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Changyan Zi, Qun Huang, Yuan Ren, Huan Yao, Tingting He, Yongxiang Gao
Published: 30 December 2021
by BMJ
Abstract:
Introduction Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disorder that primarily affects the exocrine glands such as the lacrimal and the salivary glands. Dry eye disease (DED) is one of the most prevalent manifestations of pSS and is usually classified into aqueous-deficient dry eye and evaporative dry eye. Sjögren’s syndrome dry eye (SSDE) is generally described as aqueous-deficient dry eye. However, as the leading pathophysiological mechanism of evaporative dry eye, meibomian gland dysfunction (MGD) also has influence on SSDE, which has been shown in recent studies. We speculate that SSDE is more than just an aqueous-deficient dry eye. While no related systematic review and meta-analysis has been published, the present study is designed to derive a better understanding of the association between MGD and SSDE. Methods and analysis The Preferred Reporting items for Systematic Reviews and Meta-Analysis for Protocols 2015 statement was used to prepare this protocol. PubMed, Embase, Web of Science, Cochrane Database, China National Knowledge Infrastructure and Wan Fang Database will be searched from their inception to 31 October 2021, with restrictions to publications in English or Chinese. Two reviewers will independently carry out data extraction and quality assessment. The diagnosis of pSS will meet the standard diagnostic criteria, such as American College of Rheumatology/European League against Rheumatism Classification Criteria (ACR/EULAR) or American-European Consensus Group Classification criteria (AECG), and the definition of MGD and DED will differ between studies. The quality of included studies will be judged using the Newcastle-Ottawa Quality Scale. We will carry out this meta-analysis using RevMan V.5.4.1. The incidence of MGD in patients with SSDE will be indicated as OR with 95% CI. Ethics and dissemination Ethical approval is not required as this meta-analysis is performed based on published studies and does not involve human participants. The results will be published in a peer-reviewed journal. PROSPERO registration number CRD42021226017.
Weiyu Qi, Yu Xia, Xin Li, Jianzhong Cao
Published: 23 December 2021
Abstract:
Background: Methotrexate and leflunomide are classic treatments for rheumatoid arthritis (RA), however, which is the best choice for patients of RA is still an important question clinically, and this meta-analysis is used to systematically evaluate and compare their efficacy and safety. Methods: We searched PubMed, Cochrance Library, Embase, SinoMed, China National Knowledge Infrastructure, China Science and Technology Journal Database, WanFang Data databases. The retrieval time was from the establishment to September 7, 2021. Literature screening, data extraction, and quality assessment were performed according to the Cochrane risk of bias tool. Meta-analysis of the included studies was performed using RevMan 5.3 software and Stata 12.0 software. Results: The clinical efficacy and safety of leflunomide and methotrexate are evaluated by American College of Rheumatology (ACR)20/50/70, DAS28, total effective rate, adverse reaction rate, morning stiffness, swollen joint count, tender joint count, erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor. Conclusion: The results of this meta-analysis will provide reliable evidence clinical efficacy and safety for RA. More high-quality randomized controlled trials are still needed to provide more reliable evidence for the treatment of RA. PROSPERO number: CRD42021270980
Joanne Pransky
Industrial Robot: An International Journal, Volume 49, pp 1-5; https://doi.org/10.1108/ir-10-2021-0233

Abstract:
Purpose: The purpose of this paper is to provide a “Q&A interview” conducted by Joanne Pransky of Industrial Robot Journal as a method to impart the combined technological, business and personal experience of a prominent, robotic industry engineer-turned entrepreneur regarding his pioneering efforts in starting robotic companies and commercializing technological inventions. The paper aims to discuss these issues. Design/methodology/approach: The interviewee is Jack Morrison, CEO and Co-Founder, Scythe Robotics. Morrison shares how he and his co-founders started this innovative company, the milestones and challenges he’s faced and his long-term goals. Findings: Morrison received Bachelor of Arts degrees in Computer Science and German from Bowdoin College. He attended The George Washington University as a PhD student in Computer Science but left to co-found Replica Labs, a producer of software that turns any mobile phone into a high-quality 3D scanner. Morrison served as Replica’s CTO until it was acquired by Occipital in 2016, where he stayed on as a computer vision engineer until co-founding Scythe Robotics in April 2018. Originality/value: While mowing his lawn in Colorado, Jack Morrison had a sudden insight: what if he could apply the latest robotics technology he was so familiar with to the challenge of commercialized landscaping? In 2018, Morrison teamed up with Replica Labs co-founder Isaac Roberts and Occipital’s Davis Foster, to create Scythe Robotics, a company that builds autonomous robotics solutions for the $105bn commercial landscaping industry. In June 2021, Scythe Robotics emerged from stealth with over $18m in funding with its first commercial product: a transformational, all-electric, fully autonomous mower designed to keep crew productivity high while also increasing the quality of cut and worker safety. The machine features eight high dynamic range cameras and a suite of other sensors that enable it to operate safely in dynamic environments by identifying and responding to the presence of humans, animals and other potential obstacles. Simultaneously, the machine captures valuable property and mower performance data, which helps landscape contractors improve workflow, identify upsell opportunities, schedule more efficiently and manage labor costs. The all-electric powertrain is quiet, emissions-free and radically more reliable than gas-powered manual mowers. Scythe Robotics’ business model is based on Robot as a Service. Instead of buying machines outright, customers are billed by acres mowed. This massively reduces contractors’ expenses and eliminates substantial costs. Scythe Robotics is headquartered in Boulder, Colorado and has offices in Vero Beach, FL and Austin, TX. Scythe is the recipient of the 2020 ALCC (Associated Landscape Contractors CO) Innovation Winner and the 2021 Colorado OEDIT Advanced Industries Grantee.
Atef S. Abdel-Razek, Nesreen M. Abd El-Ghany, Mohamed A. Gesraha, Tarek A. Elewa, Abdelhameed Moussa
Arab Journal of Plant Protection, Volume 39, pp 317-322; https://doi.org/10.22268/ajpp-39.4.317322

Abstract:
Abdel-Razek, A.S., N.M. Abd El-Ghany, M.A. Gesraha, T.A. Elewa and A. Moussa. 2021. Susceptibility Assessment of Two Tomato Hybrids Against Tuta absoluta Infestation Under Greenhouse Conditions. Arab Journal of Plant Protection, 39(4): 317-322. https://doi.org/10.22268/AJPP-39.4.317322 Tuta absoluta is a major insect pest which attack tomato plant varieties in Egypt. Several control attempts were carried out to avoid major crop losses by heavy application of chemical insecticides. The aim of the present study is to assess the susceptibility of infestation of T. absoluta of two tomato varieties (Shifa and Savera F1 hybrids) under greenhouse conditions. The tomato varieties were planted in two plantation periods at the district of Kom Hamada, El-Nubaria province, El-Behira Governorate. The susceptibility tests were done by random counting of leaf samples for the presence of T. absoluta mines and larvae. Both tomato varieties showed almost the same T. absoluta infestation level. Moreover, yield assessment was carried out for the two plantation periods by taking the average fruit weight yield (Kg/acre). The tomato yield results showed that Savera F1 hybrid tomato had higher yield compared to Shifa F1 hybrid variety, but such difference was not significant, However, the yield difference of both vireties between the two planting dates was significant. Keywords: Tomato, Tuta absoluta, susceptibility, leaf-mine, larvae, yield.
William Baker
Nineteenth-Century Travels, Explorations and Empires pp 207-221; https://doi.org/10.4324/9781003113447-12

Abstract:
George Jacob Holyoake is usually associated with radical politics, journalism, the co-operative movement, atheism, and prosecution for blasphemy, rather than travel writing. He visited the United States and Canada twice, the ostensible reason being to study emigration and problems of colonisation. The result of the first visit was a series of articles in the Manchester Co-operative News which formed the foundation for Among the Americans and a Stranger in America published in Chicago in 1881. For Holyoake the United States was a country bristling with possibilities, especially for emigrants. It was a country 'unhampered by prelate or king', unlike Canada where 'a visitor from the United States does not travel thirty miles into Canada without feeling that the shadow of the Crown is there'. The United States contained 'acres of plantations' which 'lie unenclosed between the beautiful houses, where a crowd of wanderers might rest unchallenged, and watch mountain, river, and sky'.
Erin Shillington
Published: 13 November 2021
Abstract:
New Zealanders have a proud tradition of living close to nature (clean and green). This high interface with nature in traditional New Zealand dwellings is referred to as the “quarter-acre dream” by Mitchell (1972). However, the recent intensification of New Zealand cities has resulted in higher-density, multi-unit dwellings that have little interface with nature. As Auckland alone is expected to require an additional 400,000 homes within the next 30 years, a medium-density housing model that has a high nature-dwelling interface is potentially useful in reducing urban sprawl. In contrast, many Japanese houses are effectively integrated with nature. The number of case studies available through books, journals and on websites suggests that it is possible to group these dwellings under the heading “garden houses”. For the purpose of this research, the term “Japanese Garden House” refers to Japanese houses in which the garden is an integral part of the architecture, as opposed to a separate spatial entity. New Zealand walk-up apartments are analysed to show how this New Zealand housing model relates to nature in addition to revealing typical design elements. Thereafter, the adaptation of the Japanese Garden House for the New Zealand context is proposed as a mechanism to further connect urban dwellings with nature, thus increasing the interface between nature and inhabited space. The significant benefits this mechanism provides, including a positive effect on psychological and physiological wellbeing, are discussed. In order to adapt the features of Japanese Garden Houses to the New Zealand context, a detailed analysis of Japanese Garden Houses is undertaken to reveal design principles and strategies that characterise this type of dwelling. The analysis is limited to houses built in the last 15 years. An investigation, through design, is carried out to determine whether the Japanese Garden House models could be used to reconnect walk-up apartments with nature. The investigation is tested on a typical Auckland site. In a case study design, principles and strategies discovered through analysis of Japanese Garden Houses are applied and, adapted to fit walk-up apartments and the New Zealand context. The outcome is a valuable new New Zealand housing model and a set of guidelines presented as a matrix including key principles, strategies and a menu of solutions with the potential to be applied more broadly by other architects, developers and city councils.
Erin Shillington
Published: 13 November 2021
Abstract:
New Zealanders have a proud tradition of living close to nature (clean and green). This high interface with nature in traditional New Zealand dwellings is referred to as the “quarter-acre dream” by Mitchell (1972). However, the recent intensification of New Zealand cities has resulted in higher-density, multi-unit dwellings that have little interface with nature. As Auckland alone is expected to require an additional 400,000 homes within the next 30 years, a medium-density housing model that has a high nature-dwelling interface is potentially useful in reducing urban sprawl. In contrast, many Japanese houses are effectively integrated with nature. The number of case studies available through books, journals and on websites suggests that it is possible to group these dwellings under the heading “garden houses”. For the purpose of this research, the term “Japanese Garden House” refers to Japanese houses in which the garden is an integral part of the architecture, as opposed to a separate spatial entity. New Zealand walk-up apartments are analysed to show how this New Zealand housing model relates to nature in addition to revealing typical design elements. Thereafter, the adaptation of the Japanese Garden House for the New Zealand context is proposed as a mechanism to further connect urban dwellings with nature, thus increasing the interface between nature and inhabited space. The significant benefits this mechanism provides, including a positive effect on psychological and physiological wellbeing, are discussed. In order to adapt the features of Japanese Garden Houses to the New Zealand context, a detailed analysis of Japanese Garden Houses is undertaken to reveal design principles and strategies that characterise this type of dwelling. The analysis is limited to houses built in the last 15 years. An investigation, through design, is carried out to determine whether the Japanese Garden House models could be used to reconnect walk-up apartments with nature. The investigation is tested on a typical Auckland site. In a case study design, principles and strategies discovered through analysis of Japanese Garden Houses are applied and, adapted to fit walk-up apartments and the New Zealand context. The outcome is a valuable new New Zealand housing model and a set of guidelines presented as a matrix including key principles, strategies and a menu of solutions with the potential to be applied more broadly by other architects, developers and city councils.
Sunghoon Hong, Asgar Ahadpour Dodaran, Taeyoon Kim, Jongyeong Kim, Van Men Huynh, Jooyong Lee, Soonchul Kwon
Journal of Coastal Research, Volume 114, pp 524-528; https://doi.org/10.2112/jcr-si114-106.1

Abstract:
Hong, S.; Dodaran, A.A.; Kim, T.; Kim, J.; Huynh, V.M.; Lee, J., and Kwon, S., 2021. Variation of irregular waves passing over an Artificial Coral Reef (ACR). In: Lee, J.L.; Suh, K.-S.; Lee, B.; Shin, S., and Lee, J. (eds.), Crisis and Integrated Management for Coastal and Marine Safety. Journal of Coastal Research, Special Issue No. 114, pp. 524–528. Coconut Creek (Florida), ISSN 0749-0208. To investigate the variation of irregular waves due to an Artificial Coral Reef (ACR), two-dimensional experiments on the wave steepness, wave period, and relative submergence were conducted. The results for the wave transmission coefficient under ACR installation indicated that the wave steepness and period conditions are closely related to wave attenuation, which has similar trends for general coastal structures, even under irregular wave conditions. Additionally, the total spectral energy decreased gradually, whereas an inconsistent peak-energy decrement occurred with a wave steepness of 0.032, which was expected because of spectral energy redistribution due to ACR. The correlation between the relative submergence and spectral energy was investigated via a spectral analysis. In high frequency domain (1.25∼2.25f/fp), the composition ratio of spectral energy increased with larger relative submergence, whereas opposite trend was observed in low frequency domain (0.25∼0.75f/fp). The main findings of this study can provide basic knowledge for understanding irregular wave variation over the ACR.
Peter Tugwell, David Tovey
Published: 1 September 2021
Journal of Clinical Epidemiology, Volume 137; https://doi.org/10.1016/j.jclinepi.2021.08.005

The publisher has not yet granted permission to display this abstract.
Corrigendum
, Johanna Elizabeth Chesham, Raphaelle Winsky-Sommerer, Nicola Jane Smyllie, Michael Harvey Hastings
Published: 5 August 2021
Frontiers in Neuroscience, Volume 15; https://doi.org/10.3389/fnins.2021.740799

Abstract:
A Corrigendum on Circadian Chimeric Mice Reveal an Interplay Between the Suprachiasmatic Nucleus and Local Brain Clocks in the Control of Sleep and Memory by Maywood, E. S., Chesham, J. E., Winsky-Sommerer, R., Smyllie, N. J., and Hastings, M. H. (2021). Front. Neurosci. 15:639281. doi: 10.3389/fnins.2021.639281 In the original article, there was an error in assignment of mouse strain identity. A correction has been made to **Materials and Methods**, **Animals and housing**, **Paragraph number 1**: All experiments were conducted in accordance with the UK Animals (Scientific Procedures) Act of 1986, with local ethical approval (MRC LMB, AWERB). Drd1a-Cre mice (Tg(Drd1-cre)EY266Gsat/Mmucd, RRID:MMRRC_030779-UCD) were purchased from the GENSAT project (Rockefeller University, New York, United States), through the Mutant Mouse Regional Resource Centers (MMRRC, United States). ROSA-YFP mice were provided by Dr. A. McKenzie (MRC LMB). Temporally chimeric mice were created by crossing Drd1a-Cre, ROSA26-EYFP mice with homozygotes for the floxed CK1ε Tau allele (Smyllie et al., 2016). All mice expressed the PER2::LUC bioluminescent reporter (Yoo et al., 2005) and had a C57/BL/6J background. This generated four genotypes: CRE-negative, CK1εWT/WT; CRE-positive, CK1εWT/WT; CRE-negative, CK1εTau/Tau (Tau controls); CRE-positive, CK1εTau/Tau (chimera). The first two groups were combined as WT, in light of no differences between them. Males aged 4–6 months old were used to avoid the estrous modulation of activity patterns. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Smyllie, N. J., Chesham, J. E., Hamnett, R., Maywood, E. S., and Hastings, M. H. (2016). Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus. Proc. Natl. Acad. Sci. U. S. A. 113, 3657–3662. doi: 10.1073/pnas.1511351113 PubMed Abstract | CrossRef Full Text | Google Scholar Yoo, S. H., Ko, C. H., Lowrey, P. L., Buhr, E. D., Song, E. J., Chang, S., et al. (2005). A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo. Proc. Natl. Acad. Sci. U. S. A. 102, 2608–2613. doi: 10.1073/pnas.0409763102 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: REM sleep, NREM sleep, electroencephalogram, circadian misalignment, suprachiasmatic nucleus Citation: Maywood ES, Chesham JE, Winsky-Sommerer R, Smyllie NJ and Hastings MH (2021) Corrigendum: Circadian Chimeric Mice Reveal an Interplay Between the Suprachiasmatic Nucleus and Local Brain Clocks in the Control of Sleep and Memory. Front. Neurosci. 15:740799. doi: 10.3389/fnins.2021.740799 Received: 13 July 2021; Accepted: 16 July 2021; Published: 05 August 2021. Edited and reviewed by: Natsuko Tsujino, University of Tsukuba, Japan Copyright © 2021 Maywood, Chesham, Winsky-Sommerer, Smyllie and Hastings. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Elizabeth Susan Maywood, [email protected]; Michael Harvey Hastings, [email protected]
, Boaz K. Karmazyn, Christine A. Waldrip, Mythreyi Chatfield, Mark E. Lockhart
Journal of the American College of Radiology, Volume 18; https://doi.org/10.1016/j.jacr.2021.03.021

The publisher has not yet granted permission to display this abstract.
, , Todd A. Schwartz
Published: 31 May 2021
Arthritis & Rheumatism, Volume 73, pp 919-920; https://doi.org/10.1002/acr.24714

The publisher has not yet granted permission to display this abstract.
F. Natalucci, F. Ceccarelli, T. Colasanti, G. Olivieri, A. I. Celia, C. Barbati, M. Speziali, F. Ucci, C. Pirone, C. Ciancarella, et al.
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 1073.1-1073; https://doi.org/10.1136/annrheumdis-2021-eular.3688

Abstract:
Background: Joint involvement represents one of the most frequent features in patients affected by Systemic Lupus Erythematosus (SLE). This manifestation is characterized by a great heterogeneity in phenotype and severity: the application of more sensitive imaging techniques identified an erosive damage in about 25% of patients (1). This damage has been associated with autoantibodies, such as anti-citrullinated (ACPA) and anti-carbamylated proteins (antiCarP), previously identified in patients Rheumatoid Arthritis (RA) patients. Recently, homocysteinylated alpha 1 antitrypsin (Hcy-1A1AT) has been identified as a new antigenic target of autoantibodies in seronegative RA patients: in detail, anti-homocysteinylated alpha 1 antitrypsin (anti – HATA) antibodies have been identified in 75.7% of patients (2). Objectives: In the present study, we aimed at determining the prevalence of anti – HATA in a cohort of SLE patients. Methods: We evaluated patients affected by SLE according to the 1997 ACR criteria. Demographic, clinical, and laboratory data were collected in a standardized computerized electronically filled form. Each subject underwent peripheral blood sample collection. Hcy-A1AT was obtained by in vitro modification of native A1AT and used as antigens by ELISA to test the presence of anti–HATA in sera obtained from enrolled subjects. Finally, we investigated the presence of ACPA and Rheumatoid Factor (RF) commercial ELISA kits and of anti-CarP (home-made ELISA) by a home-made ELISA in SLE patients’ sera. As control, we enrolled 40 patients affected by Osteoarthritis (OA) and 41 healthy subjects (HS). Results: The present analysis included 88 SLE patients (M/F 6/82 median age 47 years (IQR 17), median disease duration 156 months (IQR 180). Joint involvement was observed in 75 SLE patients (85.2%): in detail, 65 patients referred arthritis and the remaining 10 inflammatory arthralgias. We identified the presence of anti–HATA IgG in 38 SLE patients (43.2%). This prevalence was significantly higher in comparison with OA and HS subjects [15.0% (p<0.001) and 0% (p<0.0001), respectively; Figure 1A]. Focusing on the SLE cohort, no differences were observed between patients with and without joint involvement in anti–HATA IgG prevalence (41.3% versus 34.7%, respectively; p=0.34). However considering SLE patients according to the presence of arthralgia and arthritis, the prevalence of anti-HATA was significantly higher in patients with arthritis in comparison with those patients with arthralgias (46.1% versus 11.1%, p=0.02; figure 1B). Finally, no significant association between anti-HATA and the other tested autoantibodies (RF, ACPA, anti-CarP) was found. Conclusion: We evaluated the prevalence of anti-HATA in a cohort of SLE patients. The prevalence of these autoantibodies was significantly higher in SLE patients than in OA patients and in HS. The association with arthritis suggests a possible role for anti-HATA as biomarkers of SLE-related joint involvement. References: [1]Ceccarelli F. Perricone C. Cipriano E. et al. Joint involvement in systemic lupus erythematosus: From pathogenesis to clinical assessment. Seminar in Arthritis and Rheumatism, 47(1), 53 – 64. [2]Colasanti T. Sabatinelli D. Mancone et al. Homocysteinylated alpha 1 antitrypsin as an antigenic target of autoantibodies in seronegative rheumatoid arthritis patients. Journal of Autoimmunity 2020 Sep;113:102470. Disclosure of Interests: None declared
F. Cacciapaglia, E. De Lorenzis, M. G. Lazzaroni, A. Corrado, M. Fornaro, G. Natalello, F. Montini, A. Altomare, L. Urso, F. P. Cantatore, et al.
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 701.2-702; https://doi.org/10.1136/annrheumdis-2021-eular.3943

Abstract:
Background: Systemic Sclerosis (SSc) is a chronic rheumatic disease characterized by an autoimmune disorder with vasculopathy that leads to an excess in collagen and other extracellular matrix proteins deposition. This process results in progressive fibrotic and vascular damage of skin and visceral organs. According to observational studies conducted in last decades, mean survival of SSc patients had improved with significant changes in causes of death. Objectives: To assess the 10-years survival in a large Italian multicentre cohort of SSc patients in the last decade compared to previous periods published since the 1980s, and to identify features that can justify any change. Methods: We retrospectively analysed all medical records of our longitudinal SSc cohorts, fulfilling 1980 ARA and/or 2013 EULAR/ACR Classification Criteria, with a median (IQR) follow-up of 91.5 (51-120) months from 4 Scleroderma Units since January 2009. All clinical, laboratory and instrumental findings have been recorded and analysed. Survival rate was calculated with Kaplan-Meier curves and log-rank tests, and Cox proportional hazards models were used to identify any predictor. Then, observed SSc survival was compared to those previously published and to that expected in the general population, calculated using official data published on the website United Nation World Population Prospects (www.macrotrends.net/countries/ITA/italy/death-rate). Results: Of 912 SSc patients (91.6% female; mean (SD) age at first non-Raynaud symptom (RS) 51 (15.4) years; median (IQR) disease duration from non-RS 24 (0-84.7) months) diffuse cutaneous involvement was defined in 182 (20%) patients. Anti-centromere and anti-topoisomerase-I were detected in 390 (42.8%) and 302 (33.1%) patients, respectively, while 220 (24.1%) presented antibodies for other extractible nuclear antigens. Prevalent non-Raynaud manifestations were interstitial lung disease detected in 459 (50.3%), digital ulcers in 395 (43.3%) and oesophagopathy in 371 (40.7%) patients, respectively, while other gastrointestinal manifestations were reported in 234 (25.7%) patients. Chronic renal failure was observed in 61 (6.7%) patients and pulmonary arterial hypertension (PAH) was confirmed at right heart catheterization in 38 (4.2%) patients. Three hundred twenty-two (35.3%) patients received immunosuppressant, 215 (23.5%) assumed an endothelin receptor antagonist and/or a 5-phosphodiesterase inhibitor, and 72 (7.9%) were treated with a biologic agent. The global 10-years survival was 89.4%; female gender (HR 0.33, CI95% 0.17-0.67), diffuse cutaneous involvement (HR 2.14, CI95% 1.17-3.91), presence of pulmonary hypertension (HR 2.61, CI95%1.31-5.16) and older age at non-RS (HR 1.1, CI95% 1.06-1.12) affected survival. Furthermore, as compared to previous Italian studies, our cohort showed a significant improvement in rate (see Figure 1). Conclusion: Survival in SSc patients has improved in last 5 decades but still reduced compared to that expected in general population above all 5 years after diagnosis. Early diagnosis, with reduced renal involvement, along with better screening and innovative therapeutic strategies may explain these achievements. Figure 1. Ten-years survival in SSc patients since 2009 (left); comparison of survival across different Italian SSc cohorts (box: current analysis) (right). References: [1]Giordano M, et al. The Journal of Rheumatology. 1986; 13:911-916. [2]Ferri C, et al. Medicine. 2002; 81:139-53. [3]Vettori S, et al. Reumatismo. 2010; 62(3):202-209. [4]Ferri C, et al. Autoimmun Rev. 2014; 13(10):1026-34. Disclosure of Interests: None declared
M. M. Sirufo, F. De Pietro, M. Raggiunti, M. De Martinis, L. Ginaldi
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 1246.1-1246; https://doi.org/10.1136/annrheumdis-2021-eular.2268

Abstract:
Background: Systemic Sclerosis (SSc) is a generalized and systemic autoimmune disease that affects the connective tissue of the skin and internal organs, especially kidneys, heart and lungs [1].Objectives: Numerous data from recent literature confirm the regulatory action of vitamin D on the immune system and, therefore, how a deficit of this micronutrient can lead to alterations in the immune response, as is known to happen in many allergic and autoimmune diseases [2]. We studied the association between vitamin D levels and SSc, evaluating their correlation with the characteristic manifestations of the pathology.Methods: We dosed the serum levels of 25 hydroxy-vitamin D in 42 patients with SSc (average age 64.63 +/-7.33) and 40 healthy controls comparable for sex and age. The diagnosis of SSc was formulated in accordance to 2013 ACR/EULAR criteria. None of the subjects involved in the study took vitamin D products.Results: Patients’ vitamin D levels (26.22+/-9.82 ng/ml), although they tended to be lower than controls (27.80 +/- 16.53 ng/ml), showed no significant decrease. In patients with pulmonary fibrosis, vitamin D levels were 23.28 +/- 12.30 lower than in patients with trophic ulcers and compared to patients without complications 26.07 +/- 9.92, although with not statistically significant values. No statistically significant difference was found between vitamin D levels in patients with trophic ulcers compared to controls without complications.Conclusion: According to the studies in the literature, in our sample, vitamin D deficiency was therefore greater in patients with SSc, especially with pulmonary fibrosis, than in controls [3,4]. Vitamin D levels in diffused-type SSc patients were significantly lower than those in limited-type SSc patients. Further studies are needed to clarify the role that vitamin D deficiency plays in SSc, but lower vitamin D levels in these patients may suggest the need to monitor blood levels of vitamin D and supplement it appropriately.References: [1]De Martinis M, Ciccarelli F, Sirufo MM, Ginaldi L. An overview of environmental risk factors in systemic sclerosis. Expert Rev Clin Immunol. 2016;12(4):465-78. doi: 10.1586/1744666X.2016.1125782. Epub 2015 Dec 19. PMID: 26610037.[2]Yang, CY., Leung, P.S.C., Adamopoulos, I.E. et al. The Implication of Vitamin D and Autoimmunity: a Comprehensive Review. Clinic Rev Allerg Immunol45, 217–226 (2013). https://doi.org/10.1007/s12016-013-8361-3.[3]Trombetta AC, SmithV, Gotelli E, Ghio M, Paolino S, Pizzorni C, et al. (2017) Vitamin D deficiency and clinical correlationsin systemic sclerosis patients: A retrospective analysis for possible future developments. PLoS ONE 12(6): e0179062.https://doi.org/10.1371/journal. pone.0179062.[4]Sarita Gupta, Vikram K. Mahajan, Rajinder S. Yadav1, Karaninder S. Mehta, Satya Bhushan1, et al. Evaluation of Serum Vitamin D Levels in Patients with Systemic Sclerosis and Healthy Controls: Results of a Pilot Study Article July 2018 DOI: 10.4103/idoj.IDOJ_328_17.Disclosure of Interests: None declared
L. Nacef, H. Ferjani, H. Riahi, Y. Mabrouk, E. Labbene, K. Maatallah, D. Kaffel, M. Bouaziz, W. Hamdi
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 1119.3-1120; https://doi.org/10.1136/annrheumdis-2021-eular.4183

Abstract:
Background: Patients with rheumatoid arthritis (RA) are at higher cardiovascular risk (CVR) than the general population due to chronic inflammation. Several factors, both modifiable and non-modifiable, can increase this risk. Intima-media thickness (IMT) was considered as a marker for atherosclerosis.Objectives: This study aimed to identify predictor factors of increasing IMT.Methods: The prospective study was carried out on patients with RA who met the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. These patients were followed in the rheumatology department of the Kassab Institute. The socio-demographic data, biological and immunological parameters were collected.Framingham’s score quantified the cardiovascular risk at 10-years. Carotid Ultrasonography (US) using a high resolution B mode carotid measured intima-media thickness (IMT) as a subclinical marker of atherosclerosis. Carotid US was performed in the supine position, according to American Society of Echocardiography guidelines. IMT was measured in the left (LCC) and right (RCC) common carotid arteries, the left (LIC) and right (RIC) internal carotid arteries, and the left (LEC) and right (RIC) internal carotid arteries. An increased IMT was defined as ≥0.9 mm.We analyzed data by the SPSS statistical package. A p-value <0.05 was considered significant.Results: Of the 47 patients surveyed, 78.7% were female. The mean age was 52.5 ±11.06 [32-76]. The duration disease was 86.25 ±63 months [5-288] and was erosive in 81.6% of cases. The rheumatoid factor (RF) was positive in 57.8% of patients, and citrullinated antipeptide antibodies (ACPA) were present in 62.2%. Eight patients had a previous CV history (hypertension, diabetes or dyslipidemia) and 16.4% were active smokers. Among women, 43.6% were postmenopausal. ITM was significantly higher in men at LIC (0.037) and LEC (0.025). Older age was associated with increased ITM in LIC (p=0.046; r=0.295), LEC (p=0.05; r=0.412), RCC (p=0.034; r=0.317), and REC (p=0.009; r=0.382). The ITM for LCC, LIC, LEC, RCC, RIC, and REC was higher in postmenopausal women, with no significant difference (p=0.782, p=0.208, p=0.877, r=0.734, p=0.808, p=0.437, respectively).Among the modifiable factors, active smoking was associated with a higher ITM at the REC level (p=0.047). However, weight was not associated with an increased ITM (LCC: p=0.092; LIC: p=0.985; LEC: p=0.952; RCC: p=0.744; RIC: p=0.210; REC: p=0.510). In our study, there was no significant association between DAS28 disease activity or inflammatory marks and ITM (LCC: p=0.784; LIC: p=0.316; LEC: p=0.420; RCC: p=0.784; RIC: p=0.484; REC: p=0.754).Conclusion: In our study, the non-modifiable factors associated with increased ITM were advanced age and male gender. The modifiable factor impacting ITM was primarily active smoking. Surprisingly, disease activity and biological inflammation did not influence ITM.References: [1]S. Gunter and al. Arterial wave reflection and subclinical atherosclerosis in rheumatoid arthritis. Clinical and experimental rheumatology 2018; 36: clinical e.xperimental.[2]Aslan and al. Assessment of local carotid stiffness in seronegative and seropositive rheumatoid Arthritis. Scandinavian cardiovascular journal, 2017.[3]Martin i. Wah-suarez and al, carotid ultrasound findings in rheumatoid arthritis and control subjects: a case-control study. Int j rheum dis. 2018;1–7.Disclosure of Interests: None declared
A. Bankole, S. Pachigolla
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 297.1-298; https://doi.org/10.1136/annrheumdis-2021-eular.127

Abstract:
Background: Glucocorticoids (GC) are used in the treatment of various inflammatory conditions and it is estimated that about 1% of US population is treated with long term steroids. High doses of GC particularly those used by rheumatologists have adverse effects on bone health and is associated with rapid bone loss resulting in Glucocorticoid induced Osteoporosis(GIO) and an increased risk of fractures. The risk of bone loss relates to high daily dose and the high cumulative dose of the GC. Despite the availability of effective preventative and treatment options, GIO is often under treated with many patients treated only after a fracture has occurred. Objectives: The purpose of this study was to examine if providing education to care providers lead to an improvement in the identification, evaluation, and treatment of GIO. Methods: This is a single center, prospective study that was performed at a university based tertiary referral center. Patients over 40 years, receiving a total cumulative dose of GC of >5 grams and/or a single dose of >30 mg of prednisone or equivalent was enrolled. A patient list was generated by our technology group. All providers received intervention in the form of an academic Journal Club, at which the current ACR guidelines regarding GIO was reviewed. Monthly reminders were shared with all providers within our monthly communications. All the pre and post interventional data was analyzed. The continuous variables were analyzed using T-test or Mann-Whitney U test. Categorical variables were analyzed using Chi-square Tests or Fisher’s exact tests. Statistical analysis was performed using SAS9.4, and p value <0.05 was considered statistically significant. Results: Post education, there was a statistically significant increase in vitamin D replacement and the use of bisphosphonates as well as a reduction in the use of bone mineral density (BMD) tests within the at risk group while on GC. Table 1. Glucocorticoid induced Osteoporosis (GIO) Pre-treatment(N=72) Post-treatment(N=54) p-value Demographics Age (years) 58.9 ± 19.2 64.2 ± 16.7 0.11 Body Mass Index 29.0 ± 6.7 29.4 ± 8.4 0.77 Gender (Female) 73.6% 74.1% 0.95 Race White 83.3% 77.8% 0.43 Hispanic 1.4% 5.6% 0.31 Insurance ANTHEM BCBS 16.9% 26.9% Commercial 11.3% 11.5% Medicaid 12.7% 9.6% Medicare 59.2% 51.9% 0.58 Medical History Osteoporosis 68.1% 64.8% 0.70 Osteoporotic Fracture 15.3% 11.1% 0.50 Vasculitis 26.4% 22.2% 0.59 Systemic Lupus Erythematosus 18.1% 13.0% 0.44 Rheumatoid Arthritis 12.5% 25.9% 0.05 Polymyalgia Rheumatica 6.9% 11.1% 0.41 Inflammatory Muscle Disease 18.1% 20.4% 0.74 Spondyloarthritis 1.4% 1.9% 0.99 Lab Results Serum Vitamin D (Normal) 41.3% (19/46) 52.8% (19/36) 0.3 GIO Prevention Measures Calcium 2.8% 13.0% 0.04 Vitamin D 18.1% 61.1% <0.01 Bisphosphonates 9.7% 35.2% <0.01 RANKL inhibitors 4.2% 11.1% 0.17 Bone Mineral Density 43.5% (10/23) 10.5% (2/19) 0.02 Conclusion: There was a significant improvement between the GIO pre and post-educational data, with increasing use of GIO preventive measures. Importantly, there was also a reduction in BMD testing of patients while still on GC. This research show the importance of provider education as a means of disseminating information and improving the quality of patient care. References: [1]Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine. 2018 Jul;61(1):7-16. doi: 10.1007/s12020-018-1588-2. [2]2017 American college of rheumatology guideline for the prevention and treatment of Glucocorticoid-induced Osteoporosis. Arthritis & Rheumatology Vol. 69, No. 8, august 2017, pp 1521-1537. DOI 10.1002/art.40137. [3]Fardet L, Petersen I, Nazareth I. Monitoring of patients on long-term glucocorticoid therapy: a population-based cohort study. Medicine (Baltimore). 2015 Apr;94(15):e647. doi: 10.1097/MD.0000000000000647. Disclosure of Interests: None declared
S. Lugo-Perez, J. R. Azpiri-López, I. J. Colunga-Pedraza, D. Á. Galarza-Delgado, A. B. Rodriguez-Romero, N. Guajardo-Jauregui, A. Cárdenas, H. Azpiri-Diaz, O. A. Cepeda-Ayala
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 511.1-511; https://doi.org/10.1136/annrheumdis-2021-eular.2790

Abstract:
Background: Patients with Rheumatoid Arthritis (RA) have a higher prevalence of cardiovascular diseases (1) and a strong association with abnormalities in the left ventricle (LV) geometry. Both concentric and eccentric remodeling have been determined as an independent factor for sudden cardiac arrest in the general population with normal or slightly decreased ventricular function (2) but there is still controversy about the factors involved and the pathophysiology in patients with RA.Objectives: The aim of the study is to determine the characteristics of LV geometry and the impact of RA.Methods: A cross-sectional, observational, and comparative study of fifty-two RA patients that fulfilled ACR / EULAR 2010 classification criteria, aged 40-75 years. Controls were included and matched by age, gender, and comorbidities. Subjects were evaluated using a transthoracic echocardiogram performed and reviewed by two certified echocardiographers. Ventricular geometry was evaluated with indexed left ventricular mass and relative wall thickness. Distribution was evaluated with the Kolmogorov-Smirnov test. Descriptive analysis was done using measures of central tendency. Chi square, Student’s t test and Mann-Whitney U test were used for comparations between groups. A logistic binary regression was performed with the traditional cardiovascular risk factors (CVRFs), age and RA diagnosis. A p value <0.05 was considered statistically significant.Results: No significant differences were found in the traditional CVRFs (type 2 diabetes mellitus, dyslipidemia, active smoking, and hypertension) (Table 1). Most of the subjects reported normal geometry in both groups (55.8% for RA group vs 64.0% for controls). A higher prevalence of eccentric hypertrophy was found in the RA group, 13 (25%) subjects versus 3 (6%) in the control group, p = 0.009. The binary regression showed that the diagnosis of RA was the only independent risk factor for the presence of eccentric hypertrophy, OR 7.22 95% CI (1.68-31.02, p = 0.008). Table 1. Demographic characteristics and echocardiographic findings. RA(n=52) Control(n=50) p Age, years ± DE 51.4 ±6.2 51.1 ± 5.5 NS Women, n (%) 51 (98.1) 49 (98.0) NS Active smoking, n (%) 8 (15.4) 8 (16.0) NS Dyslipidemia, n (%) 11 (21.2) 13 (26.0) NS Type 2 Diabetes Mellitus, n (%) 5 (9.6) 5 (10.0) NS HTN, n (%) 8 (15.4) 10 (20.0) NS BMI kg/m2, median (p25-p75) 27.8 (24.5-31.4) 28.3 (25.4-30.3) NS BSA, median (p25-p75) 1.7 (1.6-1.8) 1.8 (1.6-1.9) 0.003 Systolic blood pressure, mmHg (p25-p75) 119.5 (110.0-127.5) 120.0 (110.7-130.0) NS Echocardiography findings LVPWTd, median (p25-p75) 0.9 (0.8-1.0) 0.9 (0.8-1.0) NS LVIDd, median (p25-p75) 4.8 (4.3-5.2) 4.6 (4.5-4.9) NS LV mass, median (p25-p75) 131.2 (119.5-155.7) 131.2 (113.2-154.3) NS LV mass index, median (p25-p75) 78.6 (69.7-95.6) 76.0 (66.7-84.6) NS RWT, mean ± SD 0.4 ± 0.09 0.4 ± 0.07 NS NS, no significant; BMI, body mass index; BSA, body surface area; LVPWTd, left ventricular posterior wall thickness at end-diastole; LVIDd, left ventricular internal dimension at end-diastole; RWT, relative wall thickness. Conclusion: There is a higher prevalence of eccentric remodeling in patients with RA independently of traditional CVRF. The diagnosis of RA is an independent risk factor for the presence of eccentric hypertrophy that is associated with higher mortality. Treatment of cardiovascular comorbidities should be intensified in those patients with abnormalities in LV geometry in order to prevent cardiovascular diseases such as heart failure.References: [1]You S, Cho CS, Lee I, et al. A systems approach to rheumatoid arthritis. PLoS One 2012;7(12):e51508. doi: 10.1371/journal.pone.0051508[2]Pascale V, Finelli R, Giannotti R, et al. Cardiac eccentric remodeling in patients with rheumatoid arthritis. Sci Rep 2018;8(1):5867. doi: 10.1038/s41598-018-24323-0 Disclosure of Interests: None declared
S. Stauder, P. M. Peloso
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 841.2-842; https://doi.org/10.1136/annrheumdis-2021-eular.872

Abstract:
Background: Dual Energy CT Scan (DECT) can detect monosodium urate crystal deposits in multiple tissues. EULAR gout guidelines (Richette, 2020) recognized the value of DECT in making a clinical diagnosis when joint aspiration is difficult. DECT shows crystal deposits in almost 50% of gout patients without tophi (Dalbeth, 2017). Tophi are known to predict all-cause and cardiovascular mortality (Vincent 2017, Perez-Ruiz 2013) and it is plausible that DECT could as well. A prognostic measure should be reliable and valid. DECT validity would be evident for death, disability and distress.Objectives: This study used a best evidence synthesis approach to synthesize the evidence for DECT as a prognostic measure in gout.Methods: PUBMED and EMBASE were searched from initiation to December 2019; keywords (Dual Energy Computed Tomography OR DECT, gout, tophaceous gout, chronic gout, monosodium urate crystals OR monosodium urate burden OR tophi OR monosodium urate volume OR flares OR pain OR distress OR death OR disability OR function). Human studies in English were considered. Titles, abstracts and full articles were reviewed. A manual search of secondary sources was conducted. Key gaps identified were considered throughout 2020 when reviewing emerging articles and presentations. Data extraction was conducted by both authors; data presented represents consensus.Results: Of 344 articles, 81 titles/abstracts met screening inclusion criteria (24%) in the 2019 search; review of the full manuscript led to 41 articles selected (51%). Additionally, 3 key papers and 2 ACR 2020 presentations were identified through 2020. DECT is highly reliable with inter-class correlation coefficients >0.9. DECT has content validity. Dalbeth (2015) showed DECT and X-Rays findings correlated in tophaceous patients, r=0.70, p<0.001. Hand function correlates with DECT burden, with r2=0.59, p=0.024 (Dalbeth 2007). Dalbeth (2017) showed DECT associated with greater flares at 3 and 12 months (p<0.01) in 152 patients. Pascart (2018) confirmed that subjects with flares had nearly doubled DECT feet volumes (0.9 vs 2.1 cm3, p=0.05) versus those not flaring. Dalbeth (2017) showed abnormal DECT scans occurred in 47% of patients with normal uric acid (<6.0 mg/dL) without palpable tophi and in 90% with elevated uric acid and palpable tophi. DECT is very sensitive to change (Araujo 2015) with 95% volume reduction in 152 patients on pegloticase treated up to 12 months. Three studies show DECT is correlated to cardiovascular risk factor prevalence (Pascart 2020, Gamala 2018, Lee 2017). Marty-Ané reported that DECT volume predicts mortality (Marty-Ané ACR 2020). Limited evidence from 3 studies suggests that the minimum important volume for DECT is 1.0 cm3 at feet and ankles, including Pascart 2020.Conclusion: DECT imaging is highly reliable, has evidence for content validity and is highly sensitive to change. DECT appears to predict future gout flares, cardiovascular risk factor prevalence and mortality. Minimum important DECT volume approximates 1.0 cm3. DECT requires further study but appears to be a relevant outcome for clinical trials and staging gout patients.References: AuthorsJournal, Volume, IssueYear Araujo, E. G., Bayat, S., et al. RMD Open 2015 Dalbeth, N., Nicolaou, S., et al. Ann Rheum Dis, 77(3) 2017 Dalbeth, N., Aati, O., et al. Ann Rheum Dis, 74(6) 2015 Dalbeth, N., Collis, J., et al. Rheumatology, 46(12) 2007 Gamala, M., Linn-Rasker, S. P., et al. Clinical Rheumatol, 37(7) 2018 Lee, K., Ryu, S., et al. Clinical Rheumatol, 37 2017 Marty-Ané, A., Norberciak, L., et al. Arthritis Rheumatol 72 (supp 10) [abstract #0954] ACR 2020. 2020 Pascart, T., Ramon, A., et al. J Clin Med, 9(5) 2020 Pascart, T., Capon, B., et al. Arthritis Res and Therapy, 20(1) 2018 Perez-Ruiz, F., Martínez-Indart, L., et al. Ann Rheum Dis, 73(1) 2013 Richette, P., Doherty, M., et al. Ann Rheum Dis, 79(1) 2020 Vincent, Z., Gamble, G., et al. J Rheumatol, 44 (3) 2017 Disclosure of Interests: Sally Stauder: None declared, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc.
E. Papichev, В. Zavodovsky, L. Seewordova, J. Polyakova, Y. Akhverdyan
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 487-488; https://doi.org/10.1136/annrheumdis-2021-eular.568

Abstract:
Background: Rheumatoid cachexia is an under-recognized pathological condition, which is characterized by a loss of muscle strength and can be presented as a low fat-free mass and normal or high BMI in patients with rheumatoid arthritis determined by dual-energy X-ray absorptiometry (DEXA) [1]. Though fetuin-A is one of a major noncollagen proteins in bone tissue it is of interest to clarify its association with rheumatoid cachexia.Objectives: To define the prevalence of rheumatoid cachexia in Caucasian patients with rheumatoid arthritis determined by DEXA method and to study the association of serum fetuin-A levels with body composition and rheumatoid cachexia in this group.Methods: 110 Caucasian patients with rheumatoid arthritis undergone DEXA with «Total Body» program. All patients fulfilled the 2010 ACR/EULAR classification criteria for rheumatoid arthritis. The diagnosis of rheumatoid cachexia was based on Engvall I.L. criteria: fat-free mass index less than 10th percentile with fat mass index above 25th percentile [1]. We used values for these indexes from the study performed in 2008 by Coin A. et al. on Italian population due to a lack of standard values [2]. Fetuin-A in serum was determined by enzyme-linked immunosorbent assay. 72 patients have been taking glucocorticoids for more than 3 months in dose equivalent or higher than 5 mg of prednisolone daily. Statistical analysis was performed using a software package “Statistica 12.0”. Parametric data is presented as M±St.dev, and nonparametric as Me [Q1-Q3].Results: Rheumatoid cachexia was diagnosed in 25 patients (22,7%) with mean age of 52,2±8,14 years. The prevalence of cachexia was the same in groups of patients who took glucocorticoids (n=16, 22,2%) and who didn’t (n=9, 23,7%; p = 0,465). Median cumulative dose of oral glucocorticoids in patients with rheumatoid cachexia was higher but fell just short of statistical significance (8,0 [2,9-13,5] g vs 5,4 [0,2-11,6] g; Z=-1,42; p = 0,156). Median serum fetuin-A levels were only slightly significantly lower in patients with rheumatoid cachexia (757,7 [700,5-932,0] µg/ml vs 769,3 [660,3-843,4] µg/ml; Z=-1,35; p=0,175). Positive statistically significant correlations were observed between serum fetuin-A levels and bone mass in right (r=0,222, p = 0,027) and left (r=0,263, p = 0,008) lower limbs, trunk (r=0,268, p = 0,007), gynoid region (r=0,293, p = 0,003), both lower limbs (r=0,246, p = 0,014) and whole-body (r=0,235, p = 0,019).Conclusion: Rheumatoid cachexia was diagnosed in 22,7% of patients with rheumatoid arthritis. No association was observed between glucocorticoids intake and rheumatoid cachexia, despite the expected influence of them on muscle mass. We may suggest that occurrence and pathogenesis of this condition is complex and should be studied more precisely. It is well-known that patients with such condition have a higher risk for metabolic syndrome, arterial hypertension and mortality. We observed positive correlations between serum fetuin-A levels and bone mass in lower limbs, trunk, gynoid region and whole-body. Considering that fetuin-A is also associated with bone mineral density [3], it may be regarded as a marker of bone remodeling.References: [1]Engvall I.L., Elkan A.C., Tengstrand B., Cederholm T., Brismar K., Hafstrom I. Cachexia in rheumatoid arthritis is associated with inflammatory activity, physical disability, and low bioavailable insulin-like growth factor. Scand J Rheumatol. 2008; 37 (5): 321–328.[2]Coin A., Sergi G., Minicuci N., Giannini S., Barbiero E., Manzato E., Pedrazzoni M., Minisola S., Rossini M., Del Puente A., Zamboni M., Inelmen E.M., Enzi G. Fat-free mass and fat mass reference values by dual-energy X-ray absorptiometry (DEXA) in a 20-80 year-old Italian population. Clinical Nutrition. 2008; 27 (1): 87-94.[3]Sari, A., & Uslu, T. The relationship between fetuin-a and bone mineral density in postmenopausal osteoporosis. Turkish Journal of Rheumatology. 2013; 28 (3): 195-201.Disclosure of Interests: None declared
E. Mozgovaya, S. Bedina, A. Trofimenko, M. Mamus, S. Spitsina, I. Zborovskaya
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 1062.1-1062; https://doi.org/10.1136/annrheumdis-2021-eular.3168

Abstract:
Background: According to modern concepts, rheumatoid arthritis (RA) refers to severe autoimmune rheumatic diseases. The activation of free radical oxidation processes is essential in the development of this disease [1]. Xanthine oxidoreductase is a significant reactive oxygen species source [2]. Despite the great advances in the treatment of rheumatoid arthritis (RA) associated with the introduction of innovative drugs and especially the improvement of the strategy for their use into clinical practice, glucocorticoids still remain an important component of RA pharmacotherapy in actual clinical practice. Objectives: to evaluate the changes in activities of xanthine oxidoreductase interconvertible forms (xanthine oxidase, ЕС 1.17.3.2 and xanthine dehydrogenase, ЕС 1.17.1.4) in lysed red blood cells of RA patients in relation with glucocorticoid treatment. Methods: 47 RA patients with verified RA and 30 healthy controls were enrolled in the study. The diagnosis was verified using the 2010 ACR/EULAR criteria 2010. All patients have moderate DAS28 scores. RA patients were randomized into 2 groups comparable in gender, age and the principal clinical manifestations. Methylprednisolone (Metipred, Orion Corp.), average dose 30 mg/day, and betamethasone (Diprospan, Schering-Plough), single dose7 mg, were administered intramuscularly in the respective groups. Хanthine oxidase (XO) and xanthine dehydrogenase (XDG) activities were measured in lysed red blood cells by spectrophotometric method as previously described [3]. The changes of these enzymes activities were studied in RA patients before and after the injection of glucocorticoids. Statistical comparison tests were selected in according to common guidelines, differences were considered significant when p<0.05. Central tendencies were expressed as means±SEM. Results: Mean age of patients in methylprednisolone group was 41.8±1.05 years, and mean RA duration (± SEM) was 7.9±0.21 years. Mean age of patients in diprospan group was 40.9±1.07 years, and mean RA duration was 8.0±0.33 years. Significant decreases of XO activity and increase of XDG activity were observed in lysed red blood cells of RA patients just after the injection of each glucocorticoid drug. Changes of the enzymatic activities in lysed red blood cells were more pronounced in methylprednisolone group. However enzymatic activity did not reach the level of healthy controls. As described previously, decreased XO activity and increased XDG activity were observed in plasma of RA patients just after the injection of the average therapeutic doses of glucocorticoids, as well as in lysed lymphocytes just after the injection of methylprednisolone [4]. Conclusion: Treatment with methylprednisolone and betamethasone can affect the balance of XO/XDG activity and increase the antioxidant potential of the blood. This effect can exert beneficial influence on autoimmune inflammation in RA. References: [1]Mateen S., et al. Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis. PLoS ONE 2016;11(4):e0152925. [2]Çimen M.Y., et al. Oxidant/antioxidant status of the erythrocytes from patients with rheumatoid arthritis. Clin Rheumatol 2000;19(4):275-277. [3]Zborovskaya I.A., et al. Influence of analgetics on plasma and lymphocytic activity of the purine metabolism enzymes in rheumatoid arthritis patients. Russian Journal of Pain 2018;3:47. [4]Mozgovaya E.E., et al. Xanthinoxidase and xanthine dehydrogenase activities in rheumatoid arthritis after glucocorticoid treatment. Osteoporosis International 2019;30(2):S433-434. Disclosure of Interests: None declared
E. Mozgovaya, A. Trofimenko, S. Bedina, S. Spitsina, M. Mamus, I. Zborovskaya
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 1444.1-1444; https://doi.org/10.1136/annrheumdis-2021-eular.3639

Abstract:
Background: Rheumatoid arthritis (RA) is severe autoimmune joint disease, accompanied by a wide variety of extra-articular manifestations. Anemia is one of the most common organ involvements in RA, being diagnosed in 36-65% patients. Iron metabolism alterations, shortened RBC lifespan, and impaired erythropoiesis in bone marrow are believed to play a leading role in RA-related anemia development. These processes in RA can be mediated by increased effect of proinflammatory cytokines, including IFNγ and TNFα, and similar mechanisms could contribute to high xanthine oxidoreductase (XOR) expression. This enzyme makes multiple pathophysiological effects, some of which can be related to the development of anemia in RA. Reactive oxygen species generated by XOR are capable, in particular, of damaging cell membranes, exerting influence on iron mobilization from ferritin in liver, and inducing changes in intestinal iron absorption.Objectives: Evaluation of changes in XOR interconvertible forms (xanthine oxidase and xanthine dehydrogenase) activities in RBC of RA patients.Methods: The research was carried out in agreement with the WMA Declaration of Helsinki principles. 75 RA patients with verified RA were enrolled in the study. The diagnosis was verified using the ACR/EULAR criteria (2010). The reference group consisted of 35 healthy individuals. Хanthine oxidase (XO, ЕС 1.17.3.2) and xanthine dehydrogenase (XDG, ЕС 1.17.1.4) activities were measured in lysed red blood cells by spectrophotometric method as previously described [1]. The enzymatic activities were expressed as nmol/min/ml and normalized to 1×109 cells/ml. Statistical comparison tests were selected in according to common guidelines. Central tendencies were expressed as means±SEM. Differences were considered significant when p<0.05.Results: Mean age of RA patients was 43.9±0.97 years, and mean RA duration was 8.5±0.3 years. Extra-articular manifestations were diagnosed in 32 (42.7%) RA patients and 17 (53.1%) of them had anemia. We revealed substantial changes in XO and XDG activities in lysed RBC of RA patients with anemia. Increased XO activity and decreased XDG activity were observed in comparison with healthy controls (р<0.001 for both enzymes). In parallel with the increase in DAS28 index, significant growth of XOD/XDG coefficient was observed, which was caused by both XOD activity elevation and XDG activity reduction in lysed RBC (p<0.001 for both enzymes). Enzymatic activities depended also on the extra-articular RA manifestations. Mean XO activity was higher and mean XDG activity were lower in patients with extra-articular manifestations (p<0.05 for both enzymes), but the extent of changes was substantially less comparing to anemia.Conclusion: Autoimmune inflammation in RA is accompanied by changes in enzymatic activities of XOR interconvertible forms and their ratio. Transformation of XDG into КО ultimately leads to significant increase in the generation of reactive oxygen species that have a damaging effect on lipids, proteins and other cellular components, and specifically in RBC. This fact may be one of the reasons for their premature damage and development of anemia in RA.References: [1]Zborovskaya I.A., et al. Influence of analgetics on plasma and lymphocytic activity of the purine metabolism enzymes in rheumatoid arthritis patients. Russian Journal of Pain 2018;3:47Disclosure of Interests: None declared
N. M. Elemam, M. Hachim, S. Hannawi, A. A. Maghazachi
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 412.1-412; https://doi.org/10.1136/annrheumdis-2021-eular.2075

Abstract:
Background: Rheumatoid arthritis (RA) is the most common inflammatory type of arthritis, with various immune players implicated in its pathogenesis. Natural killer (NK) cells are innate lymphocytes that showed controversial roles in RA, whether pathogenic or protective (Shegarfi, H. et al. 2012, Yap, H.-Y. et al. 2018). Previously, we were able to identify a gene signature in NK cells of RA patients that can aid in understanding the state of NK cells in RA disease and identify RA patients from healthy controls (Elemam, N.M. et al. 2019, Elemam, N.M. et al. 2020). Furthermore, this signature might facilitate the selection of biomarkers that can be used for early detection of RA and prediction of effectiveness of RA treatment.Objectives: In this study we aimed at exploring the effect of several RA therapeutic agents such as tocilizumab, rituximab and anti-TNFα (adalimumab, etanercept and golimumab) on the previously identified gene signature in NK cells of RA patients.Methods: Whole blood transcriptomic data from publicly available dataset (GSE93272) was used to predict the percentage of activated NK cells in the blood of RA patients using the software CIBERSORT. Then, a correlation analysis was done between the percentage of NK cells and number of days of receiving tocilizumab treatment. Whole blood samples were collected from the recruited 17 RA patients (satisfying the 2010 ACR/EULAR classification criteria for RA). NK cells were isolated using RosetteSep negative selection method and RNA was extracted and gene expression was assessed using qRT-PCR. RA patients taking tocilizumab, rituximab, or anti-TNFα (adalimumab, etanercept or golimumab but none of the patients received infliximab) were compared to those not receiving any biological DMARDs. Statistical analysis was done using Student’s t-test.Results: In silico analysis has shown that the percentage of activated NK cells is positively correlated with the number of days of tocilizumab therapy in RA patients, suggesting a direct enhancing effect of tocilizumab on NK cell activity. Then, it was crucial to investigate the effect of different biological DMARDs on NK gene expression in RA patients. All the investigated chemokines (CCL2, CXCL10, CXCL16, CXCR1, CXCR2, CXCR6 and CCR4) in the identified gene signature showed a significant change in RA patients receiving tocilizumab, rituximab, or anti-TNFα therapies. Furthermore, the other genes including RELA, ICAM, IL1RN, TLR3 and TLR10 were significantly changed in NK cells of RA patients receiving biological DMARDs in comparison to patients not receiving the treatments. However, some of the genes including CD56, BTK, IBTK, ITGB7, IL1B, PECAM-1, IL12RB2, IFNG and CKLF did not show a significant change upon receipt of biological DMARDs.Conclusion: In conclusion, NK cell activity and gene expression could be affected by the type of biological DMARDs received by RA patients. Therefore, this identified gene signature of NK cells could be used as a diagnostic tool to identify RA patients and a target for biological DMARDs in RA.References: [1]Elemam, N. M., M. Y. Hachim, S. Hannawi and A. A. Maghazachi (2019). “Natural Killer Cells Gene Expression Can Differentiate Rheumatoid Arthritis Patients from Healthy Controls [abstract].” ACR/ARP Annual Meeting, supplement of Arthritis & Rheumatology71(suppl 10).[2]Elemam, N. M., M. Y. Hachim, S. Hannawi and A. A. Maghazachi (2020). “Differentially Expressed Genes of Natural Killer Cells Can Distinguish Rheumatoid Arthritis Patients from Healthy Controls.” Genes (Basel)11(5).[3]Shegarfi, H., F. Naddafi and A. Mirshafiey (2012). “Natural killer cells and their role in rheumatoid arthritis: friend or foe?” TheScientificWorldJournal2012: 491974-491974.[4]Yap, H.-Y., S. Z.-Y. Tee, M. M.-T. Wong, S.-K. Chow, S.-C. Peh and S.-Y. Teow (2018). “Pathogenic Role of Immune Cells in Rheumatoid Arthritis: Implications in Clinical Treatment and Biomarker Development.” Cells7(10): 161. Figure 1. In silico analysis and correlation of NK cell activity with the number of days of Tocilizumab therapy in RA patients. Disclosure of Interests: None declared
P. Klemm, J. Bär, I. Aykara, K. Frommer, E. Neumann, U. Müller-Ladner, U. Lange
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 676.1-676; https://doi.org/10.1136/annrheumdis-2021-eular.1735

Abstract:
Background: More than 95% of patients with systemic sclerosis (SSc) suffer from Raynaud’s syndrome (RS) leading to digital ulcerations (DU). In severe RS, intravenous application of prostaglandins is required. Moreover, these patients profit from an additional non-pharmacological treatment using hyperthermia to increase vasodilatation and perfusion, and to reduce pain. Serial locally applied water-filtered infrared A radiation (sl-wIRAR) is a hyperthermia treatment modality using infrared heat radiation in the range of 780-1400nm with high tissue penetration and low thermal load on the skin surface [1]. wIRAR has both, temperature-dependent and non-dependent effects, which do not inherit thermal energy transfer and/or relevant temperature changes [1]. It is therefore not only used in acute and chronic wound healing as it promotes perfusion, alleviates pain and has anti-infectious effects [2], but is also used in oncology [3] and rheumatology [4]. Objectives: We conducted a randomized controlled trial with a follow-up visit after 2 weeks to evaluate the value of a high-frequent hyperthermia treatment using sl-wIRAR in comparison to a low-frequent hyperthermia treatment (our standard) in SSc patients with severe RS receiving Iloprost treatment. Methods: Eligible patients had SSc according to the 2013 ACR/EULAR classification criteria, were 18 to 80 years old and had RS requiring treatment with Iloprost in an in-patient setting. Key exclusion criteria were contraindications to any hyperthermia treatment such as infection or heat insensitivity. The trial was conducted at Campus Kerckhoff of Justus-Liebig University Giessen. Eligible patients were equally randomized to the intervention group (IG) receiving additional sl-wIRAR treatment (2 treatments for 30 min per day for 8 days) plus the standard of care (Iloprost treatment over 8 days plus daily carbon dioxide hand baths of 20 min) and the control group (CG) receiving only the standard of care. Primary outcome was the between-group difference in pain measured on a numeric rating scale (NRS) after intervention. Key secondary outcomes included a change in RS frequency, RS duration, and a change in Interleukin (IL) -6 and VEGF levels. Results: From 01.03.2020 to 31.12.2020 49 SSc patients met the inclusion criteria. 42 patients were enrolled (IG: 21, CG: 21). 38 patients (IG:19, CG: 19) completed the full trial period and were analyzed. There was no statistically significant between-group difference in pain levels (NRS) (p=0.284, Z -1.082 (Mann-Whitney U Test)) and thus the primary outcome was not met. Therefore, all p values for secondary outcomes are nominal. Intensity (Visual analogue scale 0-100mm) and duration (min) of RS were reduced in the IG (mean ± standard error) -14.579 ± 7.214 mm (p=0.058) and -2.917 ± 1.510 min (p=0.08), respectively. Intra- and inter-group comparison of IL-6 and VEGF levels showed no relevant change. Conclusion: The additive and frequent use of sl-wIRAR in the treatment of SSc patients with RS requiring Iloprost treatment does not improve outcomes regarding pain levels, RS intensity or frequency nor IL-6 and VEGF levels when compared to Iloprost treatment and low-frequent hyperthermia application. References: [1]Hoffmann G. Clinical applications of water-filtered infrared-A (wIRA) – a review. Phys Med Rehab Kuror. 2017;27(05):265–274. [2]Hoffmann G, Harte M, Mercer JB. Heat for wounds – water-fil- tered infrared-a (wIRA) for wound healing – a review. GMS Ger Med Sci. 2016;14:Doc08. [3]Notter M, Thomsen AR, Nitsche M, et al. Combined wIRA-hyperthermia and hypofractionated re-irradiation in the treatment of locally recurrent breast cancer: evaluation of therapeutic outcome based on a novel size classification. Cancers (Basel). 2020;12(3): 606. [4]Klemm P, Eichelmann M, Aykara I et al. Serial locally applied water-filtered infrared a radiation in axial spondyloarthritis – a randomized controlled trial, International Journal of Hyperthermia, 37:1, 965-970. Acknowledgements: We acknowledge the help of Carina Schreiyäck. This study was in part supported by the Dr. med. h.c. Erwin Braun Foundation, Basel, a charitable, nonprofit Swiss scientific foundation approved by the Swiss Federal Administration. The foundation supports clinical investigation of waterfiltered infrared-A. The foundation was not involved in any content- or decision-related aspect of the study. This study was prospectively registered at www.drks.de (German Registry of Clinical Studies): DRKS00021098 Disclosure of Interests: None declared
C. Chen, S. Yang, Z. Jiang, W. Wan, H. Zou, M. Liang
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 698.1-698; https://doi.org/10.1136/annrheumdis-2021-eular.3648

Abstract:
Background: Serum fibrotic markers for systemic sclerosis (SSc) remain limited. The Enhanced Liver Fibrosis (ELF) score, originally derived and validated in patients with chronic liver disease, is an algorithm combining 3 serum markers, known as procollagen type III amino terminal propeptide (PIIINP), tissue inhibitor of metalloproteinases 1 (TIMP-1), and hyaluronic acid (HA). The combined score was proved to be superior to the single components in reflecting the severity of liver fibrosis. However, the performance of ELF score and its components has not been fully validated in SSc.Objectives: To investigate PIIINP, TIMP-1, HA, and the combined algorithm ELF score as fibrotic markers for SSc skin involvement.Methods: Eighty SSc patients (44 dcSSc and 36 lcSSc), fulfilling the 2013 ACR/EULAR criteria with the absence of chronic liver diseases, were enrolled. Eighty age- and sex- matched healthy controls were also included. Serum PIIINP and HA levels were quantified by chemiluminescence immunoassay. Serum TIMP-1 levels were determined by enzyme-linked immunosorbent assay. The ELF score was calculated using the formula ELF score= 2.494 + 0.846*ln(HA) + 0.735*ln(PIIINP) + 0.391*ln(TIMP-1). Results were correlated with clinical profiles including modified Rodnan skin score (mRSS) and interstitial lung disease (ILD).Results: Compared with healthy controls, patients with SSc showed significantly elevated serum PIIINP (11.2±4.8 vs. 5.73±1.4μg/L, p<0.001), TIMP-I (123.7±78.6 vs. 67.8±26.5 ng/ml, p<0.001), and ELF score (10.5±0.9 vs. 9.7±0.4, P<0.001). Even higher levels of PIIINP, TIMP-1, and ELF score were observed in dcSSc patients, compared with lcSSc patients (p<0.001, p=0.024, p=0.003, respectively). No significant difference was found in the levels of serum HA between patients and controls. Strong correlations were observed between mRSS and ELF score (r=0.54, p<0.001), and between mRSS and PIIINP(r=0.62, p<0.001), whereas only weak correlations could be observed between mRSS and TIMP-1 (r=0.28, p=0.02), and between mRSS and HA (r=0.26, p=0.03). When stratified by ELF score, using cutoffs proposed for liver fibrosis and cirrhosis, SSc patients with ELF11.3 showed the highest (p<0.001). When stratified by serum PIIINP levels, using the 25th and 75th percentiles, SSc patients with serum PIIIINP levels14.0μg/L showed the highest (p<0.001). Neither the ELF score nor its components showed significant difference between patients with and without ILD.Conclusion: The ELF score could be used for reflecting the severity of overall skin involvement in SSc, and serum PIIINP also increased in parallel with the increase of mRSS. Longitudinal prospective studies exploring ELF score or serum PIIINP as fibrotic markers and outcome measures of SSc are warranted.References: [1]Lichtinghagen R, Pietsch D, Bantel H, et al. The Enhanced Liver Fibrosis (ELF) score: Normal values, influence factors and proposed cut-off values. Journal of Hepatology. 2013; 59: 236-42.[2]Abignano G, Blagojevic J, Bissell LA, et al. European multicentre study validates enhanced liver fibrosis test as biomarker of fibrosis in systemic sclerosis. Rheumatology. 2019; 58: 254-59. Figure 1. Correlations of mRSS with ELF score (A) and serum PIIINP (B) and distribution of mRSS among different ELF (C) and PIIINP (D) ranges. Acknowledgements: The authors have no acknowledgements to declare.Disclosure of Interests: None declared
F. Del Galdo, O. Distler, C. Denton, Y. Allanore, D. Wachtlin, M. Alves, D. Khanna
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 1244-1244; https://doi.org/10.1136/annrheumdis-2021-eular.1760

Abstract:
Background: The ACR Composite Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) was developed to measure the probability of improvement in response to treatment in patients with early diffuse cutaneous SSc (dcSSc), accounting for new/worsening cardiopulmonary involvement and/or renal crisis, and changes in modified Rodnan skin score, forced vital capacity, health assessment questionnaire disability index, and patient’s and physician’s global impressions. In patients with SSc-ILD, treatment response may be reflected as slower progression, stabilisation or improvement. Objectives: Using data from patients with dcSSc and ILD in the placebo group of the SENSCIS trial, we analysed the probability of improvement using the ACR CRISS score at week 52. We also evaluated whether the CRISS numerator could provide information on the spectrum of responses in this patient population. Methods: The SENSCIS trial enrolled subjects with SSc-ILD with onset of first non-Raynaud symptom ≤7 years before screening, FVC ≥40% predicted, and fibrotic ILD ≥10% extent on an HRCT scan. Subjects on prednisone ≤10 mg/day (or equivalent) and/or stable therapy with mycophenolate or methotrexate were allowed to participate. Subjects were randomised to receive nintedanib or placebo. Subjects were not randomised by use of mycophenolate. In patients randomised to receive placebo who had dcSSc and/or mRSS >15 at baseline, we analysed the ACR CRISS and its numerator at week 52 in subgroups by use of mycophenolate at baseline. Analyses were exploratory and descriptive. Results: Of 117 analysed subjects in the placebo group who had dcSSc and/or mRSS >15 at baseline, 60 (51.3%) were taking mycophenolate at baseline. Compared with patients not taking mycophenolate at baseline, those taking mycophenolate had a lower mean age (48.4 [SD 11.8] vs 53.1 [13.4] years), lower mean FVC % predicted (68.8 [17.0] vs 73.0 [14.6]), and a greater proportion were female (76.7% vs 71.9%); median time since first onset of non-Raynaud symptom was similar (3.9 vs 4.5 years, respectively) as was mean (SD) mRSS (16.5 [7.7] vs 15.9 [8.0], respectively). One patient (taking mycophenolate at baseline) had limited cutaneous SSc. At week 52, median (Q1, Q3) ACR CRISS score was 0.036 (0.001, 0.601) in subjects taking mycophenolate and 0.002 (0.000, 0.112) in subjects not taking mycophenolate at baseline, and mean (SD) ACR CRISS score was 0.28 (0.37) in subjects taking mycophenolate and 0.16 (0.31) in subjects not taking mycophenolate at baseline (Figure 1). In these groups, respectively, 25.0% and 14.0% of subjects had CRISS score >0.6 (considered improved) at week 52. The CRISS numerator provided a broader distribution of response values, but was not informative in this patient population. Conclusion: In exploratory analyses, among subjects with dcSSc and ILD who received placebo in the SENSCIS trial, the proportion considered improved at week 52 based on ACR CRISS score was numerically greater in patients taking than not taking mycophenolate at baseline. There remains a need for composite scores that provide better interpretation of the magnitude of response in patients with SSc. Acknowledgements: The SENSCIS trial was funded by Boehringer Ingelheim. Medical writing support was provided by FleishmanHillard Fishburn, London, UK. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Disclosure of Interests: Francesco Del Galdo Speakers bureau: Actelion and AstraZeneca, Consultant of: Actelion, AstraZeneca, Boehringer Ingelheim, Capella BioScience, ChemomAb and Mitsubishi Tanabe Pharma, Grant/research support from: Capella BioScience, Kymab and Mitsubishi Tanabe Pharma, Oliver Distler Consultant of: AbbVie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Bayer, Blade Therapeutics, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos NV, GlaxoSmithKline, Glenmark Pharmaceuticals, Horizon (Curzion) Pharmaceuticals, Inventiva, IQVIA, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Target Bioscience, Topadur Pharma and UCB, Grant/research support from: Kymera Therapeutics and Mitsubishi Tanabe Pharma, Christopher Denton Speakers bureau: Boehringer Ingelheim, Corbus, Janssen, and Mallinckrodt Pharmaceuticals, Consultant of: Acceleron Pharma, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos NV, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mallinckrodt Pharmaceuticals, Roche, Sanofi and UCB, Grant/research support from: Arxx Therapeutics, GlaxoSmithKline and Servier, Yannick Allanore Consultant of: Boehringer Ingelheim, Medsenic, Menarini and Sanofi, Grant/research support from: Alpine Pharmaceuticals, Daniel Wachtlin Employee of: Currently an employee of Boehringer Ingelheim, Margarida Alves Employee of: Currently an employee of Boehringer Ingelheim, Dinesh Khanna Shareholder of: Eicos Sciences, Inc. (less than 5%), Consultant of: Acceleron Pharma, Actelion, AbbVie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead Sciences, Galapagos NV, Genentech/Roche, GlaxoSmithKline, Horizon Therapeutics, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis and United Therapeutics, Grant/research support from: Bayer, Bristol-Myers Squibb, Horizon Therapeutics, Immune Tolerance Network, National Institutes of Health and Pfizer, Employee of: Chief Medical Officer- CiviBioPharma/Eicos Sciences, Inc.
Z. B. Özcan, F. S. Karaahmetoğlu, M. Z. Çiraci, H. H. Pençe, M. Vural, E. I. Üstün, A. Kural, S. Kuraş, B. Erdoğan
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 1086.1-1086; https://doi.org/10.1136/annrheumdis-2021-eular.1369

Abstract:
Background: The goal of treatment for patients with RA is achieve to remission, or at least a state of low disease activity. Exercise is recommended for patients with RA in addition to drug therapy. It has been found to be effective in greatly improving functionality and reducing cardiovascular risk without exacerbating disease activity. Therefore, it is recommended that all RA patients should be encouraged to include aerobic and resistant exercise training as part of their routine treatment (1). miRNAs(miRNA) are known to protect the pathophysiological process specific to RA. miRNA-146a is one of the miRNAs extensively studied in RA, its expression was found to be higher in the synovial fluid and synovial tissue of RA patients compared to healthy individuals (2). Many studies have found that miRNA-146a, along with miRNA-16 and miRNA155 may be related to disease pathology. It has also been found that high levels of miRNA-16 expression correlate with active disease and low levels of expression with inactive disease. It has been found that the increased level of miRNA-155 causes a problem in the modulation of arthritis It has been found that the expression level of miRNA-145 is increased in peripheral blood mononuclear cells of RA patients and synovium supporting osteoclastogenesis (3,4,5). Objectives: It is aimed to investigate the effect of exercise on microRNA expressions in patients with rheumatoid arthritis (RA). Methods: 30 patients and 30 healthy controls aged 18-60 years who met the 2010 ACR / EULAR RA criteria were included in the study. A program consisting of strengthening and stretching exercises 2 days a week was applied to the study group for 8 weeks. One day a week, 30 minutes of mild moderate walking was requested. Of the cases at the beginning and at the end of the treatment; 5-10 cc peripheral blood samples were taken into one EDTA tube. Then Numeric Rating Scale (NRS) was used for pain, 28-joint Disease Activity Score (DAS28) was used to calculate disease activity, Health Assessment Questionnaire (HAQ) was used to assess general health and Short Form-36 (SF-36) was used to evaluate quality of life. 5-10 cc peripheral blood samples were taken to only 1 EDTA tube of the control group. In the samples taken, gene expressions of miRNA-146a, miRNA-155, miRNA-16, miRNA-145 were determined by real-time PZR method. Results: There was a significant difference in DAS28, SF-36, NRS, HAQ scales before and after treatment in the RA group of patients (p 0.05). The expression level of MiRNA-146a does not differ significantly before and after treatment (p> 0.05). However, these two groups differ significantly with the control group (p 0.05). No significant difference was observed in the miRNA-155 and miRNA-16 expression levels in the pretreatment, posttreatment, and control groups (p> 0.05). Conclusion: Exercise therapy has a good effect on pain, disease activity, quality of life and general health in patients with RA. It has been found that exercise can affect vii some of the miRNAs involved in disease pathogenesis. However, more comprehensive studies are needed. References: [1]Cooney JK, Law RJ, Matschke V, Lemmey AB, Moore JP, Ahmad Y, et al. Benefits of exercise in rheumatoid arthritis. Journal of Aging Research. 2011. p. 14. [2]Abou-Zeid A, Saad M, Soliman E. MicroRNA 146a expression in rheumatoid arthritis: Association with tumor necrosis factor-alpha and disease activity. Genet Test Mol Biomarkers. 2011;15(11):807–12. [3]Murata K, Yoshitomi H, Tanida S, Ishikawa M, Nishitani K, Ito H, et al. Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther. 2010;12(3):86. [4]Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EKL. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 2008;10(4):101. [5]Evangelatos G, Fragoulis GE, Koulouri V, Lambrou GI. Micrornas in rheumatoid arthritis: From pathogenesis to clinical impact. Autoimmun Rev. 2019;18(11):102391. Disclosure of Interests: None declared
, Leslie J. Crofford
Published: 10 May 2021
Arthritis & Rheumatism, Volume 73, pp 765-766; https://doi.org/10.1002/acr.24641

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Frontiers in Molecular Neuroscience, Volume 14; https://doi.org/10.3389/fnmol.2021.689903

Abstract:
The global burden of CNS diseases is expected to increase dramatically within the next decades. A recent position paper in the Annals of Neurology estimates the annual cost of neurological diseases affecting nearly 100 million Americans to be in the range of 800 billion dollars [including $37B for epilepsy, $86B for traumatic brain injury (TBI), and $110B for stroke] and calls for the development of preventative and disease-modifying therapies (Gooch et al., 2017). Indeed, conventional therapies are largely symptomatic and do not influence the genesis or progression of the disease. A major gap and challenge for the development of novel disease modifying therapies is the transition from target-centric (symptomatic) approaches to globally-acting multi-modal approaches, which are able to restore complex network function in the brain. It is therefore time to develop innovative new concepts to understand better the interconnectedness of the CNS and to translate new knowledge into novel therapeutics. To achieve this goal Big Data approaches will play a major role in connecting findings from a multitude of different mechanisms and disciplines. The multidisciplinary and integrative scope of Brain Disease Mechanisms will help to bring different ideas from different disciplines under one common roof. The outbreak of the novel coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) may lead to new challenges and to a further increase in the global burden of CNS diseases. It has now become clear that SARS-CoV-2 can also attack the nervous system (Zubair et al., 2020), and it is estimated that at least 40% of COVID-19 patients develop neurological complications (Liotta et al., 2020), including encephalitis, increased risk of stroke, and injuries due to lack of oxygen (Fridman et al., 2020; Kantonen et al., 2020; Paterson et al., 2020). A wide range of injuries to the brain in turn, including stroke, traumatic brain injury, and brain infection, are known to constitute a primary cause for the development of acquired epilepsies including temporal lobe epilepsy (Klein et al., 2018). Because the latent period for the development of acquired epilepsies in humans is in the range of months to years it is still too early to assess whether COVID-19 might be linked to a future increase in epilepsy cases. An additional unknown are the consequences of SARS-CoV-2 infections during pregnancy. A leading hypothesis for the etiology of neurodevelopmental disorders such as autism or schizophrenia suggests that maternal immune activation caused by viral infections during pregnancy might play a major causative role for the derailment of developmental processes critical for normal brain development (Canetta and Brown, 2012; Lombardo et al., 2018). Again, it is still too early to assess whether SARS-CoV-2 infections during pregnancy can be linked to the development of autism or schizophrenia. The examples shown above illustrate that brain diseases and associated etiologies and mechanisms are a constantly evolving field, which may need concerted efforts to accelerate new research directions. Why should we be interested in disease mechanisms? The ultimate goal, obviously, is that better understanding of disease mechanisms leads to better treatment options for persons affected by brain disorders and to the reduction of the global health burden. Four areas deserve increased attention during the next decade: The biggest challenge for the reduction of the global health burden of neurological conditions is a paradigm shift from symptomatic to disease modifying treatments. Up until now, pharmacological treatment options are largely symptomatic. For example, antiseizure drugs (ASDs) have been designed to reduce neuronal excitability, and thereby seizures, the dominant symptom of epilepsy. They do so mostly by affecting ion channels and neurotransmitter release (Sills and Rogawski, 2020). However, despite the development of about 30 new ASDs over the past 30 years, treatment outcomes for persons with epilepsy have not significantly been improved and about one third of all persons with epilepsy remain refractory to pharmacological treatment (Chen et al., 2018). Most currently used ASDs have been discovered in screens designed to detect seizure suppression in rodent seizure models. As a default of this screening approach, compounds are identified, which have the capability to suppress the dominant symptom of epilepsy, which is the seizure. As becomes obvious, seizure-based drug screens are not able to identify compounds, which can treat comorbidities of epilepsy, such as depression, anxiety, or cognitive impairment, or which affect disease progression and epilepsy development. Therefore, there is a major unmet need to identify treatment options, which are disease modifying and thereby affect fundamental mechanisms implicated in pathogenic processes leading to disease and its progression. Treatments, which prevent disease or its progression would be a game changer not only for epilepsy but also for progressive neurodegenerative diseases such as Alzheimer's or Parkinson's disease. In order to develop novel disease modifying treatments, a better understanding of the interconnectedness of the CNS on a multi-omics level becomes a necessity. As opposed to the design of highly selective ligands that bind on individual targets, network pharmacology holds the promise to affect several beneficial targets simultaneously, an approach suitable to increase efficacy and reduce toxicity (Hopkins, 2008). Those network based approaches can be based on a rational design. If several mechanisms are involved in disease development and progression, it can be assumed that those mechanisms are connected by multiple nodes. Identification of central nodes and targeting them in a rationally designed network approach holds the promise to reconstruct network function implicated in disease pathogenesis. A proof of principle for the utility of this approach has been demonstrated recently by demonstrating that a combination of levetiracetam and topiramate altered multiple epileptogenesis-relevant targets and provided robust disease modifying effects (Schidlitzki et al., 2020). A promising alternative to target-centric conventional pharmacology is the development of biochemical interventions for the treatment of disease. It is now well-established that biochemical alterations are implicated in the pathophysiology of a majority of neurological conditions (Boison, 2016). Specifically, core metabolites, such as adenosine are uniquely linked to energy homeostasis (ATP), used as building blocks of biomolecules (RNA, including poly-A tails of mRNAs), coupled to transmethylation reactions (DNA and histone methylation), and act as receptor ligands (adenosine receptors) (Boison, 2013; Boison and Yegutkin, 2019). Thus, adenosine is a unique network regulator linking metabolism and gene expression with neuromodulation. Strikingly, adenosine deficiency is a common pathological hallmark of epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and can be the direct explanation for a wide range of symptoms including seizures, sleep alterations, depression, and changes in cognition and affective behavior (Li et al., 2008; Shen et al., 2012; Hines et al., 2013; Boison and Aronica, 2015). Consequently, adenosine augmentation therapies, e.g., through engineered stem cells (Fedele et al., 2004; Li et al., 2009), are uniquely suited to restore network homeostasis, and to not only suppress comorbid symptoms but also to exert lasting disease modifying therapeutic effects (Li et al., 2008; Boison, 2012; Shen et al., 2012; Williams-Karnesky et al., 2013). The concept of network approaches is not new. This year marks the 100th anniversary of the high-fat, low-carbohydrate ketogenic diet, a metabolic therapy, which has successfully been used for the treatment of epilepsy for decades (Neal et al., 2008; Kossoff, 2010; Stafstrom and Rho, 2012). Recent studies suggest strongly that metabolic approaches may have underappreciated antiepileptogenic and disease-modifying properties (Muller-Schwarze et al., 1999; Todorova et al., 2000; Lusardi et al., 2015; Boison, 2017; Boison and Rho, 2020) and provide benefits to a wide spectrum of additional conditions including pain, autism, brain cancer, and Alzheimer's disease (Ruskin et al., 2009, 2017; Brownlow et al., 2013; Chung and Park YRationale, 2017; Vergati et al., 2017). The benefits of metabolic therapies can be explained by combining several different mechanisms which affect network homeostasis on the levels of energy equilibrium, mitochondrial function, changes in metabolites and neurotransmitters, and epigenetic reprogramming (Kobow et al., 2013; Rogawski et al., 2016; Boison, 2017; Augustin et al., 2018; Boison and Rho, 2020). The examples above demonstrate the promise of network based treatment approaches and suggest that the biochemistry of brain disease is a new frontier to understand the complexity and interconnectedness involved in etiopathological processes. Fully understanding those mechanisms will provide the basis for rationally designed multimodal therapeutics uniquely suited to exert disease modifying properties and to treat complex comorbid syndromes. We are living in the post genomic age. Genetic mutations and polymorphisms yield cues for our understanding of CNS disorders and the development of personalized medicines. A recent PubMed search for “genomic” yielded 1.6 million hits. In contrast, the term “epigenomic” yielded only 18,000 hits. This discrepancy is surprising, given the fact that epigenetic alterations, which include modifiable changes in DNA methylation, histone methylation and acetylation, and the expression of non-coding RNAs, regulate the expression of the very genes that are the focus of genomics-based research efforts. Because epigenetic mechanisms regulate gene expression, there is an urgent need to invest in the field of epigenomics which is one of the remaining frontiers in neuroscience. The study of epigenetics and the development of “epigenetic medicines” is relatively well-developed in the field of cancer (Du et al., 2015; Huang et al., 2015; Zahnow et al., 2016), however in its infancy in our understanding of neurological disorders. For the rigorous assessment of epigenomic data sets it will be important to standardize data and methods as even minor protocol variations can have major impact on epigenomic data sets. Epigenetic changes are subject to metabolic regulation (Kobow et al., 2013; Williams-Karnesky et al., 2013; Boison and Rho, 2020; Kuchukulla and Boison, 2020) and thus may provide an interface between environment, metabolism, and gene expression. Of crucial importance for the understanding of disease mechanisms is the interconnectedness of physiological, molecular, cellular, metabolic, epigenetic, and genetic mechanisms at the subcellular, cellular, and regional levels. Finally, the burden of CNS diseases is global with tremendous regional disparities. It is not enough to focus on Alzheimer's disease, which is a prevalent problem specifically in wealthy countries with a high and rising life expectancy. Strikingly, according to data from the World Health Organization, Alzheimer's disease is five times more prevalent in high income countries as compared to low income countries, whereas meningitis is 13 times more prevalent in low income countries as compared to high income countries. Other, neglected conditions, which affect a significant share of the world population require equal attention. For example, cerebral malaria, the most severe neurological manifestation of severe malaria, has an incidence of 1,120/100,000/year in endemic areas of Africa. It is estimated that a minimum of 575,000 children in Africa develop cerebral malaria annually (Breman, 2001; Murphy and Breman, 2001). Consequences of cerebral malaria include long-term cognitive impairment (25%), speech and language impairment (11.8%), epilepsy (10%), as well as behavioral and neuropsychiatric disorders (Idro et al., 2010a,b). Those examples show major disparities in the distribution of the global burden of neurological diseases; therefore it becomes a moral necessity to invest more research into global health issues. Related to this, there is a risk of introducing bias in clinical trial design. It is important to design trials appropriately to make sure that resulting treatments work equally well across diverse population groups. The current COVID crisis has shown that public distrust in science can have catastrophic impacts on case numbers. The combination of distrust in science and medical populism has led to avoidable surges in COVID infections and deaths, specifically in countries where leaders have discredited scientific knowledge and findings, by downplaying the impacts of the pandemic, by promoting easy and scientifically unfounded solutions or treatments, and by forging divisions between believers and non-believers of science (Lasco, 2020; Hotez, 2021). On the other hand, science has produced a remarkable success story: the development of new vaccines to a new virus within a record breaking time frame of <1 year. There is hope that, if the vaccines work in significantly reducing the impacts of the pandemic and allow the return to a new normal, there will be a boost for the general trust in science. Currently, about three quarters of the population agree that science and technology make our lives better and that scientists contribute to major medical advances. This implies that scientists have a responsibility to maintain and expand this level of trust by serving the public. It means that the fruits of scientific discovery need to be shared broadly with our communities and that scientists need to build trust by demonstrating that science is not done in silos, but that scientists are members of the public and that the public is part of the scientific community. Engaging the public will be key in fighting the pandemic and there is hope that advances in fighting the pandemic will instill trust in the scientific process. Frontiers in Molecular Neuroscience is a leading journal in the area of Neuroscience publishing rigorously peer-reviewed articles with a focus on molecular mechanisms implicated in health and disease of the nervous system. Its Brain Disease Mechanisms section focuses on key pathways and molecular mechanisms involved in the genesis, progression, and maintenance of central nervous system pathologies including neurodevelopmental, neurodegenerative, neuroinflammatory, and neuropsychiatric diseases, including insults such as stroke, traumatic and spinal cord injuries, and infection, as well as mechanisms linking injury to downstream consequences such as epilepsy or neuropathic pain. Of crucial importance for the understanding of disease mechanisms is the interconnectedness of physiological, molecular, cellular, metabolic, epigenetic, and genetic mechanisms at the subcellular, cellular, and regional levels. A specific interest is the exploration of disease mechanisms and their translation into novel targeted therapeutic approaches. Brain Disease Mechanisms thereby provides an interdisciplinary platform for new developments in this highly complex field that demands the involvement of a broad range of professionals and the public to create a forum for the exchange of knowledge and the global dissemination of science. DB designed and wrote the manuscript. DB was supported through grants from the National Institutes of Health (NIH, R01-NS103740, R01-NS065957) and CURE Epilepsy. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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JAMA Neurol. 77, 1018–1027. doi: 10.1001/jamaneurol.2020.2065 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: disease burden, disease mechanism, disease modification, network pharmacology, epigenetics, global approaches, neurological disorders, CNS disorders Citation: Boison D (2021) Specialty Grand Challenge for Brain Disease Mechanisms. Front. Mol. Neurosci. 14:689903. doi: 10.3389/fnmol.2021.689903 Received: 01 April 2021; Accepted: 13 April 2021; Published: 10 May 2021. Edited and reviewed by: Jochen C. Meier, Technische Universitat Braunschweig, Germany Copyright © 2021 Boison. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Detlev Boison, [email protected]
, Wenqin Wang, Chuang Ma, Ray Ming
Published: 7 May 2021
Frontiers in Genetics, Volume 12; https://doi.org/10.3389/fgene.2021.687160

Abstract:
Editorial on the Research TopicGenomics-Enabled Crop Genetics In the genomics era, omics-based technologies have unprecedentedly promoted progress in plant biology, from plant growth and development, plant physiology to molecular genetic studies, and system and synthetic biology. While proteomics and metabolomics are becoming prevalent, genomics and transcriptomics are the most popular and widely used platforms for crop studies due to their rapidly decreased costs, improved sequencing quality, a broad spectrum of applications, and well-established bioinformatic tools. Genetic and functional genomic studies in crops, especially those in non-model crops, have been lagged far behind compared to those in model plant species for a couple of reasons. First, some crops can have a large, complex and polyploidy genome, such as wheat (Triticum aestivum) (International Wheat Genome Sequencing Consortium, 2018). Second, while a group of closely related crop species is often comparatively studied or used in breeding programs, they could have distinct genomes and/or ploidy levels, representing further technical challenges for molecular studies. For example, the peanuts include the cultivated peanut (Arachis hypogaes, AABB genome), the wild tetraploid peanut (Arachis monticola, AABB genome) and two wild diploid peanuts, Arachis duranensis (AA genome) and Arachis ipaensis (BB genome) (Bertioli et al., 2016, 2019; Chen et al., 2016, 2019; Lu et al., 2018; Yin et al., 2018, 2019; Zhuang et al., 2019). Another example is the cultivated bananas, which are interspecific or intraspecific hybrids between wild diploid Musa acuminata (AA genome) and Musa balbisiana (BB genome). They have various genotypes, including diploid (AA, BB, and AB), triploid (AAA, AAB, and ABB) and tetraploid (AAAB, AABB, ABBB) variants (D'Hont et al., 2012; Davey et al., 2013; Martin et al., 2016; Wang et al., 2019). Third, for many crops the genomic resources supporting functional studies and molecular breeding are not often available, including high-quality reference genome assemblies, high-density genetic maps, and genomics-characterized populations. Finally, in some crops (such as sorghum), genetic transformation is still challenging, and mutant resources are not well-established. When synergistically integrated with other omics approaches, genomic technologies can be compelling for crop genetics, representing a technological basis to help mitigate or circumvent the challenges mentioned above in crop studies. The papers included in this Research Topic, Genomics-Enabled Crop Genetics, illustrate this concept. The various studies collected in this Research Topic can be summarized into three major aspects: (1) the theme of “Genomic technologies promote germplasm characterization” includes contributions regarding molecular identification, characterization of crop species and accessions with genomics-based methods. (2) The subject of “Genomic technologies enhance crop population genetics” showcases the examples of population genetic studies facilitated by the genomic approaches. (3) The topic of “Genomic technologies enable functional mining of genomic components in crops,” on the other hand, presents the applications in multiple genomic and transcriptomic databases. These resources are comprehensively integrated to generate functional insights into the genomic components, e.g., genes, miRNAs and cis-regulatory elements. This Research Topic includes thirteen original research articles, one hypothesis and theory paper, one opinion paper and one review article, covering the following three aspects. Markers of simple sequence repeats (SSR) or chloroplast DNA are often used to study the phylogenetic relationship between accessions or species within a crop genus. Taking the advantages of RNA-seq that provides sequence information about functional genes in a cost-effective and high-throughput way, Karcı et al. performed transcriptome sequencing of pistachio (Pistacia vera), developed 233 genic SSR markers (gSSR) and studied the phylogenetic relationship using 55 gSSR markers from nine Pistacia species. This study exemplifies RNA-seq as a tool to contribute to the taxonomy of crop species and their relatives. Qiu et al. assembled the five fescue taxa's chloroplast genomes, including three subspecies of Festuca rubra, one Festuca brevipila, and one Festuca ovina, providing resources to screen fescue germplasm accessions and to refine species identification. With the plastid genome information, Qiu et al. reconstructed the phylogenetic relationship of the Festuca-Lolium complex. Synthetic or artificial polyploid hybrid materials within the Triticum genus or Triticum and its relative species represent essential wheat genetic improvement resources. Cytogenetic techniques can help provide insights into crop genomics, guiding further investigations on certain genomic issues. For example, to better characterize the tetraploid wheat-Aegilops ventricosa amphiploid materials, Zhang et al. observed the chromosomal behavior of the progeny plants (AABBDVDVNVNV) derived from crosses between T. turgidum (AABB) and Aegilops ventricosa (DVDVNVNV) using multicolor Fluorescence in situ hybridization (mc-FISH), providing insights into the genome stability of allopolyploidization in the wheat group. Genomic-based technologies have enhanced the traditional linkage mapping of quantitative trait loci (QTL) and enabled genome-wide association study (GWAS) by developing hundreds of thousands of markers (single nucleotide polymorphism, SNP, e.g., in most applications). In understudied crops, it is cost-effective to develop abundant SNP markers for QTL mapping by using reduced representation sequencing techniques, such as restriction-site associated DNA sequencing (RAD-seq) (Miller et al., 2007), genotyping-by-sequencing (GBS) (Elshire et al., 2011), and specific length amplified fragment sequencing (SLAF-seq) (Zhang et al., 2013). Wei et al. developed an interspecific F2 population containing 121 individuals, constructed a genetic map of eggplant (Solanum melongena) with 2,122 SNP markers and identified 19 QTLs for several morphological traits. This work lays a foundation for the fine mapping of QTLs and marker-assisted selection in eggplant breeding. In another work, Peng et al. used several SNP-identification methods (target enrichment sequencing, TES, RNA-seq and the 48K Axiom Arachis2 SNP array) to identify the genomic region and candidate genes controlling nodulation in cultivated peanut (A. hypogaea L.). They demonstrate that TES generated the highest number of SNPs, followed by RNA-seq and the SNP array with GBS being the least effective. In this work, TES and the SNP array have comparable costs per SNP per sample, while RNA-seq was the most expensive technique for SNP identification. To discover candidate genes associated with ear morphology in breeding populations, Li et al. identified SNPs for 208 maize inbred lines from two heterosis groups, Shaan A and Shaan B. The further GBS, combined GWAS and selective sweeps identified four genes associated with ear length and fruit length. Genomic technologies not only enhance QTL mapping, but also help in identifying expression QTL (eQTL). Barbey et al. identified SNPs for octoploid strawberry populations using the Affymetrix IStraw 35 Axiom SNP array and mapped 268 eQTLs for 224 genes expressed in the mature receptacle. Many of the eQTLs are known to affect fruit traits that were either described experimentally or validated via transgenic approaches. Integration of multiple genomic resources, including but not limited to genetic variation by whole genome resequencing, gene expression by RNA-seq, miRNA expression by small RNA-seq and miRNA targets' cleavage information by degradome sequencing, can significantly enhance our understanding of transcriptional and post-transcriptional regulation in crops. Glazinska et al. created an expression database for yellow lupine (Lupinus luteus L.), namely LuLuDB, by combining RNA-seq analysis of small RNA, transcriptome, and degradome libraries, providing analysis-ready information of the NGS data. They further demonstrated the usefulness of the LuLuDB by a showcase of a genome-wide analysis of the Dicer Like (DCL) gene family and a miR486-DCL2 analysis. In maize research, Xu et al. integrated 195 small RNA sequencing libraries and 19 degradome libraries. Together with the identification of phasi-RNA and GWAS results, they found many tissue-specific miRNAs and depicted evolutionary implications of small RNAs. Zhao et al. combined the heat-responsive transcriptomes of wheat and the genome-wide identified heat shock elements (HSEs) and show that a particular variant of non-canonical HSE is associated with a larger heat stress response and that the heat stress-responsive genes containing different HSEs are functionally diverged. In addition to providing large-scale gene functional implications, genomic datasets can highlight a gene of interest within a particular gene family. For example, in a genome-wide analysis of wheat heat shock protein 90 (TaHSP90), Lu et al. took advantage of PacBio Iso-seq data and identified 126 isoforms derived from the TaHSP90 genes. The highly expressed TaHSP90-AA genes showed a large magnitude of response to heat stress with differential alternative splicing patterns observed between the three TaHSP90 homologous copies, extending our understanding of the functional divergence of the HSP family. Many pan-genome studies have revealed extensive genetic variations between accessions within a crop species, including copy number and structural variations. With the three high-quality phased diploid genomes of grapevine cultivars, Cabernet Sauvignon (CS), Carménère (CR), and Chardonnay (CH), Smit et al. compared the terpene synthase (VviTPS) gene family between CS, CR, CH, and an Illumina-based reference genome PN40024 (Jaillon et al., 2007; Chin et al., 2016; Minio et al., 2017, 2019; Roach et al., 2018). The in-depth genome-wide comparison of VviTPS family identified duplicated gene copies, predicted functions of VviTPS by combining sequence homology and established knowledge of more than 40 biochemically characterized VviTPS genes (Smit et al.) Zhang et al. summarized published genome-wide analyses of gene families in the cultivated and wild peanut (Arachis) genomes (Bertioli et al., 2016, 2019; Chen et al., 2016, 2019; Lu et al., 2018; Yin et al., 2018, 2019; Zhuang et al., 2019). Zhang et al. show that the hidden Markov Model (HMM)-based search of a gene family is rapid and accurate and provides helpful suggestions regarding aspects of gene family analysis. The abundant genomic resources allow for investigation on the genomic components other than protein-coding genes and non-coding RNAs, such as untranslated regions (UTR) and cis-regulatory elements. Tu and Li (2020) developed an RNA-seq analysis method to profile alternative 3′ untranslated regions (3′UTRs), priUTR suitable for crops like sorghum and maize. Profiling of the genes with alternative 3′UTRs in Sorghum bicolor reveals a link between alternative 3′UTR and RNA N6-methyladenosine (m6A) modification, which had also been implicated in a previous maize RNA m6A profiling experiment (Luo et al., 2020). These papers provide bioinformatic evidence on the relationship between RNA m6A modification and alternative 3′UTRs/ polyadenylation. In 2021, a major breakthrough has been made to the link of m6A and alternative polyadenylation that the longer isoform of Cleavage and Polyadenylation Specificity Factor 30 (CPSF30-L) is the key protein to mediate m6A regulation of polyadenylation in Arabidopsis (Hou et al., 2021; Song et al., 2021). In this Research Topic, Galli et al. reviewed the state-of-art of our knowledge in regulatory regions and their mechanisms in controlling gene expression. Galli et al. further summarized the cutting-edge NGS technologies for detecting accessible chromatin regions (ACRs) and DNA-binding motifs of transcription factors (TFs). Particularly, the pros and cons of several methods for mapping TFs' DNA binding motifs [i.e., Chromatin immunoprecipitation sequencing (ChIP-seq), DNA Affinity Purification sequencing (DAP-seq) and cleavage under targets and release using nuclease (CUT&RUN)] have been discussed and highlighted. DAP-seq is considered a cost-efficient high-throughput method for crop regulome study. In addition, the reference genomes of closely related crops represent important resources for genome evolution studies. Yu et al. selected four pairs of genomes from the four core eudicot plant families, performed genome-wide synteny block comparison and discovered that excision of genes is much more prevalent than pseudogenization during genome fractionation. The collection of sixteen papers in this Research Topic reflects the broad spectrum of current research directions in genomics-enabled crop genetics. The current Research Topic also exemplifies that genomic technologies and resources can be applied to a wide range of crop species, from cereal crops, such as wheat, maize and sorghum, to horticultural crops, such as eggplant, pistachio, yellow lupine, fine fescue, strawberry, and peanut. As the contributions to the Research Topic “Genomics-Enabled Crop Genetics” exemplarily shows, a combination of multiple genomic technologies and/or resources can form powerful and comprehensive tools for different aspects of crop genetic studies, suitable for different crop species with distinct applications and emphases. As more genomic resources and techniques are being developed for a variety of crop species, the output will accelerate crop genetic research and, ultimately, promote crop genetic improvement. YL, CM, WW, and RM co-wrote this editorial based on this Research Topic's contributions. All authors contributed to the article and approved the submitted version. YL was funded by the Fundamental Research Funds for the Central Universities (HUST 2021XXJS070). The project was supported by National Natural Science Foundation of China Grant 32072008 (to WW). 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Genet. 51, 865–876. doi: 10.1038/s41588-019-0402-2 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: crops, genomics, transcriptomics, population genetics, germplasm characterization, gene functional studies Citation: Li Y, Wang W, Ma C and Ming R (2021) Editorial: Genomics-Enabled Crop Genetics. Front. Genet. 12:687160. doi: 10.3389/fgene.2021.687160 Received: 29 March 2021; Accepted: 15 April 2021; Published: 07 May 2021. Edited and reviewed by: Lin-Feng Li, Fudan University, China Copyright © 2021 Li, Wang, Ma and Ming. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Yin Li, [email protected]
Corrigendum
Fiorella Carla Grandi, Lara De Tomasi,
Frontiers in Molecular Neuroscience, Volume 14; https://doi.org/10.3389/fnmol.2021.686790

Abstract:
A Corrigendum onSingle-Cell RNA Analysis of Type I Spiral Ganglion Neurons Reveals a Lmx1a Population in the Cochleaby Grandi, F. C., De Tomasi, L., and Mustapha, M. (2020). Front. Mol. Neurosci. 13:83. doi: 10.3389/fnmol.2020.00083 In the original article, there was an error. Dr. Gopal Pramanik was acknowledged without his agreement. As per his request, we are removing his name and contribution from the acknowledgment paragraph. A correction has been made to the Acknowledgments. The corrected paragraph is shown below. “We sincerely thank Drs. Stefan Heller and Marta Milo for help with data analysis, and Dr. Walter Marcotti for helpful discussion. We also thank Dr. Kathleen J. Millen for generously providing the Lmx1a-cre mice and Dr. Theresa Zwingman for answering the many questions we had concerning these mice (Seattle Children's Research Institute Center for Integrative Brain Research, The University of Washington). We thank Dr. Joseph P. Sarsero (Murdoch Children's Research Institute, Australia) for sharing Peripherin-GFP mice with us and Dr. Lin Gan (Flaum Eye Institute, University of Rochester School of Medicine) for sharing Bhlhb5-cre line.” The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. Keywords: type I spiral ganglion neurons, single-cell transcriptome, Lmx1a, development, cochlea Citation: Grandi FC, De Tomasi L and Mustapha M (2021) Corrigendum: Single-Cell RNA Analysis of Type I Spiral Ganglion Neurons Reveals a Lmx1a Population in the Cochlea. Front. Mol. Neurosci. 14:686790. doi: 10.3389/fnmol.2021.686790 Received: 27 March 2021; Accepted: 01 April 2021; Published: 05 May 2021. Approved by: Copyright © 2021 Grandi, De Tomasi and Mustapha. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Mirna Mustapha, [email protected]
, Alberto E. Paniz-Mondolfi, Álvaro A. Faccini-Martínez, Andrés F. Henao-Martínez, Julian Ruiz-Saenz, Marlen Martinez-Gutierrez, Lucia E. Alvarado-Arnez, Jorge E. Gomez-Marin, Ruben Bueno-Marí, Yenddy Carrero, et al.
Frontiers in Tropical Diseases, Volume 2; https://doi.org/10.3389/fitd.2021.676905

Abstract:
Emerging diseases have significantly impacted the last few decades (1–10). The emergence and re-emergence of vector-borne and zoonotic diseases in Africa, Asia, and Latin America have reshaped the epidemiological landscape of these continents. The impact of these diseases and the establishment of local transmission in traditionally non-endemic areas, due to migration and travel, have been revealed over the last years. Diseases such as Chikungunya (11–16), Zika (17–24), Yellow Fever (25–28), Dengue (29–33), Oropouche, Madre de Dios virus, Iquitos virus (34, 35), Mayaro Fever (36, 37), Ebola (38–42), Nipah virus, arenaviruses such as Lassa (43), Machupo (44, 45), Chapare (45, 46), Junin (47), zoonotic Malaria (48), Severe Fever with Thrombocytopenia Syndrome (49), Plague (50), Crimean-Congo Hemorrhagic Fever, Acute Orally Transmitted Chagas Disease (51–54), Visceral and Diffuse Cutaneous Leishmaniasis (55, 56), Toxoplasmosis (57–59), Tick-Borne Diseases (60, 61), Rift Valley Fever, Tuberculosis (62), Leprosy (63–67), Avian Influenza (68–70), Orthohantavirus (71–75), and Toxocariasis (76, 77) have posed a significant impact to human health. Furthermore, zoonotic epidemics and pandemic coronaviruses, such as the Severe Acute Respiratory Syndrome (SARS), the Middle East Respiratory Syndrome (MERS) (78–82), and the ongoing SARS-CoV-2/COVID-19 (83, 84) pandemic, have caused a profound economical and social disruption threatening to overwhelm public health systems globally (85) (Table 1). Most of these pathogens can even cocirculate and coinfect a significant proportion of inhabitants within the same territories (11, 87–94). For example, in arboviral diseases, the occurrence of coinfections has been widely reported –such as Dengue with Chikungunya and/or with Zika virus– and affects diverse populations, including pregnant women and immunocompromised patients (94–97). This may obscure clinical suspicion, as signs and symptoms for many of these pathogens may overlap. In endemic areas, this becomes a particularly pressing issue that must be taken into account in order to ensure accurate diagnosis and provide appropriate management. The ChikDenMaZika syndrome has been previously adopted as a mnemonic device to include Chikungunya, Dengue, Mayaro, and Zika in the broad differential of acute febrile illnesses due to arboviral agents (95). More recently, emerging coinfections, including bacterial and parasitic diseases, such as tuberculosis and Chagas disease, have also been reported (98). Table 1 Lessons learned from the COVID-19 pandemic in Latin America. Current times call for more comprehensive ecoepidemiological and bioecosocial approaches (20, 99). Scarce funding and the lack of research (39, 43, 61, 81) in tropical medicine are entirely unacceptable. Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), tuberculosis (TB), and malaria combined receive approximately 70% of neglected diseases funding. As mentioned here, emerging tropical diseases, such as those mentioned here, are worldwide in scope, and many have significant regional implications. Therefore, a different funding paradigm that improves their situation is needed (100). The world is no longer a place with distant countries and shielded territories. Instead, ever increasing interconnectivity has turned it into a “small” global village, where the health status of underprivileged areas may undermine not only their lives and development but extend to the wealthiest. The Ebola crisis in 2014 highlighted how high-consequence emerging diseases could spill over to Europe and North America (38, 40). The ongoing 2020-2021 pandemic of COVID-19, which has reached as far as Antarctica, affecting almost all countries worldwide, is another clear example (8, 29, 84, 101–112). As was expected, coinfections between tropical pathogens and COVID-19 are also now increasingly being reported, especially with dengue (30). Dengue affects over 100 countries worldwide and puts about 2.5-3.9 billion people at risk of infection (113, 114). Within the next century, nearly a billion people are at risk of exposure to virus transmission by both main Aedes spp., Ae. aegypti, and Ae. albopictus (also Chikungunya and Zika) in the worst-case scenario (115). The recent first detection of Ae. vittatus in the Dominican Republic and the Americas generated concern in the region, requiring enhanced surveillance to understand the range and public health risks of this potential invasive mosquito species, deserving more studies (116). Most of these emerging tropical diseases are vector-borne, zoonotically transmitted, or environmentally spread through direct contact, food or water ingestion, as well as a consequence of environmental alterations (including the effects of climate change) (117–125), becoming significant sources of mortality and morbidity worldwide (2). The impact of these diseases extends well beyond the acute constellation of symptoms, leading in a considerable proportion of patients to chronic sequelae and complications, which can be long lasting and severely incapacitating, as is the case with Chikungunya (15, 126–132), Zika (17, 133–135), Ebola, Chagas disease (52), and even for COVID-19 (136–139). Many tools have been deployed to counteract emerging infectious diseases. Amongst these are active surveillance (some supported by artificial intelligence) (140–142), leading to the rapid identification of novel pathogens by genome sequencing and phylogenetic tracing studies (36, 105, 107, 143–146) based on computing methods to predict possible interspecies barriers spillover between humans and animals (147). Coupling biotechnological approaches with social sciences—the holistic understanding of humans and their interactions in the disease ecosystems—is also a critical element needed when studying emerging infectious diseases (148, 149). One of the most significant challenges when studying tropical infectious diseases relies on their complexity and heterogeneity, which usually requires a deep understanding not only of the disease itself but its overall context. In order to better approach these diseases one must keep a broader vision of designing proposed interventions, including multilevel ecoepidemiological studies ranging from molecular and omics to satellite epidemiology (use of data and images derived from geospatial technologies, e.g., satellites, for the study of the occurrence and distribution of health-related events in specified populations, and the application of this knowledge to control the health problems) of pathogens, vectors, hosts, abiotic variables, and other socio-environmental factors (125, 150, 151). While more research is required to fill in the numerous gaps in knowledge for many of these diseases, particular attention should be placed in designing strategies to develop methods to forecast these diseases not only in vulnerable and underserved populations from low-income countries but also in those poverty pockets located in high-income countries. A whole chapter to be considered in emerging tropical diseases is vaccines development. Innovative global partnership between public, private, philanthropic, and civil society organisations, such as the Coalition for Epidemic Preparedness Innovations (CEPI), launched in 2017, are important to develop vaccines to stop future epidemics. To accelerate the development of vaccines against emerging infectious diseases and enable equitable access to these vaccines for people during outbreaks is crucial. Nevertheless, more funding to understand biology, pathogenesis, epidemiology, prevention, and treatment of emerging tropical diseases are urgently needed and expected (152–154). Tropical Medicine is no more a clinical specialty of “exotic diseases,” as it was conceived at its beginnings, and is no more about “diseases for those entering the jungle.” One dramatic change is the urban installation of diseases that before were observed only after sylvatic or primary forest exposure. The increase of urban outbreaks of Chagas disease in South America is now a horrific reality in Brazil (155–157), Venezuela (158), and Colombia (159, 160), and it is also a new reality for visceral leishmaniasis (161–164). The integrated work of public health experts, veterinarians, entomologists, and parasitologists is an urgent need to face these new challenges and transformations of tropical diseases. Tropical diseases also include non-infectious diseases, such as animal bites and stings (e.g. myiasis and tungiasis) (165, 166). Snake bites, scorpion stings, and spider bites, account for a significant amount of the morbidity and mortality in tropical countries in these changing scenarios, including ecotourism, rural migration, and other related factors (167–170). There is no doubt that “many things are wrong in the world today”, as the legendary American rock n’roll band Aerosmith has been singing since the 90s. We are “living on the edge”, the edge of neglect and of a surge of many emerging infectious diseases with no hope for resolution in the foreseeable future. Furthermore, “it sure ain’t no surprise” that poverty, inequality, climate change, deforestation, migration, urbanization, wildlife trade, among many other factors, have all contributed to the emergence of novel tropical diseases and the resurgence of other endemic diseases (171). There is no spare place for the arrival of emerging pathogens, and over time pathogens tend to adapt to new environments leading to unforeseen consequences. The next epidemic, the next pandemic, is just around the corner (68). In response to this latent threat, we need to gather real-time information and build collaborative networks aimed to enhance surveillance activities in order to develop high-priority medical countermeasures to prevent and control emerging tropical diseases. Research in Zoonotic and Vector-Borne Emerging Tropical Diseases remains the most critical aspect and the foundation to determine the drivers of emerging and re-emerging infectious diseases. With that vision, our new Section Emerging Tropical Diseases in the journal Frontiers in Tropical Diseases offers to contribute to the scientific advancement and fill in the many knowledge gaps based on a multi and transdisciplinary approach. Our team of Associate Editors is comprised of a diverse group of experts from different countries, diverse backgrounds, and varied interrelated expertises in a wide range of conditions within the tropical diseases spectrum of diseases, following the One Health approach vision (8, 172). Grand challenges exist in the fight against the threat of emerging tropical diseases. In the laboratory, our daily work, in the hospitals, in the field, in the community, and in many other places, our shared goal is to understand the drivers of emergence and address their root-causes. We are working collaboratively in social networks to reduce the impact of emerging tropical diseases. Let’s work on this together! We value your work and welcome your submissions to this new section of Frontiers in Tropical Diseases. All authors contributed to manuscript conception and design, literature review, manuscript preparation, and critical review. All authors contributed to the article and approved the submitted version. RB-M was employed by Laboratorios Lokímica, Spain. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AR-M is the Specialty Chief Editor in Emerging Tropical Diseases of Frontiers in Tropical Diseases. 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One Health (2020) 10:100147. doi: 10.1016/j.onehlt.2020.100147 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: vector-borne diseases, zoonotic diseases, emerging, SARS-CoV-2/COVID-2, tropical diseases, challenges Citation: Rodriguez-Morales AJ, Paniz-Mondolfi AE, Faccini-Martínez ÁA, Henao-Martínez AF, Ruiz-Saenz J, Martinez-Gutierrez M, Alvarado-Arnez LE, Gomez-Marin JE, Bueno-Marí R, Carrero Y, Villamil-Gomez WE, Bonilla-Aldana DK, Haque U, Ramirez JD, Navarro J-C, Lloveras S, Arteaga-Livias K, Casalone C, Maguiña JL, Escobedo AA, Hidalgo M, Bandeira AC, Mattar S, Cardona-Ospina JA and Suárez JA (2021) The Constant Threat of Zoonotic and Vector-Borne Emerging Tropical Diseases: Living on the Edge. Front. Trop. Dis 2:676905. doi: 10.3389/fitd.2021.676905 Received: 06 March 2021; Accepted: 06 April 2021; Published: 04 May 2021. Edited and reviewed by: Jerome Kim, International Vaccine Institute, South Korea Copyright © 2021 Rodriguez-Morales, Paniz-Mondolfi, Faccini-Martínez, Henao-Martínez, Ruiz-Saenz, Martinez-Gutierrez, Alvarado-Arnez, Gomez-Marin, Bueno-Marí, Carrero, Villamil-Gomez, Bonilla-Aldana, Haque, Ramirez, Navarro, Lloveras, Arteaga-Livias, Casalone, Maguiña, Escobedo, Hidalgo, Bandeira, Mattar, Cardona-Ospina and Suárez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Alfonso J. Rodriguez-Morales, [email protected]
Frontiers in Molecular Biosciences, Volume 8; https://doi.org/10.3389/fmolb.2021.641932

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Editorial on the Research TopicStructural Studies of Protein Complexes in Signaling Pathways Now, as never before in the history of humankind, people are constantly communicating and aware of their surroundings. It is astonishing to see how similar our society is to a basic cellular organism, a society of cells. In order to function and survive, cells need to communicate with each other and gather information about the external environment. They do not use mobiles or social media, but they are able to codify and transfer information using signaling pathways. Signaling pathways are defined by an intricate network of protein-protein and protein-nucleic acid interactions that governs intra- and inter-cellular activities. Nearly all cellular processes are controlled by such interactions, including motility, growth, proliferation, gene expression, survival, and apoptosis. Structural biology has offered unprecedented insight into the function and regulation of protein-interaction networks. Advances at third generation synchrotron sources and the use of XFELs is having a massive impact on elucidating the structural rationale and dynamics of macromolecules (Moreno-Chicano et al., 2019). The technical advances in crystallography have also fueled developments in cryo-electron microscopy (cryo-EM), facilitating the determination of previously elusive protein structures at atomic or near-atomic resolutions. Recently, by optimizing the electron source for energy spread and reducing the noise by using a new energy filter and camera, the structures of two proteins, human GABAAR and mouse apoferritin, were solved at atomic resolution using cryo-EM, 1.7 and 1.2 Å, respectively (Nakane et al., 2020). At the other end of the structural biology spectrum there is NMR, historically considered highly complementary to crystallography. NMR presents major advantages in measuring the kinetic and thermodynamic parameters of a molecular system, and detecting and mapping transient or weak interactions. In their perspective article, Purslow et al. provide a technical overview of solvent Paramagnetic Relaxation Enhancement (solvent-PRE), Intermolecular Nuclear Overhauser Effect (NOE) and Residual Dipolar Coupling (RDC) for the study of protein complexes, and Chemical Shift Perturbation (CSP) for the determination of binding modes and KD values for protein-ligand with weak interactions (KD in the μM-mM range) in fast exchange regime (μs−1 NMR timescale). The authors also discuss several approaches to study medium size protein (~100 kDa) and overcome the molecular weight limit of solution NMR, focusing mostly on solid-state NMR sequences, like REDOR and PAINCP. Signaling pathways are stimulated by the binding of extra- or intra-cellular signaling molecules to receptors, which relay signals via binding to downstream targets. The flow of information through the cell is mediated by specific, selective interactions, which determine the functional outcome of signaling networks. The resulting processes are tightly regulated and their misregulation has been associated with complex human pathologies, including cancer and neurodegenerative disorders. This Research Topic collects articles focusing on the use of structural biology and hybrid methods to characterize protein complexes and, most importantly, the formation of the correct protein complexes in response to specific signals. Fenn et al. discussed the advances in the characterization of Mycobacterium tuberculosis Mce proteins, a class of membrane spanning proteins which promote bacterial survival within humans by manipulating host cell signaling. In a mini-review, the authors emphasized the roles of Mce beyond lipid transport and described the structural-functional features of three Mce complexes (Mce3E/Mce2E-ERK1/2, Mce2E-eEF1A1, and Mce3C-β2 integrin), highlighting the diverse mechanisms adopted by M. tuberculosis to downregulate cytokine expression and promote entry into macrophages. Marshall and Bavro used a combination of structure-guided mutational studies to characterize another system linked to bacterial survival, the Escherichia coli tripartite efflux-pump AcrAB-TolC, assembly of which relies on the recognition and interaction of the outer-membrane factor TolC with the periplasmic adapter protein AcrA. Their results support the presence of a deep interpenetration of the AcrA-TolC interface and indicate that TolC contributes to the substrate selection during efflux events, uncovering an overlooked feature of the outer-membrane factor protein family. Transmembrane proteins involved in cellular interactions or extracellular environment sensing are fascinating examples of highly spatial and temporal regulated signaling complexes. Khan and Goult reviewed the diverse range of interactions triggered by integrin binding to talin and kindlin in the cytoplasm, and the extracellular matrix, highlighting the key role microscopy played in dissecting the organization of integrin adhesion complexes. The authors provide an elegant mechanosensitivity regulation model, describing extensively the link between auto-inhibition and the formation of inactive pre-complexes, further discussing the role autoinhibition plays in driving the correct protein interaction in response to a specific signal. Similarly, Guarino et al. provided a comprehensive review of the structural features that guide the clustering of acetylcholine receptors (AChRs), essential for the formation and maintenance of Neuromuscular junctions (NMJ) and synaptic connections. The authors critically discussed the well-characterized “canonical” (or agrin-induced) AChRs clustering model that involves interaction between the AChRs and the LRP4-MuSK complex bound to agrin, as well as the less well-characterized “non-canonical” model, exploring the possibility that the AChRs clustering is mediated by interactions with the Wnt-LRP4-MuSK complex. Chataigner et al. embarked on a challenging task to review the molecular mechanisms used by type-I transmembrane proteins to control adhesion and activation of signaling, focusing mostly on the extracellular portion of the proteins. Using different examples of prototypical transmembrane proteins, the authors focused on the roles X-Ray crystallography, NMR and cryo-EM played in unraveling proteins interactions, protein complexes structures and conformational changes underlying activation of signaling processes. Despite the astonishing technical advances of the last 10–15 years in structural biology, experimental approaches are intrinsically time and resource demanding and computational studies, spanning from classic molecular dynamics simulations to more recent machine learning algorithms and network topology and proximity measures, have the potential to bypass some of these shortcomings. Zhang et al. present a quintessential application of computational study to explore the diverse functions of SMYD3 by analyzing its interactome. Using a pathway enrichment analysis coupled with structural analysis and sequence motif scanning, the authors identified two major classes of proteins forming transient interactions with SMYD3: epigenetic transcriptional regulators, like histone H3-4, and proteins related to calcium dependent signaling, such as PLCB3, supporting the hypothesis that SMYD3 is not merely a methyltransferase involved in histones modification, but could be an integral part of calcium signaling pathways. The studies collected in this Research Topic represent just the tip of the iceberg of the possibilities offered by structural biology applications in understanding and characterizing signaling pathways, helping define future direction of research in biology and related fields. As the structural biology technologies and resources continue to improve, it will be possible to address additional biological challenges. We envision that in the next 10 years, a thorough structural understanding of larger and more complex systems will be possible, offering possibilities to map the dynamic processes in signaling networks in order to better understand the transmission of signals and the roles that different structural components have in relaying those signals within an organism. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors would like to thank the Leverhulme Trust (RPG-2018-230 to FP), the Wellcome Trust (205767/Z/16/Z to FP), and the Medical Research Council (MR/N010051/1 to PF) for research funding. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We wish to thank all the authors who participated in this Research Topic and the reviewers for their insightful comments. Moreno-Chicano, T., Ebrahim, A., Axford, D., Appleby, M. V., Beale, J. H., Chaplin, A. K., et al. (2019). High-throughput structures of protein-ligand complexes at room temperature using serial femtosecond crystallography. IUCrJ 6, 1074–1085. doi: 10.1107/S2052252519011655 PubMed Abstract | CrossRef Full Text | Google Scholar Nakane, T., Kotecha, A., Sente, A., McMullan, G., Masiulis, S., Brown, P., et al. (2020). Single-particle cryo-EM at atomic resolution. Nature 587, 152–156. doi: 10.1038/s41586-020-2829-0 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: signaling pathways, structural biology, protein structural and functional analysis, protein interaction network, proteins complexes, transmembrane proteins Citation: Prischi F and Filippakopoulos P (2021) Editorial: Structural Studies of Protein Complexes in Signaling Pathways. Front. Mol. Biosci. 8:641932. doi: 10.3389/fmolb.2021.641932 Received: 15 December 2020; Accepted: 05 March 2021; Published: 30 April 2021. Edited and reviewed by: Annalisa Pastore, King's College London, United Kingdom Copyright © 2021 Prischi and Filippakopoulos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Filippo Prischi, [email protected]; Panagis Filippakopoulos, [email protected]
Published: 20 April 2021
Frontiers in Radiology, Volume 1; https://doi.org/10.3389/fradi.2021.615138

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Radiology has been significantly reshaped and innovated by advancements of technologies, such as imaging instruments, artificial intelligence (AI), and information technology, and it has also been substantially impacted by its interactions with other disciplines. Therefore, our perspective of grand challenges in radiology is mainly concerned with technological and multidisciplinary obstacles to overcome in the years to come. We will address specific challenges associated the six sub-fields of radiology, namely, neuroradiology, diagnostic radiology, interventional radiology, emergency radiology, cardiothoracic imaging, and AI in radiology. Modern neuroimaging technologies and protocols generate much information such as various types of parametric maps and activity patterns on the human brain (1). One of the grand challenges is how to best represent and visualize such rich information to neuroradiologists so that they will take the full advantage of available information and do not feel overloaded. Developing novel brain mapping methods and tools will be very helpful to represent and visualize such multimodal parametric maps and activity information in a more neuroanatomically meaningful context (2), which will fundamentally assist neuroradiologist to understand and interpret. Neuroradiologists frequently interact with other disciplines such as neurology, neuropathology, neurosurgery, neuro-oncology, and psychiatry, and thus developing new paradigms and tools that can enable, facilitate, and support such multidisciplinary interactions and discussions will be enormously useful. Neuroradiology is naturally rooted in neuroscience, and brain science information sources from molecular-level genes/genomes to human behaviors could be relevant to neuroradiology. It would be a daunting yet important task for neuroradiologists to integrate and comprehend such complex brain science information into their practice. In this sense, efficient integration and representation of brain science knowledge and discoveries into neuroradiology is a grand challenge. Diagnosis radiology provides a main source of information for assessment of human diseases and it plays a major role in clinical diagnosis and disease management. Advancements in biomedical engineering and biotechnology in the past few decades have offered novel ways of acquiring in-depth information about human diseases such as molecular imaging and genomics. How to fuse and integrate such multiscale and multimodal information into diagnostic radiology is a grand challenge. Also, diagnostic radiology has been frequently interacting with other disciplines such as nuclear medicine, molecular imaging, neurology, oncology, cardiology, pathology, surgery, and laboratory medicine, and it will be vitally important to develop new approaches and paradigms for diagnostic radiologists to collaborate with other physicians as a team. Finally, in the era of big data and AI, how to improve the accuracy, efficiency and productivity in diagnostic radiology by incorporating novel information technology and AI systems will be a grand challenge, which will be discussed from an AI angle in the last section. Interventional radiology is associated with a wide range of biomedical imaging modalities (such as X-rays, MRI, fluoroscopy, CT, and ultrasounds) and interventional procedures (such as treating tumors, biopsies, and placing stents) to make diagnosis and treatment inside of the human body. Thus, one of the grand challenges in interventional radiology is integration and fusion of imaging multimodalities within the context of interested tissues or organs, in nature. Thus, developing smart and informative interventional navigation systems will be a key to meet such needs. Second, interventional radiology is at the frontier of integrated diagnosis and therapy, thus integration of novel technologies in targeted drug delivery, molecular targeted imaging and therapeutics, and AI-enable target recognition into interventional procedures will be quite challenging yet rewarding. Third, in interventional radiology, a big challenge and also a big next step is how to improve accuracy of targeted interventional procedures through the introduction and integration of imaging-compatible medical robots (3). Such robots-assisted interventional radiology will bring in a variety of benefits for patients and physicians. Emergency radiology is defined and characterized by rapid imaging scan and quick turnaround of radiological reading (4). Main technical challenges are associated with these two defining characteristics. First, developing rapid imaging scan setup and fast data acquisition technologies will be of main interest and concern in emergency radiology, which will significantly increase imaging capacity and reduce risk of delaying emergent patient management. Second, developing novel AI technologies and systems can significantly reduce emergency radiologists' burden and improve their scan reading efficiency. Such user-friendly AI systems can substantially benefit emergency radiologists' mental and physical health and improve their productivity. For instance, AI-assisted imaging data interpretation and structural emergency radiology report generation could dramatically streamline and improve the clinical workflow in emergency radiology. Cardiothoracic imaging mainly deals with diagnosis of pulmonary, cardiac, and vascular diseases, and it is closely related to disciplines including pulmonary medicine, thoracic surgery, cardiology, vascular surgery, oncology, and pathology. One of the grand challenges in cardiothoracic imaging concerns with how to effectively deal with the anatomic, mechanical, physiologic, physiopathological and therapeutic cardiopulmonary correlations (5), thus advancing the sub-field of integrated cardiothoracic imaging. Second, developing faster and smarter cardiothoracic imaging data acquisition and reconstruction technologies remains as a grand challenge, partly due to the cardiac and pulmonary motion. Those novel technologies that can effectively compensate or correct cardiac/pulmonary motion will be much needed. Third, from a computational perspective, increasing effort has been put into the integration of novel AI technologies into cardiothoracic imaging data interpretation and understanding, e.g., computational simulation and modeling of cardiac motion patterns. A growing number of academic and industrial efforts have been put in developing new AI technologies for radiology (6) and promising pilot results have been reported. However, grand challenges still exist to take the full advantages of AI in advancing radiology, and those challenges have been already discussed in the literature (7). From our perspectives, there are at least four urgent challenges that should be addressed by the field. First, new AI technologies should be developed for fast and high-quality imaging data reconstruction, with potentially smaller doses of intravenous contrast material and lower radiation dose in some scenarios. These new imaging data acquisition technologies will be very beneficial to patients, radiologists and radiology clinical flow. Second, as annotated imaging data is typically required for training AI models and algorithms, it is much needed to develop effective automated labeling and annotation methods to produce training data for radiology AI research. These automated annotation and labeling technologies will significantly improve current manual labeling/annotation processes that are both costly and time-consuming. Third, although AI is deemed to be promising in radiology, it requires large-scale, well-curated, well-integrated, and controlled dataset for training and testing AI algorithms. Thus, developing novel paradigms for effective, privacy-enabled, and safe radiology data sharing is urgently needed. Fourth, as AI systems are becoming more prominent in radiology practice, it is important to develop novel human-machine interaction frameworks for radiologists to smoothly interact and cooperate with AI systems. These novel AI-radiologists cooperation and teamwork models will both significantly improve radiologists' efficiency and reduce AI system's risks. The author confirms being the sole contributor of this work and has approved it for publication. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 1. Brammer M. The role of neuroimaging in diagnosis and personalized medicine–current position and likely future directions. Dialogues Clin Neurosci. (2009) 11:389–96. doi: 10.31887/DCNS.2009.11.4/mbrammer PubMed Abstract | CrossRef Full Text | Google Scholar 2. He B, Coleman T, Genin GM, Glover G, Hu X, Johnson N, et al. Grand challenges in mapping the human brain: NSF Workshop Report. IEEE Trans Biomed Eng. (2013) 60:2983–92. doi: 10.1109/TBME.2013.2283970 PubMed Abstract | CrossRef Full Text | Google Scholar 3. Kassamali RH, and Ladak B. The role of robotics in interventional radiology: current status. Quant Imaging Med Surg. (2015) 5:340–3. doi: 10.3978/j.issn.2223-4292.2015.03.15 PubMed Abstract | CrossRef Full Text | Google Scholar 4. Chong ST, Robinson JD, Davis MA, Bruno MA, Roberge EA, Reddy S, et al. Emergency radiology: current challenges and preparing for continued growth. J Am Coll Radiol. (2019) 16:1447–55. doi: 10.1016/j.jacr.2019.03.009 PubMed Abstract | CrossRef Full Text | Google Scholar 5. Marano R, Pirro F, Silvestri V, Merlino B, Savino G, Rutigliano C, et al. Comprehensive CT cardiothoracic imaging: a new challenge for chest imaging. Chest. (2015) 147:538–51. doi: 10.1378/chest.14-1403 PubMed Abstract | CrossRef Full Text | Google Scholar 6. Shen D, Wu G, and Suk H-I. Deep learning in medical image analysis. Ann Rev Biomed Eng. (2017) 19:221–48. doi: 10.1146/annurev-bioeng-071516-044442 CrossRef Full Text | Google Scholar 7. Langlotz CP, Allen B, Erickson BJ, Kalpathy-Cramer J, Bigelow K, Cook TS, et al. A roadmap for foundational research on artificial intelligence in medical imaging: from the 2018 NIH/RSNA/ACR/The Academy Workshop. Radiology. (2019) 291:781–91. doi: 10.1148/radiol.2019190613 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: artificial intelligence, cardiothoracic imaging, interventional radiology, diagnostic radiology, emergency radiology Citation: Shen D (2021) Grand Challenges in Radiology. Front. Radiol. 1:615138. doi: 10.3389/fradi.2021.615138 Received: 08 October 2020; Accepted: 16 March 2021; Published: 20 April 2021. Edited and reviewed by: Tianming Liu, University of Georgia, United States Copyright © 2021 Shen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Dinggang Shen, [email protected]
Published: 13 April 2021
Frontiers in Radiology, Volume 1; https://doi.org/10.3389/fradi.2021.629992

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AI technologies and methodologies have started to empower all aspects of radiology in the past decade, from imaging data acquisition, to imaging data interpretation, and to clinical decision making. Despite exciting advancements made in the field of AI in radiology, there are also grand challenges associated with technological and translational aspects of AI in radiology (1). Following the Field Chief Editor Dr. Dinggang Shen's perspective in his statement of grand challenges in radiology1, here we elaborate four grand challenges in AI in radiology in more detail. Fast and high-quality radiological image acquisition has been a major challenge for decades and it remains as a grand challenge. How to speed up imaging data acquisition, such as MRI and CT scans, has been of major interest to improve efficiency and patient safety, among other considerations. In response, many AI technologies have been developed and reported for fast and high-quality radiological image reconstruction (2), with substantially smaller doses of intravenous contrast material and lower radiation dose in some scenarios. It is envisioned that these new imaging data acquisition technologies will continue to be developed for the benefits of patients, radiologists, and radiology clinical flow. Also, AI can play a major role in integrating and optimizing radiological data acquisition workflow, for instance, a recent successful example is the contactless patient positioning system during the COVID-19 pandemic (3), which automated calibration, positioning, and multi-view synthesis components that enable patient scans without physical proximity. This journal's specialty of AI in radiology will encourage and welcome contributions that address all aspects of AI-empowered imaging data acquisition. Modern AI systems in radiology typically rely on machine learning and deep learning algorithms that are trained and tested on a large number of annotated radiological images (4). Thanks to significant progresses made in the AI field, algorithms can now take advantage of accurately and reliably annotated imaging data. However, manual annotation of radiological images is still a key bottleneck in translating advanced AI algorithms into clinically useful systems. Typically, manual labeling and annotation processes in radiology AI systems are quite costly and time-consuming. Thus, developing effective automated labeling and annotation methods to produce high-quality training and testing data for radiology AI research and application is much needed (1). Recent efforts in integrating natural language processing (NLP) technologies and human-computer interaction (HCI) methodologies into radiology will be a promising direction to explore and pursue in the future. Although radiology AI systems are deemed to be promising in improving efficiency and accuracy, they require a sufficiently large, well-curated, well-integrated, and controlled dataset for training and testing AI algorithms. In particular, radiology AI systems for many human diseases/conditions are heavily dependent on a variety of co-factors such as disease stages or subtypes, patient populations, and genotypes, among many others. Given the large number of combinations of the co-factors, the data from one single institution are vastly insufficient for AI algorithms to achieve their full potential. In addition, in order to have complete and diversified data to minimize healthcare disparities, radiological data sharing among multiple institutions is required to meet such requirements. Unfortunately, the concerns of data security and patient privacy in data sharing and other social/economic considerations prevent people from sharing radiological data in a large scale effectively, which significantly prevents the clinical applications of radiology AI systems. This is a grand challenge for radiology AI that truly deserves attention and effort from all stakeholders to overcome. From a technical perspective, recent decentralized approaches such as blockchain and the InterPlanetary File System (IPFS)2 possess great promise in dealing with security and privacy concerns in data sharing and thus they are worthy of future exploration for radiological image sharing. Radiology AI systems are used by clinical radiologists during their daily practice, and thus AI systems and radiologists must adapt to each other and build up a co-worker relationship. However, it is known that such human-machine co-working is challenging, which is formulated as the human-technology frontier in the NSF's 10 big ideas3. There will be many research opportunities to understand and build the radiologist-AI system relationship, to design and develop new technologies to augment radiologist's performance, and to foster radiologist's lifelong and pervasive learning with AI systems. It is hopeful that these effective AI-radiologists co-working models will significantly increase radiologists' efficiency and reduce AI system errors and risks. TL wrote this article as a sole author. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 1. ^ https://www.frontiersin.org/journals/radiology#about 2. ^ https://ipfs.io/ 3. ^ https://www.nsf.gov/news/special_reports/big_ideas/ 1. Langlotz CP, Allen B, Erickson BJ, Kalpathy-Cramer J, Bigelow K, Cook TS, et al. A roadmap for foundational research on artificial intelligence in medical imaging: from the 2018 NIH/RSNA/ACR/The Academy Workshop. Radiology. (2019) 291:781–91. doi: 10.1148/radiol.2019190613 PubMed Abstract | CrossRef Full Text | Google Scholar 2. The Ubiquity of AI at RSNA (2019). Available online at: https://www.appliedradiology.com/communities/Artificial-Intelligence/the-ubiquity-of-ai-at-rsna-2019 3. Karanam S, Li R, Yang F, Hu W, Chen T, Wu Z. Towards contactless patient positioning. IEEE Trans Med Imaging. (2020) 39:2701–10. doi: 10.1109/TMI.2020.2991954 CrossRef Full Text | Google Scholar 4. Shen D, Wu G, and Suk HI. Deep learning in medical image analysis. Annu Rev Biomed Eng. (2017) 19:221–48. doi: 10.1146/annurev-bioeng-071516-044442 CrossRef Full Text | Google Scholar Keywords: artificial intelligence, imaging, radiology, deep learning, data sharing Citation: Liu T (2021) Grand Challenges in AI in Radiology. Front. Radiol. 1:629992. doi: 10.3389/fradi.2021.629992 Received: 10 December 2020; Accepted: 10 March 2021; Published: 13 April 2021. Edited and reviewed by: Dinggang Shen, ShanghaiTech University, China Copyright © 2021 Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Tianming Liu, [email protected]
Arizona Mustikarini, Desi Adhariani
Published: 6 April 2021
Meditari Accountancy Research; https://doi.org/10.1108/medar-11-2020-1062

Abstract:
Purpose This study aims to review the auditor-client relationship (ACR) literature spanning 1976 to 2019 to provide future research directions. Design/methodology/approach The study analysed 140 articles from the Web of Science database, authored by 259 scholars across 28 countries and published in 47 journals. It identified three major research streams to understand the ACR dynamics: auditor tenure, ACR attributes and auditor-client negotiation. Findings Three major findings emerged based on this review. First, few studies examine auditor-client negotiation relative to other streams; thus, it offers scope for further research. Second, given that various fields have used diverse frameworks as theoretical underpinnings in prior studies, continuing this trend can better portray ACR from multiple perspectives. Finally, despite strong international regulations on ACR aspects such as auditor independence, tenure and rotation, implementation in several countries warrants special considerations, specifically on legal enforcement and investor protection, given diverse cultures and country-level institutional environments. Originality/value This study contributes to the synthesis of existing and emerging research streams and provides future research suggestions.
, Miroslav Vosátka, Christopher Rensing, Helena Freitas
Published: 25 March 2021
Frontiers in Microbiology, Volume 12; https://doi.org/10.3389/fmicb.2021.634891

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Editorial on the Research TopicAdvanced Microbial Biotechnologies for Sustainable Agriculture Plant responses to various environmental or climatic stresses are immensely complex and implicate changes at the transcriptome, cellular, and physiochemical levels, consequently hindering crop growth as well as yield quantity and quality. Agriculture has been considered a complex network of plant-microbe interactions. The use of microorganisms of agricultural importance [e.g., plant growth-promoting microorganisms (PGPM)] represent a major ecological strategy for integrated agricultural practices such as nutrient addition, biological control, abiotic stress (e.g., drought, salinity, heavy metals) alleviation to minimize the use of agrichemicals (e.g., fertilizers and pesticides) in agriculture as well as to improve crop performance (Ma et al., 2011, 2016a,b). While the immense diversity of soil microorganisms represents a tremendous opportunity for selecting PGPM, the interactions with plants and the cooperative and competitive interactions among microbes themselves make it extremely challenging to determine which microbes are responsible for synergistic ecosystem functions. The essential aspects for the effectiveness of PGPM application biotechnology are the utilization of a proper inocula formulation and a suitable carrier, as well as delivery methods. Thus, considering the detrimental effects of biotic and abiotic stresses on agricultural production and food security, the development of technologies for exploring the microbial microenvironment and improving our understanding of how microbes communicate/interact with plants to enhance nutrient use-efficiency could pay substantial dividends. Therefore, this Research Topic “Advanced Microbial Biotechnologies for Sustainable Agriculture” was launched to advance our knowledge of underlying mechanisms of plant-microbe interactions and review recent progress on the relationship between the microbiome and crop productivity and health that is at the frontier of agricultural sciences, with the potential to progress and transform agricultural systems in the field. The cogent review and synthesis embodying all the scattered information about drought and salinity stress responses and microbe-induced tolerance in crop plants were provided by Ma G. et al. They also provide insight as a means to develop an understanding of the mechanisms strongly involved in plants respond/adapt to the selected environmental stresses (e.g., drought and salinity) at the morphological, physiological, biochemical, and metabolomic levels, as well as plant-microbe interactions that confer abiotic stress tolerance in plants. So far, in most of the topics, the literature references regarding drought and salt stress are simply listed close to each other, without an integrated approach. In this review, the comparison between plant responses to drought and salinity was thoroughly highlighted and explained. Salinity stress has been the main restraint to agriculture, limiting crop growth and productivity. Many studies have focused on utilizing PGPM to improve plant tolerance to salinity (Ma Y. et al.). It has been demonstrated that inoculation of plants with 1-aminocyclopropane-1-carboxylate (ACC) deaminase producing PGPB can enhance plant growth under salinity stress (Ma et al., 2019b). Orozco-Mosqueda et al. assessed ACC deaminase activity and trehalose accumulation of PGPB Pseudomonas sp. UW4, using constructed mutant strains (acdS, treS, or both) and a trehalose over-expressing strain (OxtreS). The findings indicate the synergistic action of ACC deaminase and trehalose in Pseudomonas sp. UW4 plays an essential role in protecting host plants against salinity stress. To cope with drought stress, PGPM were found to secrete osmolytes to alleviate drought stress, which act synergistically with plants internal osmolytes stimulating plant growth (Paul et al., 2008). The trehalose accumulation is an adaptive mechanism in microbes in response to drought stress to protect cells and proteins from osmotic shock and desiccation (Reina-Bueno et al., 2012). Sharma et al. explore the biological importance and the role of trehalose in the tripartite symbiotic relationship between plants, rhizobia, and AMF, as well as physiological functions and molecular investigations using omics-based approaches. The review provides a critical discussion on the role of microbe-mediated trehalose accumulation in improving stress tolerance. The use of PGPM has been considered an alternative to protect plants from diseases and improve crop productivity, reducing the amount of chemical pesticides needed (Ma Y. et al.). The ability to deconstruct fungal cell walls is a defining characteristic of fungal antagonism and anti-fungal biocontrol (Mesa-Arango et al., 2016). Schönbichler et al. explore the ability of B. subtilis natto to use complex fungal fruiting body and cell wall as a carbon source by secreting chitinases and proteases. The findings show that chitin does not allow bacterial growth nor induce the secretion of chitinolytic enzymes, and protease secretion might be the key mechanism for nutrient scavenging and depredating fungal cell walls by B. subtilis natto. There have been thousands of scientific papers published that contribute to our knowledge on individual features of microbes, their behavior in soil, and after all their interaction with plants both in natural ecosystems and agroecosystems. Numerous papers revealed potentially huge positive effects of soil microorganisms on plant tolerance to stress and resulting ability to produce more biomass or other target yields (Reina-Bueno et al., 2012; Ma et al., 2019b; Ma Y. et al.). Nevertheless, a further step is needed to bring this knowledge closer to practice that would allow to formulate the new products and implement new biotechnologies of crop cultivation. The present Research Topic shows important advances in the understanding of the mechanisms behind plant beneficial microbial activities that help host plants cope with environmental stresses and fills the gap to translate scientific knowledge into sustainable applications. As examples, Rocha et al. and Ferreira et al. show that the knowledge transfer to real agriculture can be feasible since there are numerous beneficial microbes that we know and have isolated and even established effective procedures for their mass production. However, the delivery systems for their large-scale applications in the field represent the most common bottleneck. Seed coating has been considered a precise and cost-effective method to deliver microbial inoculants. A delivery system based on seed coating of various microbes seems to be economically feasible and applicable even in broad-acre agriculture (Ma et al., 2019a). As discussed in Rocha et al., there are still numerous considerable factors that hamper the wider use of microbial seed coating and in general the use of microbes as bioagents in general agriculture practice. The most important ones are the self-life of microbes after coating, their compatibility among themselves, and their ultimate efficacy when they are used in mixtures. There is also a crucial factor in production and application costs. The seed companies are not always keen to change their long-term practices and use biologicals instead of chemical treatment of their seeds (also taking into account that those two treatments are unlikely to be compatible with each other). Moreover, farmers are usually not equipped to do the seed treatment themselves and they have little incentives to ask seed companies for microbially coated seeds (charged premium price) until they see significant evidence of better-coated seed performance. Last but not least there is a general issue of final cost per hectare and especially for low-value crops like cereals where there are generally low-profit margins, it is difficult to accommodate any extra costs. Moreover, the special issue for biocontrol microbes mandates a very strict and costly registration (in particular within the EU). Nevertheless, with proceeding soil degradation, increasing effects of global climatic change and after all growing awareness and demands for agrochemical reduction, healthy and secure food crops, the microbial seed coating technology will certainly be growing in its implementation and wider use. The transition of scientific knowledge to a real commercial application has been happening at a large scale already for some important crops and it holds a strong potential for the near future for other microbes and crops worldwide. A very good example of a fundamental science study conducted by Ferreira et al. that can be transformed into real agriculture is the testing of bacteria-based fertilizer that can alleviate iron-deficiency-induced chlorosis (IDIC). In this work, the ability of two new Fe freeze-dried fertilizer products, prepared from the filtrate cultures of A. vinelandii and B. subtilis was tested using an important soybean crop. Plants treated with A. vinelandii Fe fertilizer developed a dry mass comparable to that of o,o-EDDHA and the A. vinelandii-treated plants had higher Fe content. The results indicated that the freeze-dried product, prepared from A. vinelandii, represents a very promising, sustainable, and environment-friendly Fe-fertilizer alternative for application in the IDIC amendment in calcareous soils. Similar calcareous soils that are naturally alkaline or are being threatened by increasing salinity are becoming more abundant globally (Yadav et al., 2011). Also, the Fe deficiency is generally increasing in arable soils of numerous regions of the world and therefore similar fertilizers can be a biologically-based solution for that. Interactions between plants and microbes including fungi are mediated by a chemical language containing multiple compounds, infochemicals, such as terpenes (Schmidt et al., 2017). We are slowly deciphering this communication that could be called signalomics (Mhlongo et al., 2018) to understand the interplay between environment, plants, and not only microbes but also other organisms. Phytohormones produced not only by plants but also by microbes play a crucial role in these interactions as described in a review by Kudoyarova et al.. Auxin-producing bacteria were shown to influence processes such as root elongation but both root elongation and inhibition of root elongation could be observed depending on the plant, the environment, and the dosage and the auxins. Other phytohormones include cytokinins such as zeatin riboside produced by certain bacteria also influence plant physiology but is so far even less elucidated. Other important phytohormones generated by microbes include ACC deaminase and abscisic acid (ABA). ACC deaminase lowers ethylene production but the effect of ABA accumulation is not often defined by a clear-cut physiological effect. In a paper dealing with a related topic, Luziatelli et al. examine the effect of plant growth-promoting Pantoea agglomerans on the rooting of Pyrus communis. It could be shown that exometabolites such as indole-3-acetic acid (IAA) of P. agglomerans promoted adventitious rooting. Of interest is that the synergy between auxin-related compounds such as IAA and other metabolites produced by P. agglomerans such as cinnamic-related compounds was shown to be very delicate and concentration-dependent. As previously shown for IAA, there is an optimal concentration and more is not necessarily better. Here it was demonstrated that the optimal concentration of auxin-like products is also dependent on the simultaneous production of other yet to be defined products. In another article, Xu et al. examine the relationship between soybean genotype, arbuscular mycorrhiza fungi, and rhizobium inoculation. The soybean genotype directly influenced the establishment of the rhizosphere fungal community and additionally, rhizobium inoculation also determined the composition of the rhizosphere fungal community. We are only at the beginning of understanding these complicated interkingdom dynamics. In conclusion, there is great potential for near future enhancements in the use of PGPM in world agriculture. A paramount need is to bridge the gap between fundamental, applied science, and agricultural practice. As early as a possible transition of knowledge to the farmers as end-users of innovative products and biotechnologies can ensure efficient commercialization of scientific results and can also fuel new research on the way to achieve more sustainable use of natural resources and more efficient biologically/ecologically based agriculture. YM, MV, and CR drafted the editorial text. YM and HF revised and approved the final version of the editorial text. All authors contributed to the article and approved the submitted version. This work is carried out at the R&D Unit Center for Functional Ecology—Science for People and the Planet (CFE), with reference UIDB/04004/2020, financed by FCT/MCTES through national funds (PIDDAC). The FCT supported the research contract of YM (SFRH/BPD/76028/2011). Research in the lab of CR was funded by National Natural Science Foundation of China (NSFC) (Grant number: 31770123). Technology Agency of the Czech Republic – National Center of Competence BIOCIRTECH (No. TN010000048) and the project of the Czech Academy of Sciences (RVO 67985939). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ma, Y., Látr, A., Rocha, I., Freitas, H., Vosátka, M., and Oliveira, R. S. (2019a). 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Causes of salinity and plant manifestations to salt stress: a review. J. Environ. Biol. 32, 667–685. PubMed Abstract | Google Scholar Keywords: plant growth-promoting microorganisms, behavior of inoculated microorganisms, biotechnological interventions, biotic and abiotic stresses, inoculum delivery, colonization pattern, sustainable agriculture Citation: Ma Y, Vosátka M, Rensing C and Freitas H (2021) Editorial: Advanced Microbial Biotechnologies for Sustainable Agriculture. Front. Microbiol. 12:634891. doi: 10.3389/fmicb.2021.634891 Received: 29 November 2020; Accepted: 03 March 2021; Published: 25 March 2021. Edited by: Reviewed by: Copyright © 2021 Ma, Vosátka, Rensing and Freitas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Ying Ma, [email protected]; [email protected]
Justin Mellette
Abstract:
Chapter 2 focuses on Erskine Caldwell and seeks to complicate understandings of his best-known works Tobacco Road and God's Little Acre. Though often derided for mocking the poor and using them as comic relief, Caldwell works to instil a sense of anger in readers as he reveals the economic plight of tenant farming during the Great Depression. In addition, the chapter looks at Caldwell's nonfiction work, including his phototext You Have Seen Their Faces, written with photographer Margaret Bourke-White, and contrasts its cultural context with the comparatively better known Let Us Now Praise Famous Men. In addition, the chapter considers Caldwell's journalism, which originally raised national attention to the plight of the farmers he later immortalized in his fiction. Finally, the chapter closes by considering Caldwell’s later career and fall from critical favour.
Frontiers in Rehabilitation Sciences, Volume 1; https://doi.org/10.3389/fresc.2020.617782

Abstract:
Like many ground-breaking innovations, the conceptual thinking that went into The World Health Organization's International Classification of Functioning, Disability and Health (ICF) in the early 1990s had been anticipated in the literature for decades, although formally endorsed by the WHO in 2001, the result was a true paradigm shift (1). With the ICF, WHO made it clear that, although health states are purely biological phenomena, what matters to people about their health is not merely these biological processes but also the concrete impact on their daily lives: what they can do and be, the actions they perform and the life goals and aspirations they can achieve. The ICF made it clear that challenges to our health—disease, injuries, and the natural process of aging itself—bring about decrements in body functions and alterations of body structure, and these changes, in interaction with the environment, can negatively affect—sometimes trivially, sometimes profoundly—what we can do and achieve in our lives. To capture this multifaceted and continuous phenomena, the ICF proposes the term functioning—the sum total of functions and structures of the body and mind, the actions people perform, and the complex and socially-embed life activities they participate in. Functioning, as a term of science, requires both a conceptual description or model and, for scientific description, operationalization and measurement, a classification of the lived experience of health. The ICF provided both. The notion of functioning has in the last 20 years made it possible to clarify the concept and practice of healthcare, and most particular the concept and practice of rehabilitation. The ICF notion of functioning provides a clearer understanding of the health and social impact of future trends in population aging and increased prevalence of non-communicable diseases, trends that will reveal the increasing need for, and social value of rehabilitation as a health strategy. Since 2001, the ICF has been widely and diversely applied as a standard classification, an international reference language for the collection of information about the lived experience of health. The ICF complements and supplements the WHO's International Classification of Diseases (ICD) (2) as well as, more recently, the International Classification of Health Intervention (ICHI) (3). WHO's primary purpose in promulgating each of these standards is to ensure comparability of international health information—information that is of practical use to practitioners and researchers to explain and influence functioning both clinically and at the population level, and to policy-makers striving to improve the performance of national health systems to respond to the functioning needs of individuals and populations. The future of e-health and all digital applications of health information depends on data standardization, as does a more comprehensive epidemiology that goes beyond the standard health indicators of mortality and morbidity. The conceptual foundations of the ICF notion of human functioning has also spurred research and applications that have had a fundamental and diverse impact on health sciences and health and social policy. Functioning is conceptualizes in the ICF in terms of a person-environment interaction, which in turn has led to the important conceptual distinction between a person's intrinsic health capacity and the person's actual, real world performance in which her or his physical, human-built, attitudinal, and socio-political environment may hinder or enhance performance. This model has been particularly useful in clarifying the notion of disability as a problem, decline, or non-optimal functioning in one or more domains. This understanding of disability has lead to a rethinking of the most prominent policy applications of the notion of disability, and in particularly that of disability assessment and determination processes for health and social benefits, including the need for vocational rehabilitation. Rather than understanding disability purely from the perspective of biomedical phenomena, the ICF has underwritten the more robust and valid notion of disability as the outcome of an interaction between intrinsic health capacity, personal factors, and the environment. The last two decades of research and application of the ICF and its key notion of functioning point to an active future of grand challenges for rehabilitation. As one of the five health strategies recognized by the WHO, rehabilitation has historically been undervalued and misunderstood, in part because, unlike curative medicine and health promotion and disease prevention, rehabilitation seemed to have a somewhat vague aim and purely reactive posture. Recent work on the conceptualization of rehabilitation (4–7), however, has argued that the notion of functioning may be the key to a new understanding in which the aim of rehabilitation is to optimize functioning in the face of demographic and epidemiological trends that point to a future of increased population disability. It remains a challenge how this insight can be used to further clarify the role and purpose of rehabilitation as a fundamental health strategy. Equally challenging is to ensure that rehabilitation is not merely a high-income country health strategy but its aim and scope can be effectively implemented in low- and middle-income countries as well. In practical terms, clinicians require tools and an operational language in which to assess their patients and evaluate the quality and effectiveness of rehabilitation interventions. Given the importance of this area of clinical practice, there is a growing literature on the use of ICF and functioning in the development of clinical assessment, evaluation and quality management tools and methodologies (8–11). The challenge in the future is to both to continue this development, and as far as possible, to ensure comparability between approaches to rehabilitation assessment and evaluation, and recognition of the importance of rehabilitation across health and social sectors. The other major component of intervention planning for rehabilitation is goal-setting that is patient-oriented (12–14) as well as the development and application of clinical (15–17) and patient-reported (18, 19) outcome measures and related tools that reflect these goals. There is perhaps nothing more important to rehabilitation as a clinical practice than that practitioners are able to set goals and identify outcomes that represents what is of importance to the beneficiary of rehabilitation interventions. For this the notion of functioning is ideal as it captures the lived experience of health and so what actually matters to be able their health in the daily lives and over the life course. For functioning to play a role in clinical practice—either in assessment, goal-planning, outcomes, and evaluation—work needs to be done on standardized clinical reporting of the functioning information (20, 21). The case needs to be made, to the satisfaction of health policy-makers, that functioning information should be fully integrated into health information systems (22, 23), potentially within electronic health records (24). Although the groundwork for using ICF as an international reference framework for functioning information has been laid, the challenge remains to break down the barriers to an increased demand for functioning information from clinical and a recognition on the part of policy makers of the need for routine collection of functioning information in order to strengthening rehabilitation within the health system. A companion challenge is to facilitate the role of functioning information in evidence-based policy development, responsive to the relevance and value of this information, not merely in the health sector, but in the social, labor, and education sectors as well. One of the challenges identified in the WHO?s call for action Rehabilitation 2030 is to convince countries of the importance of strengthening rehabilitation within national health systems, especially in light of anticipated increased need for rehabilitation given population aging and the increased prevalence of non-communicable diseases (25). Making this case, at the national level, requires a demonstration that rehabilitation is not an added cost, but an important economic investment. The economic argument, recent work has suggested, can best be made where the economic benefit of rehabilitation is expressed in terms of functioning improvements (26, 27), but far more work needs to be done in order to fully make the economic investment argument. Around the globe, countries are realizing that it no longer makes economic or political sense to use pensions and other social policy mechanisms to exclude people experiencing disability from entering and participating in the labor market. With support, even those with severe and long-lasting impairments can be employed: it is a fundamental human rights issue (28). Vocational rehabilitation can open the door to employment and the notion of functioning has been shown to be the key metric for assessment of work capacity (29, 30), the need for vocational rehabilitation (31), and job matching (32). It remains a challenge to explore the role of functioning as the basis for return-to-work and other work related social strategies, and developing tools that ensure that people experiencing disability are, and remain, active participants in the labor market. At the heart of the ICF concept of functioning is the insight that human functioning is an outcome of complex interactions between a person's intrinsic health capacity, determined by the extent and severity of health conditions that are present, and the physical, human-being, attitudinal, social, and political environment in which the individual lives and carries out her or his life. This constituents ICF's “paradigm shift” in the understanding of the concepts of functioning, disability, and health. Yet, although the health sciences have made considerable progress toward understanding and explaining the kinds of problems and limitations in health capacity that human experience, we are just beginning to develop the science of describing and measuring the impact of the environment on functioning (33, 34). Understanding how our environment, in all of its diversity, shapes human functioning remains a challenge for the future. Finally, and in a sense most fundamentally, the notion of functioning has the potential of reorienting the basic health science of epidemiology itself, an epidemiology that includes but moves beyond biomedical epidemiology toward a more comprehensive understanding of health: an epidemiology of functioning in the light of health conditions (35). An epidemiology of functioning would seek to understand the health capacity and environmental determinants of people's actual experience of living with health conditions in their environments. Developing population metrics of functioning (36) and with the availability of very large data sets constructing functioning trajectories of aging (37) should assist in identifying identify epidemiological patterns that would greatly enhance our ability to determine the efficacy of functioning-based intervention along the life-course. As our understanding of functioning improves, and our assessment and measurement instrumentation is perfected, the challenge of a true epidemiological of functioning may be within our reach. The notion of human functioning, grounded in the ICF has in the past two decades led to a growing body of scientific literature in health generally, and rehabilitation in particular. These challenges, and undoubtedly many others that reveal themselves in future years, will raise questions that demand the highest quality scientific investigation and research. The future for research in human functioning is indeed bright. The author confirms being the sole contributor of this work and has approved it for publication. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 1. World Health Organization. International Classification of Functioning, Disability and Health. (2001). 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(2016) 48:486–93. doi: 10.2340/16501977-2109 PubMed Abstract | CrossRef Full Text | Google Scholar 36. Oberhauser C, Chatterji S, Sabariego C, and Cieza A. Development of a metric for tracking and comparing population health based on the minimal generic set of domains of functioning and health. Popul Health Metr. (2016) 14:19. doi: 10.1186/s12963-016-0088-y PubMed Abstract | CrossRef Full Text | Google Scholar 37. Chatterji S, Byles J, Cutler D, Seeman T, and Verdes E. Health, functioning, and disability in older adults—present status and future implications. Lancet. (2015) 385:563–75. doi: 10.1016/S0140-6736(14)61462-8 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: functioning, challenge, epidemiology, clinical practice, research, International Classification of Functioning, Disability and Health Citation: Bickenbach J (2021) Human Functioning: Developments and Grand Challenges. Front. Rehabilit. Sci. 1:617782. doi: 10.3389/fresc.2020.617782 Received: 15 October 2020; Accepted: 04 December 2020; Published: 10 March 2021. Edited and reviewed by: Michaela Coenen, Ludwig Maximilian University of Munich, Germany Copyright © 2021 Bickenbach. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Jerome Bickenbach, [email protected]
Angalla Affleck Romaric Ledier, Lamini Norbert, Ntsiba Honoré, Akoli Ekoya, Nkouala Kidédé Chabel, Omboumahou Bakale Francina, Salémo Anah Précieu
European Scientific Journal ESJ, Volume 17, pp 51-51; https://doi.org/10.19044/esj.2021.v17n3p51

Abstract:
Objective: To describe characteristics of complementary and alternative medicine (CAM) in patients with knee osteoarthritis. Materials and Methods: A cross-sectional, descriptive, and analytical study was carried out on patients with knee osteoarthritis. This was followed by Rheumatology consultation at the University Hospital of Brazzaville from 2017 to 2018 within a period of one (1) year. The diagnosis of knee osteoarthritis was made European Scientific Journal, ESJ ISSN: 1857-7881 (Print) e - ISSN 1857-7431 January 2021 edition Vol.17, No.3 www.eujournal.org 53 on the basis of ACR 1986 criteria. The elements of the CAM were obtained by questioning the patients. Results: Out of the one hundred and five cases, 101 were female (96.2%) and 4 were male (3.8%). The sex ratio was 0.03. The mean age was 56, 44 +/- 10, 29 years (range 30-80 years). Knee osteoarthritis was bilateral (86.7%), unilateral right (9.5%) and left (3.8%). 68 patients (64.8%) used CAM, 97.1% women and 2.9% men. 77.5% of patients used CAM during the diagnosis, 15.5% before diagnosis, and 7% after. The type of CAM are: massages of essential oils (72%), scarifications (61%), thermal cures (51.5%), phytotherapy (22%), cupitherapy (17.6 %), and acupuncture in 10.3% of cases. 58.2% of patients used CAM to relieve pain, 18.4% to cure, 15.3% to improve function, and 7.1% of cases to reduce the side effects of treatment. Conclusion: Our study reports a great diversity of CAM types used in knee osteoarthritis, which is dominated by essential oils in topical application. Objectif : Rapporter les caractères de la médecine complémentaire et alternative (CAM) chez les patients gonarthrosiques. Matériels et Méthodes : Etude transversale, descriptive et analytique portant sur les patients présentant une gonarthrose et suivis en consultation de Rhumatologie au CHU de Brazzaville de 2017 à 2018, soit 1 an. Le diagnostic de gonarthrose était retenu sur la base des critères ACR 1986. Les éléments de la CAM ont été obtenus par l’interrogatoire des patients. Résultats : Nous avons inclus cent cinq cas, dont 101 de sexe féminin (96,2%) et 4 cas de sexe masculin (3,8%). Le sexe ratio était de 0,03. L’âge moyen était de 56 ,44+/-10 ,29 ans (extrêmes European Scientific Journal, ESJ ISSN: 1857-7881 (Print) e - ISSN 1857-7431 January 2021 edition Vol.17, No.3 www.eujournal.org 52 30-80 ans). Le siège de la gonarthrose était bilatéral (86,7%), unilatéral droit (9,5%) et gauche (3,8%).68 patients (64,8%) ont fait recours à la CAM dont 97,1% des femmes et 2,9% d’hommes. 77,5% des patients ont utilisé la CAM au cours de l’annonce du diagnostic, 15,5% avant le diagnostic et 7% après. Le type de la CAM était : les massages d’huiles essentielles (72%) des cas, les scarifications (61%), les cures thermales (51,5%), la phytothérapie (22%), la cupitherapie (17,6%) et l’acupuncture dans 10,3% des cas. 58,2% des patients utilisaient la CAM pour soulager la douleur, 18,4% pour guérir,15,3% pour améliorer la fonction et 7,1% des cas pour atténuer les effets secondaires des traitements. Conclusion : Notre étude rapporte la grande diversité des types de CAM utilisés dans la gonarthrose, dominés par les huiles essentielles en application topique.
Corrigendum
Nida Mubin, Mohd. Saad Umar, ,
Published: 20 January 2021
Frontiers in Microbiology, Volume 11; https://doi.org/10.3389/fmicb.2020.621067

Abstract:
A Corrigendum onSelective Targeting of 4SO4-N-Acetyl-Galactosamine Functionalized Mycobacterium tuberculosis Protein Loaded Chitosan Nanoparticle to Macrophages: Correlation With Activation of Immune Systemby Mubin, N., Umar, M. S., Zubair, S., and Owais, M. (2018). Front. Microbiol. 9:2469. doi: 10.3389/fmicb.2018.02469 In the original article, there was a mistake in Figure 5 as published. The figure panels were arranged incorrectly. The corrected Figure 5 appears below. Figure 5. Confocal microscope image showing M. smegmatis biofilm inhibition by CNPs as visualized in 63X oil immersion magnification: anti-biofilm activity of CNPs was assessed by incubating M. smegmatis with increasing concentrations of CNPs for 36 h in a six-well plate. The treated biofilm was stained with SYTO-9/PI. The addition of increasing concentration (100–200 μg/ml) of CNPs inhibited M. smegmatis biofilm formation. Red-dye showing PI-stain corresponds to killing activity, Green dye showing viable bacteria in pre formed biofilm. Yellow color corresponds to co-localization of merged green and red dye at same place. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. Keywords: Acr-1 (Rv2031c), M. smegmatis, RAW264.7, 4-SO4-GalNAc, CNPs Citation: Mubin N, Umar MS, Zubair S and Owais M (2021) Corrigendum: Selective Targeting of 4SO4-N-Acetyl-Galactosamine Functionalized Mycobacterium tuberculosis Protein Loaded Chitosan Nanoparticle to Macrophages: Correlation With Activation of Immune System. Front. Microbiol. 11:621067. doi: 10.3389/fmicb.2020.621067 Received: 24 October 2020; Accepted: 21 December 2020; Published: 20 January 2021. Edited and reviewed by: Arunas Ramanavicius, Vilnius University, Lithuania Copyright © 2021 Mubin, Umar, Zubair and Owais. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Swaleha Zubair, [email protected]; Mohammad Owais, [email protected]
Yelda Kasimoğlu, Merve Esen, Nisanur Firat, Elif Bahar Tuna-Ince
Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi pp 1-1; https://doi.org/10.17567/ataunidfd.706809

Abstract:
Amaç: Bruksizm, çocukları ve erişkinleri etkileyen bir parafonksiyonel alışkanlıktır. Bu çalışmada ebeveynlerin çocuklar ve genç erişkinlerde görülen bruksizm üzerine bilgi ve tutumlarının incelenmesi amaçlanmıştır. Gereç ve Yöntem: Çalışma kapsamında kliniğe başvuran çocukların ebeveynlerine 52 adet çok seçenekli sorudan oluşan anket soruları yöneltilmiştir. 367 ebeveynin anket yanıtları çalışmaya dahil edilmiştir. İstatistiksel analizde tanımlayıcı istatistikler, Ki-kare testi, Fisher’ın kesin Ki-kare testi ve Spearman’ın korelasyon testi kullanılmış ve p değeri 0.05 olarak belirlenmiştir. Bulgular: Ebeveynlerin %38,7’si bruksizmin tanımını bildiklerini belirtmişlerdir. Çalışmaya dahil edilen çocukların %29,4’ünde bruksizm olduğu, %45.5’inde bruksizm olmadığı ve kalan %25,1’inde ebeveynlerinin bir fikri olmadığı görülmüştür. Bruksizmin nedenleri arasında duygusal (%45,8), dişlerle ilgili (%16,9), ilaçlara bağlı (%3,5), dini/ruhani (%3) ve diğer faktörler (%0,5) gösterilmiştir. Bruksizmin tedavisinin psikolojik tedavi ile (%34,1), diş tedavileri ile (%23,7), tıbbi tedaviler ile (%6,5) ve dini yöntemler ile (%0,8) yapılabileceği belirtilmiştir. Çocuklarında bruksizm olduğu bildirilen ebeveynlerin %72,2’si çocuklarda bruksizm ile ilgili daha fazla bilgi edinmek istediklerini, %15,7’si ise isteksiz olduklarını, %12’si ise kararsız olduklarını bildirmişlerdir. Evli ve ayrılmış ebeveynlerin çocuklarında bruksizm varlığı arasında istatistiksel olarak anlamlı bir farklılık bulunmuştur (p Anahtar Kelimeler bruksizm, çocuk, genç erişkin Kaynakça 1. Patıroğlu AM, Didinen S, Tuğba E. Çocuklarda tüm yönleriyle bruksizm. Atatürk Üni Diş Hek Fak Derg 2016; 16: 114-9. 2. Rossi D, Manfredini D. Family and school environmental predictors of sleep bruxism in children. J Orofac Pain 2013; 27(2): 135-41. 3. Bortoletto CC, da Silva FC, da Costa Silva PF, de Godoy CHL, Albertini R, Motta LJ, et al. 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Ayrıntılar Birincil Dil tr Konular Diş Hekimliği Yazarlar Orcid: 0000-0003-1022-2486Yazar: Yelda KASIMOĞLU Kurum: İSTANBUL ÜNİVERSİTESİ, DİŞ HEKİMLİĞİ FAKÜLTESİ, DİŞ HEKİMLİĞİ (DR)Ülke: Andorra Orcid: 0000-0003-1386-5954Yazar: Merve ESEN Kurum: İSTANBUL ÜNİVERSİTESİ, DİŞ HEKİMLİĞİ FAKÜLTESİ, TEMEL BİLİMLER BÖLÜMÜÜlke: Andorra Orcid: 0000-0002-5879-7660Yazar: Nisanur FIRAT Kurum: İSTANBUL ÜNİVERSİTESİ, DİŞ HEKİMLİĞİ FAKÜLTESİ, TEMEL BİLİMLER BÖLÜMÜÜlke: Andorra Orcid: 0000-0001-6450-6869Yazar: Elif Bahar TUNA-İNCE Kurum: İSTANBUL ÜNİVERSİTESİ, DİŞ HEKİMLİĞİ FAKÜLTESİ, TEMEL BİLİMLER BÖLÜMÜÜlke: Andorra Tarihler Yayımlanma Tarihi : 19 Ocak 2021 Kaynak Göster Bibtex @araştırma makalesi { ataunidfd706809, journal = {Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi}, issn = {1300-9044}, eissn = {2667-5161}, address = {}, publisher = {Atatürk Üniversitesi}, year = {2021}, pages = {1 - 1}, doi = {10.17567/ataunidfd.706809}, title = {EBEVEYNLERİN ÇOCUK VE GENÇ ERİŞKİNLERDE BRUKSİZM İLE İLGİLİ BİLGİ VE TUTUMLARININ DEĞERLENDİRİLMESİ}, key = {cite}, author = {KASIMOĞLU, Yelda and ESEN, Merve and FIRAT, Nisanur and TUNA-İNCE, Elif Bahar} } APA KASIMOĞLU, Y , ESEN, M , FIRAT, N , TUNA-İNCE, E . (2021). EBEVEYNLERİN ÇOCUK VE GENÇ ERİŞKİNLERDE BRUKSİZM İLE İLGİLİ BİLGİ VE TUTUMLARININ DEĞERLENDİRİLMESİ. Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi , , 1-1 . DOI: 10.17567/ataunidfd.706809 MLA KASIMOĞLU, Y , ESEN, M , FIRAT, N , TUNA-İNCE, E . "EBEVEYNLERİN ÇOCUK VE GENÇ ERİŞKİNLERDE BRUKSİZM İLE İLGİLİ BİLGİ VE TUTUMLARININ DEĞERLENDİRİLMESİ". Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi (2021 ): 1-1 Chicago KASIMOĞLU, Y , ESEN, M , FIRAT, N , TUNA-İNCE, E . "EBEVEYNLERİN ÇOCUK VE GENÇ ERİŞKİNLERDE BRUKSİZM İLE İLGİLİ BİLGİ VE TUTUMLARININ DEĞERLENDİRİLMESİ". Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi (2021 ): 1-1 RIS TY - JOUR T1 - EBEVEYNLERİN ÇOCUK VE GENÇ ERİŞKİNLERDE BRUKSİZM İLE İLGİLİ BİLGİ VE TUTUMLARININ DEĞERLENDİRİLMESİ AU - Yelda KASIMOĞLU , Merve ESEN , Nisanur FIRAT , Elif Bahar TUNA-İNCE Y1 - 2021 PY - 2021 N1 - doi: 10.17567/ataunidfd.706809 DO - 10.17567/ataunidfd.706809 T2 - Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi JF - Journal JO - JOR SP - 1 EP - 1 SN - 1300-9044-2667-5161 M3 - doi: 10.17567/ataunidfd.706809 UR - https://doi.org/10.17567/ataunidfd.706809 Y2 - 2020 ER - EndNote %0 Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi EBEVEYNLERİN ÇOCUK VE GENÇ ERİŞKİNLERDE BRUKSİZM İLE İLGİLİ BİLGİ VE TUTUMLARININ DEĞERLENDİRİLMESİ %A Yelda KASIMOĞLU , Merve ESEN , Nisanur FIRAT , Elif Bahar TUNA-İNCE %T EBEVEYNLERİN ÇOCUK VE GENÇ ERİŞKİNLERDE BRUKSİZM İLE İLGİLİ BİLGİ VE TUTUMLARININ DEĞERLENDİRİLMESİ %D 2021 %J Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi %P 1300-9044-2667-5161 %R doi: 10.17567/ataunidfd.706809 %U 10.17567/ataunidfd.706809 ISNAD KASIMOĞLU, Yelda , ESEN, Merve , FIRAT, Nisanur , TUNA-İNCE, Elif Bahar . "EBEVEYNLERİN ÇOCUK VE GENÇ ERİŞKİNLERDE BRUKSİZM İLE İLGİLİ BİLGİ VE TUTUMLARININ DEĞERLENDİRİLMESİ". Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi (Ocak 2021): 1-1 . https://doi.org/10.17567/ataunidfd.706809 AMA KASIMOĞLU Y , ESEN M , FIRAT N , TUNA-İNCE E . EBEVEYNLERİN ÇOCUK VE GENÇ ERİŞKİNLERDE BRUKSİZM İLE İLGİLİ BİLGİ VE TUTUMLARININ DEĞERLENDİRİLMESİ. Ata Diş Hek Fak Derg. 2021; 1-1. Vancouver KASIMOĞLU Y , ESEN M , FIRAT N , TUNA-İNCE E . EBEVEYNLERİN ÇOCUK VE GENÇ ERİŞKİNLERDE BRUKSİZM İLE İLGİLİ BİLGİ VE TUTUMLARININ DEĞERLENDİRİLMESİ. Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi. 2021; 1-1. Tam Metin ( )
Katherine J. Aney,
Published: 14 January 2021
The Journal of Pathology; https://doi.org/10.1002/path.5619

Abstract:
The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains dismal. Multiple genome wide association studies (GWAS) have implicated the nuclear receptor NR5A2 in modulating PDAC risk, but mechanisms for this association are not understood. NR5A2 is a transcription factor that maintains acinar cell identity, and heterozygous loss of Nr5a2 in mice accelerates oncogenic KRAS‐driven formation of pancreatic intraepithelial neoplasia (PanIN), a PDAC precursor derived from acinar cells. In a recent issue of The Journal of Pathology, Cobo et al. characterize a novel mouse model that uses Ptf1a:Cre to drive oncogenic Kras as well as heterozygous Nr5a2 inactivation. In addition to the expected PanIN lesions, these mice exhibited a surprising phenotype: large pancreatic cystic lesions which have not been previously reported. Comparing expression of oncogenic Kras and heterozygous Nr5a2 in various mouse models reveals several possible explanations for these cystic lesions. Importantly, these differences across mouse models suggest that NR5A2 may contribute to PDAC precursors in ways beyond its previously characterized acinar cell autonomous role. These observations highlight that pathways implicated by GWAS may have roles in unexpected cell types, and an understanding of these roles will be critical to guide new preventive and treatment strategies for PDAC.
Published: 1 January 2021
Radiology, Volume 298, pp 28-35; https://doi.org/10.1148/radiol.2020202903

Abstract:
Inaugural consensus statements were developed and endorsed by the American College of Radiology (ACR) and the National Kidney Foundation to improve and standardize the care of patients with kidney disease who have indication(s) to receive ACR-designated group II or group III intravenous gadolinium-based contrast media (GBCM). The risk of nephrogenic systemic fibrosis (NSF) from group II GBCM in patients with advanced kidney disease is thought to be very low (zero events following 4931 administrations to patients with estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m2; upper bounds of the 95% confidence intervals: 0.07% overall, 0.2% for stage 5D chronic kidney disease [CKD], 0.5% for stage 5 CKD and no dialysis). No unconfounded cases of NSF have been reported for the only available group III GBCM (gadoxetate disodium). Depending on the clinical indication, the potential harms of delaying or withholding group II or group III GBCM for an MRI in a patient with acute kidney injury or eGFR less than 30 mL/min per 1.73 m2 should be balanced against and may outweigh the risk of NSF. Dialysis initiation or alteration is likely unnecessary based on group II or group III GBCM administration. This article is a simultaneous joint publication in Radiology and Kidney Medicine. The articles are identical except for stylistic changes in keeping with each journal’s style. Either version may be used in citing this article. © 2020 RSNA and the National Kidney Foundation published by Elsevier Inc. This is an open access article under the CC BY NC-ND license.
Two centuries of the Russian classics, Volume 3; https://doi.org/10.22455/2686-7494-2021-3-3-6-21

Abstract:
The article discusses two points of view on the primary education, literacy — I. S. Turgenev’s and A. A. Fet’s. The author describes the landmark clash between Turgenev and Fet, and also shows the mood and plans of both writers in the early 1860s. In August 1860, in anticipation of the abolition of serfdom, while in England, on the Isle of Wight, Turgenev conceived and drew up a “Draft Program for the Society for the Promotion of Literacy and Primary Education”. And Fet, forced to leave literature as a result of “persecution” of “pure art”, acquired 200 acres of black soil in the Mtsensk district. On the eve of the abolition of serfdom, the poet, who did not have his own estate and serfs, found himself in the position of a farmer, who had to endure fully on his own experience the endless troubles associated with the introduction of reforms in all spheres of economic and political life. His journalism touched upon a variety of issues, one of which was literacy. Fet’s opinion on this issue looks paradoxical. However, he was not alone, urging not to equate literacy, education and upbringing, giving preference to the moral upbringing of the people in solving the problem. A similar position was taken by V. I. Dal, whose letter to the publisher of the journal “Russkaya Beseda” A. I. Koshelev is analyzed in the article.
Miaomiao Han, Yiqiang Chen, Juntao Li, Yuanyang Dong, Zhiqiang Miao, Jianhui Li,
Journal of the Science of Food and Agriculture, Volume 101, pp 3917-3926; https://doi.org/10.1002/jsfa.11053

Abstract:
BACKGROUND Trivalent chromium (Cr) is involved in carbohydrate, lipid, protein and nucleic acid metabolism in animals. This study evaluated the effects of different organic Cr forms with Cr methionine (CrMet), Cr picolinate (CrPic), Cr nicotinate (CrNic), and Cr yeast (Cr‐yeast) at the level of 400 μg kg−1 Cr, on growth performance, lipid metabolism, antioxidant status, breast amino acid and fatty acid profiles of broilers. In total, 540 one‐day‐old Arbor Acres male broilers were randomly assigned to five treatments with six replicates (18 broilers per replicate) until day 42. RESULTS The results showed growth performance was not affected by Cr sources. The Cr‐yeast group had lower serum cortisol levels than the CrNic group (P< 0.05). Besides, Cr‐yeast increased methionine and cysteine content in breast compared with the control group. Liver malondialdehyde content was lower in the CrMet group than the CrPic group on day 42 (P< 0.05). The n‐3 polyunsaturated fatty acid (PUFA) values were increased, but the n‐6/n‐3 PUFA ratio was decreased in both CrMet and CrNic groups (P< 0.05). There were no significant effects on broilers’ serum antioxidant status and breast total essential amino acid content among all treatments. CONCLUSIONS Diets supplemented with organic Cr could regulate lipid metabolism, and improve amino acid and fatty acid profiles in broiler breast. Moreover, Cr‐yeast was the most effective source in improving methionine and cysteine content, whereas CrMet was more effective than CrNic in increasing n‐3 PUFA value and decreasing n‐6/n‐3 PUFA ratio in breast meat and effectively strengthened liver antioxidant ability than CrPic. © 2020 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Corrigendum
, J. A. A. S. Jayaweera, W. Kumbukgolla, M. V. M. L. Jayasundara
Frontiers in Cellular and Infection Microbiology, Volume 10; https://doi.org/10.3389/fcimb.2020.631515

Abstract:
A Corrigendum onAssociation of Hantavirus Infections and Leptospirosis With the Occurrence of Chronic Kidney Disease of Uncertain Etiology in the North Central Province of Sri Lanka: A Prospective Study With Patients and Healthy Personsby Sunil-Chandra NP, Jayaweera JAAS, Kumbukgolla W and Jayasundara MVML (2020). Front. Cell. Infect. Microbiol. 10:556737. doi: 10.3389/fcimb.2020.556737 In the original article, there was an error in the ethical clearance number. The correct number for ethical clearance is ERC/2012/33. A correction has been made to Materials and Methods, Paragraph 3:According to CKDu case definition, an individual identified with an albumin-to-creatinine ratio (ACR) ≥ 30 mg/g urine creatinine during the initial visit and at a follow-up visit, a normal glycosylated hemoglobin (HbA1c <6.5%), not on treatment for diabetes, no elevated blood pressure, and no past history of kidney disease or snake bite were included. Patients with other known causes of chronic kidney disease (CKD) and those who did not consent were excluded from the study (16,13). Studies involving human patients/participants were reviewed and approved by the Research, Ethical Review and Higher degree committee of the faculty of Medicine and Allied Sciences, Rajarata University, Sri Lanka. Patients/participants provided their written informed consent to participate in this study (ERC/2012/33). The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. Keywords: hantaviruses, leptospira, sero-prevalence, chronic kidney disease, CKDu Citation: Sunil-Chandra NP, Jayaweera JAAS, Kumbukgolla W and Jayasundara MVML (2020) Corrigendum: Association of Hantavirus Infections and Leptospirosis With the Occurrence of Chronic Kidney Disease of Uncertain Etiology in the North Central Province of Sri Lanka: A Prospective Study With Patients and Healthy Persons. Front. Cell. Infect. Microbiol. 10:631515. doi: 10.3389/fcimb.2020.631515 Received: 20 November 2020; Accepted: 25 November 2020; Published: 17 December 2020. Approved by: Frontiers Editorial Office, Frontiers Media SA, Switzerland Copyright © 2020 Sunil-Chandra, Jayaweera, Kumbukgolla and Jayasundara. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: N. P. Sunil-Chandra, [email protected]
Mehmet Alagoz, Joseph Besho
Published: 1 December 2020
Journal of Vascular Surgery, Volume 72, pp 2215-2216; https://doi.org/10.1016/j.jvs.2020.04.531

The publisher has not yet granted permission to display this abstract.
Journal of Neuro-Ophthalmology, Volume 40, pp 572-577; https://doi.org/10.1097/wno.0000000000001147

Abstract:
In this issue of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD, and Mark L. Moster, MD will discuss the following 6 articles: Li L, Dmytriw AA, Krings T, Feng Y, Jiao L. Visualization of the human intracranial vasa vasorum in vivo using optical coherence tomography. JAMA Neurol. 2020;77:903–905. Lee KE, Zehri A, Soldozy S, Syed H, Catapano JS, Maurer R, Albuquerque FC, Liu KC, Wolfe SQ, Brown S, Levitt MR, Fargen KM. Dural venous sinus stenting for treatment of pediatric idiopathic intracranial hypertension. J Neurointerv Surg. [published online ahead of print July 30, 2020] doi:10.1136/neurintsurg-2020-016183. Matza MA, Fernandes AD, Stone JH, Unizony SH. Ustekinumab for the treatment of giant cell arteritis. Arthritis Care Res (Hoboken). [published online ahead of print April 5, 2020] doi:10.1002/acr.24200. Kunchok A, Aksamit AJ Jr, Davis JM III, Kantarci OH, Keegan BM, Pittock SJ, Weinshenker BG, McKeon A. Association between tumor necrosis factor inhibitor exposure and inflammatory central nervous system events. JAMA Neurol. 2020;77:937–946. Mac Grory B, Nackenoff A, Poli S, Spitzer MS, Nedelmann M, Guillon B, Preterre C, Chen CS, Lee AW, Yaghi S, Stretz C, Azher I, Paddock J, Bakaeva T, Greer DM, Shulman JG, Kowalski RG, Lavin P, Mistry E, Espaillat K, Furie K, Kirshner H, Schrag M. Intravenous fibrinolysis for central retinal artery occlusion: a cohort study and updated patient-level meta-analysis. Stroke. 2020;51:2018–2025. Lopez-Chiriboga S, Sechi E, Buciuc M, Chen JJ, Pittock SJ, Lucchinetti CF, Flanagan EP. Long-term outcomes in patients with myelin oligodendrocyte glycoprotein immunoglobulin G–associated disorder. JAMA Neurol. [published online ahead of print August 31, 2020] doi:10.1001/jamaneurol.2020.3115.
, Santiago Medrano, José María Maiques, Jaume Capellades
Published: 30 November 2020
Frontiers in Neurology, Volume 11; https://doi.org/10.3389/fneur.2020.579079

Abstract:
Since the first case of infection was reported in December 2019, in Wuhan, China, SARS CoV 2 has spread all over the world, and was declared as a pandemia on the 11th of March by the WHO. The reported mortality rate is between 0.3 and 1% in the general population, rising to 14% in hospitalized cases (1). Even though Covid-19 infection causes a predominantly respiratory disease, its explosive eruption worldwide has affected all medical specialties. Health care systems and workers have had to react rapidly. Each region and hospital has adapted differently depending on their specific characteristics, the prevalence of the infection and the recommendations of governments and preventative medical services. The practice of Neuroradiology, along with Radiology departments, have not escaped the effects and have had to face up to the new circumstances (2). Some works (articles, webinars and guidelines) have appeared giving recommendations and sharing their experience to face the challenge that the Covid-19 pandemia implies for the Neuroradiology. In this article, we present and discuss these recommendations in the different phases of the pandemia. In the early stages of the pandemia, crisis committees, connected with the local, regional and state public institutions, were created to establish new guidelines and protocols for each center (3–7). A general practice adopted in Radiology and Neuroradiology, was the creation of departmental co-ordination groups (typically comprising a radiologist/neuroradiologist, a radiographer and a secretary), to work in conjunction with these committees (8–10). In addition, general measures were implemented to limit the exposure of healthcare workers and patients and for early viral detection. Securing the supply of medical material and personal protective equipment (PPE) was also a priority (6). As the rapid and explosive spread of the Covid-19 infection required a rapid response, this coordination and reorganization of Radiology departments, a common strategy followed in hospitals, was, in our opinion, key to achieving this. The supply of PPE for staff, another critical point during the early stages of the pandemia, was a great challenge, due to the high worldwide demand (11). In this phase various measures have been recommended. One of these is the strict selection of neuroimaging tests. Although each center has had to set their own criteria depending on their particular idiosyncrasies, there have been some general recommendations (4, 5, 12, 13). In the case of critical examinations, where the neuroimaging could impact the immediate management of patients, the recommendation has been to perform the test despite the pandemic situation, subject to a risk/benefit analysis. In the case of non-critical neuroradiological examinations, the recommendation has been to postpone them and establish levels of priority (13–16). In some cases, examinations could even be canceled (15). In this phase, the increased pressure on hospitals due to the number of Covid patients, with the consequent lack of material and human resources, and the need for social distancing, has made it impossible to carry out the usual volume of examinations. For this reason, even if there have been no specific recommendations on which particular neuroradiological examinations to maintain, we believe that the prioritization of tests during the peak of the pandemia has been key to ensure that the most critical patients received an optimal radiological diagnosis. The establishment of different priority levels in the elective tests has been essential for their orderly rescheduling. To give an objective view of the impact, neuroradiological examinations during the pandemic peak decreased by almost 50% (17, 18). We think it has also been important, as emphasized in some articles, the need of a fluid communication between neurologists, neurosurgeons and other clinicians, to highlight any special situations arising in particular cases. Special mention should be made of patients with acute stroke, who present a particular challenge for neuroradiology departments, due to the existing relationship reported between patients with severe coronavirus infection and cerebrovascular stroke disease (19). As these patients usually undergo a brain CT and angio-CT scan, some studies have recommended the incorporation of a chest CT to rule out the possible existence of a concomitant pneumonia due to Covid-19, which would require isolation of the patient (20, 21). It seems a sensible recommendation when the prevalence of the infection in the population is high. In terms of patient protection, the first step has been to detect potential cases in patients coming for a neuroradiological test. To this end screening questionnaires (3–5, 9) have been carried out, often even conducted by telephone before the arrival of the patient, followed by PCR tests if necessary and available. Specific circuits have been established within Neuroradiology departments to avoid contact between infected and uninfected patients. “Clean” radiological equipment has been kept for uninfected patients and “dirty” for infected patients (5, 13, 22–25). Social distancing has been enforced in waiting rooms and masks made mandatory for all patients (5, 13, 26). Cleaning, disinfection and air purification frequency have also been increased (5, 13, 22–25). These are reasonable measures which are recommended in guidelines and have been adopted generally in hospitals and imaging centers. We think it is important that each hospital establishes their own protocols, as these recommendations can be carried out in different ways according to particular characteristics. For example, in relation to air purification, some of the recommended measures have been the use of a high-efficiency particulate air (HEPA) filter, ultraviolet irradiation or simply lengthening the time between two patients. The choice as to which to use is a decision that depends on multiple factors. In relation to the use of masks or other medical devices, such as ventilators, in Neuroradiology departments, we think it is important to highlight that they need to be compatible with the MRI environment, for both safety and image quality reasons. In the case of CT examinations, they must not contain metallic elements which could distort the image (26–29). In terms of healthcare staff protection, education about security measures, the provision of PPE and the establishment of physical barriers, such as plastic screens and equipment covers, have been some of the more extensively adopted precautionary measures (5, 13, 14). Tele-neuroradiology has been another widely adopted practice to reduce the exposure of departmental staff, with the use of “Picture Archiving and Communication System” PACS. Where telematic work has not been possible, the establishment of groups, working different hours or days, has been an extensively used option, along with the use of individual workstations and maintaining social distancing in the work-space (7, 26, 29). In order to maintain clinical and educational communication, the use of phone calls (instead of personal interactions) and teleconference applications for virtual sessions has been widespread, especially for essential clinical care meetings (30). These applications allow communication from workstations or even phones, and also screen sharing to show neuro-radiological images (25). Probably one of the most specific challenge for Neuroradiology, related to the staff protection, has been the rapid deployment of Home PACS Workstations and the expansion of teleradiology (31–33). Once the peak of the pandemic has passed, the most emphasized recommendation for Radiology departments has been to recover activity in a tiered manner (13–15, 34–36). The postponed examinations should be re-scheduled following the degrees of priority established during the peak of the pandemia (13–15). The new petitions generated by the recovery of activity in hospitals also need to be taken into account. We think that all these common measures to recover radiological activity, have to be adapted to each situation, as the prevalence of the pandemia and the resources of health care systems could be very variable. In this regard we found the work of Madhuripan et a. (17) interesting, which related the radiology volume recovery after the pandemia to different variants, such as regional pandemic severity, the lifting of government restrictions, patient Covid-19 infection concern, management during the pandemic peak, impact of the economic recession and Radiology practice profile. General measures to avoid the transmission of Covid-19 have still been recommended in this phase and are likely to be necessary for some time (35). For example, the obligatory use of masks and enforcing of social distancing in the hospital, the use of PPE for health workers and the increased disinfection and ventilation of imaging suites. As a result of these measures, Radiology departments still need to allow for longer times between patient examinations. Many hospitals have responded to this by increasing the hours of radiological assistance, extending the activity of the MRI and CT scans during the night and weekend shifts (34, 35). We think this may be necessary to re-schedule all the postponed activity, but hospital management must take into account that it may mean hiring more staff or agreeing new shifts with workers. The continued use of tele-radiology, at least partially, is still recommended at this stage (13, 34, 35). This has been one of the most widespread measures adopted in neuroradiology and has generally been implemented successfully (31–33). After these experiences and in line with other articles (37), we believe that for neuroradiologists, the coronavirus pandemic may contribute to the permanent establishment of tele-neuroradiology, or at least to a mixed model with part of the time physically present and part of the time reporting remotely. The particular challenges for the practice of Neuroradiology during the Covid pandemia have been different during the distinct phases. In the early stage, the main challenge was the need for a rapid response. During the peak of the pandemia, the challenge was to maintain critical neuroimaging assistance, whilst preventing the spread of the infection amongst patients and healthcare workers. After the peak of the pandemia the challenge has been to recover neuroradiological activity while maintaining some Covid-19 measures, which seem likely to continue for a while. Some of the strategies with which Neuroradiology has faced the challenges of each phase have been general, and others more specific to the specialty. Broadly they have been quite consistent throughout the different articles and guidelines published. After the peak of the Covid-19 pandemia we have to stay alert and know how to react on time to possible next waves, using what we have already learnt during these months. Neuroradiology assistance should be maintained taking into account the general care of the patients and the global health situation. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 1. World Health Organization. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 COVID-19. (2020). Available online at: https://www.who.int/docs/defaultsource/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf Google Scholar 2. Mahajan A, Hirsch JA. Novel coronavirus: what neuroradiologists as citizens of the world need to know. Am J Neuroradiol. (2020) 41:552–4. doi: 10.3174/ajnr.A6526 PubMed Abstract | CrossRef Full Text | Google Scholar 3. Chen RC, Tan TT, Chan LP. Adapting to a new normal? 5 key operational principles for a radiology service facing the COVID-19 pandemic. 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(2020) 17:1053–5. doi: 10.1016/j.jacr.2020.06.009 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: neuroradiology, radiology, tele-radiology, personal protective equipment, COVID-19 Citation: González-Ortiz S, Medrano S, Maiques JM and Capellades J (2020) Challenges in Neuroimaging in COVID-19 Pandemia. Front. Neurol. 11:579079. doi: 10.3389/fneur.2020.579079 Received: 02 July 2020; Accepted: 14 October 2020; Published: 30 November 2020. Edited by: Reviewed by: Copyright © 2020 González-Ortiz, Medrano, Maiques and Capellades. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Sofía González-Ortiz, [email protected]
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