bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large Shareholder Portfolio Diversification and Voluntary Disclosure*
Authors: Akamah Herita , Shu Sydney Qing 
Published: June 2021

ABSTRACTAlthough large shareholders have sufficient influence to engage privately with management, extant literature provides inconclusive evidence on the relation between large equity positions and corporate disclosure. This study examines whether large shareholders' portfolio diversification affects voluntary corporate disclosure. We define diversification as the extent to which investors spread investments among portfolio stocks. We predict that holding a diversified portfolio deters large shareholders from incurring the costs of private information gathering about a portfolio firm. We document that firms provide more voluntary disclosure when their large shareholders hold a more diversified portfolio, consistent with investors relying more on public disclosure about portfolio firms when their portfolio diversification is higher. Evidence from cross‐sectional analyses suggests that, as predicted, the positive relation between portfolio diversification and voluntary disclosure is weaker as the net benefit of acquiring private information increases for large shareholders (i.e., when portfolio firms are more connected, have alternative information channels, or are more complex). Overall, our results suggest that diversified large shareholders' preference for a richer public disclosure environment creates a positive externality of lowering the information costs for external stakeholders without private access to management.
The Impact of Mandatory Auditor Tenure Disclosures on Ratification Voting, Auditor Dismissal, and Audit Pricing*
Authors: Dunn Ryan T. , Lundstrom Nathan G. , Wilkins Michael S. 
Published: June 2021

ABSTRACTRecent amendments to Auditing Standard (AS) 3101 require disclosure of the initial year of the auditor‐client relationship in the audit report. As the standard was being discussed, auditors, clients, and some PCAOB members expressed reservations about the necessity of tenure disclosures and were particularly concerned about disclosing tenure in the audit report. Our purpose is to investigate whether the tenure disclosures mandated by AS 3101 are associated with changes in stakeholder behavior. We predict and find that after the implementation date, ratification votes against the auditor and the probability of subsequent auditor dismissal increase for long‐tenured versus short‐tenured auditors. Results from a path analysis further suggest that the relative increase in dismissal for long‐tenured auditors appears to be influenced directly through tenure disclosures and indirectly through ratification voting. We also predict and find that negotiating power decreases for long‐tenured auditors as evidenced by lower audit fees. Our results are comparable for companies that voluntarily disclosed and companies that did not disclose auditor tenure in their proxy statements prior to the AS 3101 amendment. Overall, our study suggests that mandatory disclosure of auditor tenure in the audit report significantly affects stakeholder behavior. The PCAOB should consider our findings carefully as they evaluate whether AS 3101 is achieving its intended purpose.
Oral health status of newly admitted residents living in residential aged care
Authors: Chu K‐Y , Cockrell D , Naganathan V , Stanaway F , Wright FAC 
Published: June 2021

AbstractBackgroundIt is important to understand whether older people are admitted into residential care with existing dental diseases or their oral health deteriorates while residing in residential care. There is, however, little research available exploring the oral health status of people newly admitted into residential care. Understanding this disease trend would lead to effective prevention and treatment strategies to be trialled and implemented prior to admission. In this cross‐sectional study, we hypothesize that older people with one or more natural teeth might have poor oral health prior to admission to residential care.MethodThe study was carried out using the de‐identified oral health assessment database of an established domiciliary oral health care program in metropolitan New South Wales, Australia. Four hundred and nine participants with mean participant age of 85.56 years from 13 facilities from 2015 to 2018 fulfilled the inclusion criteria for this study.ConclusionThis study confirmed that dentate, newly admitted residents to residential care had pre‐existing dental problems and oral health concerns. Almost half of the newly admitted residents had an unsatisfactory oral cleanliness score when examined in their residential care setting.
Decompression strategy for critical‐sized lesions: A case series and literature review
Authors: Umer Fahad , Javed Faizan 
Published: June 2021

AbstractCritical‐sized lesions are defined as the smallest sized intraosseous wound in a particular bone that will not heal spontaneously during the lifetime of that animal. These critical‐sized entities pose a unique challenge in endodontics, where these lesions are most likely cystic, with dimensions extending over 10 mm. This paper describes a structured methodology to treat such cases whilst also highlighting inconsistencies and variability between practitioners regarding management of critical‐sized lesions. The case series demonstrates that non‐surgical root canal therapy followed by surgical decompression may be the treatment of choice for such pathosis. A 16 gauge nasogastric tube was used as a decompression device and sutured to surrounding mucosa. Healing was evaluated using both two‐ and three‐dimensional radiographs. Decompression of critical‐sized lesions would appear to be a reliable, conservative and an altogether complete procedure that may not warrant second‐stage surgery.
3D reconstruction of the rat adrenal medulla
Authors: Kemoklidze Konstantin Gerbertovich , Tyumina Natalia Andreevna , Leonenko Pavel Sergeevich 
Published: June 2021

AbstractWe performed 3D reconstruction of the microscopic structure of the adrenal medulla of the adult rats using serial histological sections with histochemical differentiation of adrenaline‐storing (A) and noradrenaline‐storing (NA) cells. Medulla volume is 1.18 ± 0.17 mm3. Chromaffin tissue consists of 82.9 ± 2.6% of A and 17.1 ± 2.6% of NA cells. Cords of the chromaffinocytes run along the nerves in the adrenal cortex and form cones when merging with medulla bulk. There is no unambiguously greater prevalence of A cells over NA in the areas of the medulla bordering on the cortex as compared to deep layers of medulla. NA cells form a network of beams. Their concentration increases with distance from the entry site of the nerves and is maximal on the opposite side. This testifies to the fallacy of the point of view about the disordered distribution of NA cells in the medulla. Based on the polar asymmetric arrangement of the adrenal chromaffin tissue, if it is necessary to completely remove the medulla with the keeping or reimplantation of the cortex, the subcapsular cortex zone located on the pole opposite to the entrance of nerves should be chosen. In addition, comparable results in the stereological examination of the medulla can be obtained only if taking its areas similar in location. The pronounced relationship in the arrangement of A and NA cells with nerves clearly indicates that in vivo nerve factors play a key role in differentiation and stabilization of the A and NA cells phenotypes.
How rural nurses in Southern New Zealand navigate their ethical landscape—A qualitative study
Authors: Doolan‐Noble Fiona , Tumilty Emma , McAuley Kathryn , Stokes Tim 
Published: June 2021

AbstractObjectiveTo explore rural nurse experiences of ethical issues and their management of these as a first step in a programme of work to address rural nurses' ethical needs.DesignThis study was qualitative, using mixed qualitative techniques to gather data, which was analysed using a general inductive approach.SettingPrimary health care in 2 regions of Aotearoa New Zealand.ParticipantsEleven nurses working in the West Coast (District Health Board) region and 9 working within the Southern District Health Board region.InterventionParticipants took part in either a focus groups or an interview with members of the research team.Main outcome measuresTo document ethical issues that confronted these rural nurses and how they navigated these issues.ResultsThree themes were identified: ‘Signals and Silences,’ ‘One and Other’ and ‘Frustrations and Freedoms.’ A continuous thread through these themes was the concept of phronesis, or what is sometimes called practical virtue. This practical virtue largely developed through their own experiences, rather than through educational or health system specific support or resources.ConclusionsWe found that rural nurses' deal with specific issues related to the rural setting, such as resourcing and isolation, while maintaining a relationship with the communities they serve and their professional autonomy. Additionally, we discovered the ways in which rural nurses deal with the ethical issues they encounter to be practically focussed. However, rural nurses need supportive leadership not only to sustain the moral agency they demonstrate but also to further develop their ethical decision‐making practices. The provision of a clinical ethics tele‐service delivering both training opportunities and an on‐call consult support service would provide a potential solution.
Mother‐Newborn Couplet Care from theory to practice to ensure zero separation for all newborns
Authors: Klemming Stina , Lilliesköld Siri , Westrup Björn 
Published: June 2021

AbstractWith an increasing awareness of the importance of nurturing care and within a framework of Infant‐ and Family‐Centred Developmental Care (IFCDC), zero separation, keeping parent and infant in continuous close physical and psychological proximity to each other, is key. In modern neonatology, high technological and pharmaceutical treatments are consistently integrated with caregiving considerations. Mother‐Newborn Couplet Care is a concept of care where the dyad of the ill or prematurely born infant and the mother, needing medical care of her own, are cared for together, from the birth of the baby to its discharge. Mother‐Newborn Couplet Care requires systems changes in both obstetrics and paediatrics considering planning and organisation of care, equipment and design of units. Accordingly, strong leadership setting clear goals and changing the professional mindset by providing targeted education and training is crucial to ensure the warranted high quality of care of all mother‐baby dyads.
3‐Quinuclidinyl benzilate (agent BZ) toxicokinetics in rats
Authors: Dlabkova Alzbeta , Herman David , Cechova Lenka , Hroch Milos , Vanova Nela , Zdarova Karasova Jana 
Published: June 2021

Abstract3‐Quinuclidinyl benzilate (BZ) ranks among incapacitating military warfare agents. It acts as a competitive inhibitor on muscarinic receptors leading to non‐lethal mental impairment. The present study aimed to investigate toxicokinetics of BZ in rats. Moreover, BZ can be exploited to produce a pharmacological model of Alzheimer's disease; thus, this paper focuses mainly on the BZ distribution to the brain. Wistar rats were administered i.p. with BZ (2 and 10 mg/kg). The BZ concentration was determined using LC‐MS/MS in plasma, urine, bile, brain, kidney and liver. The sample preparation was based on a solid phase extraction (liquids) or protein precipitation (organ homogenates). The plasma concentration peaked at 3 min (204.5 ± 55.4 and 2185.5 ± 465.4 ng/ml). The maximal concentration in the brain was reached several minutes later. Plasma elimination half‐life was 67.9 ± 3.4 in the 2 mg/kg group and 96.6 ± 27.9 in the 10 mg/kg group. BZ concentrations remained steady in the brain, with slow elimination (t1/2 506.9 ± 359.5 min). Agent BZ is excreted mainly via the urine. Steady BZ concentration in the brain could explain the previously published duration of the significant impairment in passive avoidance tasks in rats after an injection of BZ.
Dark times for cosmopolitanism? An ethical framework to address private agri‐food governance and planetary stewardship
Authors: Alcaraz Jose M. , Tirado Francisco , Gálvez Ana 
Published: June 2021

AbstractThe scholarly tradition of cosmopolitanism (illustrated by the old saying, “I am a citizen of the world”) offers important insights into the examination of agri‐food multinational corporations (MNCs) as powerful global actors. Acknowledging that agriculture is the business sector with the highest planetary environmental impact, in this paper, we advance existing discussions around cosmopolitanism and the normative implications of considering agri‐food MNCs as political actors. Relying on an integrative literature review, we propose a tripartite ethical framework that gives a new momentum to the ideals and tenets of cosmopolitanism. This novel lens offers an integrated, seamless ethical approach and revolves around three dimensions:culture,morality, andgovernance. The first dimension examines key agri‐food cultural and social‐ecological issues, the second acknowledges interdependence and causality as central to understanding MNCs’ ethical responsibilities, and the third outlines several governance parameters around legitimacy, planetary reach and efficiency. Hence, our integrative framework resituates the planetary geographical imagination of cosmopolitanism within the biophysical parameters outlined by the planetary boundaries concept, advancing key issues on private agri‐food environmental governance and planetary stewardship.
Trametinib overcomes KRAS‐G12V–induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR‐mutant lung cancer
Authors: Fukuda Koji , Otani Sakiko , Takeuchi Shinji , Arai Sachiko , Nanjo Shigeki , Tanimoto Azusa , Nishiyama Akihiro , Naoki Katsuhiko , Yano Seiji 
Published: June 2021

AbstractLeptomeningeal carcinomatosis (LMC) occurs frequently in non–small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR‐TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third‐generation EGFR‐TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR‐mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next‐generation sequencing. We detected the Kirsten rat sarcoma (KRAS)‐G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS‐G12V overexpression in parental cells revealed the involvement of KRAS‐G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS‐G12V–harboring osimertinib‐resistant LMC in EGFR‐mutant NSCLC.
Novel metastatic burden‐stratified risk model in de novo metastatic hormone‐sensitive prostate cancer
Authors: Shiota Masaki , Terada Naoki , Kitamura Hiroshi , Kojima Takahiro , Saito Toshihiro , Yokomizo Akira , Kohei Naoki , Goto Takayuki , Kawamura Sadafumi , Hashimoto Yasuhiro , Takahashi Atsushi , Kimura Takahiro , Tabata Ken‐ichi , Tomida Ryotaro , Hashimoto Kohei , Sakurai Toshihiko , Shimazui Toru , Sakamoto Shinichi , Kamiyama Manabu , Tanaka Nobumichi , Mitsuzuka Koji , Kato Takuma , Narita Shintaro , Yasumoto Hiroaki , Teraoka Shogo , Kato Masashi , Osawa Takahiro , Nagumo Yoshiyuki , Matsumoto Hiroaki , Enokida Hideki , Sugiyama Takayuki , Kuroiwa Kentaro , Inoue Takahiro , Sugimoto Mikio , Mizowaki Takashi , Kamoto Toshiyuki , Nishiyama Hiroyuki , Eto Masatoshi ,   Japanese Urological Oncology Group
Published: June 2021

AbstractThe metastatic burden is a critical factor for decision‐making in the treatment of metastatic hormone‐sensitive prostate cancer (HSPC). This study aimed to develop and validate a novel risk model for survival in patients with de novo low‐ and high‐burden metastatic HSPC. The retrospective observational study included men with de novo metastatic prostate cancer who were treated with primary androgen‐deprivation therapy at 30 institutions across Japan between 2008 and 2017. We created a risk model for overall survival (OS) in the discovery cohort (n = 1449) stratified by the metastatic burden (low vs high) and validated its predictive ability in a separate cohort (n = 951). Based on multivariate analyses, lower hemoglobin levels, higher Gleason grades, and higher clinical T‐stage were associated with poor OS in low‐burden disease. Meanwhile, lower hemoglobin levels, higher Gleason grade group, liver metastasis, and higher extent of disease scores in bone were associated with poor OS in patients with high‐burden disease. In the discovery and validation cohorts, the risk model using the aforementioned parameters exhibited excellent discriminatory ability for progression‐free survival and OS. The predictive ability of this risk model was superior to that of previous risk models. Our novel metastatic burden‐stratified risk model exhibited excellent predictive ability for OS, and it is expected to have several clinical uses, such as precise prognostic estimation.
Beneficiaries of radical surgery among clinical complete responders to neoadjuvant chemoradiotherapy in rectal cancer
Authors: Zhang Shu , Zhang Rong , Li Rong‐zhen , Wang Qiao‐xuan , Chang Hui , Ding Pei‐rong , Li Li‐ren , Wu Xiao‐jun , Chen Gong , Zeng Zhi‐fan , Xiao Wei‐wei , Gao Yuan‐hong 
Published: June 2021

AbstractThis study aimed to identify patients who benefit from radical surgery among those with rectal cancer who achieved clinical complete response (cCR). Patients with locally advanced rectal cancer (LARC; stage II/III) who achieved cCR after neoadjuvant chemoradiotherapy (nCRT) were included (n = 212). Univariate/multivariate Cox analysis was performed to validate predictors for distant metastasis‐free survival (DMFS). A decision tree was generated using recursive partitioning analysis (RPA) to categorize patients into different risk stratifications. Total mesorectal excision (TME) was compared with the watch‐and‐wait (W&W) strategy in each risk group. Two molecular predicators of CEA and CA19‐9 were selected to establish the RPA‐based risk stratification, categorizing LARC patients into low‐risk (n = 139; CA19‐9 < 35 U/mL and CEA < 5 ng/mL) and high‐risk (n = 73; CA19‐9 ≥ 35 U/mL or CEA ≥5 ng/mL) groups. Superior 5‐y DMFS was observed in the low‐risk group vs. the high‐risk group (92.9% vs. 76.2%, P = .002). Low‐risk LARC patients who underwent TME had significantly improved 5‐y DMFS compared with their counterparts receiving the W&W strategy (95.9% vs. 84.3%; P = .028). No significant survival difference was observed in high‐risk patients receiving the 2 treatment modalities (77.9% vs. 94.1%; P = .143). LARC patients with cCR who had both baseline CA19‐9 < 35 U/mL and CEA < 5 ng/mL may benefit from radical surgery.
Alginate oligosaccharide alleviates senile osteoporosis via the RANKL–RANK pathway in D‐galactose‐induced C57BL/6J mice
Authors: Wang Shan , Feng Wenjing , Liu Jianya , Wang Xufu , Zhong Lina , Lv Chengxiu , Feng Meiping , An Nina , Mao Yongjun 
Published: June 2021

AbstractOsteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density (BMD) and bone quality and increased bone porosity, which increase the risk of bone fracture. Inflammation, one of the important mechanisms related to aging, is associated with osteoporosis. Treatment with anti‐inflammatory agents is effective for alleviating senile osteoporosis. Alginate oligosaccharide (AOS) can prevent and treat diseases related to inflammation, oxidative stress, and immunity. This study evaluates the effect of AOS on osteoporosis and investigates the underlying mechanism. Osteoporosis model was induced by D‐galactose (D‐gal) (200 mg kg−1 day−1) for eight weeks. Three groups were administered via AOS (50, 100, and 150 mg kg−1 day−1) for four weeks, while a control group received sterile water (5 ml kg−1 day−1) for 8 weeks. The results showed that AOS improved bone density and bone microstructure in D‐gal‐induced osteoporosis mice. AOS inhibited osteoclast proliferation, probably through the suppression of receptor activator of nuclear factor‐kappa B ligand (RANKL)‐associated nuclear factor kappa B (NF‐κB) and c‐Fos signaling pathway. AOS also increased osteoprotegerin (OPG) expression and competitively inhibited the binding between RANK and RANKL in senile osteoporosis. Further, AOS decreased the secretion of serum osteocalcin and reduced bone conversion. Together, these results demonstrate the anti‐osteoporosis activity of AOS in mice with osteoporosis.
Cytometric analysis of T cell phenotype using cytokine profiling for improved manufacturing of an EBV-specific T cell therapy
Authors: Cooper Rachel S , Kowalczuk Aleksandra , Wilkie Gwen , Vickers Mark A , Turner Marc L , Campbell John D M , Fraser Alasdair R 
Published: June 2021

Abstract
Adoptive immunotherapy using Epstein–Barr Virus (EBV)-specific T cells is a potentially curative treatment for patients with EBV-related malignancies where other clinical options have proved ineffective. We describe improved good manufacturing practice (GMP)-compliant culture and analysis processes for conventional lymphoblastoid cell line (LCL)-driven EBV-specific T cell manufacture, and describe an improved phenotyping approach for analysing T cell products. We optimized the current LCL-mediated clinical manufacture of EBV-specific T cells to establish an improved process using xenoprotein-free GMP-compliant reagents throughout, and compared resulting products with our previous banked T cell clinical therapy. We assessed effects of changes to LCL:T cell ratio in T cell expansion, and developed a robust flow cytometric marker panel covering T cell memory, activation, differentiation and intracellular cytokine release to characterize T cells more effectively. These data were analysed using a t-stochastic neighbour embedding (t-SNE) algorithm. The optimized GMP-compliant process resulted in reduced cell processing time and improved retention and expansion of central memory T cells. Multi-parameter flow cytometry determined the optimal protocol for LCL stimulation and expansion of T cells and demonstrated that cytokine profiling using interleukin (IL)-2, tumour necrosis factor (TNF)-α and interferon (IFN)-γ was able to determine the differentiation status of T cells throughout culture and in the final product. We show that fully GMP-compliant closed-process culture of LCL-mediated EBV-specific T cells is feasible, and profiling of T cells through cytokine expression gives improved characterization of start material, in-process culture conditions and final product. Visualization of the complex multi-parameter flow cytometric data can be simplified using t-SNE analysis.