bluuebunny/crossref_metadata_2025 huggingface dataset:
The Confucian concept of human dignity and its implications for bioethics
Authors: Li Yaming
Published: March 2021

Human dignity is a crucial concept in contemporary ethical, political and legal studies. However, people have different, even opposite understandings of human dignity, which has caused lots of confusion in related discourses. The Confucian notion of human dignity provides an important perspective for reflecting various theories of human dignity. In Confucian ethics, the basis of human dignity is the moral potential that every human being naturally has. Moral potential grants everyone universal dignity, while the development of moral potential grants people acquired dignity. Since all human beings have moral potential to the same extent, everyone owns universal dignity equally. Different people develop their moral potential to different extents. One’s acquired dignity is positively associated with the development of her moral potential. Universal dignity is a moral status but acquired dignity is not. To pursue acquired dignity is the moral demand of universal dignity and protects people’s universal dignity. Confucian discussions on human dignity provide not only a way to justify the equality of human moral status, but also a way to justify the moral obligation of protecting and developing human nature, thereby constituting a reliable theoretical basis for coping with ethical issues caused by biomedical technologies today.
Spinning in Helices: Design and the Question of Value
Authors: Ely Philip , Geneste Louis
Published: March 2021

Whereas those who practice, research, or teach in design are cognizant of the agency of the discipline and its effectiveness for situational change, potential commissioners or clients of design are still to be persuaded of its worth. A number of recent attempts to measure the effectiveness of design have helpfully reignited an interest in design’s value to commercial and societal interests, yet such models for evaluation are not unified to a point where different types of organizations—ranging from the commercially competitive to the socially motivated—can apply them to understand the value of particular design interventions. This paper develops a framework for analysis of the knowledge value of design to an organization or a society, building on the theoretical model of the quintuple helix and “modalities of knowledge,” respectively, and then applies this analytical frame to 10 design (research and practice) projects conducted over a 24‐month period. The paper concludes with recommendations on how such a framework—the Design Value Helix—may be developed for future analysis of design value for research, business, and societal use.
Outside‐inside‐out Frame Creation Model for the Innovation of Meaning in a B2B Industry
Authors: Goto Satoru , Ando Takuo , Yaegashi Kazaru
Published: March 2021

This study developed a frame creation model for innovation of meaning involving the designer’s iterative outside‐in and inside‐out practices. The model includes four types of frames: organizational frame, intrinsic frame, interpreter frame, and user frame. The model allows us to understand that an engineer have an organizational frames and intrinsic frames inside themselves. This distinction revealed that engineers could not generate ideas by mobilizing the intrinsic frame if they were adherent to the organizational frame. We suggest that understanding the interpreter frames enables the engineer to overcome adherence to the organizational frame. Additionally, the organizational innovation capability, underpinned by the design‐oriented innovation strategy, is also an enabler to mobilize intrinsic frames in a technology‐centered or solution‐centered organization.
Touch and Go: Fast Interprofessional Collaboration Relief
Authors: Doehler Steven , Goodin Jeanine
Published: March 2021

Working collaboratively through interprofessional education is highly effective when solving problems in community health. Unlike in industry, academic collaborations are limited to class time and are often sporadic. This fragmentation often translates into teams not finding their stride until midsemester.

The Design + Nursing Collaboration (D + NC) developed the "Touch and Go" collaboration method to address this lag. This method focuses on bringing students together early to unite under easily completed tasks via in‐person and distance collaboration. This method strategically brings designers and nurses together and then breaks them apart at appropriate moments to enable them to focus and excel in their area of specialty. The collaboration method allows students to come together and solve wicked problems as a large team. This method requires a diverse mindset, one that can see the broad view and address significant challenges from various perspectives. However, as the problems become more complex, disciplinary experts need to shine without compromise and break away and perform the tasks in their field of expertise.

The authors will outline and demonstrate the process, the outcomes, and how "Touch and Go" moved the solution further faster.
Soluble programmed cell death protein 1 (sPD‐1) and the soluble programmed cell death ligands 1 and 2 (sPD‐L1 and sPD‐L2) in lymphoid malignancies
Authors: Mortensen Julie B. , Monrad Ida , Enemark Marie B. , Ludvigsen Maja , Kamper Peter , Bjerre Mette , d'Amore Francesco
Published: March 2021

Background

The programmed cell death protein 1 (PD‐1) and its ligand 1 and 2 (PD‐L1/PD‐L2) regulate the immune system, and the checkpoint pathway can be exploited by malignant cells to evade anti‐tumor immune response. Soluble forms (sPD‐1/sPD‐L1/sPD‐L2) exist in the peripheral blood, but their biological and clinical significance is unclear.

Method

Time‐resolved immunofluorometric assay (TRIFMA) and enzyme‐linked immunosorbent assay (ELISA) were used to measure sPD‐1, sPD‐L1, and sPD‐L2 levels in serum from 131 lymphoma patients and 22 healthy individuals.

Results

Patients had higher sPD‐1 and sPD‐L2 levels than healthy individuals. In diffuse large B‐cell lymphoma, patients with high International Prognostic Index score had higher sPD‐1 levels and sPD‐L2 levels correlated with subtype according to cell of origin. Compared to other lymphoma types, follicular lymphoma displayed higher sPD‐1 and lower sPD‐L1 levels along with lower ligand/receptor ratios.

Conclusion

This is the first study to simultaneously characterize pretherapeutic sPD‐1, sPD‐L1, and sPD‐L2 in a variety of lymphoma subtypes. The relation between higher sPD‐1 levels and adverse prognostic factors suggests a possible biological role and potential clinical usefulness of sPD‐1. Moreover, the reverse expression pattern in follicular lymphoma and T‐cell lymphoma/leukemia may reflect biological information relevant for immunotherapy targeting the PD‐1 pathway.
Cytokine gene polymorphisms are associated with response to blinatumomab in B‐cell acute lymphoblastic leukemia
Authors: Jeyakumar Nikeshan , Aldoss Ibrahim , Yang Dongyun , Mokhtari Sally , Gendzekhadze Ketevan , Khaled Samer , O'Donnell Margaret , Palmer Joycelynne , Song Joo Y. , Marcucci Guido , Stein Anthony S. , Forman Stephen J. , Pullarkat Vinod A. , Chen Wei , Wu Xiwei , Nakamura Ryotaro
Published: March 2021

Blinatumomab is a bispecific T cell‐engaging antibody approved for treatment of relapsed/refractory (r/r) ALL, with 40%‐50% complete response (CR)/CR with incomplete count recovery (CRi). Cytokine release syndrome (CRS) as a major adverse effect after blinatumomab therapy. Here, we evaluated the possible association between single‐nucleotide polymorphisms (SNPs) in cytokine genes, disease response, and CRS in r/r ALL patients who received blinatumomab between 2012 and 2017 at our center (n = 66), using patients’ archived DNA samples. With a median duration of 9.5 months (range: 1‐37), 37 patients (56.1%) achieved CR/CRi, 54 (81.8%) experienced CRS (G1: n = 35, G2: n = 14, G3: n = 5), and 9 (13.6%) developed neurotoxicity. By multivariable analysis, after adjusting for high disease burden, one SNP on IL2 (rs2069762), odds ratio (OR) = 0.074 (95% CI: NE‐0.43, P = .01) and one SNP on IL17A (rs4711998), OR = 0.28 (95% CI: 0.078‐0.92, P = .034) were independently associated with CR/CRi. None of the analyzed SNPs were associated with CRS. To our knowledge, this is the first study demonstrating a possible association between treatment response to blinatumomab and SNPs. Our hypothesis‐generated data suggest a potential role for IL‐17 and IL‐2 in blinatumomab response and justify a larger confirmatory study, which may lead to personalized blinatumomab immunotherapy for B‐ALL.
Greater, but not necessarily better: The influence of biochar on soil hydraulic properties
Authors: Rabbi Sheikh M.F. , Minasny Budiman , Salami Shuaib T. , McBratney Alex. B. , Young Iain M.
Published: March 2021

Biochar is recommended as a soil amendment for its positive influence on soil hydrological properties, which results in improved soil fertility and crop yield. Much research in the last decade has been conducted in field and laboratory conditions on the effect of biochar on the hydraulic properties of soil. However, reported results in the literature are substantially inconsistent. Here we performed a meta‐analysis to capture the variations in change in hydraulic properties of arable soils after application of different rates of biochar. The meta‐analysis revealed that high biochar rates (>50 t ha−1) compared to low rates (<20 t ha−1) significantly improved dry bulk density in sandy and clay soils, in field and laboratory experiments. However, field capacity only improved in laboratory experiments on sandy soils. The plant available water, permanent wilting point and saturated hydraulic conductivity did not significantly increase at high rates of biochar application compared to the low rates when applied to different types of soils in both field and laboratory experiments. We discuss possible reasons for this, including hydrophobicity of the biochar with future research directions. We concluded that the current evidence does not support the notion that the application of biochar improves soils' available water capacity.

Highlights

Meta‐analysis clarifies the influence of biochar on soil hydraulic properties.

Biochar addition at higher rates only improves the water holding capacity of sandy soils.

Biochar types and pyrolysis temperatures do not influence soil hydraulic properties.

The efficiency of biochar may depend on its pore size distribution and hydrophobicity.
Clinical characteristics and outcomes of thymoma‐associated myasthenia gravis
Authors: Álvarez‐Velasco Rodrigo , Gutiérrez‐Gutiérrez Gerardo , Trujillo Juan Carlos , Martínez Elisabeth , Segovia Sonia , Arribas‐Velasco Marina , Fernández Guillermo , Paradas Carmen , Vélez‐Gómez Beatriz , Casasnovas Carlos , Nedkova Velina , Guerrero‐Sola Antonio , Ramos‐Fransi Alba , Martínez‐Piñeiro Alicia , Pardo Julio , Sevilla Teresa , Gómez‐Caravaca María Teresa , López de Munain Adolfo , Jericó Ivonne , Pelayo‐Negro Ana L. , Martín María Asunción , Morgado Yolanda , Mendoza María Dolores , Pérez‐Pérez Helena , Rojas‐García Ricard , Turon‐Sans Janina , Querol Luis , Gallardo Eduard , Illa Isabel , Cortés‐Vicente Elena
Published: March 2021

Background and purpose

Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG.

Methods

This multicenter study was based on data from a Spanish neurologist‐driven MG registry. All patients were aged >18 years at onset and had anti‐acetylcholine receptor antibodies. We compared the clinical data of thymomatous and nonthymomatous patients. Prognosis of patients with recurrent or nonresectable thymomas was assessed.

Results

We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma‐associated MG. Median follow‐up time was 4.6 years. At onset, thymoma‐associated MG patients were younger (52.0 vs. 60.4 years, p < 0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95–4.68, p < 0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15–2.21, p = 0.005). Disease severity based on MGFA postintervention status (MGFA‐PIS) was higher in thymomatous patients at 1 year, 5 years, and the end of follow‐up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43–3.63, p = 0.001; hazard ratio: 2.46, 95% CI: 1.47–4.14, p = 0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long‐term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA‐PIS and higher mortality at the end of follow‐up.

Conclusions

Thymoma‐associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long‐term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.
A potential contribution of decreased serum galectin‐10 levels to systemic inflammation and pulmonary vascular involvement in systemic sclerosis
Authors: Awaji Kentaro , Miyagawa Takuya , Fukui Yuki , Toyama Satoshi , Omatsu Jun , Norimatsu Yuta , Ikawa Tetsuya , Watanabe Yusuke , Yoshizaki Ayumi , Sato Shinichi , Asano Yoshihide
Published: March 2021

Objective

Galectin‐10 (Gal‐10) is a key molecule involved in eosinophil‐mediated suppression of T‐cell immune response. Systemic sclerosis (SSc) is characterized by T helper (Th) 2/Th17 immune response and impaired function of regulatory T cells, but the pathological role of Gal‐10 has not been studied so far. Therefore, we investigated the clinical correlation of serum Gal‐10 levels in SSc patients.

Methods

Serum Gal‐10 levels were determined by enzyme‐linked immunosorbent assay in 38 patients with diffuse cutaneous SSc (dcSSc), 30 with limited cutaneous SSc and 20 healthy controls. Clinical correlations of serum Gal‐10 levels were examined.

Results

Serum Gal‐10 levels were significantly lower in SSc patients than in healthy controls, especially in dcSSc patients, and inversely correlated with skin score, the percentage of predicted diffusion lung capacity for carbon monoxide and estimated right ventricular systolic pressure (RVSP). Furthermore, serum Gal‐10 levels had negative correlations with leucocyte counts and inflammatory parameters. Multivariate regression analysis identified C‐reactive protein and RVSP as explanatory parameters for serum Gal‐10 levels.

Conclusion

Decreased serum Gal‐10 levels may reflect the impairment of eosinophil‐mediated regulatory system for T‐cell immune response in SSc, possibly contributing to pulmonary vascular involvement leading to pulmonary arterial hypertension.
Mothering managers: (Re)interpreting older women's organizational subjectivity
Authors: Cutcher Leanne
Published: March 2021

This paper explores motherhood as an organizational subjectivity. Highlighting the experience of older women in a global engineering firm, and my own experience as an academic leader, the paper shows how the maternal body is culturally produced and how discourses of motherhood perpetuate highly gendered notions of who can give and receive care in organizations. This paper argues that the patriarchal construction of women as endlessly maternal, but never complete, limits the possibility for gendered agency. The paper calls for a reinterpretation of the maternal in organizations that would allow women to reclaim a feminine space where they can draw on the full repertoire of their embodied potentialities in order to experiment and assert their subjectivity. This reinterpretation of the maternal would also facilitate an uncoupling of notions of care and motherhood which would allow for a degendered reciprocal care offered and received by all members of the organization.
Painful nails: A practical approach to the diagnosis and management of painful nail conditions
Authors: Olvera‐Rodríguez Valeria , Gatica‐Torres Michelle , Carrillo‐Córdova Dulce María , Barrera‐Godínez Alejandro , Domínguez‐Cherit Judith
Published: March 2021

Because several nail disorders share similar clinical features, their diagnosis and management can be challenging to clinicians. The physical examination may disclose localized abnormalities or point to an underlying systemic disease, requiring additional workup. Furthermore, cosmetic distress and nail‐related symptoms (e.g., tingling, stinging, numbness, and pain) are common factors that influence the patient's search for medical assistance. Nail pain (i.e., onychalgia) can accompany both localized and systemic pathology. Onychalgia can be acute or chronic according to the time of evolution; patients may describe it as intermittent or constant, and as a throbbing, burning, sharp, or shooting sensation denoting the nature of the pain. It may be exacerbated by colder temperatures, touch, and increased activity (e.g., manipulating objects, walking). We present four main groups of conditions that might cause nail pain: nail tumors, nail deformities, inflammatory or infectious diseases, and external or traumatic agents. Our article includes an overview of the clinical features, as well as diagnosis and management pearls for each entity. Physicians (dermatologists and nondermatologists) should be aware that abnormalities of the ungual and subungual space are not exclusive of dermatological disorders but may also be present in noncutaneous contexts.
Does the open shop harm union collective action?
Authors: Zullo Roland
Published: March 2021

In the United States, right‐to‐work (RTW) laws impose the open shop on labour unions. I test whether RTW affects the frequency and outcomes of union representation petitions. Quasi‐experimental tests reveal no association between RTW law and the volume of certification petitions filed and that fewer certification petitions are withdrawn under RTW. Thus, unions do not appear to retreat from new member organizing under RTW law. Moreover, RTW correlates with a decline in decertification and unit clarification petitions, implying that under the open shop, RTW law reduces internal union dissension. Although fewer decertification cases go to an election under RTW law, unions are more likely to lose cases that proceed to a referendum. These changes benefit smaller more than larger bargaining units. I infer that the law nudges the system away from an industrial union model in favour of smaller, craft or occupation‐based units.
A criterion space search algorithm for mixed integer linear maximum multiplicative programs: a multiobjective optimization approach
Authors: Saghand Payman Ghasemi , Charkhgard Hadi
Published: March 2021

We study a class of mixed integer optimization problems with linear constraints and a multilinear objective function, the so‐called mixed integer linear maximum multiplicative programs (MIL‐MMPs). Such a problem can be transformed into a second‐order cone program (SOCP) and can be solved effectively by a commercial solver such as CPLEX. However, MIL‐MMPs can also be viewed as special cases of the problem of optimization over the set of efficient solutions in multiobjective optimization. Using this observation, we develop a criterion space search algorithm for solving any MIL‐MMP. An extensive computational study on around 2000 instances illustrates that the proposed algorithm significantly outperforms not only the CPLEX mixed integer SOCP solver but also a state‐of‐the‐art algorithm that is capable of solving special cases of MIL‐MMPs. Moreover, the computational study illustrates that even if we linearize the objective function and solve the linearized problem by CPLEX, the proposed algorithm still performs significantly better.
Alpha‐mangostin improves endothelial dysfunction in db/db mice through inhibition of aSMase/ceramide pathway
Authors: Jiang Meng , Huang Shanya , Duan Wang , Liu Qiaoshu , Lei Minxiang
Published: March 2021

Diabetic vascular complications are the leading causes of death and disability in patients with diabetes. Alpha‐mangostin has been reported to have anti‐diabetic capacity in recent years. Here, we investigated the protective function of alpha‐mangostin on endothelium in vitro and in vivo experiments. We also observed that alpha‐mangostin improved impaired endothelium‐dependent vasodilation (EDV) of diabetic animals while it limited the aSMase/ceramide pathway and up‐regulated eNOS/NO pathway in aortas from diabetic mice. Meanwhile, alpha‐mangostin inhibited elevated aSMase/ceramide pathway and reversed impaired EDV induced by high glucose in isolated mouse aortas. In addition, alpha‐mangostin increased phosphorylation of eNOS and NO production in high glucose‐treated aortas. Alpha‐mangostin normalized high glucose‐induced activation of aSMase/ceramide pathway and improved eNOS/NO pathway in endothelial cells with high glucose. In conclusion, alpha‐mangostin regulates eNOS/NO pathway and improves EDV in aortas of diabetic mice through inhibiting aSMase activity and endogenous ceramide accumulation.
Two novel qualitative transcriptional signatures robustly applicable to non‐research‐oriented colorectal cancer samples with low‐quality RNA
Authors: Cheng Jun , Guo Yating , Guan Guoxian , Huang Haiyan , Jiang Fengle , He Jun , Wu Junling , Guo Zheng , Liu Xing , Ao Lu
Published: March 2021

Currently, due to the low quality of RNA caused by degradation or low abundance, the accuracy of gene expression measurements by transcriptome sequencing (RNA‐seq) is very challenging for non‐research‐oriented clinical samples, majority of which are preserved in hospitals or tissue banks worldwide with complete pathological information and follow‐up data. Molecular signatures consisting of several genes are rarely applied to such samples. To utilize these resources effectively, 45 stage II non‐research‐oriented samples which were formalin‐fixed paraffin‐embedded (FFPE) colorectal carcinoma samples (CRC) using RNA‐seq have been analysed. Our results showed that although gene expression measurements were significantly affected, most cancer features, based on the relative expression orderings (REOs) of gene pairs, were well preserved. We then developed two REO‐based signatures, which consisted of 136 gene pairs for early diagnosis of CRC, and 4500 gene pairs for predicting post‐surgery relapse risk of stage II and III CRC. The performance of our signatures, which included hundreds or thousands of gene pairs, was more robust for non‐research‐oriented clinical samples, compared to that of two published concise REO‐based signatures. In conclusion, REO‐based signatures with relatively more gene pairs could be robustly applied to non‐research‐oriented CRC samples.
Opportunity, Presence and Entrepreneurship: Why the EU Acts Externally on Higher Education*
Authors: Gerards Carsten , Schunz Simon , Damro Chad
Published: March 2021

In recent times, the European Union’s external engagement has expanded in originally internal policy areas. This process is particularly intriguing in areas where the EU possesses only supplementary competences. Examining the case of EU higher education policy, this contribution sets out to understand and explain EU external engagement in such areas. To this end, it employs an explanatory framework that argues that EU external action emerges when a structural policy window of external ‘opportunity’ and domestic ‘presence’ opens, which is exploited by ‘policy entrepreneurs’. The contribution compares two pillars of EU higher education policy – the Tempus and Erasmus Mundus programmes – which it sets in relation to the emergence of external action in other EU higher education initiatives. Offering an explanation of why the EU engages externally in higher education, the contribution concludes by discussing the broader generalizability of its findings.
The Oral Status Survey Tool: construction, validity, reliability and feasibility among people with mild and moderate intellectual disabilities
Authors: Mac Giolla Phadraig C. , Ishak N. S. , van Harten M. , Al Mutairi W. , Duane B. , Donnelly‐Swift E. , Nunn J.
Published: March 2021

Background

A lack of robust data about the oral health of people with intellectual disabilities (IDs) contributes to health disparities. Appropriate research tools are therefore needed. This study reports the construction and evaluation of the Oral Status Survey Tool (OSST), designed to be administered with people with disabilities by non‐dental personnel.

Method

Oral Status Survey Tool construction and evaluation was achieved adopting a non‐clinical construction and content validation phase and a clinical phase to test concurrent validity, reliability and feasibility. Final refinements were also made.

Results

The OSST conceptual framework covered oral function (tooth count, denture wear and opposing pairs of teeth) and oral disease/treatment need (soft tissue status, oral cleanliness, gum condition, carious teeth and oral pain). A systematic literature review identified no existing suitable indices. Candidate items were identified and validated by experts generating content validation ratios. This framework was modified later to expand the function construct. In the initial clinical phase, 49 out of 60 participants underwent examination with OSST and standard dental assessments. All had mild to moderate IDs. Mean age was 43 years (SD = 16), and mean number of teeth was 22.1 (SD = 8.6). Data collectors included two dentists and three non‐dentists. Later, a further 17 adults (nine female and eight male) with mild/moderate IDs were included for refinement. At this stage, data collectors included two dentists and five non‐dentists. Concurrent validity was established for tooth count [intraclass correlation coefficient = 0.99 (95% confidence interval, CI: 0.99–0.99)], carious teeth [Gwet's AC2 = 0.94 (95% CI: 0.89–0.99)] and gum condition [Gwet's AC1 = 0.84 (95% CI: 0.64–1)]. For all final OSST items, inter‐rater reliability ranged from moderate to very good; median test–retest reliability ranged from moderate to good. Acceptability was demonstrated for data collectors and participants. Mean time to complete the OSST was 7 min.

Conclusions

The OSST is a novel tool that can record a range of clinical oral features including tooth count, denture wear, occluding pairs of teeth and functional dentition, oral cleanliness, gum condition, carious cavitation and oral pain that will be useful within health surveys of people with mild–moderate IDs and similarly neglected populations. The tool demonstrates promising attributes and acceptability. From this study, the OSST appears to be a robust tool that can be incorporated into general data collection for people with mild–moderate IDs and similar populations. A key feature is that it can be administered by well‐trained non‐dentists.
Evidence that synaptic plasticity of glutamatergic inputs onto KNDy neurones during the ovine follicular phase is dependent on increasing levels of oestradiol
Authors: Porter Danielle T. , Goodman Robert L. , Hileman Stanley M. , Lehman Michael N.
Published: March 2021

Neurones in the arcuate nucleus co‐expressing kisspeptin, neurokinin B (NKB) and dynorphin (KNDy) play a critical role in the control of gonadotrophin‐releasing hormone (GnRH) and luteinising hormone (LH) secretion. In sheep, KNDy neurones mediate both steroid‐negative‐ and ‐positive‐feedback during pulsatile and preovulatory surge secretions of GnRH/LH, respectively. In addition, KNDy neurones receive glutamatergic inputs expressing vGlut2, a glutamate transporter that serves as a marker for those terminals, from both KNDy neurones and other populations of glutamatergic neurones. Previous work reported higher numbers of vGlut2‐positive axonal inputs onto KNDy neurones during the LH surge than in luteal phase ewes. In the present study, we further examined the effects of the ovarian steroids progesterone (P) and oestradiol (E2) on glutamatergic inputs to KNDy neurones. Ovariectomised (OVX) ewes received either no further treatment (OVX) or steroid treatments that mimicked the luteal phase (low E2 + P), and early (low E2) or late follicular (high E2) phases of the oestrous cycle (n = 4 or 5 per group). Brain sections were processed for triple‐label immunofluorescent detection of NKB/vGlut2/synaptophysin and analysed using confocal microscopy. We found higher numbers of vGlut2 inputs onto KNDy neurones in high E2 compared to the other three treatment groups. These results suggest that synaptic plasticity of glutamatergic inputs onto KNDy neurones during the ovine follicular phase depend on increasing levels of E2 required for the preovulatory GnRH/surge. These synaptic changes likely contribute to the positive‐feedback action of oestrogen on GnRH/LH secretion and thus the generation of the preovulatory surge in the sheep.
Information Models Offer Value to Standardize Electronic Health Record Flowsheet Data: A Fall Prevention Exemplar
Authors: Lytle Kay S. , Westra Bonnie L. , Whittenburg Luann , Adams Mischa , Akre Mari , Ali Samira , Furukawa Meg , Hartleben Stephanie , Hook Mary , Johnson Steven G. , Settergren Theresa (Tess) , Thibodeaux Mariaelena
Published: March 2021

Purpose

The rapid implementation of electronic health records (EHRs) resulted in a lack of data standardization and created considerable difficulty for secondary use of EHR documentation data within and between organizations. While EHRs contain documentation data (input), nurses and healthcare organizations rarely have useable documentation data (output). The purpose of this article is to describe a method of standardizing EHR flowsheet documentation data using information models (IMs) to support exchange, quality improvement, and big data research. As an exemplar, EHR flowsheet metadata (input) from multiple organizations was used to validate a fall prevention IM.

Design

A consensus‐based, qualitative, descriptive approach was used to identify a minimum set of essential fall prevention data concepts documented by staff nurses in acute care. The goal was to increase generalizable and comparable nurse‐sensitive data on the prevention of falls across organizations for big data research.

Methods

The research team conducted a retrospective, observational study using an iterative, consensus‐based approach to map, analyze, and evaluate nursing flowsheet metadata contributed by eight health systems. The team used FloMap software to aggregate flowsheet data across organizations for mapping and comparison of data to a reference IM. The FloMap analysis was refined with input from staff nurse subject matter experts, review of published evidence, current documentation standards, Magnet Recognition nursing standards, and informal fall prevention nursing use cases.

Findings

Flowsheet metadata analyzed from the EHR systems represented 6.6 million patients, 27 million encounters, and 683 million observations. Compared to the original reference IM, five new IM classes were added, concepts were reduced by 14 (from 57 to 43), and 157 value set items were added. The final fall prevention IM incorporated 11 condition or age‐specific fall risk screening tools and a fall event details class with 14 concepts.

Conclusion

The iterative, consensus‐based refinement and validation of the fall prevention IM from actual EHR fall prevention flowsheet documentation contributes to the ability to semantically exchange and compare fall prevention data across multiple health systems and organizations. This method and approach provides a process for standardizing flowsheet data as coded data for information exchange and use in big data research.

Clinical Relevance

Opportunities exist to work with EHR vendors and the Office of the National Coordinator for Health Information Technology to implement standardized IMs within EHRs to expand interoperability of nurse‐sensitive data.
Phylogenomic analysis restructures the ulvophyceae
Authors: Gulbrandsen Øyvind Sætren , Andresen Ina Jungersen , Krabberød Anders Kristian , Bråte Jon , Shalchian‐Tabrizi Kamran
Published: March 2021

Here, we present new transcriptome sequencing data from seven species of Dasycladales (Ulvophyceae) and a phylogenomic analysis of the Chlorophyta with a particular focus on Ulvophyceae. We have focused on a broad selection of green algal groups and carefully selected genes suitable for reconstructing deep eukaryote evolutionary histories. Increasing the taxon sampling of Dasycladales restructures the Ulvophyceae by identifying Dasycladales as closely related to Scotinosphaerales and Oltmannsiellopsidales. Contrary to previous studies, we do not find support for a close relationship between Dasycladales and a group with Cladophorales and Trentepohliales. Instead, the latter group is sister to the remainder of the Ulvophyceae. Furthermore, our analyses show high and consistent statistical support for a sister relationship between Bryopsidales and Chlorophyceae in trees generated with both homogeneous and heterogeneous (heterotachy) evolutionary models. Our study provides a new framework for interpreting the evolutionary history of Ulvophyceae and the evolution of cellular morphologies.
Interstates of Infection: Preliminary Investigations of Human Mobility Patterns in the COVID‐19 Pandemic
Authors: Souch Jacob M. , Cossman Jeralynn S. , Hayward Mark D.
Published: March 2021

Purpose

The COVID‐19 pandemic has illuminated various heterogeneities between urban and rural environments in public health. The SARS‐CoV‐2 virus initially spread into the United States from international ports of entry and into urban population centers, like New York City. Over the course of the pandemic, cases emerged in more rural areas, implicating issues of transportation and mobility. Additionally, many rural areas developed into national hotspots of prevalence and transmission. Our aim was to investigate the preliminary impacts of road travel on the spread of COVID‐19. This investigation has implications for future public health mitigation efforts and travel restrictions in the United States.

Methods

County‐level COVID‐19 data were analyzed for spatiotemporal patterns in time‐to‐event distributions using animated choropleth maps. Data were obtained from The New York Times and the Bureau of the Census. The arrival event was estimated by examining the number of days between the first reported national case (January 21, 2020) and the date that each county attained a given prevalence rate. Of the 3108 coterminous US counties, 2887 were included in the analyses. Data reflect cases accumulated between January 21, 2020, and May 17, 2020.

Findings

Animations revealed that COVID‐19 was transmitted along the path of interstates. Quantitative results indicated rural–urban differences in the estimated arrival time of COVID‐19. Counties that are intersected by interstates had an earlier arrival than non‐intersected counties. The arrival time difference was the greatest in the most rural counties and implicates road travel as a factor of transmission into rural communities.

Conclusion

Human mobility via road travel introduced COVID‐19 into more rural communities. Interstate travel restrictions and road travel restrictions would have supported stronger mitigation efforts during the earlier stages of the COVID‐19 pandemic and reduced transmission via network contact.
Health‐related quality of life in head and neck cancer survivors: Evaluating the rural disadvantage
Authors: Adamowicz Jenna L. , Christensen Alan , Howren M. Bryant , Seaman Aaron T. , Kendell Nicholas D. , Wardyn Shylo , Pagedar Nitin A.
Published: March 2021

Purpose

Head and neck cancer (HNC) survivors often experience distress and health‐related quality of life (HRQOL) impairment. Research suggests that rural cancer patients may have poorer outcomes than urban patients. This study examined whether HNC patient emotional and HRQOL outcomes differ in those living in a rural versus urban location at 6 and 12 months postdiagnosis.

Methods

A total of 261 HNC patients were included from a longitudinal study of HNC outcomes. The majority were diagnosed with advanced stage cancer (51.3%); the most common cancer site was oral cavity (41.0%). Rurality was measured using the US Department of Agriculture Rural Urban Commuting Area codes. Depression was measured using the Beck Depression Inventory (BDI), general HRQOL using the Short Form‐36 (SF‐36), and HNC‐specific HRQOL using the Head and Neck Cancer Inventory (HNCI). Analyses were 2 (group) × 3 (assessment) repeated measures ANCOVAs, controlling for demographic and clinical characteristics.

Findings

Approximately 45% of the sample lived in a rural location. Follow‐up comparisons of significant overall models indicated that rural patients reported significantly more nonsomatic depression symptoms at 6‐month follow‐up. Rural patients were also more likely to report significantly poorer general mental HRQOL at 12‐month follow‐up, significantly poorer HNC‐specific HRQOL related to eating at 6‐ and 12‐month follow‐up, and marginally worse aesthetics at 12‐month follow‐up.

Conclusions

These findings are consistent with suggestions that rural HNC patients may be at heightened risk for depression symptoms and decrements in HRQOL. Patients should be screened and regularly monitored for issues with depression and HNC‐specific HRQOL throughout the survivorship period.
Jointly determining the state dimension and lag order for Markov‐switching vector autoregressive models
Authors: Li Nan , Kwok Simon S.
Published: March 2021

This article studies the problem of joint selection of the state dimension and lag order for a class of Markov‐switching vector autoregressive models, in which all parameters are presumed to be regime‐dependent. To this end, three complexity‐penalized criteria are considered, and a new criterion is derived by minimizing the Kullback–Leibler divergence. The efficacy of the procedure is evaluated by means of Monte Carlo experiments. We illustrate the usefulness of the joint model selection procedure with empirical applications to the modeling of business cycles in the USA and Australia.
Resistance‐associated substitutions after sofosbuvir/velpatasvir/voxilaprevir triple therapy failure
Authors: Garcia‐Cehic Damir , Rando Ariadna , Rodriguez‐Frias Francisco , Gregori Josep , Costa Juan Garcia , Carrión José Antonio , Macenlle Ramiro , Pamplona Javier , Castro‐Iglesias Angeles , Cañizares Angelina , Tabernero David , Campos Carolina , Buti Maria , Esteban Juan Ignacio , Quer Josep
Published: March 2021

Direct‐acting antivirals (DAAs) resolve chronic HCV infection in >95% of patients, but a small percentage do not respond to DAA‐based therapy. These may be difficult to treat because of resistance‐associated substitutions (RAS) emerging after treatment failure. Triple therapy with sofosbuvir (SOF)/velpatasvir (VEL)/voxilaprevir (VOX) is the recommended retreatment after DAA‐based failure. However, in rare cases, failure to triple therapy occurs, and there is little information characterizing the viruses that relapse. To determine the RAS profile after failing SOF/VEL/VOX, and seek suitable alternatives for retreatment, samples from 5 patients were analysed using MiSeq Illumina deep sequencing before and after triple therapy. All patients were men, aged 59–78 years, 2 HCV genotype (G) 1b and 3 G3a. The most prevalent NS3 substitutions after SOF/VEL/VOX failure were Y56F and A166T. Four patients had the NS5A RAS, Y93H, after triple failure, and Y93H was observed in both G1b patients before retreatment and after SOF/ledipasvir failure. In 2 G3a patients, Y93H appeared at triple failure, and on the other G3a, A30K persisted in 100% of viral genomes. Finally, G1b patients showed C316N in NS5B, associated with SOF failure, but G3a patients had no known NS5B substitutions. HCV RAS analysis identified the following substitutions present at higher rates after triple failure: Y56F in NS3 (G1b), A166T in NS3 (G3a), A30K or Y93H in NS5A, and C316N in NS5B (G1b). A RAS‐based salvage treatment (SOF + glecaprevir/pibrentasvir + RBV) was successfully used in one G3a patient.
Pharmacokinetics and pulmonary distribution of Draxxin®(tulathromycin) in healthy adult horses
Authors: Leventhal Hannah R. , McKenzie Harold C. , Estell Krista , Council‐Troche McAlister , Davis Jennifer L.
Published: March 2021

The objective of this study was to determine the pharmacokinetics and tolerability of tulathromycin (Draxxin®; 2.5 mg/kg once) after intramuscular (IM), subcutaneous (SC), and slow intravenous (IV) administration to six adult horses. A three‐phase design and 4‐week washout period were used. Drug concentrations in blood and bronchoalveolar lavage (BAL) samples were determined by ultra‐performance liquid chromatography tandem mass spectrometry and pharmacokinetic parameters calculated using noncompartmental analysis. Following SC and IM administration, all horses exhibited sweating, discomfort, and periods of recumbency. As signs were more severe after SC administration this route was only used in 3/6 horses. Intravenous administration of tulathromycin was well tolerated in all horses. Mean bioavailability was 99.4% IM and 115% SC. Mean maximum plasma concentration was 645 ng/ml IM and 373 ng/ml SC. Mean half‐life was 59.8 h, 54.8 h, and 57.9 h for IV, IM, and SC administration, respectively. Mean clearance was 3.25 ml/kg/min, and mean volume of distribution was 16.8 L/kg following IV administration. Drug was detectable in plasma and BAL samples for 120 h following all routes; however, adverse effects may prevent IM use and SC use is not recommended. Tulathromycin may be a practical and affordable antimicrobial for use in adult equine patients.
The char of migration inhibitory factor and Cathepsin B from Asian swamp eel (Monopterus albus) and their response to challenge with Aeromonas hydrophila
Authors: Du Zongjun , Wang Tianzhu , Lin Rongnan , Luo Wei , Wu Qing , Wang Dongjie , Xu Zhou , Wen Anxiang
Published: March 2021

Aeromonas hydrophila causes sepsis and is responsible for significant economic losses in Asian finless eel (Monopterus albus) aquaculture. Previous studies have found that macrophage migration inhibitory factor (MIF) and Cathepsin B (CTSB) may be expressed in many vertebrate tissues and organs. However, there have been no reports discussing the importance of MIF and CTSB in Asian swamp eel. The complete ORF sequences of MAMIF and MACTSB were found to be 348 and 993 bp, respectively. The adaptive analysis showed that the sequences of MAMIF and MACTSB were highly conserved, and only two positive selection sites were identified in MAMIF. Quantitative real time polymerase chain reaction (qRT‐PCR) demonstrated that MAMIF and MACTSB genes were expressed in all tissues evaluated with the highest expression occurring in the head kidney, spleen and liver. Challenge with Aeromonas hydrophila resulted in a significant increase in the expression of MAMIF and MACTSB in skin, liver, head kidney and spleen that peaked at 12‐h post‐infection. The results show that MAMIF and MACTSB play important roles in the immune function of Monopterus albus.
Characterization of the gut‐liver‐muscle axis in cirrhotic patients with sarcopenia
Authors: Ponziani Francesca Romana , Picca Anna , Marzetti Emanuele , Calvani Riccardo , Conta Giorgia , Del Chierico Federica , Capuani Giorgio , Faccia Mariella , Fianchi Francesca , Funaro Barbara , Josè Coelho‐Junior Helio , Petito Valentina , Rinninella Emanuele , Paroni Sterbini Francesco , Reddel Sofia , Vernocchi Pamela , Cristina Mele Maria , Miccheli Alfredo , Putignani Lorenza , Sanguinetti Maurizio , Pompili Maurizio , Gasbarrini Antonio ,   the GuLiver study group
Published: March 2021

Background & Aim

Sarcopenia is frequent in cirrhosis and is associated with unfavourable outcomes. The role of the gut‐liver‐muscle axis in this setting has been poorly investigated. The aim of this study was to identify gut microbiota, metabolic and inflammatory signatures associated with sarcopenia in cirrhotic patients.

Methods

Fifty cirrhotic patients assessed for the presence of sarcopenia by the quantification of muscle mass and strength were compared with age‐ and sex‐matched controls. A multiomic analysis, including gut microbiota composition and metabolomics, serum myokines and systemic and intestinal inflammatory mediators, was performed.

Results

The gut microbiota of sarcopenic cirrhotic patients was poor in bacteria associated with physical function (Methanobrevibacter, Prevotella and Akkermansia), and was enriched in Eggerthella, a gut microbial marker of frailty. The abundance of potentially pathogenic bacteria, such as Klebsiella, was also increased, to the detriment of autochthonous ones. Sarcopenia was associated with elevated serum levels of pro‐inflammatory mediators and of fibroblast growth factor 21 (FGF21) in cirrhotic patients. Gut microbiota metabolic pathways involved in amino acid, protein and branched‐chain amino acid metabolism were up‐regulated, in addition to ethanol, trimethylamine and dimethylamine production. Correlation networks and clusters of variables associated with sarcopenia were identified, including one centred on Klebsiella/ethanol/FGF21/Eggerthella/Prevotella.

Conclusions

Alterations in the gut‐liver‐muscle axis are associated with sarcopenia in patients with cirrhosis. Detrimental but also compensatory functions are involved in this complex network.
Using seasonal genomic changes to understand historical adaptation to new environments: Parallel selection on stickleback in highly‐variable estuaries
Authors: Garcia‐Elfring Alan , Paccard Antoine , Thurman Timothy J. , Wasserman Ben A. , Palkovacs Eric P. , Hendry Andrew P. , Barrett Rowan D. H.
Published: March 2021

Parallel evolution is considered strong evidence for natural selection. However, few studies have investigated the process of parallel selection as it plays out in real time. The common approach is to study historical signatures of selection in populations already well adapted to different environments. Here, to document selection under natural conditions, we study six populations of threespine stickleback (Gasterosteus aculeatus) inhabiting bar‐built estuaries that undergo seasonal cycles of environmental changes. Estuaries are periodically isolated from the ocean due to sandbar formation during dry summer months, with concurrent environmental shifts that resemble the long‐term changes associated with postglacial colonization of freshwater habitats by marine populations. We used pooled whole‐genome sequencing to track seasonal allele frequency changes in six of these populations and search for signatures of natural selection. We found consistent changes in allele frequency across estuaries, suggesting a potential role for parallel selection. Functional enrichment among candidate genes included transmembrane ion transport and calcium binding, which are important for osmoregulation and ion balance. The genomic changes that occur in threespine stickleback from bar‐built estuaries could provide a glimpse into the early stages of adaptation that have occurred in many historical marine to freshwater transitions.