bluuebunny/crossref_metadata_2025 huggingface dataset:
Criteria for selecting actors for the value co-creation in startups
Authors: Bonamigo Andrei , da Silva Adrianne Alves , da Silva Beatriz Pereira , Werner Steffan Macali
Published: January 2022

Purpose

The purpose of this paper is to identify the main criteria for selecting actors to compose these business platforms and addressing the co-creation of value and improve the performance of startups.

Design/methodology/approach

The methodology is based on the search for key factors for the selection of actors and the understanding of co-creation of value and the concept of startups. The content of this paper is substantiated on an extensive review of the literature related to the subjects’ value-cocreation and new startups, and the review is based on the articles found in the databases of Ebsco, Emerald, Science Direct, Scopus, Village and Web of Science.

Findings

This paper identifies the main key-factors found in the literature for selecting actors to co-create value in startups and organizes the findings in five categories: value creation, interaction, actor behavior, client and partnership. It also presents the possibility of future research that will be able to put the study in practice.

Research limitations/implications

The results of this research have not been tested empirically, which opens the door for future studies that can prove the effectiveness of the findings. It is also important to mention that there are few articles in the literature that directly address this topic, and some definitions of actor/co-creation of value/business model may also change.

Practical implications

The selection criteria of the actors listed are useful for service entrepreneurs and managers to assist in decision-making at the stage of choosing their partners for value co-creation in startups. Furthermore, it involves mitigating waste in startups and maximizing the economic gains of partners through value co-creation in startups.

Originality/value

This study is one of the first attempts to recognize the key factors for selecting actors to co-create value in startups, aiming at their success in the market.
“I can read, I just can't see”: a disability rights-based perspective on reading by listening
Authors: Lundh Anna
Published: January 2022

Purpose

The aim of the paper is to create a greater understanding of how people who are blind or vision impaired describe their use of audio-based reading technologies, with a particular focus on how they reason about whether the use of these technologies can be understood in terms of reading.

Design/methodology/approach

The study is part of the emerging research area Critical Studies of Reading and draws theoretical inspiration from Document Theory, New Literacy Studies and Critical Disability Studies. The article presents a discourse analysis of how 16 university students in Australia who are blind or vision impaired and use audio-based reading technologies describe this use in semi-structured interviews.

Findings

The participants relate to a division between ‘real' reading and reading by listening, where the latter is constructed as an exception and is connected to the subject position of being blind or vision impaired. However, resistance is also noticeable, where reading by listening is constructed as something that is normal, and as a right.

Originality/value

The article is a theoretical and empirical contribution to the ongoing discussion on the use of audio-based reading technologies. It presents perspectives from the users of these technologies and argues why a specific understanding of this use is important.
Exploring connections within the technology-based entrepreneurial ecosystem (EE) in emerging economies: understanding the entrepreneurship struggle in the Indonesian EE
Authors: Qoriawan Terra , Apriliyanti Indri Dwi
Published: January 2022

Purpose

Tech startup is the new hope for sustaining economic growth and job creation in a knowledge-based economy. However, research on the entrepreneurial ecosystem (EE) is always constructed upon macro-level analysis and is still very limited to the developed economies. This study aims to tackle those issues by exploring the connections within an EE in an emerging economies context with a micro and meso-level social network approach to unravel the pattern of networks and interactions between each actor in the EE.

Design/methodology/approach

This research used multi-layered social network analysis, exploring actors in the ecosystem and their interactions. The authors conducted interviews with startups, support organizations and government agencies. The authors used Atlas.ti software to visualize the network structures.

Findings

The authors found that the content of interaction within the EE in the emerging economies differs greatly with EE in the developed economies and they produced distinctive characteristics as follows: lack of a dense network, resource scarcities and structural gaps and weak institutional policies.

Research limitations/implications

The research is based on a case study of tech-based EE in Yogyakarta, Indonesia. Therefore, the authors encourage other researchers to investigate networks and connections in other EEs in emerging economies. This research contributes a conceptual framework to better understand the network of connections in an emerging-economies-based EE.

Practical implications

The research shows grants provision alone cannot contribute to the functioning of EE. The authors argue strategic networks which promote collaboration among actors can reduce holes and structural gaps, as well as resource scarcities in the ecosystem. In addition to that, strong institutional policies and effective policy integration are needed to create a successful EE.

Social implications

This research promotes the importance of networks, particularly networks between tech startups and strategic organizations to provide resources and support productive entrepreneurship in hopes of sustaining and accelerating tech startup growth within an EE.

Originality/value

The research proposes to add to the existing EE literature by shedding light on governance of EE, as well as exploring network of connection and interaction among actors within the ecosystem. As a result, the study addresses the need for a more micro or operational-level understanding of an EE. Recent calls for EEs literature have also focused on a certain actor’s dynamic function in the ecosystem. By focusing on the role of the government, the research added to the underdeveloped EE literature.
Collaborative public service provision archetypes in healthcare emergencies: a case of COVID-19 administration in Sri Lanka
Authors: Jayasinghe Kelum , Wijesinghe Chandana , Wijethilake Chaminda , Prasanna Raj
Published: January 2022

Purpose

This paper examines how the properties and patterns of a collaborative “networked hierarchy” incident command system (ICS) archetype can provide incident command centres with extra capabilities to manage public service delivery during COVID-19.

Design/methodology/approach

The paper illustrates the case of Sri Lanka's COVID-19 administration during its “first wave” (from 15 February to 1 September 2020). Primary data were collected through in-depth interviews with government officials who were directly involved in the administration of the COVID-19 outbreak. Secondary data sources were government publications and web sources. The data were analysed and interpreted by using narrative analysis and archetype theory respectively.

Findings

The findings highlight how Sri Lanka's public sector responses to COVID-19 have followed a collaborative “networked hierarchy” ICS archetype. More specifically, the government changed its normative ICS “properties” by incorporating a diverse group of intergovernmental agencies such as the police, the military, the health service and administrative services by articulating new patterns of collaborative working, namely, organisational values, beliefs and ideas that fit with the Sri Lankan public service context.

Originality/value

In responding to high magnitude healthcare emergencies, the flexibility of a collaborative networked ICS hierarchy enables different balances of organisational properties to be incorporated, such as hierarchy and horizontal networking and “patterns” in public service provision.
Auditor switching, lowballing and conditional conservatism: evidence from selected Asian countries
Authors: Kamarudin Khairul Anuar , Islam Ainul , Habib Ahsan , Wan Ismail Wan Adibah
Published: January 2022

Purpose

This paper aims to investigate the effect of auditor switching and lowballing on conditional conservatism, particularly how different types of auditor switching, namely, upward, downward and lateral switching to/from Big 4 and industry specialists, affect earnings quality in the following selected Asian countries: Indonesia, Malaysia, the Philippines, South Korea and Thailand.

Design/methodology/approach

Using conditional conservatism as a proxy for earnings quality, this study hypothesises that upward switching from non-Big 4 to Big 4 auditors, or from non-specialist to specialist auditors, would result in high conditional conservatism, while downward switching would lead to low conditional conservatism. The study further tests whether lowballing provides a viable explanation for reduced earnings conservatism in firms that switch from Big 4 to non-Big 4 auditors, or from specialist to non-specialist auditors.

Findings

The analysis, on a sample of 28,073 firm-year observations from 2007 to 2016, shows that the decision to downgrade auditors leads to lower conditional conservatism in the year of switching, compared with other firms and the pre-switching year. The evidence further shows that, when firms downgrade their auditors, lowballing contributes to a decrease in conditional conservatism in the first year of audit switching. Further, this research finds that switching to specialist auditors will result in increased conditional conservatism, while switching from specialist auditors to non-specialist auditors will result in reduced conditional conservatism.

Practical implications

The findings of this study are useful to investors who are looking to diversify their investment portfolio in developing markets, as evidence about auditor switching and quality of financial reporting may be an important factor in their investment decisions. Downward auditor switches and lowballing could act as red flags to investors in the sense that these events could signal a decrease in conditional conservatism and, hence, quality of earnings.

Originality/value

This research offers new evidence to support the view that management decisions to switch to lower-quality auditors will force newly appointed auditors to acquiesce to clients’ demands for reporting low-quality earnings.
Overcoming organizational politics with tenacity and passion for work: benefits for helping behaviors
Authors: De Clercq Dirk , Shu Chengli , Gu Menglei
Published: January 2022

Purpose

This study unpacks the relationship between employees' perceptions of organizational politics and their helping behavior, by explicating a mediating role of employees' affective commitment and moderating roles of their tenacity and passion for work.

Design/methodology/approach

Quantitative survey data were collected from 476 employees, through Amazon Mechanical Turk.

Findings

Beliefs that the organizational climate is predicated on self-serving behaviors diminish helping behaviors, and this effect arises because employees become less emotionally attached to their organization. This mediating role of affective commitment is less salient to the extent that employees persevere in the face of challenges and feel passionate about working hard.

Practical implications

For human resource managers, this study pinpoints a lack of positive organization-oriented energy as a key mechanism by which perceptions about a negative political climate steer employees away from assisting organizational colleagues on a voluntary basis. They can contain this mechanism by ensuring that employees are equipped with energy-boosting personal resources.

Originality/value

This study addresses employees' highly salient emotional reactions to organizational politics and pinpoints the critical function of affective commitment for explaining the escalation of perceived organizational politics into diminished helping behavior. It also identifies buffering effects linked to two pertinent personal resources.
Effects of demographic and clinical character on differences in self‐care behavior levels with arteriovenous fistula by hemodialysis patients: An ordinal logistic regression approach
Authors: Sousa Clemente Neves , Teles Paulo , Paquete Ana Rita Cabral , Dias Vanessa Filipa Ferreira , Manzini Carlene Souza Silva , Nicole Andressa Garcia , Sousa Rui André Saldanha Santos , de Souza Lara Helk , Ribeiro Olga Maria Pimenta Lopes , Lira Marta Nunes , de Queiroz Frazão Cecília Maria Farias , Ramos Vânia Pinheiro , Leal Luciana , Ribeiro Rita Cássia Helú Mendonça , Magalhães Anna Luiza Pereira , de Sá Basílio Lins Sílvia Maria , Mendonça Ana Elza Oliveira , Delgado Millena Freire , Pressi Maira Maria Trevisan , Pressi Nicole Trevisan , Campos Luís , Campos Tiago , Gonçalves Diana , Ribeiro Edgar , Ozen Nurten
Published: January 2022

Introduction

Hemodialysis (HD) patients should be trained to develop self‐care behaviors in order to prevent and preserve their arteriovenous fistula (AVF). The aim of this study was identifying the factors that affect the levels of self‐care behavior with AVF by HD patients.

Methods

A cross‐sectional study was conducted involving 89 patients.

Results

Self‐care levels were negatively affected by patients' location (Azores) and positively affected by marital status, education, employment, AVF duration, and absence of complications with the AVF. Concerning the management of signs and symptoms, self‐care levels were negatively affected by patients' location. Regarding prevention of complications, self‐care levels were negatively affected by age and marital status and positively affected by marital status, employment, chronic kidney disease etiology, AVF duration, and previous AVF.

Conclusion

Further studies are required in order to confirm whether the considered factors affect levels of self‐care behaviors with AVF, or whether other factors are needed as well.
Staying afloat: The effect of algae contamination on Lake Erie housing prices
Authors: Wolf David , Gopalakrishnan Sathya , Klaiber H. Allen
Published: January 2022

Lake Erie has experienced unprecedented harmful algal blooms since the early 2000s, prompting the 2012 Great Lakes Water Quality Agreement between the United States and Canada, which aims to reduce lake‐wide phosphorous loadings by 40%. Little is known about the economic benefits from this agreement, especially to near lake homeowners. We provide key information on the benefits of harmful algal bloom cleanup by linking housing transactions in 2003 to 2015 from seven Ohio counties bordering Lake Erie with measures of water quality using remote‐sensing images. We further control for endogenous algae production using instrumental variables derived from hydrological processes that link Maumee River runoff to nutrient concentrations in Lake Erie. Using a semiparametric approach, we find the impact of harmful algal blooms on housing prices is spatially limited to properties within 1.2 km of Lake Erie. For the average near lake homeowner, a 1 μg/L increase in algae concentrations is expected to decrease property values by 1.7% ($2205). In aggregate, fulfilling the Great Lakes Water Quality Agreement will provide a yearly benefit of up to $42.9 million, fully covering the current annual expenditure on water quality improvement.
Ablation of microRNAs in VIP+ interneurons impairs olfactory discrimination and decreases neural activity in the olfactory bulb
Authors: Wu Jing , Liu Penglai , Mao Xingfeng , Qiu Fang , Gong Ling , Wu Jinyun , Wang Dejuan , He Miao , Li Anan
Published: January 2022

Aim

MicroRNAs (miRNAs) are abundantly expressed in vasoactive intestinal peptide expressing (VIP+) interneurons and are indispensable for their functional maintenance and survival. Here, we blocked miRNA biogenesis in postmitotic VIP+ interneurons in mice by selectively ablating Dicer, an enzyme essential for miRNA maturation, to study whether ablation of VIP+ miRNA affects olfactory function and neural activity in olfactory centres such as the olfactory bulb, which contains a large number of VIP+ interneurons.

Methods

A go/no‐go odour discrimination task and a food‐seeking test were used to assess olfactory discrimination and olfactory detection. In vivo electrophysiological techniques were used to record single units and local field potentials.

Results

Olfactory detection and olfactory discrimination behaviours were impaired in VIP+‐specific Dicer‐knockout mice. In vivo electrophysiological recordings in awake, head‐fixed mice showed that both spontaneous and odour‐evoked firing rates were decreased in mitral/tufted cells in knockout mice. The power of ongoing and odour‐evoked beta local field potentials response of the olfactory bulb and anterior piriform cortex were dramatically decreased. Furthermore, the coherence of theta oscillations between the olfactory bulb and anterior piriform cortex was decreased. Importantly, Dicer knockout restricted to olfactory bulb VIP+ interneurons recapitulated the behavioural and electrophysiological results of the global knockout.

Conclusions

VIP+ miRNAs are an important factor in sensory processing, affecting olfactory function and olfactory neural activity.
Peripheral giant cell granuloma associated with dental implants: Case‐series
Authors: Abofoul Samar , Hurvitz Ayelet Zlotogorski , Grienstein Osnat Koren‐ , Shuster Amir , Vered Marilena , Edel Jeremy , Kaplan Ilana
Published: January 2022

Purpose

The objectives were to characterize clinico‐pathologically a large series of peri‐implant peripheral giant cell granuloma (PGCG), and investigate the role of foreign material as a possible etiological factor.

Material and methods

The study was retrospective, conducted on peri‐implant specimens submitted for histology between 2005 and 2021.

Results

Three hundred and thirty‐five peri‐implant biopsies were retrieved, of which 52 (15.5%) were PGCG. The study population included 28 females and 24 males, age 35–92 years, mean 61. 51.2% reported bone involvement. The lesion involved the margins of the specimen in 65.3%, recurrence was reported in 46.1%. In 58.8% the implant was removed at the same time the specimen was submitted for histopathological analysis. Small foci of black granular foreign material were observed in 53.8% of cases of which 67.8% were birefringent under polarized light. The foreign material granules were not ingested inside multinucleated giant cells, but were scattered in the stromal compartment.

Conclusions

Peri‐implant PGCG is locally aggressive, with frequent bone involvement and high recurrence rate, resulting in implant loss in the majority of cases. The high recurrence rate may be related to conservative or inadequate surgery. Foreign material although common does not seem to have a role in its development.
Predictive value of serum cholinesterase in the mortality of acute pancreatitis: A retrospective cohort study
Authors: Wei Mei , Xie Xiaochun , Yu Xianqiang , Lu Yingying , Ke Lu , Ye Bo , Zhou Jing , Li Gang , Li Baiqiang , Tong Zhihui , Lu Guotao , Li Weiqin , Li Jieshou
Published: January 2022

Background

Severe acute pancreatitis has a high mortality of 20%–40%, but there is a lack of optimal prognostic biomarker for the severity of acute pancreatitis (AP) or mortality. This study is designed to investigate the relationship between serum cholinesterase (ChE) level and poor outcomes of AP.

Methods

A total of 1904 AP patients were screened in the study, and we finally got 692 patients eligible for analysis. Patients were divided into 2 groups based on serum ChE. The primary outcome was mortality, and multivariable logistic regression analysis for mortality was completed. Additionally, we used receiver operating characteristic (ROC) curve analysis to clarify the predictive value of serum ChE for mortality and organ failure.

Results

Three hundred and seventy eight patients and 314 patients were included in the ChE‐low and ChE‐normal group, respectively. Patients in the ChE‐low group were older (46.68 ± 12.70 vs. 43.56 ± 12.13 years old, p = .001) and had a lower percentage of man (62.4% vs. 71.0%, p = .017) when compared to the ChE‐normal group. Mortality was significantly different in two groups (10.3% vs. 0.0%, p < .001). Moreover, organ failure also differed significantly in two groups (46.6% vs. 8.6%, p < .001). Decreased ChE level was independently associated with mortality in acute pancreatitis (odds ratio: 0.440; 95% confidence interval, 0.231, 0.838, p = .013). The area under the curve of serum ChE was 0.875 and 0.803 for mortality and organ failure, respectively.

Conclusions

Lower level of serum ChE was independently associated with the severity and mortality of AP.
From Shared Meals to Interreligious Conversations
Authors: Schlenker Lea
Published: January 2022

This article describes three levels of interreligious dialogue today and observes a lack of exchange between these levels. For the future of interreligious dialogue, it proposes to link the theory and practice of interreligious dialogue more closely, that is, to interrelate academic reflections and actual interreligious encounter. Taking up the term “hospitality,” the author shows that, while the notion of interreligious hospitality plays a key role in comparative theology, the concrete practice of hospitality is rarely used as a resource for theological reflection. Consequently, the article refers to the practice of hospitality at the table and provides some starting points for interreligious conversations evolving around shared meals. Based on the notion of “embodiment,” it points to the central role of theological reflection of everyday life and to the potential of interreligious dialogues as a tool and resource in a pluralistic, quickly changing world.
A Jewish Perspective on the Work of the World Council of Churches in Jewish–Christian Relations
Authors: Polish Daniel F.
Published: January 2022

The article takes note of the recent re‐establishment of relations between the World Council of Churches and the International Jewish Committee on Interreligious Consultations, the organized Jewish community’s official representative for international interreligious dialogue. It examines the asymmetries between the two bodies and explores the significant features that will pose challenges to that relationship, such as the different natures of the Jewish and Christian communities and the impact of the constituencies of the two organizations on their respective positions on the Israeli–Palestinian conflict.
The Holy and Great Council of the Orthodox Church and Its Interreligious Dialogue Approach
Authors: Christodoulakis Ioannis
Published: January 2022

The main purpose of this article is to emphasize the role of the modern Orthodox Church in interreligious dialogues, focusing on the texts of the Holy and Great Synod of the Orthodox Church of 2016 in Crete. Moreover, at the beginning, reference is made to various examples from the history of the church that underline the inseparable unity and historical continuity of tradition and present, as the Orthodox Church has never ceased to be in dialogue with other religions. Then, the article analyzes the main positions of the Holy and Great Synod that concern interreligious dialogue and highlights obstacles and concerns that arise from the dialogue. Finally, it emphasizes the need for interfaith dialogue in the years of late modernity, as religions can work together to help address global problems such as ecological destruction, war, and poverty.
Progressive Secular Sindhi Sufism in the Making of Decolonial Islamic Thinking in Pakistan
Authors: Wassan M. Rafique
Published: January 2022

This study, informed by anthropology, introduces the political modernist imagination of the Sindhi Sufi tradition in postcolonial Pakistan. The central argument of the article is premised on the discussion and analysis of the progressive political agency of the Sindhi Sufi tradition enacted by the Sindhi intelligentsia that stands out against the exclusivist process of Islamization in Pakistan. Crucially, the article brings out the case study of G. M. Syed (d. 1995), a prominent political figure and founder of modern Sindhi nationalism in Pakistan. His intellectual political project of Sufism in postcolonial Pakistan has formed a keystone category that counters the political Islam of Mullah, or theocratic political Islamism. Arguably, G. M. Syed’s political work offers a dialogical potential of Sufi Islam that has a vital role to play in the formation of an inclusive, tolerant, and peaceful society in Pakistan and globally. The article informs progressive secular imagination inspired by the Sufi tradition in Muslim cultural contexts.
World(‐)Systems, West Africa, and the Global Middle Ages
Authors: Abney Graham
Published: January 2022

Though West Africa and West African gold is generally acknowledged to have played a critical role in the high and later medieval world economy, the full extent of the region's global influence remains understudied in Global Middle Ages scholarship. This is not a new development but instead a continuation of a trend begun with the development of world systems theory, a key methodological paradigm used in the production of Global Middle Ages scholarship. By tracing the development of world systems theory and contextualizing it in historiography of West Africa and the Latin West, this essay seeks to offer answers for this analytical lacuna and provide potential strategies for producing more holistic scholarship.
How long should urologists observe patients with prostate cancer after radical prostatectomy? Weibull analysis
Authors: Hasegawa Masanori , Yamada Koichiro , Shigeta Keisuke , Yuzuriha Soichiro , Kawakami Masayoshi , Kim Hakushi , Nakano Mayura , Nitta Masahiro , Kawamura Yoshiaki , Shoji Sunao , Miyajima Akira
Published: January 2022

Objectives

There is no recommended observation time for patients who have undergone radical prostatectomy for prostate cancer. This study was undertaken to determine the postoperative observation time by investigating the hazard rate for prostate‐specific antigen failure and other‐cause death using Weibull analysis.

Methods

We included 612 patients who underwent laparoscopic radical prostatectomy for localized prostate cancer between June 2002 and December 2017. Risk classification was categorized by the D’Amico risk classification, and the patients were divided into three age groups: <60, 60–69 and ≥70 years. The hazard rates at each point were derived using Weibull analysis. The optimal observation time after laparoscopic radical prostatectomy was determined as the intersection point at which the hazard rate of other‐cause death overtakes the hazard rate of prostate‐specific antigen failure.

Results

In all groups classified by age, the hazard rate of other‐cause deaths increased over time. In contrast, the hazard rate of prostate‐specific antigen failure decreased gradually. The ≥70 years age group showed the highest hazard rate. The hazard rate of prostate‐specific antigen failure was highest in the high‐risk group. The patients aged ≥70 and 60–69 years in the low‐risk group were recommended 6 years 6 months and 14 years 8 months, respectively, for observation. The remaining patients were recommended >25 years of postsurgical observation.

Conclusions

The observation time after laparoscopic radical prostatectomy could be estimated by comparing the estimated hazard rates of prostate‐specific antigen failure and other‐cause death based on Weibull analysis. Urologists should pay attention to age and risk classifications for optimal postoperative observation.
Prevention of retinal ganglion cell death by GPR81 agonist treatment
Authors: Vohra Rupali , Tams Anna Luna Mølgaard , Morello Berta Sanz , Mouhammad Zaynab Ahmad , Hannibal Jens , Bergersen Linda Hildegaard , Kolko Miriam
Published: January 2022

Purpose

Retinal ganglion cell (RGC) death is a common characteristic for ocular neurodegenerative diseases such as glaucoma and optic neuropathies. Recently, GPR81 agonist treatment has been identified as a key modulator of mitochondrial function and cell survival. Thus, we aimed to test whether GPR81 agonist treatment likewise promotes RGC survival and energy metabolism in retinal explants and wholemounts from mice.

Methods

Retinal explants were treated with 5 mM of the GPR81 agonist, 3,5‐DHBA, for two, four, 24 & 72 hours, and compared to conditions with no treatment. Additionally, explants were also treated with 15 mM of L‐glutamate to induce toxicity and simultaneously treated with GPR81 agonist. Tissue survival was assessed through lactate dehydrogenase (LDH) viability assays. Retinal ganglion cell survival was measured in murine wholemount retinas through immunohistochemical staining (IHC). Total ATP levels were quantified through bioluminescence assays.

Results

GPR81 agonist treatment increased retinal explant survival after 24 and 72 hours of exposure. No significant effect was seen in retinal explants survival after GPR81 agonist treatment alone for two hours. However, during glutamate‐induced death, supplemented GPR81 agonist treatment increased survival compared to conditions with glutamate toxicity. IHC analysis revealed that GPR81 agonist treatment for two hours promoted RGC survival in retinal wholemounts compared with no treatment. GPR81 agonist treatment also enhanced ATP levels in retinal explants after two, 24, and 72 hr of exposure.

Conclusions

The present study reveals that GPR81 agonist treatment has a neuroprotective effect on specifically RGCs and on glutamate‐induced retinal degeneration. Hence, GPR81 agonist administration may be a potential new strategy to sustain RGCs, ultimately preventing visual disability as a consequence of RGC death.
Pinosylvin extract Retinari™ sustains electrophysiological function, prevents thinning of retina and enhances cellular response to oxidative stress in NFE2L2 knock‐out mice
Authors: Tamminen Toni , Koskela Ali , Toropainen Elisa , Gurubaran Iswariyaraja Sridevi , Winiarczyk Mateusz , Liukkonen Mikko , Paterno Jussi J. , Lackman Petri , Sadeghi Amir , Viiri Johanna , Hyttinen Juha M. T. , Koskelainen Ari , Kaarniranta Kai
Published: January 2022

Purpose

Chronic oxidative stress eventually leads to protein aggregation in combination with impaired autophagy, which has been observed in age‐related macular degeneration (AMD). We have recently developed a dry AMD mice model with a nuclear factor‐erythroid 2‐related factor‐2 (NFE2L2) knock‐out (KO). Pinosylvin, a polyphenol abundant in bark waste, improves retinal pigment epithelial cell (RPE) cell viability in vitro. Therefore, one can estimate that pinosylvin slow down the progression of dry AMD.

Methods

We investigated the effects of commercial natural pinosylvin extract, Retinari™, on the electroretinogram, optical coherence tomogram, autophagic activity, antioxidant capacity, and inflammation markers. Wild type (WT) and NFE2L2 KO mice were raised in 12:12 until the age of 14.8 ± 3.8 months. They were fed with either regular or Retinari™ chow (50–250 mg/kg/day of pinosylvin) for 10 weeks before the assays.

Results

Retinari™ treatment preserved significant retinal function in scotopic and photopic ERG and prevented thinning of the retina in the NFE2L2 KO mice. The NFE2L2 KO mice showed reduced ubiquitin‐tagged protein accumulation in addition to upregulation of the antioxidant enzymes superoxide dismutase 1 and catalase. Furthermore, the treatment seemed to reduce inflammation in NFE2L2 KO mice by causing a climb in the concentration of complement factor H.

Conclusions

Our results demonstrate a strong protective effect of Retinari™ on the AMD disease model. We believe that pinosylvin in the Retinari™ elicits the positive effects. Thus, pinosylvin could potentially lower the risk of AMD onset and slow down its progression for which clinical trials with the compound are highly anticipated.
Oxidative stress and mitochondrial damage evoke complement component C5 activation independent of component C3 in dry age‐related macular degeneration like NFE2L2/ PGC‐1α ‐/‐ mouse model
Authors: Gurubaran Iswariyaraja Sridevi , Heloterä Hanna , Marry Stephen , Koskela Ali , Hyttinen Juha M. T. , Paterno Jussi J. , Urtti Arto , Chen Mei , Xu Heping , Kauppinen Anu , Kaarniranta Kai
Published: January 2022

Purpose

Aging‐associated chronic oxidative stress and inflammation are known to be involved in various diseases, e.g. age‐related macular degeneration (AMD). Previously, we reported elevated oxidative stress, dysfunctional mitophagy and the accumulation of detrimental oxidized materials in the pigment epithelial (RPE) cells of dry AMD‐like nuclear factor erythroid 2‐related factor 2, and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (NFE2L2/PGC1α) in a double knockout (dKO) mouse model. In this study, we show that mitochondrial‐derived oxidative stress leads to a buildup of complement component C5a, whereas the complement component C3a remains unaffected.

Methods

Immunohistochemical stained retina samples from one‐year‐old NRF2/PGC1α ‐/‐ and age‐matched wild‐type mice were used for confocal microscopy analysis.

Results

Immunohistochemical analysis of pathogen recognition receptors (PRRs) revealed an increase in levels of Toll‐like receptors 3 (TLR3) and 9 (TLR9), while those of NOD‐like receptor 3 (NLRP3) were decreased in NFE2L2/PGC1α ‐/‐ retina. Further analysis showed a significant increase in complement component C5a independent of component C3, tightly regulated by complement factor H (CFH). Interestingly, we found that thrombin, a serine protease enzyme, was involved in enhancing the terminal pathway producing C5a, independent of C3. We also detect an increase in primary acute phase C‐reactive protein (CRP) and receptor for advanced glycation end products (RAGE) in NFE2L2/PGC1α ‐/‐ retina.

Conclusions

Our study reveals previously unknown thrombin mediated C3 independent activation of C5a in the dry AMD like retina of NRF2/PGC1α double knockout mice model.
p38/MAPK is required for protein aggregate formation and removal by autophagy upon proteasome dysfunction
Authors: Koskela Ali , Ruuth Johanna , Felszeghy Szabolcs , Kaarniranta Kai
Published: January 2022

Purpose

Age‐related macular degeneration (AMD) can be classified as an aggregation disease where cellular protein waste starts to accumulate in the retinal pigment epithelial (RPE) cells. Decline of autophagy and dysfunction of proteasomes have been identified as one the main reasons for the eventually detrimental protein aggregation. p38/mitogen‐activated protein kinases (MAPK) seem to play a regulatory role in autophagy. However, the function of p38/MAPK in proteasome dysfunction remains unveiled.

Methods

ARPE‐19 cells were treated with proteasome inhibitor MG‐132 (5 µM) to create a need for autophagosomal removal of protein waste. Simultaneously, commercial p38/MAPK inhibitor PD169316 (5 µM) were introduced to the cells to study it’s role in autophagy regulation. Autophagy flux was inhibited with Bafilomycin A1 (50 nM). Western blot for ubiquitin (marker of degradation‐destined proteins), p62 (protein aggregation marker) and LC3 (autophagosome marker) was performed. Similarly, immunocytochemistry of ubiquitin, p62 and LC3 to reveal their expression levels and cellular localization was conducted.

Results

Proteasome inhibition resulted strong accumulation of ubiquitin‐tagged proteins, protein aggregates (p62) and autophagosomes (LC3‐II). p38/MAPK inhibition upon proteasome dysfunction blocked aggregate formation as p62 remained at basal level. Furthermore, despite the need for autophagosomal removal of protein waste due to proteasome inhibition, p38/MAPK inhibitor treated cells did not show increased autophagy. Immunocytochemistry revealed spread of ubiquitin‐ and p62‐tagged proteins throughout the cytosol upon p38/MAPK inhibition, autophagy‐related perinuclear accumulation of protein aggregates was not observed.

Conclusions

p38/MAPK inhibition seemed to prevent protein aggregate formation upon proteasome inhibition and thereby autophagic degradation. Securing correct function of p38/MAPK may be a potential therapy target for aggregation diseases such as AMD.
The use of virtual three‐dimensional anatomy software in teaching ophthalmology
Authors: Scantling‐Birch Yarrow , Naveed Hasan , Okorie Michael , Rajak Saul
Published: January 2022

Purpose

Medical education is changing at both the undergraduate and postgraduate level. There are less hours dedicated to the basic sciences, especially anatomy. These changes threaten to marginalise ophthalmology education, which relies heavily on basic science knowledge for clinical application. Technology‐enhanced learning (TEL) can assist in the efficient knowledge transfer of basic ophthalmic knowledge. Our study scoped the literature and evaluated the use of a three‐dimensional (3D) virtual anatomy software to learn clinical and surgically relevant ocular anatomy at the undergraduate level.

Methods

A literature search was conducted of the following databases: Embase, Medline and Cochrane Library. A national, cross‐sectional study was conducted via webinar teaching with 36 undergraduate medical students. A 60‐min lesson was used to teach ocular anatomy using a blended learning approach with novel virtual anatomy software (BioDigital, USA) and a didactic Powerpoint (Microsoft, USA) lecture. Anatomical knowledge gain was measured using validated multiple‐choice questions and a surgical video quiz. Student perceptions using questionnaires were measured before and after the online teaching session.

Results

The literature showed a paucity of studies validating 3D virtual anatomy software in ophthalmology education. Software identified in the search included BioDigital, Essential Anatomy, Complete Anatomy and Visible Body. A significant improvement in mean knowledge gain was observed for both clinical and surgical quizzes after the use of BioDigital (17.9%, p < 0.0001). Significant confidence gain with respect to ocular anatomy was observed after the blended teaching session (40%, p < 0.0001). 100% of students enjoyed and agreed that 3D virtual anatomy software is an effective method of teaching ocular anatomy. 70% stated they will integrate digital anatomy software with their future ophthalmology learning, and 60% agreed the software could replace traditional teaching methods.

Conclusions

The declining importance given to ophthalmology teaching sets the tone for ophthalmic knowledge amongst graduating doctors and specialist trainees. TEL using 3D virtual anatomy software is an innovative, time‐efficient and student‐friendly teaching adjunct for ocular anatomy.
Diabetic db/db mouse presents intravitreal vessels protruding from the optic disc
Authors: Bonet Aina , Pampalona Judit , Segarra Irene , Ruberte Jesús
Published: January 2022

Purpose

It is widely known that the main lesions that occur in diabetic retinopathy are oedema and neovascularization, but, still, there is not an accurate model that can reproduce both. In this study, we used a well‐established model of type 2 diabetes, the db/db mice, to assess the presence of retinal oedema and/or neovascularization.

Methods

12 weeks old db/+ and db/db mouse (n=8) were used in this study. We studied blood retinal barrier integrity by means of vascular leakage in fundus angiography by fluorescein injection and immunocytochemistry against albumin. Furthermore, we used transmitted electron microscopy to observe tight junction status. Finally, to visualize and assess retinal vascularization, eye fundus angiography and histology were performed.

Results

Fluorescein and albumin remained inside the vessels proving the integrity of blood retinal barrier, in both controls and db/db retinas. However, retinal fundus angiography revealed that 50% of db/db mice presented intravitreal vessels protruding from the optic disc. Moreover, histological analysis showed a significant increment in the number of vessels in the db/db vitreous compared to db/+, in accordance with the angiography findings.

Conclusions

Retinal fundus angiography and histological analysis showed the presence of intravitreal vessels in diabetic db/db mice, suggesting the existence of a current angiogenic process. However, apparently, twelve old week’s db/db mice did not show signs of retinal oedema.
Epithelial lip mucosa transplant re‐populates corneal anterior surface. An ex vivo study
Authors: Gerasimov Maxim , Ostrovskiy Dmitriy , Shatskikh Anna , Borzenok Sergey , Malyugin Boris
Published: January 2022

Purpose

To establish a new ex vivo model and study the labial mucosal epithelium grafting as a potential approach for cornea re‐epithelization in patients with bilateral limbal stem cell deficiency.

Methods

Four human donor corneal buttons were collected from the Eye tissue bank in corneal cold storage solution and left at 4°C for 32–52 days. Labial oral mucosa strips were dissected from four patients during fornix reconstruction after they signed an informed consent. The labial mucosa epithelial graft was prepared by dissecting substantia propria. The resulted graft was sutured near the limbus of the corneal button with running sutures (construct). Each construct was cultured under the standard conditions with the concave side upwards. After 21 days of culture, constructs were removed, washed and fixed. First half of the constructs were stained with hematoxylin and eosin (HE). 5 um crosscut cryo‐sections of the second half were stained with anti‐ keratin 13, 19, and p63, and paired secondary fluorescent antibodies. Nuclei were counterstained with Hoechst. Sections were accessed and photographed.

Results

After the culture, all constructs were integral with the attached epithelium graft and non‐loosened sutures. The graft became slightly flattened and brighter. HE staining demonstrated absence of the native cells in donor corneas. The labial mucosa grafts were located on the surface of the Bowman's membrane (BM) at the cornea periphery. Epithelial outgrowths were found to be transit from the labial mucosa graft to the BM. Cellular outgrows of the constructs had positive staining for keratin 13 and 19. Few cells were p63‐positive in nuclei.

Conclusions

In the study, a new ex vivo model composed of processed human donor cornea and live human donor labial mucosal epithelium graft was successfully established. The study confirmed the consistency of the new approach for corneal re‐epithelization by transplantation of an oral mucosal epithelial graft.
Endothelial cell viability after DMEK graft preparation
Authors: Miron Alina , Sajet Anita , Groeneveld‐van Beek Esther A , Kok Jet , Dedec Mehtap , de Jong Maloeke , Melles Gerrit R.J. , Oellerich Silke , van der Wees Jacqueline
Published: January 2022

Purpose

To evaluate the effect of graft preparation and organ‐culture storage on endothelial cell density (ECD) and viability of Descemet membrane endothelial keratoplasty (DMEK) grafts.

Methods

DMEK grafts (n = 27) were prepared at Amnitrans EyeBank Rotterdam from 27 corneas (15 donors) that were eligible for transplantation but could not be allocated due to the Covid‐19‐related cancellation of elective surgeries. Cell viability (by Calcein‐AM staining) and ECD of 5 grafts originally scheduled for transplantation, were evaluated on the originally planned surgery day, whereas 22 grafts from paired donor corneas were evaluated either directly post‐preparation or after 3–7 days of storage. ECD was analyzed by light microscopy (LM ECD) and Calcein‐AM staining (Calcein‐ECD)

Results

Light microscopy (LM) evaluation of all grafts showed an unremarkable endothelial cell monolayer directly after preparation. However, median Calcein‐ECD for the 5 grafts initially allocated for transplantation was 18% (range 9–73%) lower than median LM ECD. For the paired DMEK grafts, Calcein‐ECD determined by Calcein‐AM staining on the day of graft preparation and after 3–7 days of graft storage showed a median decrease of 1% and 2%, respectively. Median percentage of central graft area populated by viable cells after preparation and after 3‐7 days of graft storage was 88% and 92%, respectively.

Conclusions

Cell viability of most of the grafts will not be affected by preparation and storage. Endothelial cell damage may be observed for some grafts within hours after preparation with insignificant additional ECD changes during 3–7 days of graft storage. Implementing an additional post‐preparation step in the eye bank to evaluate cell density before graft release for transplantation may help to reduce postoperative DMEK complications
A multicentre randomised trial comparing the efficacy and safety of Remogen® Omega versus Cationorm® in the treatment of patients suffering from dry eye
Authors: Pisella Pierre‐Jean , Marsousi Niloufar , Doan Serge , Douat Julien , Girard Brigitte , Cochener Béatrice , Christophe Baudouin
Published: January 2022

Purpose

Remogen® Omega is the first omega‐3 containing drop indicated in the treatment of dry eye syndrome (DES). It contributes to the maintenance of the physicochemical balance of the tear film and facilitates eye recovery. The aim of this study was to compare the efficacy and safety of Remogen® Omega and Cationorm® in patients with moderate to severe DES.

Methods

This was a randomised controlled, masked‐observer multicentre trial. Patients used 4 drops of Remogen® Omega or Cationorm® per day for 3 months. The primary efficacy endpoint was the change from baseline at D28 in the score of ocular surface staining with fluorescein (OSSF) using Oxford scale. Other efficacy parameters included the score of ocular surface staining with lissamine green, Schirmer I test, tear film break‐up time, ocular surface disease index score, symptoms intensity and frequency, treatment comfort and overall efficacy at D28 and D84. Safety was evaluated based on intraocular pressure, best‐corrected visual acuity, general external examination, slit lamp examination and occurrence of adverse events.

Results

In total, analysed intent‐to‐treat population consisted on 23 patients who were randomly assigned to Remogen® Omega (n = 10) or Cationorm® (n = 13) arms. Patients were in average 67.1 years old and 91.3% were women. Demographics were balanced between the two arms. Mean (standard deviation) reductions of ‐1.0 (1.1) and ‐0.7 (1.7) were observed for OSSF scores in Remogen® Omega (p = 0.01) and Cationorm® (p = 0.05) arms at D28 versus baseline, respectively. Similarly, improvements were observed in both treatment groups for other efficacy criteria. The only between‐arm difference detected was the duration of blur vision which was longer after administration of Remogen® Omega compared with Cationorm® at D28 and D84 (p < 0.01). Both treatments were considered as comfortable and satisfying by patients and investigators. No statistically significant between‐arm differences were observed for safety parameters and no safety issues were raised.

Conclusions

Observed results suggest that both treatments have a beneficial effect on DES symptoms alleviation.