SCRAs in prisons is also considered. tert‐Leucinate‐ and valinate‐indole‐ and indazole‐3‐carboxamides were the most common SCRA detections, and MDMB‐4en‐PINACA was one of the most commonly detected SCRAs in all jurisdictions by September 2020. However, despite there being a global production and supply market, there were notable regional differences. Analog controls in German and US legislation may have led to increased compound diversity that is not reflected in the UK which has both analog controls and a blanket ban on psychoactive substances. While there were regional differences, SCRA prevalence in prisons closely aligned with the SCRAs detected on the local market, demonstrating that SCRA (and possibly other NPS) monitoring programs in prisons can act as early warning systems for the wider population in that given jurisdiction.
The Ethics of Research That May Disadvantage Others
Authors: Robertson Christopher
Published: January 2021

In prospective interventional research, a treatment may provide an advantage for the recipient over other people who do not receive it. If the intervention proves successful, the treated are better able to compete for such things as a scarce ventilator, a class grade, or a litigation outcome, potentially risking the deaths, jobs, or incomes of nontreated persons. Discussions of ethical concerns related to “bystanders” have typically focused on direct harms (such as infecting them with a virus), rather than the competition for a rivalrous good (such as a ventilator or clinical outcome). After broadly scoping this problem of advantage, this article reveals several reasons that such interventional research is typically permissible, notwithstanding the potential setbacks to nonparticipants. I consider the almost‐dispositive concept of clinical equipoise and then glean insights from the harm principle, status quo bias, the leveling‐down problem, and a potential bias against prospective interventional research versus program interventions with retrospective study. My consideration of institutional relationships does not change the analysis that such research is permissible.
Genetic response to human‐induced habitat changes in the marine environment: A century of evolution of European sprat in Landvikvannet, Norway
Authors: Quintela María , Richter‐Boix Àlex , Bekkevold Dorte , Kvamme Cecilie , Berg Florian , Jansson Eeva , Dahle Geir , Besnier François , Nash Richard D. M. , Glover Kevin A.
Published: January 2021

Habitat changes represent one of the five most pervasive threats to biodiversity. However, anthropogenic activities also have the capacity to create novel niche spaces to which species respond differently. In 1880, one such habitat alterations occurred in Landvikvannet, a freshwater lake on the Norwegian coast of Skagerrak, which became brackish after being artificially connected to the sea. This lake is now home to the European sprat, a pelagic marine fish that managed to develop a self‐recruiting population in barely few decades. Landvikvannet sprat proved to be genetically isolated from the three main populations described for this species; that is, Norwegian fjords, Baltic Sea, and the combination of North Sea, Kattegat, and Skagerrak. This distinctness was depicted by an accuracy self‐assignment of 89% and a highly significantFSTbetween the lake sprat and each of the remaining samples (average of ≈0.105). The correlation between genetic and environmental variation indicated that salinity could be an important environmental driver of selection (3.3% of the 91 SNPs showed strong associations). Likewise, Isolation by Environment was detected for salinity, although not for temperature, in samples not adhering to an Isolation by Distance pattern. Neighbor‐joining tree analysis suggested that the source of the lake sprat is in the Norwegian fjords, rather than in the Baltic Sea despite a similar salinity profile. Strongly drifted allele frequencies and lower genetic diversity in Landvikvannet compared with the Norwegian fjords concur with a founder effect potentially associated with local adaptation to low salinity. Genetic differentiation (FST) between marine and brackish sprat is larger in the comparison Norway‐Landvikvannet than in Norway‐Baltic, which suggests that the observed divergence was achieved in Landvikvannet in some 65 generations, that is, 132 years, rather than gradually over thousands of years (the age of the Baltic Sea), thus highlighting the pace at which human‐driven evolution can happen.
Rise and fall of †Pycnodontiformes: Diversity, competition and extinction of a successful fish clade
Authors: Cawley John J. , Marramà Giuseppe , Carnevale Giorgio , Villafaña Jaime A. , López‐Romero Faviel A. , Kriwet Jürgen
Published: January 2021

†Pycnodontiformes was a successful lineage of primarily marine fishes that broadly diversified during the Mesozoic. They possessed a wide variety of body shapes and were adapted to a broad range of food sources. Two other neopterygian clades possessing similar ecological adaptations in both body morphology (†Dapediiformes) and dentition (Ginglymodi) also occurred in Mesozoic seas. Although these groups occupied the same marine ecosystems, the role that competitive exclusion and niche partitioning played in their ability to survive alongside each other remains unknown. Using geometric morphometrics on both the lower jaw (as constraint for feeding adaptation) and body shape (as constraint for habitat adaptation), we show that while dapediiforms and ginglymodians occupy similar lower jaw morphospace, pycnodontiforms are completely separate. Separation also occurs between the clades in body shape so that competition reduction between pycnodontiforms and the other two clades would have resulted in niche partitioning. Competition within pycnodontiforms seemingly was reduced further by evolving different feeding strategies as shown by disparate jaw shapes that also indicate high levels of plasticity. Acanthomorpha was a teleostean clade that evolved later in the Mesozoic and which has been regarded as implicated in driving the pycnodontiforms to extinction. Although they share similar body shapes, no coeval acanthomorphs had similar jaw shapes or dentitions for dealing with hard prey like pycnodontiforms do and so their success being a factor in pycnodontiform extinction is unlikely. Sea surface temperature and eustatic variations also had no impact on pycnodontiform diversity patterns according to our results. Conversely, the occurrence and number of available reefs and hardgrounds as habitats through time seems to be the main factor in pycnodontiform success. Decline in such habitats during the Late Cretaceous and Palaeogene might have had deleterious consequences for pycnodontiform diversity. Acanthomorphs occupied the niches of pycnodontiforms during the terminal phase of their existence.
Frequency‐dependent tree growth depends on climate
Authors: Diez Jeffrey M. , Boone Rohan , Bohner Teresa , Godoy Oscar
Published: January 2021

Climate and competition interact to affect species’ performance, such as growth and survival, and help determine species distributions and coexistence. However, it is unclear how climatic conditions modulate frequency‐dependent performance, that is, how performance changes as a species becomes locally rare or common. This is critical because declines in performance as a species becomes more common (negative frequency dependence) is a signature of niche differences among species that stabilize coexistence, whereas positive frequency dependence leads to priority effects and hampers species coexistence. Here, we used dendrochronology and hierarchical models to test whether frequency‐dependent growth of sugar pine (Pinus lambertiana) depends on climatic conditions. We found that growth rates were strongly dependent on annual precipitation, but no frequency dependence was evident across all years. However, there was a strong interaction between precipitation and frequency dependence, revealing stabilizing niche differences in dry years but positive frequency dependence in wet years. These differences emerged because of precipitation‐driven changes in the direction and strength of both con‐ and heterospecific competition. Overall, these results show how stabilizing and destabilizing effects can be temporally dynamic for long‐lived species and interact with climate variation.
Real‐world outcomes in cardiac resynchronization therapy patients: design and baseline demographics of the SMART‐ Registry
Authors: Gardner Roy S. , D'Onofrio Antonio , Mark George , Gras Daniel , Hu Yan , Veraghtert Sara , Garcia‐Bolao Ignacio
Published: January 2021

Aims

The SMART (Strategic MAnagement to optimize response to cardiac Resynchronization Therapy) Registry was designed to assess real‐world outcomes for patients receiving a cardiac resynchronization therapy defibrillator (CRT‐D) and to better understand which programming and optimization techniques are used and how effective they are.

Methods and results

The SMART Registry is a global, multicentre, prospective, observational, post‐market CRT‐D registry with a planned enrolment of 2000 subjects from a maximum of 200 sites in Europe, North America, and Asia‐Pacific region. Each subject will be followed up for a minimum of 12 months. The primary endpoint of CRT response rate at 12 months is defined by a clinical composite score of all‐cause mortality, heart failure events, New York Heart Association Class, and quality of life as assessed by a patient global assessment instrument. A subgroup composed of the first 103 consecutive European subjects implanted with an NG4 device will have left ventricular multisite pacing feature enabled at any time during the initial 12 months of follow‐up. The primary endpoint for this sub‐analysis will be the NG4 PG‐related complication‐free rate at 36 months.

Conclusions

The SMART Registry achieved its recruitment target in August 2019, with 2014 patients enrolled. The baseline demographics demonstrated that patients were generally older, with greater co‐morbidity, and on more contemporary medical therapy than in the key CRT trials. The results of the SMART Registry will determine which programming and optimization techniques are effective in this real‐world population.
The impact of COVID‐19 on the management of heart failure: a United Kingdom patient questionnaire study
Authors: Sankaranarayanan Rajiv , Hartshorne‐Evans Nick , Redmond‐Lyon Sam , Wilson Jill , Essa Hani , Gray Alastair , Clayton Louise , Barton Carys , Ahmed Fozia Z. , Cunnington Colin , Satchithananda Duwarakan K. , Murphy Clare L.
Published: January 2021

Aims

The coronavirus disease 2019 (COVID‐19) pandemic has created significant challenges to healthcare globally, necessitating rapid restructuring of service provision. This questionnaire survey was conducted amongst adult heart failure (HF) patients in the United Kingdom (UK), to understand the impact of COVID‐19 upon HF services.

Methods and results

The survey was conducted by the Pumping Marvellous Foundation, a UK HF patient charity. ‘Survey Monkey’ was used to disseminate the questionnaire in the Pumping Marvellous Foundation 's online patient group and in 10 UK hospitals (outpatient hospital and community HF clinics). There were 1050 responses collected (693/1050—66% women); 55% (579/1050) were aged over 60 years. Anxiety level was significantly higher regarding COVID‐19 (mean 7 ± 2.5 on anxiety scale of 0 to 10) compared with anxiety regarding HF (6.1 ± 2.4; P < 0.001). Anxiety was higher amongst patients aged ≤60 years about HF (6.3 ± 2.2 vs. 5.9 ± 2.5 in those aged >60 years; P = 0.005) and COVID‐19 (7.3 ± 2.3 vs. 6.7 ± 2.6 those aged >60 years; P < 0.001). Sixty‐five per cent of respondents (686/1050) reported disruption to HF appointments (cancellation or postponement) during the lockdown period. Thirty‐seven per cent reported disruption to medication prescription services, and Thirty‐four per cent reported inability to access their HF teams promptly. Thirty‐two per cent expressed reluctance to attend hospital (25% stated they would only attend hospital if there was no alternative, and 7% stated that they would not attend hospital at all).

Conclusions

The COVID‐19 pandemic has caused significant anxiety amongst HF patients regarding COVID‐19 and HF. Cancellation or postponement of scheduled clinic appointments, investigations, procedures, prescription, and monitoring services were implicated as sources of anxiety.
Visible Light‐Driven Efficient Synthesis of Amides from Alcohols using Cu−N−TiO2 Heterogeneous Photocatalyst
Authors: Singha Krishnadipti , Ghosh Subhash Chandra , Panda Asit Baran
Published: January 2021

Amides were synthesized from alcohols and amines in high yields using an in situ generated active ester of N‐hydroxyimide with our developed Cu−N−TiO2 catalyst at room temperature using oxygen as a sole oxidant under visible light. The catalyst can be easily prepared, robust, and recycled four times without a considerable change in catalytic activity. This developed protocol applies to a wide substrate scope and has good functional group tolerance. The application of this amidation reaction has been successfully demonstrated for the synthesis of moclobemide, an antidepressant drug, and an analog of the itopride drug on a gram scale.
Synthesis of Enantiopure 6,11‐Methylene Lipoxin B4 Methyl Ester
Authors: Trippe Lukas , Nava Analuisa , Frank Andrea , Nubbemeyer Udo
Published: January 2021

The synthesis of Lipoxin B4 analogs (LXB4) to gain access to stabilized inflammation resolving compounds is an actual field of research. Focusing on variation and stabilization of the conjugated E,Z,E,E C6–C13 tetraene moiety of natural LXB4, a methylene bridge introduced between C6 and C11 suppresses any Z/E isomerization of the C8–C9 olefin. Intending to enable prospective structure variations in connection with the C1–C5 and C14–C20 fragments, a convergent total synthesis has been developed. Optically active C1–C12 building blocks were build‐up from cycloheptatriene 1‐carbonester (C6–C11, C21) and glutaryl chloride (C1–C5) using Friedel‐Crafts‐type acylation and chiral HPLC. The C13–C20 segment had been generated via a five‐step sequence starting from heptanoyl chloride. Horner key olefination enabled the assembly of the carbon backbone. A final five‐step sequence including a chelate Cram reduction of the unsaturated ketone moiety afforded the target 6,11‐methylene LXB4 methyl ester.
Food ingredients and food made with plant cell and tissue cultures: State‐of‐the art and future trends
Authors: Gubser Geraldine , Vollenweider Sabine , Eibl Dieter , Eibl Regine
Published: January 2021

Climate change and an increasing world population means traditional farming methods may not be able to meet the anticipated growth in food demands. Therefore, alternative agricultural strategies should be considered. Here, plant cell and tissue cultures (PCTCs) may present a possible solution, as they allow for controlled, closed and sustainable manufacturing of extracts which have been or are still being used as colorants or health food ingredients today. In this review we would like to highlight developments and the latest trends concerning commercial PCTC extracts and their use as food ingredients or even as food. The commercialization of PCTC‐derived products, however, requires not only regulatory approval, but also outstanding product properties or/and a high product titer. If these challenges can be met, PCTCs will become increasingly important for the food sector in coming years.
A configuration optimization framework for renewable energy systems integrating with electric‐heating energy storage in an isolated tourist area
Authors: Lingmin Chen , Jiekang Wu , Changjie Li , Huiling Tang , Xiaoming Mao , Kangxing Li
Published: January 2021

The renewable energy system integrates various power generating units, heating units, energy conversion devices, and energy storage devices, which is an effective way to improve energy efficiency and realize clean energy utilization. In this paper, a renewable energy system integrating with photovoltaic electric power generation systems, wind‐driven generators, gas‐driven generators, gas‐fired boilers, electric chillers, electric and heating energy storage devices is constructed in an isolated tourist area. Considering the complex multi‐energy flows in renewable energy systems, an energy hub with power and heat is established to concentrate and distribute electric and heating energy flow for balancing energy supply and demand in a CCHP system. Introducing the constraints of renewable energy penetration index and energy supply reliability index, a collaborative optimization framework for system configuration is constructed to minimize annual capital cost, fuel cost, and maintenance cost. The simulation results show that the model and algorithm in this paper are feasible and applicable, and the optimization scheme has good economic benefits and optimal performance, which can promote the consumption of renewable energy and reduce the surplus of electric energy and heat energy.
Toxicity Screening of Bisphenol A Replacement Compounds: Cytotoxicity and mRNA Expression in Primary Hepatocytes of Chicken and Double-Crested Cormorant
Authors: Sharin Tasnia , Williams Kim L. , Chiu Suzanne , Crump Doug , O'Brien Jason M.
Published: January 2021

A market for bisphenol A (BPA) replacement compounds has emerged as a result of restrictions on the use of BPA. Some of these compounds have been detected in the environment; however, little is known about their toxicological properties. In the present study, an avian in vitro toxicogenomic approach was used to compare the effects of 5 BPA alternatives. Cell viability and mRNA expression were compared in primary embryonic hepatocytes of chicken (CEH) and double-crested cormorant (DCEH) exposed to 4,4′-(propane-2,2-diyl) diphenol (BPA), bis (4-hydroxyphenyl) methane (BPF), bis (3-allyl-4-hydroxyphenyl) sulfone (TGSH), 7-bis (4-hydroxyphenylthio)-3,5-dioxaheptane (DD-70), 2,2-bis (4-hydroxyphenyl) hexafluoropropane (BPAF), and 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP). Changes in gene expression were determined using 2 polymerase chain reaction (PCR) arrays: 1) species-specific ToxChips that contain genes representing toxicologically relevant pathways, and 2) chicken-specific AestroChip that measures estrogen responsive genes. In CEH and DCEH, BPA alternatives TGSH, DD-70, and BPAF were most cytotoxic. Some of the replacement compounds changed the expression of genes related to xenobiotic metabolism, bile acid, and cholesterol regulation. The rank order based on the number of genes altered on the chicken ToxChip array was TGSH > DD-70 > BPAF = BPF > 17β estradiol (E2) > BPSIP > BPA. On the cormorant ToxChip array, BPSIP altered the greatest number of genes. Based on the chicken AestroChip data, BPSIP and BPF were slightly estrogenic. These results suggest that the replacement compounds have comparable or even greater toxicity than BPA and act via different mechanisms. Environ Toxicol Chem 2021;40:1368–1378. © 2021 Her Majesty the Queen in Right of Canada. Reproduced with the permission of the Minister of Environment and Climate Change Canada.

Abstract

Effects of 5 bisphenol A replacements on cytotoxicity and gene expression in avian hepatocytes. BPA = bisphenol A; BPF = bis (4-hydroxyphenyl) methane; TGSH = bis (3-allyl-4-hydroxyphenyl) sulfone; DD-70 = 7-bis (4-hydroxyphenylthio)-3,5-dioxaheptane; BPAF = 2,2-bis (4-hydroxyphenyl) hexafluoropropane; BPSIP = 4-hydroxyphenyl 4-isoprooxyphenylsulfone; E2 = 17β estradiol; PCR = polymerase chain reaction.
The “plastic cycle”: a watershed‐scale model of plastic pools and fluxes
Authors: Hoellein Timothy J , Rochman Chelsea M
Published: January 2021

Research on plastics in global ecosystems is rapidly evolving. Oceans have been the primary focus of studies to date, whereas rivers are generally considered little more than conduits of plastics to marine ecosystems. Within a watershed, however, plastics of all sizes are retained, transformed, and even extracted via freshwater use or litter cleanup. As such, plastic litter in terrestrial and freshwater ecosystems is an important but underappreciated component of global plastic pollution. To gain a holistic perspective, we developed a conceptual model that synthesizes all sources, fluxes, and fates for plastics in a watershed, including containment (ie disposed in landfill), non‐containment (ie persists as environmental pollution), mineralization, export to oceans, atmospheric interactions, and freshwater extraction. We used this model of the “plastic cycle” to illustrate which components have received the most scientific attention and to reveal overlooked pathways. Our main objective is for this framework to inform future research, offer a new perspective to adapt management across diverse waste governance scenarios, and improve global models of plastic litter.
Synergistic effects of copper and ethylene on resveratrol synthesis in peanuts
Authors: Bao Xuefeng , Lin Guolin , Dong Xuan , Ma Xinyu , Han Xiaori , Zhang Hui
Published: January 2021

This study aimed to investigate the effects of exogenous copper and ethylene on resveratrol biosynthesis in peanut buds. In this study, different concentrations of copper sulfate and ethephon were used to induce peanut bud roots. Resveratrol content was determined using high‐performance liquid chromatography (HPLC). The interaction effects of the two inducers were analyzed using regression and response surface methodology. Results showed that resveratrol biosynthesis increased with the increase in copper sulfate concentration. Resveratrol synthesis showed an increasing trend when the concentration of ethephon was from 5 to 7 mmol/L. The resveratrol content reached a maximum value of 7.7 μg/g when the concentration of ethephon was 7 mmol/L and then decreased with an increase in ethephon. Response surface analysis revealed that the combination of 0.1 mmol/L copper sulfate and 5 mmol/L ethephon was effective and resulted in the induction of resveratrol biosynthesis in peanut buds.
Green tea dietary supplementation in broiler chickens: Effect on the development of chicken intestine
Authors: Liu Wuyi , Rouzmehr Fariba , Wang Xin , Seidavi Alireza
Published: January 2021

This experiment explored the dietary effects of green tea (Camellia sinensis) in feed supplementation on the development of broiler chicks. Totally, two hundred and seventy‐day‐old male broiler chicks were assigned to 27 broiler groups each with 10 individuals (initial mean body weight 44.2 ± 1.3 g) in a 4 × 2 factorial arrangement. Each chicken group was supplemented with the feed additives of green tea powder. The trial data were measured and obtained based on the records of carcass traits and intestine characteristics of broiler chicken fed with four different additive levels of green tea (0.25%, 0.50%, 0.75%, and 1.00%). The experiment lasted for two trial periods of 21 days and 42 days for each treatment of the green tea supplement with full records of broiler traits. There were interesting results recorded in the majority of broiler intestinal traits between the two trial periods. There are a few significant differences (p < .05) observed among multiple comparisons of some intestinal traits in broiler chicks such as colon diameter (p = .022) and jejunum width (p = .01). The most significant differences exist in these intestinal traits of chicken right and left cecum among broiler chicks fed with dietary green tea powder (p < .05). The other intestinal characteristics of broiler chicks were recorded from single treatment are insignificantly distinguished compared with the control groups. There are also some near significant differences of chicken intestinal carcass traits and characteristics. These results and experimental data of this study extend the current knowledge on the dietary effects of green tea in chicken raising and feeding with dietary supplementation.
A Futile Use of Futility
Authors: Goldberg Aryeh
Published: January 2021

As the rates of intravenous opioid use have increased, so have its associated medical complications, such as endocarditis, and known interventions, such as heart‐valve replacements. For many patients, including Jacob, whose case was brought to my psychiatric consult service and to my colleagues in the clinical ethics service, relapse increases the risk of repeat endocarditis and the need for repeat surgical interventions. Previous works have posed the bioethical quandary regarding the responsibilities of a surgeon in these repeat procedures and whether a surgeon may ethically refuse to perform a repeat intervention in a patient who has relapsed. Notions of futility are commonly used to navigate this complex terrain, and they were the focus of the ethics consideration given to Jacob's case, in which surgeons were reluctant to perform valve replacements. In this narrative essay, I interrogate the concept of futility by appealing to its history and variable meanings, and I argue against its relevance in cases like Jacob's. I propose that a more suitable bioethical approach in such cases would consider resource allocation, the sociocultural stigma of addiction, and the interpersonal and narrative factors that make each case unique.
A Small‐Town Heart
Authors: Lahey Tim , Herbst Jennifer L. , Gross Marielle S. , Scully Brandi Braud
Published: January 2021

Melanie presented at twenty weeks of gestation to an obstetrics clinic in a critical access hospital in rural Vermont. She was excited to undergo routine fetal ultrasonography, but her obstetrician gave her grave news: the ultrasound revealed hypoplastic left heart syndrome, a devastating congenital heart defect. Initially, Melanie agreed in general to pursue surgical care for her fetus—a three‐stage process that has somewhat uncertain results and could only be done in tertiary care facilities far from her home in Vermont. A week later, while the maternal fetal medicine and pediatric cardiology units made arrangements with colleagues in Boston, Melanie began having second thoughts. An ethics meeting was called to discuss conflicting clinician reactions to Melanie's dilemma. Most of the clinicians were stunned that the patient would change her mind. What advice should the ethics consultant offer the team about caring for Melanie?
Prescription Requirements and Patient Autonomy: Considering an Over‐the‐Counter Default
Authors: Kilbride Madison , Joffe Steven , Lynch Holly Fernandez
Published: January 2021

When new drugs are approved by the Food and Drug Administration, the default assumption is that they will be available by prescription only, safe for use exclusively under clinical supervision. The paternalism underlying this default must be interrogated in order to ensure appropriate respect for patient autonomy. Upon closer inspection, prescription requirements are justified when nonprescription status would risk harm to third parties and when a large segment of the population would struggle to exercise their autonomy in using a drug safely and effectively on their own. Although these justifications can support prescription status for many drugs, we propose that reversing the FDA's current default to instead begin with a presumption in favor of over‐the‐counter status is the best way to avoid interference with valid claims of patient autonomy. Under this approach, a range of drug products could be considered for an OTC switch, including oral contraceptives, statins, and HIV‐prevention drugs.