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Nuklearmedizin - NuclearMedicine, Volume 60, pp 458-459; https://doi.org/10.1055/a-1668-8055

Abstract:
Im April 2021 ist Herr Dr. rer. nat. Johannes Notni ([Abb. 1]) zum Professor der Universität Duisburg-Essen (UDE) ernannt worden und seitdem dort an der Medizinischen Fakultät als Leiter der Experimentellen Radiopharmazie tätig. Herr Professor Notni studierte Chemie an der Friedrich-Schiller-Universität Jena. Während seiner Diplomarbeit und Dissertation am Institut für Organische Chemie und Makromolekulare Chemie erforschte er Wirkmechanismen von Zinkenzymen und promovierte über "Zinkthiolat- und Hydrogensulfidkomplexe als vielseitige Enzymmodelle". Als DAAD-Stipendiat am Lehrstuhl für Koordinations- und Bioanorganische Chemie der Karls-Universität Prag initiierte er in den Jahren 2007 und 2008 ein Forschungsprogramm zu innovativen Ga-68-Chelatoren zur Anwendung in Kontrastmitteln für die Positronenemissionstomografie. Ab 2009 führte er diese Tätigkeiten an der TU München fort, wobei er seine Forschungsinteressen auf Radiometall-Komplexe für nuklearmedizinische Bildgebung und Therapie, MRT-Kontrastmittel, sowie präklinische Evaluation und klinische Translation innovativer Radiodiagnostika und -therapeutika erweiterte. Er habilitierte sich im Jahr 2015 im Fach Chemie und blickt mittlerweile auf 20 Jahre Lehrtätigkeit in den Fachgebieten Organische sowie Anorganischer Chemie, Radiochemie und Radiopharmazie zurück. Seine Forschung wurde mehrfach ausgezeichnet, unter anderem im Jahr 2011 mit dem "SNM Radiopharmaceutical Chemistry Young Investigator Award, 1st Prize" und im Jahr 2013 mit dem Innovationspreis in Medizinisch-Pharmazeutischer Chemie der GdCh und DPhG. 2016 erhielt er den EANM Springer Prize für das meistzitierte Paper im Journal „EJNMMI Research“ und 2017 den Georg von Hevesy-Preis der Deutschen Gesellschaft für Nuklearmedizin. Die DGN gratuliert Herrn Professor Notni sehr herzlich. Publication Date: 24 November 2021 (online) © 2021. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany
Corrigendum
Xiaoyi Wang, Anbang Wang, Yujia Li, Yi Xu, Qing Wei, Jiashui Wang, Fei Lin, Deyong Gong, Fei Liu, Yanting Wang, et al.
Published: 8 November 2021
Frontiers in Plant Science, Volume 12; https://doi.org/10.3389/fpls.2021.796904

Abstract:
A Corrigendum onA Novel Banana Mutant “RF 1” (Musa spp. ABB, Pisang Awak Subgroup) for Improved Agronomic Traits and Enhanced Cold Tolerance and Disease Resistanceby Wang, X., Wang, A., Li, Y., Xu, Y., Wei, Q., Wang, J., Lin, F., Gong, D., Liu, F., Wang, Y., Peng, L., and Li, J. (2021). Front. Plant Sci. 12:730718. doi: 10.3389/fpls.2021.730718 In the published article, there was an error regarding the order of funding agencies as listed in the Funding statement. The correct Funding statement appears below. This work was financially supported by the Youth Foundation of Natural Science Foundation of Hainan Province (320QN306), the China Agriculture Research System of MOF and MARA (CARS-31-02), and the Lancang-Mekong Cooperation Special Fund. 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. Keywords: “ReFen 1” mutant, Pisang Awak (ABB), ethyl methanesulfonate (EMS)-mutagenesis, semi-dwarfing, agronomic traits, cold tolerance, sigatoka disease resistance, banana breeding Citation: Wang X, Wang A, Li Y, Xu Y, Wei Q, Wang J, Lin F, Gong D, Liu F, Wang Y, Peng L and Li J (2021) Corrigendum: A Novel Banana Mutant “RF 1” (Musa spp. ABB, Pisang Awak Subgroup) for Improved Agronomic Traits and Enhanced Cold Tolerance and Disease Resistance. Front. Plant Sci. 12:796904. doi: 10.3389/fpls.2021.796904 Received: 18 October 2021; Accepted: 20 October 2021; Published: 08 November 2021. Approved by: Copyright © 2021 Wang, Wang, Li, Xu, Wei, Wang, Lin, Gong, Liu, Wang, Peng and Li. 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: Jingyang Li, [email protected] These authors have contributed equally to this work ORCID: Fei Liu orcid.org/0000-0003-0979-9982
Juliana E. Hidalgo-Lopez, Gail J. Roboz, Brent Wood, Michael Borowitz, Elias J. Jabbour, Kelly Velasco, Ehab Elkhouly, Babatunde Adedokun, Faraz Zaman, Karim Iskander, et al.
Published: 5 November 2021
Blood, Volume 138, pp 4478-4478; https://doi.org/10.1182/blood-2021-144353

Abstract:
Background: MRD testing in BCP-ALL is critical for appropriate patient management, but little is known regarding sample acquisition and testing heterogeneity across clinical practice settings. These factors may impact the quality and reliability of MRD assessment. Methods: Thirty-minute online surveys were conducted in May 2021 with hematologists/oncologists (HEME/ONCs) in the United States in both academic (acad) and community (comm) settings. Respondents were licensed physicians board certified in oncology and/or hematology who treated ≥2 BCP-ALL patients/year or ≥10 patients in the past 5 years, with over 25% of time spent in the clinical setting; pediatric HEME/ONCs were excluded. Survey enrollment is ongoing, with interim results presented here; a related survey for pathologists (PATHs) is underway. Results: HEME/ONC respondents (acad n=40, comm n=57, from 29 states) had been practicing as specialists for a median of between 11-15 years (choices were ranges, eg 6-10, 11-15, min-max was 1-34 years), and typically spent over 75% of their time in the clinic; 94% of respondents had ≥5 BCP-ALL patients/year and 92% ordered MRD tests for ≥5 patients/year. Typical timepoints for MRD testing included the end of induction/suspected complete remission, the end of consolidation, and at suspected disease progression; testing after the end of consolidation was infrequent in both groups (Table). Testing for MRD at the end of consolidation was notably more frequent in the academic setting. In both settings, the HEME/ONC ordering the MRD test generally also performed the bone marrow collection procedure (acad: 78%, comm: 56%). Resources consulted on bone marrow collection best practices included UpToDate (21%), ASH and ASCO (13%), NCCN guidelines (13%), and hematology/oncology journals. About half of practices had defined institutional protocols for bone marrow collection (acad: 55%, comm: 47%), nearly all of which were developed internally. The amount of bone marrow sample collected showed high variability, ranging from 1-10 draws (median=3) and 1-30 mL sample per draw (median=5 mL). While 49% of HEME/ONCs performed <5 draws and extracted ≤6 mL per draw, 22% collected 10 mL/draw, and 10% collected 20 mL/draw; the remaining 18% reported >5 draws and/or >6 mL per draw. In both settings, the first pull was identified and labeled in 35% of procedures; in those cases, the first-pull samples were used primarily for MRD testing in 60% of cases as recommended by NCCN guidelines (vs for morphology assessment and cytogenetic studies). HEME/ONCs typically relied on the expertise of pathologists to choose MRD testing methodology.Survey results indicate that external labs (both national clinical reference labs and commercial labs) were most commonly used for MRD assessments (63%); comm HEME/ONCs were more likely to use external reference labs and acad HEME/ONCs were more likely to use in-house labs. When asked to estimate the frequency with which different MRD methods were used, mean responses were 54% flow cytometry and 40% next-generation sequencing. While all HEME/ONCs indicated that MRD results were presented clearly in lab reports, there was a desire to include more guideline information about MRD interpretation and BCP-ALL treatment. Conclusion: Interim results identified broad heterogeneity in clinical practices affecting sample collection for MRD assessment in Ph- BCP-ALL in the US, indicating several opportunities for harmonization of routine MRD assessment in BCP-ALL. These opportunities include optimization of bone marrow sample collection techniques (volume/draw and identification/use of first pull for MRD), timing/frequency of specimen collection, serial MRD surveillance after consolidation, MRD method chosen, and standardizing reports to include guideline information. There were gaps in awareness of FDA-approved methods of MRD testing for BCP-ALL. Initiatives supporting provider education and harmonization of best practices from professional guideline committees/organizations are needed to optimize outcomes of BCP-ALL patients. Figure 1 Figure 1. Disclosures: Hidalgo-Lopez: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Roboz: Janssen: Research Funding; Daiichi Sankyo: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Mesoblast: Consultancy; Bayer: Consultancy; Blueprint Medicines: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Astex: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jasper Therapeutics: Consultancy; Helsinn: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Wood: Pfizer, Amgen, Seattle Genetics: Honoraria; Juno, Pfizer, Amgen, Seattle Genetics: Other: Laboratory Services Agreement. Borowitz: Amgen, Blueprint Medicines: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Velasco: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Elkhouly: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Adedokun: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Zaman: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Iskander: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding.
Ahmad Nanaa, Aref Al-Kali, David S. Viswanatha, James M. Foran, Talha Badar, Lisa Z. Sproat, Rong He, Phuong L Nguyen, Dragan Jevremovic, Mohamed E Salama, et al.
Published: 5 November 2021
Blood, Volume 138, pp 3691-3691; https://doi.org/10.1182/blood-2021-144400

Abstract:
Background: The DEAD-box helicase 41 (DDX41), an RNA helicase, have been described as a component of the RNA spliceosome (Cheah et al. International Journal of Hematology 2017). Although DDX41 mutations predispose to late-onset higher grade myeloid neoplasms (MN), these patients may have a trend toward favorable prognosis and outcomes. In this work, we describe the clinical characteristics and survival outcomes of isolated and co-mutated DDX41 patients (pts). Methods: We retrospectively analyzed 4,524 consecutive pts who underwent next-generation sequencing (NGS) (OncoHeme 42 genes panel, Mayo Clinic) testing and included 32 pts harboring pathogenic DDX41 mutation and one pt with proven DDX41 germline variant of unknown significance (VUS). Chart review of DDX41-mutated (m) cases between 2009 and 2021 was conducted after IRB approval. We compared overall survival (OS) of unmatched 27 t(8;21)AML and 40 inv(16) AML pts with 10 m DDX41-AML pts. JMP® Pro 14.1.0 Software was used for statistical analysis. Results: DDX41 mutations characteristics: Our cohort included 19 (58%) myelodysplastic syndromes (MDS), 10 (30%) acute myelogenous leukemia (AML), 2 (6%) myeloproliferative neoplasms (MPN), one clonal cytopenia of undetermined significance (CCUS) (3%) and one (3%) germline carrier. Germline testing was carried out in 10 pts, 9 of whom (90%) were confirmed to be germline). The start-loss variant (p.M1I) was the most common mutation type (N=10, 31%). Other types were frameshift (N=9, 28%), missense mutation (N=8, 25%), nonsense (N=3, 9%), and splice site mutation (N=2, 2%). Twenty-one (65.6%) DDX41 mutations clustered in the N-terminus (NT), 7 (22%) in the helicase-C domain (HCD), and 4 (12.5%) in the DEAD-box domain. Compared to NT mutations, patients with HCD mutation had no family history of solid tumors and were more likely to have an accompanying additional DDX41-VUS (0% vs 70%; p=.001) and (N=6, 86% vs. N=2,10%; p=.0001); respectively. I solated vs. co-mutated DDX41: Twenty (60%) pts were isolated-DDX41 and 13 (40%) were co-mutated. The median DDX41-VAF was 48% vs. 45% (p= .2) in the isolated compared to the co-mutated cases, respectively. The median number of co-mutations in the 13 co-mutated cases was 1 (range,1-3) with DNMT3A (38%), ASXL1 (30%), JAK2 (N=3, 23%), and EZH2 (N=2, 15%) were the most common co-mutations detected. Isolated DDX41 had more males (85% vs. 54%, p=.05), the p.M1I variant (47% vs. 8%, p=.02), normal cytogenetics (100% vs. 91%, p= .02), and less family history of solid tumors (77% vs. 33%, p= .02) compared to their co-mutated counterparts. However, there was no difference in OS (p=.99). Comparison of clinical characteristics and hematological features of isolated and co-mutated DDX41 pts are reported in (Table 1). Treatment and survival outcomes in DDX41-MDS/AML : Twenty-three (80%) patients were treated, MDS pts received hypomethylating agents (HMA) (N=10, 71%), HMA plus Venetoclax (HMA+VEN) (N=1, 7%), erythropoiesis-stimulating agents (N=2, 14%) and lenalidomide (N=1 ,7%). AML pts were treated with induction chemotherapy (N=6, 67%) and HMA+VEN (N=3, 33%). Overall response rate of MDS/AML patients was 77% and 100% of AML pts achieved complete remission (CR) when treated with induction chemotherapy or HMA+VEN regimen. There was no significant difference in OS between responders vs. non-responders 2-yr-OS (90% vs. 50%; p=.38) and treated vs. untreated 2-yr-OS (83% vs. 100%; p=.52). Comparing m DDX41-AML vs. core binding factor-AML: After a median follow-up of 33.3 months, all m DDX41-AML patients were alive. There was a significantly better OS in mDDX41-AML patients compared to pts with t(8;21) AML with 2-yr-OS (100% vs. 51%; p=.024) and a trend of better survival when compared to inv(16) AML 2-yr-OS (100% vs. 84%; p=.2). Conclusion We describe the characteristics and outcomes of m DDX41 patients. We demonstrated that isolated and co-mutated m DDX41 patients have different features. Isolated DDX41 patients had male predominance, more p.M1I variant, normal cytogenetics and less family history of solid tumors. In this study we found that m DDX41 AML has high response to treatment and has comparable (if not possibly better) OS compared to other "favorable risk" AML. This study, although limited by the small number of patients, supports the universal testing for DDX41 mutation in adults with MN diagnosis. Figure 1 Figure 1. Disclosures: Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Foran: abbvie: Research Funding; OncLive: Honoraria; boehringer ingelheim: Research Funding; trillium: Research Funding; pfizer: Honoraria; takeda: Research Funding; revolution medicine: Honoraria; bms: Honoraria; gamida: Honoraria; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; servier: Honoraria; taiho: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; certara: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Litzow: Astellas: Research Funding; Biosight: Other: Data monitoring committee; Amgen: Research Funding; AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board. Patnaik: Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees.
Saad Z. Usmani, Shaji Kumar, Torben Plesner, Robert Z. Orlowski, Philippe Moreau, Nizar J. Bahlis, Supratik Basu, Hareth Nahi, Cyrille Hulin, Hang Quach, et al.
Published: 5 November 2021
Blood, Volume 138, pp 1646-1646; https://doi.org/10.1182/blood-2021-146940

Abstract:
Introduction: The phase 3 MAIA study (NCT02252172) evaluated the addition of daratumumab (D) to lenalidomide and dexamethasone (Rd) in patients (pts) with transplant-ineligible newly diagnosed multiple myeloma (NDMM). At a median follow-up of 56.2 months, D-Rd prolonged progression-free survival (PFS) and overall survival (OS) versus Rd alone, despite almost half of the pts in the Rd arm who received subsequent therapy receiving a daratumumab-containing regimen as any subsequent line of therapy (Facon T, et al. Presented at: European Hematology Association 2021 Virtual Congress. Abstract LB1901). Approximately 20% to 50% of pts with MM have baseline renal impairment that can affect the choice and efficacy of therapy (Dimopoulos MA, et al. Journal of Clinical Oncology. 2016;34[13]:1544-1557). Here, we report results from MAIA for D-Rd vs Rd in pts with impaired renal function based on lenalidomide starting dose at a median follow-up of 56.2 months. Methods: Pts with NDMM ineligible for high-dose chemotherapy and autologous stem-cell transplantation due to age ≥65 years or comorbidities were randomized 1:1 to receive D-Rd or Rd. Pts in both arms received 28-day cycles of oral Rd (R: 25 mg [10 mg recommended if creatinine clearance (CrCl) was 30-50 mL/min] on Days 1-21; d: 40 mg [20 mg if aged >75 years or body-mass index <18.5 kg/m 2] on Days 1, 8, 15, 22). Pts in the D-Rd arm also received intravenous D (16 mg/kg once weekly for Cycles 1-2, once every 2 weeks for Cycles 3-6, and once every 4 weeks thereafter). Pts in both arms were treated until disease progression or unacceptable safety events. The primary endpoint was PFS, and a secondary endpoint was OS. Renal impairment was defined as a baseline CrCl of ≤60 mL/min. Results: 737 pts were randomized (D-Rd, n=368; Rd, n=369); 162 (44%) pts in the D-Rd arm and 142 (38%) pts in the Rd arm had renal impairment as defined. At a median follow-up of 56.2 months, in pts with renal impairment who received a lenalidomide starting dose of 25 mg (25 mg subgroup; D-Rd, n=60 [37%]; Rd, n=62 [44%]), a PFS and OS advantage was observed with D-Rd versus Rd (Table). In pts with renal impairment who received a lenalidomide starting dose of <25 mg (<25 mg subgroup; D-Rd, n=98 [60%]; Rd, n=75 [53%]), median PFS and OS were prolonged with D-Rd versus Rd (Table). Among pts in the 25 mg subgroup who died (D-Rd, n=12; Rd, n=29), disease progression was the primary cause of death in 6 (50%) pts in the D-Rd arm and 10 (34%) pts in the Rd arm. Among pts in the <25 mg subgroup who died (D-Rd, n=44; Rd, n=37), disease progression was the primary cause of death in 16 (36%) pts in the D-Rd arm and 11 (30%) pts in the Rd arm. Conclusion: After ~5 years of follow-up, D-Rd showed a PFS improvement versus Rd in transplant-ineligible pts with NDMM and renal impairment regardless of lenalidomide starting dose. An OS advantage for D-Rd versus Rd was observed in pts with renal impairment who received a lenalidomide starting dose of 25 mg; in pts with renal impairment who received a lenalidomide starting dose of <25 mg, median OS was prolonged for D-Rd versus Rd, but the OS benefit was less pronounced. Overall, among pts with renal impairment, PFS and OS benefits of D-Rd versus Rd were observed regardless of lenalidomide starting dose; however, dose recommendations per the lenalidomide prescribing information should be followed. Many transplant-ineligible pts with NDMM may not receive a second line of therapy; our results support the frontline use of D-Rd to provide prolonged disease control in transplant-ineligible pts with NDMM and renal impairment. Figure 1 Figure 1. Disclosures: Usmani: Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau. Kumar: Novartis: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Plesner: CSL Behring: Other: Advisor; Genentech: Other: Advisor, Research Funding; Oncopeptides: Other: Advisor, Research Funding; Takeda: Research Funding; Celgene: Other: Advisor, Research Funding; AbbVie: Other: Advisor, Research Funding; Janssen: Other: Advisor, Research Funding; Genmab: Research Funding. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides...
Efficacy and Mechanism Evaluation, Volume 8, pp 1-90; https://doi.org/10.3310/eme08170

Abstract:
High cure rates with licensed durations of therapy for chronic hepatitis C virus suggest that many patients are overtreated. New strategies in individuals who find it challenging to adhere to standard treatment courses could significantly contribute to the elimination agenda. To compare cure rates using variable ultrashort first-line treatment stratified by baseline viral load followed by retreatment, with a fixed 8-week first-line treatment with retreatment with or without adjunctive ribavirin. An open-label, multicentre, factorial randomised controlled trial. Randomisation was computer generated, with patients allocated in a 1 : 1 ratio using a factorial design to each of biomarker-stratified variable ultrashort strategy or fixed duration and adjunctive ribavirin (or not), using a minimisation algorithm with a probabilistic element. NHS. A total of 202 adults (aged ≥ 18 years) infected with chronic hepatitis C virus genotype 1a/1b or 4 for ≥ 6 months, with a detectable plasma hepatitis C viral load and no significant fibrosis [FibroScan® (Echosens, Paris, France) score F0–F1 or biopsy-proven minimal fibrosis], a hepatitis C virus viral load < 10,000,000 IU/ml, no previous exposure to direct-acting antiviral therapy for this infection and not pregnant. Patients co-infected with human immunodeficiency virus were eligible if human immunodeficiency virus viral load had been < 50 copies/ml for > 24 weeks on anti-human immunodeficiency virus drugs. Fixed-duration 8-week first-line therapy compared with variable ultrashort first-line therapy, initially for 4–6 weeks (continuous scale) stratified by screening viral load (variable ultrashort strategy 1, mean 32 days of treatment) and then, subsequently, for 4–7 weeks (variable ultrashort strategy 2 mean 39 days of duration), predominantly with ombitasvir, paritaprevir, ritonavir (Viekirax®; AbbVie, Chicago, IL, USA), and dasabuvir (Exviera®; AbbVie, Chicago, IL, USA) or ritonavir. All patients in whom first-line treatment was unsuccessful were immediately retreated with 12 weeks’ sofosbuvir, ledipasvir (Harvoni®, Gilead Sciences, Inc., Foster City, CA, USA) and ribavirin. The primary outcome was overall sustained virological response (persistently undetectable) 12 weeks after the end of therapy (SVR12). A total of 202 patients were analysed. All patients in whom the primary outcome was evaluable achieved SVR12 overall [100% (197/197), 95% confidence interval 86% to 100%], demonstrating non-inferiority between fixed- and variable-duration strategies (difference 0%, 95% confidence interval –3.8% to 3.7%, prespecified non-inferiority margin 4%). A SVR12 following first-line treatment was achieved in 91% (92/101; 95% confidence interval 86% to 97%) of participants randomised to the fixed-duration strategy and by 48% (47/98; 95% confidence interval 39% to 57%) allocated to the variable-duration strategy. However, the proportion achieving SVR12 was significantly higher among those allocated to variable ultrashort strategy 2 [72% (23/32), 95% confidence interval 56% to 87%] than among those allocated to variable ultrashort strategy 1 [36% (24/66), 95% confidence interval 25% to 48%]. Overall, a SVR12 following first-line treatment was achieved by 72% (70/101) (95% confidence interval 65% to 78%) of patients treated with ribavirin and by 68% (69/98) (95% confidence interval 61% to 76%) of those not treated with ribavirin. A SVR12 with variable ultrashort strategies 1 and 2 was 52% (25/48) (95% confidence interval 38% to 65%) with ribavirin, compared with 44% (22/50) (95% confidence interval 31% to 56) without. However, at treatment failure, the emergence of viral resistance was lower with ribavirin [12% (3/26), 95% confidence interval 2% to 30%] than without [38% (11/29), 95% confidence interval 21% to 58%; p = 0.01]. All 10 individuals who became undetectable at day 3 of treatment achieved first-line SVR12 regardless of treatment duration. Five participants in the variable-duration arm and five in the fixed-duration arm experienced serious adverse events (p = 0.69), as did five participants receiving ribavirin and five participants receiving no ribavirin. SVR12 rates were significantly higher when ultrashort treatment varied between 4 and 7 weeks, rather than between 4 and 6 weeks. We found no evidence of ribavirin significantly affecting first-line SVR12, with unsuccessful first-line short-course therapy also not compromising subsequent retreatment with sofosbuvir, ledipasvir and ribavirin. A priority for future work needs to be the development and evaluation of robust predictive measures to identify those patients who can be cured with ultrashort courses of therapy. Current Controlled Trials ISRCTN37915093, EudraCT 2015-005004-28 and CTA 19174/0370/001-0001. This project was funded by the Efficacy and Mechanism Evaluation programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 17. See the NIHR Journals Library website for further project information.
Bulletin of the British Ornithologists’ Club, Volume 141, pp 245-247; https://doi.org/10.25226/bboc.v141i3.2021.a1

Abstract:
The Club's next meeting will be on Monday 18 October, at 6pm, via the online medium of Zoom, and will feature a presentation by Alexander Lees (Manchester Metropolitan University) on the topic Does bird feeding help or hinder avian conservation? Further details of forthcoming meetings in 2021 will be announced online via the Club's website: https://boc-online.org/meetings/upcomingmeeting, or follow the Club's Twitter(@online_BOC) and Facebook accounts ( https://www.facebook.com/onlineBOC). Be sure to keep an eye on them!William Richmond Postle Bourne, MA, MB, B CH, MBOU (1930–2021)Bill Bourne died peacefully at Keith, in Scotland, on 31 May 2021, aged 91. Bill wrote so much: papers in this Bulletin are noted below, and are illustrative of the breadth and depth of his ornithological interests and knowledge. Much has been written about him over his working life as a medic, in travel, in research and writing. Bill featured as the 12th in the series ‘Personalities’ in the April 1978 issue of British Birds. The authors’ perception of Bill, a legend of energy, knowledge and eccentricity were shown to stand the test of time. He joined the BOC in 1956. When I first met him in 1969 at the Autumn Scientific meeting of the British Ornithologists’ Union he encouraged me to do so too, and he proved to be a great friend as I forged my early contacts in the world of exploration, museums, research and societies.Bill's energy and resourcefulness are well illustrated in his 1951 solo W. R. P. Bourne (© Sheila expedition to the Cape Verdes, as a result of which he contributed to the Bourne) Bannermans' History of the birds of the Cape Verde Islands. His early enthusiasm for birds and their nests was imparted by three maiden aunts. At age seven his father introduced him to egg collecting, which he pursued for ten years, then saw the error, destroyed his collection, and joined the British Trust for Ornithology. He spent most of the war in Bermuda enjoying tropicbirds and terns, and learning about boats and seabirds. From this time his particular interest was the Tubinares. David Bannerman recounts how at the hottest time of year, with little money and no transport of any kind, Bill relied entirely on his wits in his solo Cape Verde endeavour. It says much for his stamina and enthusiasm that he walked across all of São Tiago, over the roughest country, while his journeys between the islands were perforce made in local schooners. With an interest more in ecology than in specimen collecting just one was taken, an example of a Purple Heron Ardea purpurea, from a colony he discovered on São Tiago. He was struck by the paleness of their plumage and the specimen he secured was sent to Paris. After some years, a new race was named by the Abbé René de Naurois in Bill's honour, A. p. bournei.Bill read medicine and zoology at Cambridge, and completed his training at St Bartholomew's Hospital, London. Service in the RAF took him to Malta, Jordan and the Middle East at the time of the Suez crisis, then Cyprus, where he was co-founder and first recorder of the Cyprus Ornithological Society. His passionate interest in islands and seabirds came to the fore when, in 1961, he proposed to found the Seabird Group, which eventually formed in 1965, a timely formation ahead of the Torrey Canyon disaster in March 1967. He became its first secretary, whilst in the role of adviser to the Royal Naval Bird Watching Society (RNBWS) he codified the collection of avian data from ships at sea (Sea Swallow 13: 9–16), including ocean weather ships in the eastern Atlantic at a time when reports were pouring in. During this period, when I first met Bill, he worked at Watford General Hospital as a geriatrician. Each year he would diligently analyse the RNBWS seabird reports and write them up for Sea Swallow, teasing out the distribution of various petrels and shearwaters. In the 1980s he was at sea himself, as a ship's surgeon and medic with the Royal Fleet Auxiliary ships (RFA) that serve to support the fleet at sea. In 1983 RFA Olwen took him to high latitudes in the South Atlantic after the Falklands War. A letter from the Vice Chief of the Naval Staff forwarded Bill's report of watches in ten-minute blocks covering voyages to the Falklands and South Georgia via Ascension Island, where landing was not possible, but he made useful observations offshore. In the Falklands HMS Bristol gave Bill the chance to visit New Island and see one of the main seabird colonies. He also visited the British Antarctic Survey base on Bird Island. The RFA also took him beyond the Southern Ocean on one of three voyages to the Arabian Sea. RFA Tidespring saw him off Fujairah, from where he wrote complaining of being ‘called back from leave three weeks early because they are six doctors under strength’. He noted the temperature regularly over 100°F, and said to be 145° in the boiler room; ‘everyone including me has prickly heat, and if I do not look out as much as possible the trip will be wasted – there were Persian Shearwaters [Puffinus persicus] this morning, 10th August 1988’.Many research papers on the taxonomy of petrels emanated from Bill and were published in journals on both sides of the Atlantic. In Europe, one of the islands to attract Bill was Madeira, and its enigmatic Pterodroma petrels. Frank Zino recalls their voluminous correspondence and Bill and his wife Sheila's visit in October 1993, including to the breeding site at Pico do Areeiro. He was a great help to those tracking down the freira, as it was known to the locals, or Pterodroma madeira. Bill came up with the suggestion that it be known as Zino's Petrel to honour the Zino family, who put so much effort into conserving the bird.So, with that glimpse of a life filled to the brim with action, activity and results, I will sign off in the same way his perfectly typed letters came to me:...
Ke Stull, Lk Corron
Published: 12 August 2021
by Zenodo
Abstract:
The dental and skeletal indicators were collected from full body CT images of individuals aged between birth and 22 years, generated in the past ~10 years. There are 64 variables in the dataset and include diaphyseal lengths, epiphyseal fusion, and dental development. Diaphyseal lengths were taken to the nearest hundredth of a millimeter. See Stull et al (2014) for a detailed methodology. The remaining variables are ordinal. Depending on the element and location there was a different epiphyseal fusion staging system employed: a seven-stage system was used for the long bone epiphyses and the calcaneal tuberosity; a three-stage system for the pelvis; a binary absent/present was used for the carpals and tarsals, ossification of the elements of the proximal and distal humerus (e.g., humeral head, lesser tubercle, greater tubercle, capitulum, trochlea, composite epiphyses), and the patella. Dental development was scored using a 13-stage system (from 1 to 13) defined by AlQahtani, Hector, & Liversidge (2010). See Corron et al. (2021) for detailed information regarding ordinal data collection methodology; the publication includes the abbreviations and full variable names along with its staging system. Basic Key Code: *DL_L/R or *DB_R/L == diaphyseal lengths *EF_L/R == epiphyseal fusion *Oss == ossification *man_ and max_ == dental development References AlQahtani, S., Hector, M., & Liversidge, H. (2010). Brief communication: the London atlas of Human tooth development and eruption. 142, 461-490. Corron, LK, et al., Standardizing ordinal subadult age indicators: Testing for observer agreement and consistency across modalities. Forensic Science International 320, 110687 (2021). Stull, K., L'Abbé, E., & Ousley, S. (2014). Using multivariate adaptive regression splines to estimate subadult age from diaphyseal dimensions. American Journal of Physical Anthropology, 154(3), 376-386.
Ke Stull, Lk Corron
Published: 12 August 2021
by Zenodo
Abstract:
The dental and skeletal indicators were collected from full body CT images of individuals aged between birth and 22 years, generated in the past ~10 years. There are 64 variables in the dataset and include diaphyseal lengths, epiphyseal fusion, and dental development. Diaphyseal lengths were taken to the nearest hundredth of a millimeter. See Stull et al (2014) for a detailed methodology. The remaining variables are ordinal. Depending on the element and location there was a different epiphyseal fusion staging system employed: a seven-stage system was used for the long bone epiphyses and the calcaneal tuberosity; a three-stage system for the pelvis; a binary absent/present was used for the carpals and tarsals, ossification of the elements of the proximal and distal humerus (e.g., humeral head, lesser tubercle, greater tubercle, capitulum, trochlea, composite epiphyses), and the patella. Dental development was scored using a 13-stage system (from 1 to 13) defined by AlQahtani, Hector, & Liversidge (2010). See Corron et al. (2021) for detailed information regarding ordinal data collection methodology; the publication includes the abbreviations and full variable names along with its staging system. Basic Key Code: *DL_L/R or *DB_R/L == diaphyseal lengths *EF_L/R == epiphyseal fusion *Oss == ossification *man_ and max_ == dental development References AlQahtani, S., Hector, M., & Liversidge, H. (2010). Brief communication: the London atlas of Human tooth development and eruption. 142, 461-490. Corron, LK, et al., Standardizing ordinal subadult age indicators: Testing for observer agreement and consistency across modalities. Forensic Science International 320, 110687 (2021). Stull, K., L'Abbé, E., & Ousley, S. (2014). Using multivariate adaptive regression splines to estimate subadult age from diaphyseal dimensions. American Journal of Physical Anthropology, 154(3), 376-386.
Leila Lax
Journal of Biocommunication, Volume 45; https://doi.org/10.5210/jbc.v45i1.10832

Abstract:
The 2019 Toronto Symposium, THE VIENNA PROTOCOL: Medicine's Confrontation with Continuing Legacies of its Nazi Past, was sponsored by Biomedical Communications, Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto and the Neuberger Centre for Holocaust Education. https://www.holocaustcentre.com/hew-2019/the-vienna-protocol Prof. Leila Lax, coordinated the Symposium and was inspired by its presenters to create an online collection of Holocaust education resources. She is grateful to the Editor-in-Chief, Gary Schnitz and the Journal of Biocommunication Management Board for their dedication to scholarship, ethics, and the advancement of knowledge, in support of this Special Issue, that deals with contemporary controversies from a dark time in history, that is part of our professional legacy - and memory. This Special Issue is dedicated to the memory of the victims portrayed in the Pernkopf atlas. Image credit: Table of Contents image provided by the Medical University of Vienna, MUW-AD-003250-5-ABB-151.
Gary W. Schnitz
Journal of Biocommunication, Volume 45; https://doi.org/10.5210/jbc.v45i1.10831

Abstract:
Welcome to the Journal of Biocommunication’s Special Issue 45-1. We have designated this publication as a JBC “Special Issue,” as it is devoted entirely to one topic. Our current Special Issue includes articles and commentaries all related to Eduard Pernkopf’s, Atlas of Topographical and Applied Human Anatomy. Our authors have provided in-depth discussions about the Pernkopf’s atlas’ dark history, the uncertain origin of cadavers used as references for the atlas, and medical crimes of the Third Reich. Seven of the articles are authored by some of the world’s leading historians and authorities on the subject of the Pernkopf atlas and the abuses of Nazi medicine. These authors presented papers at a Holocaust Education Week Symposium that was held on Nov. 10, 2019, at the Temerty Faculty of Medicine, University of Toronto, Toronto, Canada. This landmark Symposium was called, “The Vienna Protocol: Medicine’s Confrontation with Continuing Legacies of its Nazi Past.” The Symposium faculty included Susan Mackinnon, MD, Rabbi Joseph Polak, William E. Seidelman, MD, Sabine Hildebrandt, MD, Philip Berger, MD, Anne Agur, PhD, and Leila Lax, PhD, who also served as the Symposium coordinator and host. Table of Contents image credit: Medical University of Vienna, MUW-AD-003250-5-ABB-81.
M Luisetto, Edbey Khaled, Gr Mashori, Ilman Ahnaf, Ar Yesvi, Oy Latyschev
Archives of Biotechnology and Biomedicine, Volume 5, pp 049-056; https://doi.org/10.29328/journal.abb.1001028

Abstract:
Related the physio-pathological process of COVID-19 disease it is interesting to focus to the aspect. Played by interaction of Sars-Cov-2 protein with integrins of human epithelial pulmonary cell. A bio molecular approach help in to deeply verify the involved factors and the results of this Activation RGD mediated. Of Great interest also the relationship with some vaccine strategy followed by the various pharmaceutical industry. The results of this work will be useful to think modification in some vaccine increasing the global safety and related some rare ADR.
Corrigendum
S. T. Raterman, J. R. Metz, Frank A. D. T. G. Wagener, Johannes W. Von Den Hoff
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.650948

Abstract:
A Corrigendum on Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors by Raterman, S. T., Metz, J. R., Wagener, F. A. D. T. G., and Von den Hoff, J. W. (2020). Front. Cell Dev. Biol. 8:600926. doi: 10.3389/fcell.2020.600926 In the original article, there was an error. The error concerned reported exposure percentages. A correction has been made to reported percentages in Alcohol, paragraph three: “In search of ethanol sensitivity windows for craniofacial development, zebrafish embryos were exposed to a—rather extreme—regime of 10% ethanol during defined developmental stages (Ali et al., 2011). At 25 and 31 hpf (developmental stages prim-6 and prim-16, respectively) embryos were most susceptible to defects of the branchial arches and Meckel's cartilage (Ali et al., 2011). Furthermore, in the late blastula and early gastrula stages, embryos appeared to be specifically sensitive for the induction of cyclopia after exposure to 2.4% ethanol (Blader and Strahle, 1998). Upon chronic exposure, distinct craniofacial effects have been observed depending on ethanol dosage. Ethmoid plate development and head width were reduced at concentrations as low as 3 mM (0.01%), which can be reached in women upon drinking only one alcoholic beverage (Carvan et al., 2004; Ferdous et al., 2017). Interestingly, with rising concentrations, a sensitivity shift was reported. At 10 mM ethanol (0.04%), neurocranium structures were more severely affected than structures of the viscerocranium, while at 30 mM (0.13%) the opposite was observed (Carvan et al., 2004). Variations in sensitivity to ethanol exposure between zebrafish strains are also reported. Upon exposure, Ekkwill strain zebrafish presented with a severely affected viscerocranium and increased apoptosis, whereas AB strain zebrafish had affected neurocranial cartilages such as the ethmoid plate. In Tübingen strain zebrafish larvae a high mortality rate was observed, but this strain was less prone to craniofacial defects (Loucks and Carvan, 2004). The strain specific sensitivity to ethanol implicates that predisposing genetic factors and GxE interactions are involved.” A correction has been made to reported percentages in Vitamins and ExE Interactions, Vitamin A, paragraph four: “Epidemiological studies showed that the risk of FASD and craniofacial malformation were higher in pregnancies with alcohol exposure in low socioeconomic environments. In these environments, maternal malnutrition and vitamin (A) deficiency are more frequent (Jiang et al., 2020). Ethanol competes with retinol for a dehydrogenase that converts retinol into RA and ethanol into acetaldehyde (Marrs et al., 2010). In zebrafish, RA and ethanol appear to exert opposing effects on ethmoid plate development. Zebrafish larvae treated with 100 mM (0.6%) ethanol showed a reduced ethmoid plate width, which was rescued by a low dose (1 nM) of exogenous RA. In the same study, RA addition without alcohol exposure resulted in a wider ethmoid plate (Marrs et al., 2010). Disruption of RA signaling appears to be a distinct mechanism of alcohol teratogenesis and is an example of an ExE interaction.” The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. Ali, S., Champagne, D. L., Alia, A., and Richardson, M. K. (2011). Large-scale analysis of acute ethanol exposure in zebrafish development: a critical time window and resilience. PLoS One 6:e20037. doi: 10.1371/journal.pone.0020037 PubMed Abstract | CrossRef Full Text | Google Scholar Blader, P., and Strahle, U. (1998). Ethanol impairs migration of the prechordal plate in the zebrafish embryo. Dev. Biol. 201, 185–201. doi: 10.1006/dbio.1998.8995 PubMed Abstract | CrossRef Full Text | Google Scholar Carvan, M. J. III., Loucks, E., Weber, D. N., and Williams, F. E. (2004). Ethanol effects on the developing zebrafish: neurobehavior and skeletal morphogenesis. Neurotoxicol. Teratol. 26, 757–768. doi: 10.1016/j.ntt.2004.06.016 PubMed Abstract | CrossRef Full Text | Google Scholar Ferdous, J., Mukherjee, R., Ahmed, K. T., and Ali, D. W. (2017). Retinoic acid prevents synaptic deficiencies induced by alcohol exposure during gastrulation in zebrafish embryos. Neurotoxicology 62, 100–110. doi: 10.1016/j.neuro.2017.05.01 PubMed Abstract | CrossRef Full Text | Google Scholar Jiang, Q., Lu, D., Wang, F., Zhang, Y., Cao, L., Gui, Y., et al. (2020). Folic acid supplement rescues ethanol-induced developmental defects in the zebrafish embryos. Acta Biochim. Biophys. Sin. 52, 536–545. doi: 10.1093/abbs/gmaa030 PubMed Abstract | CrossRef Full Text | Google Scholar Loucks, E., and Carvan, M. J. I. I. I. (2004). Strain-dependent effects of developmental ethanol exposure in zebrafish. Neurotoxicol. Teratol. 26, 745–755. doi: 10.1016/j.ntt.2004.06.017 PubMed Abstract | CrossRef Full Text | Google Scholar Marrs, J. A., Clendenon, S. G., Ratcliffe, D. R., Fielding, S. M., Liu, Q., and Bosron, W. F. (2010). Zebrafish fetal alcohol syndrome model: effects of ethanol are rescued by retinoic acid supplement. Alcohol 44, 707–715. doi: 10.1016/j.alcohol.2009.03.004 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: zebrafish, craniofacial malformations, neural crest cells, environment, gene, interaction Citation: Raterman ST, Metz JR, Wagener FADTG and Von den Hoff JW (2021) Corrigendum: Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors. Front. Cell Dev. Biol. 9:650948. doi: 10.3389/fcell.2021.650948 Received: 08 January 2021; Accepted: 27 May 2021; Published: 24 June 2021. Edited by: Reviewed by: Copyright © 2021 Raterman, Metz, Wagener and Von den Hoff. 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...
A. O’Shea, J. Drennan, C. Littlewood, H. Slater, J. Sim, J. Mcveigh
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 293.1-293; https://doi.org/10.1136/annrheumdis-2021-eular.1279

Abstract:
Background: Shoulder pain is a significant cause of pain and disability in the general population.1 Current research suggests that shoulder pain can be resistant to treatment and is often recurrent.2 Systematic review-level evidence shows modest short-term benefits for most current treatments.3 Effective self-management strategies that equip patients with the necessary tools to self-manage their condition are urgently required. However, engagement with self-management is poor, potentially compromising treatment outcomes and contributing to ongoing disability.4 Objectives: The objectives of this review were to: •Systematically identify and appraise relevant qualitative evidence on barriers and facilitators relating to self-management from the perspectives of people with shoulder pain and healthcare professionals. •Collate and synthesise this evidence, to gain an understanding of factors that influence self-management of shoulder pain. •Develop evidence-based recommendations to inform the implementation and delivery of self-management programmes for shoulder pain. Methods: A meta-aggregative approach to the synthesis of qualitative evidence was used. Twelve databases were searched, from inception to 13 July 2020, to identify studies exploring barriers and facilitators related to self-management of shoulder pain from the perspectives of people with shoulder pain and clinicians involved in the care of such patients. Two independent reviewers identified eligible articles, extracted the data and conducted critical appraisal. Two reviewers independently identified and developed categories, with validation by two further researchers. Categories were discussed among the wider research team and a comprehensive set of synthesized findings was derived. Results: Sixteen studies were included in the review, exploring several shoulder conditions: shoulder instability; rotator cuff-related pain; dysfunction post rotator cuff surgery; and degenerative rotator cuff tears. From the perspective of patients, three synthesized findings were identified that influenced self-management: (1) support for self-management, including subthemes related to patient-centred support, knowledge, time, access to equipment, and patient digital literacy; (2) personal factors, including patient beliefs, patient expectations, patient motivation, pain, and therapeutic response; and (3) external factors, including influence of the clinician and therapeutic approach. From the perspective of clinicians, two synthesized findings were identified that influenced adherence to self-management: (1) support for self-management, including education, patient-centred support, patient empowerment, time, and clinician digital literacy; and (2) preferred management approach, including clinician beliefs, expectations, motivation, therapeutic approach, and therapeutic response. Conclusion: Patients and clinicians identified several barriers and facilitators that influenced self-management of shoulder pain. Clinicians’ awareness of these factors could positively influence patient management, enhance patients’ ability to self-manage, and improve treatment outcomes. References: [1]Walker-Bone K, Palmer KT, Reading I, Coggon D, Cooper C. Prevalence and impact of musculoskeletal disorders of the upper limb in the general population. Arthritis and Rheumatism. 2004;51(4): 642-651. [2]Croft P, Pope D, Silman A. The clinical course of shoulder pain: prospective cohort study in primary care. Primary Care Rheumatology Society Shoulder Study Group. British Medical Journal. 1996;313(7057): 601-602. [3]Littlewood C, May S, Walters S. A review of systematic reviews of the effectiveness of conservative interventions for rotator cuff tendinopathy. Shoulder & Elbow. 2013;5(3): 151-167. [4]Littlewood C, Malliaras P, Mawson S, May S, Walters S. Patients with rotator cuff tendinopathy can successfully self-manage, but with certain caveats: a qualitative study. Physiotherapy. 2014;100(1): 80-85. Disclosure of Interests: Aidan O’Shea: None declared, Jonathan Drennan: None declared, Chris Littlewood: None declared, Helen Slater Speakers bureau: AbbVie PTY LTD 2018, Julius Sim: None declared, Joseph McVeigh: 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.
C. Kelly, E. Matteson, M. Aringer, G. R. Burmester, H. Mueller, L. Moros, K. Rohr, M. Kolb
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 69.2-69; https://doi.org/10.1136/annrheumdis-2021-eular.969

Abstract:
Background: In the INBUILD trial in subjects with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 57% compared with placebo. Objectives: To assess the rate of decline in FVC in subjects with RA-ILD in the INBUILD trial. Methods: Subjects in the INBUILD trial had a chronic fibrosing ILD other than IPF, reticular abnormality with traction bronchiectasis (with or without honeycombing) of >10% extent on high-resolution computed tomography (HRCT), forced vital capacity (FVC) ≥45% predicted, diffusing capacity of the lungs for carbon monoxide ≥30%–20 mg/day. We analysed the rate of decline in FVC (mL/year) over 52 weeks and adverse events in subjects with RA-ILD. Results: Of 663 subjects who received trial medication, 89 had RA-ILD (42 nintedanib, 47 placebo), of whom 60.7% were male, 64.0% were current or former smokers, 86.5% had a usual interstitial pneumonia (UIP)-like pattern on HRCT; 93.3% had received confirmation of their RA diagnosis from a rheumatologist. At baseline, 21.3% of subjects were taking biologic disease-modifying anti-rheumatic drugs (DMARDs), 53.9% were taking non-biologic DMARDs and 73.0% were taking glucocorticoids (≤20 mg/day prednisone or equivalent). At baseline, mean (SD) age was 66.9 (9.6) years, time since RA diagnosis was 9.9 (9.4) years, time since ILD diagnosis was 3.6 (3.2) years, FVC was 71.5 (16.2) % predicted and C-reactive protein was 13.7 (22.5) mg/L. The adjusted mean (SE) rate of decline in FVC over 52 weeks was -82.6 (41.3) mL/year in the nintedanib group versus -199.3 (36.2) mL/year in the placebo group (difference 116.7 mL/year [95% CI 7.4, 226.1]; nominal p=0.037), consistent with findings in the overall trial population (Figure). As in the overall trial population, the most common adverse event in subjects with RA-ILD was diarrhoea (reported in 54.8% of the nintedanib group and 25.5% of the placebo group). Adverse events led to permanent discontinuation of trial drug in 19.0% of subjects in the nintedanib group and 12.8% of subjects in the placebo group. Conclusion: In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing RA-ILD, with adverse events that were manageable for most patients. The efficacy and safety of nintedanib in subjects with RA-ILD were consistent with those observed in the overall trial population. Acknowledgements: The INBUILD trial was funded by Boehringer Ingelheim. Medical writing support was provided by Fleishman Hillard Fishburn, London, UK. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Disclosure of Interests: Clive Kelly Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Eric Matteson Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim and Gilead Sciences, Grant/research support from: Sun Pharmaceuticals and Pfizer, Martin Aringer Speakers bureau: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Gilead, GlaxoSmithKline, HEXAL, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and UCB, Consultant of: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi and UCB, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Lilly, Merck Sharp & Dohme, Pfizer, Roche and Sanofi, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Lilly, Merck Sharp & Dohme, Pfizer, Roche and Sanofi, Heiko Mueller Employee of: Currently an employee of Boehringer Ingelheim, Lizette Moros Employee of: Currently an employee of Boehringer Ingelheim, Klaus Rohr Employee of: Currently an employee of Boehringer Ingelheim, Martin Kolb Consultant of: Algernon, Boehringer Ingelheim, Pieris Pharmaceuticals and Roche, Grant/research support from: Boehringer Ingelheim, Pieris Pharmaceuticals and Prometic
T. Maher, A. Bourdin, E. Volkmann, S. Vettori, J. H. W. Distler, M. Alves, C. Stock, O. Distler
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 671-672; https://doi.org/10.1136/annrheumdis-2021-eular.897

Abstract:
Background: In the randomized SENSCIS trial in subjects with SSc-ILD, nintedanib reduced the rate of decline in FVC over 52 weeks (mL/year) by 44% compared to placebo. Healthy individuals have varied FVC depending on age, sex, ethnicity and height; expected values can be determined using internationally recognised reference equations. Objectives: To provide further context to the FVC declines observed in the SENSCIS trial, we compared the decline in FVC observed in subjects with SSc-ILD in the SENSCIS trial with the decline in FVC that would be expected in hypothetical subjects without ILD matched for age, sex, ethnicity and height. Methods: The SENSCIS trial enrolled subjects with SSc-ILD aged ≥18 years with first non-Raynaud symptom ≤7 years before screening, extent of fibrotic ILD ≥10% on HRCT, FVC ≥40% predicted and DLco 30–89% predicted. Baseline FVC (mL) and changes in FVC (mL) at week 52 were assessed in the nintedanib and placebo groups, with missing values at week 52 imputed using predictions from the primary analysis model (random slope and intercept model). Changes in FVC in the SENSCIS trial were compared to values in hypothetical healthy reference subjects matched to the SENSCIS subjects for age, sex, ethnicity and height. FVC values in these healthy reference subjects were derived from the equations published by the European Respiratory Society Global Lung Function Initiative in 2012, which were derived from data from over 70,000 subjects.1 Results: In the nintedanib and placebo groups of the SENSCIS trial, respectively, mean (SD) time since onset of first non-Raynaud symptom was 3.5 (1.6) and 3.5 (1.8) years. In the nintedanib group, mean (SD) FVC at baseline was 2460 (737) mL, compared with 3403 (787) mL in the healthy reference subjects. In the placebo group, mean (SD) FVC at baseline was 2544 (817) mL compared with 3516 (887) mL in the healthy reference subjects. The difference in the change from baseline in FVC at week 52 between the nintedanib-treated subjects in the SENSCIS trial (n=287) and the healthy reference subjects was 26.6 mL ([95% CI: 1.2, 52.0]; p=0.04). The difference in the change from baseline in FVC at week 52 between the placebo-treated subjects in the SENSCIS trial (n=286) and the reference subjects was 77.5 mL ([95% CI: 51.4, 103.7]; p<0.001) (Figure 1). Conclusion: Subjects with SSc-ILD who participated in the SENSCIS trial had marked lung function impairment at baseline compared with healthy matched reference subjects, despite a mean duration of SSc of 3.5 years. Over 52 weeks, the decline in FVC in subjects with SSc-ILD who received placebo was 4-fold greater than in healthy reference subjects. Subjects with SSc-ILD who were treated with nintedanib had a decline in FVC that was only slightly greater than the decline observed in the matched healthy subjects. These data support the clinical relevance of the reduction in the rate of FVC decline provided by nintedanib in patients with SSc-ILD. References: [1]Quanjer et al. Eur Respir J 2012;40:1324−43. 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: Toby Maher Speakers bureau: Boehringer Ingelheim and Roche/Genentech, Consultant of: Acelleron Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline and Roche/Genentech, Arnaud Bourdin Speakers bureau: Actelion/Janssen (personal fees and other), AstraZeneca (personal fees and other), Boeringher Ingelheim (personal fees and other), Chiesi (personal fees and other), GlaxoSmithKline (personal fees and other), Novartis (personal fees and other), Pulsar Therapeutics (other), Roche (personal fees and other), Sanofi Regeneron (personal fees and other), Teva (other) and United Therapeutics (other), Consultant of: Actelion/Janssen (personal fees and other), AstraZeneca (personal fees and other), Boeringher Ingelheim (personal fees and other), Chiesi (personal fees and other), GlaxoSmithKline (personal fees and other), Novartis (personal fees and other), Pulsar Therapeutics (other), Roche (personal fees and other), Sanofi Regeneron (personal fees and other), Teva (other) and United Therapeutics (other), Grant/research support from: Actelion/Janssen (grants and other), AstraZeneca (grants and other), Boeringher Ingelheim (grants and other), Chiesi (other), GlaxoSmithKline (grants and other), Novartis (other), Pulsar Therapeutics (other), Roche (other), Sanofi Regeneron (other), Teva (other) and United Therapeutics (other), Elizabeth Volkmann Consultant of: Boehringer Ingelheim, Grant/research support from: Corbus and Forbius, Serena Vettori Paid instructor for: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Jörg H.W. Distler Speakers bureau: Actelion, Active Biotech, AnaMar, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Celgene, Galapagos NV, GlaxoSmithKline, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Consultant of: AnaMar, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Galapagos NV, Inventiva, JB Therapeutics and UCB, Grant/research support from: Active Biotech, AnaMar, Array BioPharma, Arxx Therapeutics, aTyr, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Galapagos NV, GlaxoSmithKline, Inventiva, Novartis, Sanofi-Aventis, Redx and UCB, Margarida Alves Employee of: Currently an employee of Boehringer Ingelheim, Christian Stock Employee of: Currently an employee of Boehringer Ingelheim, 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...
S. Erdes, E. Agafonova, D. Rumiantceva, S. Davidian, E. Zemerova, A. Kulikov, O. Markova, E. Lukyanova, V. Achikyan
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 709-710; https://doi.org/10.1136/annrheumdis-2021-eular.299

Abstract:
Background: Coxitis (hip joint inflammation) in AS is associated with worse BASFI scores due to hip joint involvement and more severe axial disease [1]. Radiological index of BASRI-hip, US and MRI findings may be used for evaluation of hip joint impairment [2, 3, 4]. Number of studies on coxitis in AS patients treated with biologics was limited at time of this study initiation. Objectives: To evaluate clinical changes measured by BASFI, BASMI, BASDAI, ASDAS-CRP and radiological changes in AS patients with coxitis (BASRI-hip, hip MRI [STIR- and T1-weighted sequences], hip US) after 12 and 24 months of treatment with TNF alpha inhibitor golimumab from baseline. Methods: A non-interventional prospective cohort study. Bio-naïve patients with AS and coxitis were treated with golimumab according to daily clinical practice in 5 clinics across Russia and followed up for 24 months. 39 patients participated. This analysis includes data from 30 patients who completed the follow up. The whole cohort’s data to be presented after consolidation of safety data. MRI and US data were collected for 12 months in up to 28 of 30 patients. The primary endpoint was mean change of BASFI which was expected to be -2.5 (± 2.12) from baseline at week 52 weeks (12 months) of therapy [5]. The power of the study was 90% with minimum sample size of 18 patients. Student’s paired t-criteria, Wilcoxon signed rank test were used to compare quantitave and Chi-square test for qualitative variables. Results: Majority of participants (66,7%; 20 out of 30) were male, with mean (SD) age of 33.2 (9.4) years, mean (SD) duration of AS was 36.2 (42.1) months, mean (SD) duration of coxitis was 36.9 (44.1) months. Baseline mean (SD) scores were: BASFI 3.9 (2.5), BASMI 3.1 (2.5), BASDAI 4.9 (2.0), ASDAS-CRP 3.5 (1.2). Changes of mean clinical scores from baseline after 12 and 24 months of treatment with golimumab were: ΔBASFI= -2.2 (p=0.0001), -2.1 (p=0.0000); ΔBASMI= -1.5 (p=0.0000), -1,8 (p=0.0000); ΔBASDAI= -3.0 (p=0.0000), -3.1 (p=0.0000); ΔASDAS-CRP= -2.0 (p=0.0000), -2.1 (p=0.0000), correspondingly (n=30). The clinical results (medians, interquartile ranges, min and max) are presented below. Baseline mean (SD)/median BASRI-hip was 1.1 (0.8)/1.0 on the right and on the left. Changes of mean/median BASRI-hip score at 12 and 24 months compared to baseline were: 0.3/0.0 (n=25; p=0.2344) and 0.3/0.0 (n=25; p=0.1368) on the right; 0.4/0.0 (n=25; p=0.0352) and 0.4/1.0 (n=25; p=0.0735) on the left. Rates of patients with MRI and US findings are presented below. Hip MRI, paired analysis Patients (%), n=27 Patients (%), n=23 Baseline At 6 months Baseline At 12 months Right No findings 33.3 48.1 39.1 56.5 Subchondral bone marrow edema (SBME) 37.0 11.1 34.8 8.7 Joint effusion 74.1 25.9* 73.9 17.4* Enthesitis 33.3 11.1 34.8 21.7 Fatty degeneration 37.0 55.6 34.8 52.2 Left No findings 29.6 51.9 30.4 52.2 SBME 18.5 3.7 8.7 4.3 Joint effusion 63.0 22.2* 60.9 21.7 Enthesitis 22.2 18.5 17.4 21.7 Fatty degeneration 33.3 55.6 30.4 52.2 Hip US, paired analysis Patients (%), n=28 Patients (%), n=27 Baseline At 6 months Baseline At 12 months Right No findings 14.3 50.0* 18.5 51.9* Joint effusion 46.4 25.0 51.9 11.1* Enthesitis 25.0 14.3 18.5 14.8 Left No findings 14.3 50.0* 18.5 55.6* Joint effusion 42.9 28.6 48.1 25.9 Enthesitis 17.9 17.9 11.1 18.5 *p<0.05 Conclusion: Therapy with TNF alpha inhibitor golimumab for 24 months in AS patients with coxitis was accompanied with statistically significant improvement of clinical scores with primary endpoint achieved (mean BASFI change -2.5 at 12 months), improvement of MRI and US findings without obvious structural progression measured with BASRI-hip score compared to baseline. References: [1]Cruyssen B.V. et al. Rheumatology 2010; 49: 73-81. [2]Boonen A. et al. J Rheumatol 2009; 36; 1249-1255. [3]Cruyssen B.V. et al. Curr Opin Rheumatol 2013, 25: 448-454. [4]Zhen-Guo H. et al. European Journal of Radiology 82 (2013) 1487-1493. [5]Konsta et al. Clin Rheumatol (2013) 32:1229-1232.Braun J. et al. Ann Rheum Dis 2012; 71: 661–667. Disclosure of Interests: Shandor Erdes Speakers bureau: Paid as a speaker during educational activities supported by pharmaceutical companies (MSD, Pfizer, AbbVie, BIOCAD), Ekaterina Agafonova Speakers bureau: Paid as a speaker during educational activities supported by pharmaceutical companies (MSD)., Daria Rumiantceva Speakers bureau: Paid as a speaker during educational activities supported by pharmaceutical companies (Novartis), Satenik Davidian: None declared, Elena Zemerova Speakers bureau: Paid as a speaker during educational activities supported by pharmaceutical companies (MSD, Pfizer), Aleksey Kulikov Speakers bureau: Paid as a speaker during educational activities supported by pharmaceutical companies (MSD, AbbVie, UCB, BIOCAD, Novartis, Sanofi), Olga Markova Speakers bureau: Paid as a speaker during educational activities supported by pharmaceutical companies (MSD, Novartis, Medac, GSK), Ekaterina Lukyanova Employee of: MSD Pharmaceutical LLC (Russia), Director of Medical Affairs., Vladimir Achikyan Employee of: MSD Pharmaceutical LLC (Russia), Therapeutic Area Lead
F. Milatz, M. Niewerth, J. Klotsche, J. Hörstermann, S. Hansmann, T. Kallinich, C. Rietschel, R. Trauzeddel, J. Peitz, M. Hartmann, et al.
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 246.2-246; https://doi.org/10.1136/annrheumdis-2021-eular.2356

Abstract:
Background: Physical activity (PA), including sport participation is essential for children throughout their growth and maturation. It improves physiological and psychosocial health and limits the risk of developing metabolic disorders. The beneficial effect of PA specifically in patients with JIA has also been linked to its potential regulatory effect on the balance between pro- and anti-inflammatory responses [1]. Objectives: The study aimed i) to quantify the frequency of PA and participation in (organised) sports compared to the general population, ii) to determine self-reported reasons for not practicing sports, and iii) to identify clinical parameters associated with non-participation in sports. Methods: Data from children and adolescents with JIA recorded in the National Paediatric Rheumatological Database (NPRD) in the year 2019 were considered for the analyses. In accordance with the methodology used in the general population survey (KIGGS) [2], achievement of the WHO recommendations on PA for at least 60 minutes per day as well as sport-related data were determined on the basis of self-reported outcomes in individuals aged 3 to 17 years. In order to compare PA-related data with the general population, a sex- and age-matched sample was drawn. A logistic regression model was used to explore the association between non-participation in sports and patients’ clinical outcomes. Results: Data of 5.333 matched-pairs (mean age 11.0 ± 4.3 years, female 67%, patients’ disease duration 4.8 ± 3.8 years, persistent oligoarthritis 43%) were available for evaluation. Almost 38% of patients aged 3 to 17 years met the recommended PA amount (76% aged 3 to 6; 48% aged 7 to 10; 30% aged 11 to 13; 15% aged 14 to 17). In matched controls, 21% fulfilled the WHO recommendations on PA (41% aged 3 to 6; 23% aged 7 to 10; 17% aged 11 to 13; 10% aged 14 to 17). Largest differences across JIA categories were found in persistent oligoarthritis (43%) and enthesitis-related arthritis (22%). 64% of patients and 74% of controls reported participating in sports, of which 72% of patients and 58% of controls stating to participate in a formally organised way. In both groups, boys indicated organised sports participation more often than girls. Among those who declared not participating in sports, “no interest” (patients 27% vs. controls 29%), “no suitable offer nearby” (patients 25% vs. controls 31%), “health restrictions” (patients 22% vs. controls 4%) and “no time” (patients 15% vs. controls 23%) were the most frequently mentioned reasons (multiple responses possible). CJADAS-10 (OR = 1.02, 95% CI = 1.00-1.04), CHAQ (OR = 1.79, 95% CI = 1.50-2.14), DMARD use (OR = 1.32, 95% CI = 1.15-1.53) and disease duration (OR = 0.97, 95% CI = 0.95-0.99) were significantly associated with non-participation in sports. Conclusion: Based on self-reported data, children and adolescents with JIA meet the WHO recommendation on PA more often than general population controls. Patients are less frequently engaged in sports, but more often involved in formally organised forms. In order to bring joyful, interesting PA opportunities in line with WHO recommendations, further components (e.g. intensity), facilitators and barriers to PA and sports need to be addressed in the future while controlling for JADAS and CHAQ. References: [1]Rochette E et al. JIA and physical activity: possible inflammatory and immune modulation and tracks for interventions in young populations. Autoimmun Rev 2015;14:726–734. [2]Finger JD et al. Körperliche Aktivität von Kindern und Jugendlichen in Deutschland - Querschnittergebnisse aus KiGGS Welle 2 und Trends. Journal of Health Monitoring 2018;3:24-31. Acknowledgements: The National Paediatric Rheumatological Database has been funded by AbbVie, Chugai, Novartis and GSK. Disclosure of Interests: Florian Milatz: None declared, Martina Niewerth: None declared, Jens Klotsche: None declared, Jana Hörstermann: None declared, Sandra Hansmann: None declared, Tilmann Kallinich: None declared, Christoph Rietschel: None declared, Ralf Trauzeddel: None declared, Joachim Peitz: None declared, Matthias Hartmann: None declared, Hermann Girschick: None declared, Kirsten Minden Speakers bureau: Pfizer, AbbVie, Consultant of: Novartis.
W. Gerhart, M. T. Duruöz, J. Lowe, D. Webb, L. Wermskog, J. Davies, R. Howard, M. Mallinson, C. L. Koehn
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 167.1-167; https://doi.org/10.1136/annrheumdis-2021-eular.2368

Abstract:
Background: The current delay to diagnosis from symptom onset represents one of the greatest challenges in axial spondyloarthritis (axSpA). Research shows an average global delay of almost 7 years1 – and as long as 15 years in some cases2 – during which time the condition can progress considerably and lead to irreversible damage. Data indicates that women wait longer than men for a diagnosis3, and there has been very limited progress in reducing the time to axSpA diagnosis. The axSpA diagnosis delay has a hugely detrimental impact on an individual’s quality of life. Because the disease frequently has early onset1, individuals are left with untreated or incorrectly-treated symptoms at a formative period in their life course, whilst they await their diagnosis. Objectives: The Axial Spondyloarthritis International Federation (ASIF) set out to coordinate a comprehensive evidence-based global review of the factors influencing the current axSpA diagnosis delay and to produce a definitive report that shines a light on these barriers, as well as providing a resource that can ultimately empower a range of international stakeholders to reduce this delay. Methods: A full literature review was carried out to identify relevant available global evidence exploring the axSpA diagnosis delay. In autumn 2020 ASIF held two virtual global forum events, involving patients and patient group representatives, researchers, rheumatologists and other healthcare professionals, to methodically explore key diagnosis challenges across different healthcare systems and the opportunities for addressing these. Break-out discussions were held and participants were asked to identify the personal and societal effects of the diagnostic delay; the reasons it occurs; and initiatives to tackle the challenge. Alongside key stakeholder testimonies, best practices from around the world were also identified. 92 stakeholders participated in the events; they represented patients and healthcare professionals from 23 countries across five continents. Results: The findings from these activities were incorporated within a new ‘Delay to Diagnosis’ report, which for the first time definitively sets out the lived realities from a global perspective of the axSpA diagnosis delay. The report identified important commonalities across different countries and healthcare systems contributing to the current average global 7-year diagnosis delay, including: •Poor awareness of axSpA, particularly in primary care services •Complexities in diagnosing the disease •Poorly defined referral pathways •Insufficient patient access to rheumatologists and appropriate diagnostics The report also highlights the significant impact this delay has on individuals and wider society, providing a foundation for future advocacy work. A series of recommendations have also been identified, the implementation of which will help to instigate tangible progress in reducing the current delay. Conclusion: Despite longstanding challenges, there are now clear opportunities for transforming how axSpA is diagnosed around the world. This message needs to be heard and acted upon urgently by all those involved in the management and delivery of axSpA care. The future programme of work for ASIF’s Delay to Diagnosis project will respond to these findings and be centred around supporting axSpA patient associations globally to take this call to action forward throughout 2021 and beyond. References: [1]Zhao et al; Diagnostic delay in axial spondyloarthritis: a systematic review and meta-analysis; Rheumatology, 2021 [2]Garrido-Cumbrera, M., Poddubnyy, D., Gossec, L. et al. The European Map of Axial Spondyloarthritis: Capturing the Patient Perspective—an Analysis of 2846 Patients Across 13 Countries. Curr Rheumatol Rep 21, 19 (2019) [3]Jovani et al; Understanding How the Diagnostic Delay of Spondyloarthritis Differs Between Women and Men: A Systematic Review and Metaanalysis; The Journal of Rheumatology December 2016 Disclosure of Interests: Wendy Gerhart Employee of: I was employed by Janssen Canada from 1992 - 2017, Mehmet Tuncay Duruöz: None declared, Jo Lowe Grant/research support from: No financial grants received individually. However, my role as Project Manager at ASIF is currently funded partially by UCB Global and partially by Novartis Global, Dale Webb Speakers bureau: Janssen and Novartis, Grant/research support from: Individually, no. But NASS receives grants from AbbVie, Biogen, Eli Lilly, Janssen, Novartis and UCB, Lillann Wermskog Grant/research support from: Individually, no. But Spafo Norge receives a small amount of funding for ongoing projects from Novartis., Jo Davies Grant/research support from: Individually, no. However, ASIF are currently funded by UCB, Lilly, Boehringer Ingelheim, Janssen and Novartis; this funding partially covers staff salaries as well as a range of projects, the content and outputs of which are not influenced by the funders., Richard Howard Shareholder of: AbbVie, Amgen, Bristol-Myers Squibb, GSK, Johnson & Johnson, Eli Lilly, Merck, Novartis, Pfizer, and Teva. I own <20 shares of any one stock and these stocks represent <4% of personal investments, Consultant of: Yes, GSK, Novartis - but then donated to Spondylitis Association of America, Grant/research support from: I have not personally received financial grants. SAA has received financial support from AbbVie, Amgen, BI, J&J, Lilly, Novartis, Pfizer, UCB., Michael Mallinson Consultant of: No. But, for full disclosure: I have received honoraria in the past, for participating in patient advisory board activities, from Abbvie, Novartis, Pfizer and UCB., Cheryl L Koehn Grant/research support from: OUR ORGANIZATION, ARTHRITIS CONSUMER EXPERTS, HAS. I HAVE NOT AS AN INDIVIDUAL. HERE IS OUR PUBLICLY AVAILABLE DISCLOSURE ON ALL ONLINE AND PRINT MATERIALS, PRESENTATIONS, MEETINGS, GOVERNMENT CONSULTATIONS:...
A. Ogdie, A. Gustafson, A. Lieberman, J. Mason, A. Armstrong, N. Mehta, R. Beidas, J. Gelfand
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 810.2-810; https://doi.org/10.1136/annrheumdis-2021-eular.902

Abstract:
Background: Psoriatic arthritis (PsA) is an immune-mediated musculoskeletal disease associated with excess risk for cardiovascular disease (CVD). New US-based guidelines recognize psoriasis as a CVD risk enhancer; however, patients with PsA often do not have CVD risk factors identified nor managed. Objectives: This study examines strategies to improve CVD prevention care from the perspective of rheumatologists and patients with PsA. Methods: Semi-structured qualitative interviews were conducted using an interview guide based on the Consolidated Framework for Implementation Research to examine the perspectives of rheumatologists (N = 8) and patients with psoriatic arthritis managed by rheumatologists (N = 8) on barriers/facilitators to CVD prevention. Interviews were transcribed and coded using an integrated approach designed to enhance reliability and validity facilitated by NVivo software. Results: Most rheumatologists confirmed that they were not regularly engaging in CVD prevention care with psoriatic arthritis patients. Providers reported sometimes counseling and screening for CVD risk, but they were not regularly prescribing statins and not as willing to do so. Reasons included a lack of familiarity or comfort with guidelines, concern about working outside of their scope of practice, confusing boundaries between other clinicians, and time constraints. Most patients confirmed that it was uncommon for their rheumatologists to engage them in CVD prevention care but expressed desire for their rheumatologists inform them of the risk, and were open to CVD prevention care from them. Conclusion: We identified several potentially modifiable barriers to CVD screening and management. These findings will inform the design of a clinical trial comparing the effectiveness of rheumatologist implementation of CVD guideline-based counseling, screening and prescribing statins when appropriate in patients with PsA. Figure 1. Barriers to CVD screening and management among patients with PsA in a rheumatology practice setting and potential strategies to address those barriers. Abbreviations: CV = cardiovascular; SOC = standard of care. Disclosure of Interests: Alexis Ogdie Consultant of: Abbvie, Amgen, BMS, Celgene, Corrona, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB, Grant/research support from: Pfizer to Penn, Novartis to Penn, Amgen to Forward/NDB, Alix Gustafson: None declared, Adina Lieberman: None declared, Jennifer Mason: None declared, April Armstrong: None declared, Nehal Mehta Consultant of: Amgen, Eli Lilly, and Leo Pharma receiving grants/other payments, Grant/research support from: AbbVie, Celgene, Janssen Pharmaceuticals, Inc, and Novartis receiving grants and/or research funding and as a principal investigator for the National Institute of Health receiving grants and/or research funding., Employee of: NNM is a full-time US government employee, Rinad Beidas Consultant of: Camden Coalition of Healthcare Providers in the past 3 years. She currently is a consultant for United Behavioral Health. She serves on the Optum Behavioral Health Clinical and Scientific Advisory Council. Dr. Beidas receives royalties from Oxford University Press., Joel Gelfand Shareholder of: Dr Gelfand is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma, and he is a deputy editor for the Journal of Investigative Dermatology, receiving honoraria from the Society for Investigative Dermatology., Paid instructor for: CME work related to psoriasis that was supported indirectly by Eli Lilly and Company and Ortho Dermatologics, Consultant of: Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen Biologics, Novartis Corp, UCB (Data Safety and Monitoring Board), Sanofi, and Pfizer Inc, Grant/research support from: research grants (to the Trustees of the University of Pennsylvania) from AbbVie, Janssen, Novartis Corp, Celgene, OrthoDermatologics, and Pfizer Inc.
E. Volkmann, M. Kreuter, A. M. Hoffmann-Vold, M. Wijsenbeek, V. Smith, D. Khanna, C. Denton, W. Wuyts, C. Miede, M. Alves, et al.
Published: 19 May 2021
by BMJ
Annals of the Rheumatic Diseases, Volume 80, pp 101.2-102; https://doi.org/10.1136/annrheumdis-2021-eular.834

Abstract:
Background: Some patients with SSc-ILD develop dyspnoea secondary to parenchymal lung disease, while others do not report dyspnoea even when their lung function is impaired. It is unclear whether the presence of dyspnoea is associated with a worse course of SSc-ILD or with response to therapy. Objectives: To investigate the rate of decline in FVC in patients with SSc-ILD in the SENSCIS trial in subgroups by patient-reported dyspnoea at baseline. Methods: The SENSCIS trial enrolled patients with SSc-ILD with first non-Raynaud symptom within ≤7 years before screening, extent of fibrotic ILD ≥10% on HRCT and FVC ≥40% predicted. Patients were randomised to receive nintedanib or placebo until the last patient reached week 52. In post-hoc analyses, we analysed the rate of decline in FVC (mL/year) over 52 weeks in patients with and without dyspnoea at baseline based on the question about dyspnoea in the St. George’s Respiratory Questionnaire (SGRQ). Patients who reported having shortness of breath “most days a week”, “several days a week” or “a few days a month” (rather than “only with chest infection” or “not at all”) over the last month were considered to have dyspnoea at baseline. A random slope and intercept model was used to assess the rate of decline in FVC (mL/year) and an interaction test was applied to assess potential heterogeneity in the treatment effect of nintedanib between the subgroups. Results: Of 576 patients, 69.8% had dyspnoea at baseline. At baseline, in patients with and without dyspnoea, respectively, mean (SD) extent of fibrotic ILD on HRCT was 37.7 (21.7)% and 31.6 (19.4)%; mean (SD) FVC was 71.0 (16.3) and 76.5 (16.8) % predicted; 50.7% and 44.8% were taking mycophenolate; 53.5% and 41.9% were taking corticosteroids. In the placebo group, the rate of decline in FVC (mL/year) was similar in patients with and without dyspnoea at baseline (Figure). The effect of nintedanib versus placebo on reducing the rate of decline in FVC (mL/year) was numerically more pronounced in patients without dyspnoea (difference: 79.8 [95% CI: 9.8, 149.7]) than with dyspnoea (difference: 25.7 [-19.9, 71.3]), but the exploratory interaction p-value did not indicate heterogeneity in the treatment effect between subgroups (p=0.20). Conclusion: In the SENSCIS trial, patients with SSc-ILD who had dyspnoea at baseline had a numerically greater extent of fibrotic ILD on HRCT and numerically lower FVC % predicted at baseline. The rate of decline in FVC in the placebo group was similar in patients with and without dyspnoea. Nintedanib had a numerically greater treatment effect in patients without dyspnoea. These data suggest that the presence of dyspnoea should not be used as a criterion for starting nintedanib in patients with SSc-ILD. Acknowledgements: The SENSCIS trial was funded by Boehringer Ingelheim. Medical writing support was provided by Fleishman Hillard Fishburn, London, UK. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Disclosure of Interests: Elizabeth Volkmann Consultant of: Boehringer Ingelheim, Grant/research support from: Corbus and Forbius, Michael Kreuter Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim and Roche, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Lilly, Merck Sharp & Dohme and Roche, Consultant of: Actelion, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche, Grant/research support from: Boehringer Ingelheim, Marlies Wijsenbeek Speakers bureau: Boehringer Ingelheim (fees paid to institution) and Hoffmann-La Roche (fees paid to institution), Consultant of: Boehringer Ingelheim (fees paid to institution), Bristol-Myers Squibb (fees paid to institution), Galapagos NV (fees paid to institution), Hoffmann-La Roche (fees paid to institution), NeRRe Therapeutics (fees paid to institution), OncoArendi Therapeutics (fees paid to institution), Respivant Sciences (fees paid to institution) and Savara (fees paid to institution), Grant/research support from: Boehringer Ingelheim (fees paid to institution) and Hoffmann-La Roche (fees paid to institution), Vanessa Smith Speakers bureau: Boehringer Ingelheim and Janssen-Cilag NV, Consultant of: Boehringer Ingelheim, Grant/research support from: Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim, Janssen-Cilag NV and Research Foundation - Flanders (FWO), 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 Sharp & Dohme, 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., 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, Wim Wuyts: None declared, Corinna Miede Employee of: Currently an employee of mainanalytics GmbH, contracted by Boehringer Ingelheim, Margarida Alves Employee of: Currently an employee of Boehringer Ingelheim, Steven Sambevski Employee of: Currently an employee of Boehringer Ingelheim, Yannick Allanore Consultant of: Boehringer Ingelheim, Medsenic, Menarini and Sanofi, Grant/research support from:...
, Reida El Oakley, Mohammed Saad, Ali H Mokdad, Giamal A Etolhi,
Journal of Global Health, Volume 11; https://doi.org/10.7189/jogh.11.04025

Abstract:
Health Care provision in terms of prevention, detection and treatment is primarily dependent on the quality of the hosting Health System. In its health report 2000, the WHO's attempt to assess and rank health systems’ quality Worldwide was heavily criticized. We propose a novel framework for health system performance and ranking using three indicators for three domains; general health system performance, clinical outcome of treatment applied to the main causes of death and health system sustainability domains. Each domain was rated as “A – high”, “B – intermediate” or “C – poor” according to the aggregate score values of its three indicators. Hence the highest rank a health system can achieve is “AAA” and the lowest is “CCC”. If there is a need to define a “numerical rank” to further differentiate health systems with similar rating from one another, the total health expenditure per capita per year was used as an additional “number 10” indicator to achieve that level of differentiation. The framework was applied to Health Systems serving most of the World population including China, India, Brazil, USA, Russia, Germany, Japan, UK, France, Singapore and Switzerland. Data pertinent to each indicator was captured from published reports in peer-reviewed journals and/or from official websites. A Delphi survey was conducted for data not available online. Among the 11 health systems tested, no one scored AAA, Switzerland, France, Germany and Japan scored AAB, Singapore scored ABB, UK scored BBB, USA, Russia and China scored BBC, Brazil scored BCC while India scored CCC. Total health expenditure per capita per year lead to ranking Switzerland first followed by France, Germany, and Japan. This novel ranking system is a practical and an applicable tool that test health system performance and sustainability. It can be utilized to guide all organizations, people and actions whose primary intent is to promote, restore or maintain health to achieve their targets. An International Health System Ranking database that will be hosted by the Institute of Global, Health, Faculty of Medicine, University of Geneva, Switzerland.
Anna Marie Roos
Martin Folkes (1690-1754) pp 141-182; https://doi.org/10.1093/oso/9780198830061.003.0005

Abstract:
Although he failed in his first bid to be Royal Society President, Folkes continued to promote Newtonianism abroad. Folkes took a Grand Tour from 1732/3 to 1735, recording the Italian leg of his journey from Padua to Rome in his journal. Chapter five examines Folkes’s travel diary to analyse further his Freemasonry, his intellectual development as a Newtonian and his scientific peregrination in which he used metrology to understand not only the aesthetics but the engineering principles of antique buildings and artefacts, as well as their context and place in the Italian landscape. For Folkes, natural philosophy and antiquarianism went hand in hand. Using Folkes’s diary of his journey, and letters to/from natural philosophers such as Francesco Algarotti, Anders Celsius and Abbé Antonio Conti, this chapter analyses to what extent Folkes’s tour established his reputation as an international broker of Newtonianism as well as the overall primacy of English scientific instrumentation to Italian virtuosi.
, Roland Herzog
Published: 8 April 2021
OP-JOURNAL, Volume 37, pp 97-97; https://doi.org/10.1055/a-1203-3340

Abstract:
Passend zum Titelthema dieses OP-Journals: „Digitalisierung“: Das neue Homeoffice 2021 mit einer WLAN-gesteuerten Espressomaschine ist von einem „Home-Officer“ aus Tübingen und einem Forschungsinstitut in den Schweizer Bergen entwickelt worden ([Abb. 1]). Sie sind die Ersten, die den Prototypen sehen. Publication Date:08 April 2021 (online) © 2021. Thieme. All rights reserved. Georg Thieme Verlag KGRüdigerstraße 14, 70469 Stuttgart, Germany
Ute Schneider-Moser, Lorenz Moser, Manuel Nienkemper
Informationen aus Orthodontie & Kieferorthopädie, Volume 53, pp 75-81; https://doi.org/10.1055/a-1254-5571

Abstract:
Fehlende Zähne in der ästhetischen Zone – Lücke auf oder Lücke zu? MN: Liebe Ute, lieber Lorenz, vielen Dank, dass ihr euch Zeit nehmt, der IOK auf einige brennende Fragen bezüglich des heißen Themas „Fehlende Zähne in der ästhetischen Zone – Lücke auf oder Lücke zu?“ zu antworten. Lasst uns gleich mit des Pudels Kern starten: Was ist eure Meinung? Liest man eure Veröffentlichungen im American Journal of Orthodontics 2016, dem Journal of Clinical Orthodontics 2018 und der vorletzten Ausgabe von Seminars in Orthodontics dieses Jahres, könnte man den Eindruck bekommen, dass ihr im Oberkieferfrontzahnbereich lieber öffnet als schließt [1] [2] [3]. Ist das so? U&L: Lieber Manuel, das wäre eine falsche Schlussfolgerung, denn auch wir ziehen, wenn es möglich ist, den kieferorthopädischen Lückenschluss der Lückenöffnung vor ([Abb. 1], [2]) Wir sind aber in unserer Indikationsstellung nicht so rigoros wie unsere geschätzten Freunde und Kollegen Marco Rosa, Björn Ludwig oder Benedikt Wilmes, die seit geraumer Zeit den kieferorthopädischen Lückenschluss bei allen Patienten unabhängig von der gegebenen Fehlstellung anstreben [4] [5] [6] [7] [8]. Wir halten es eher mit Renato Cocconi, der je nach den individuellen Gegebenheiten sowohl den Lückenschluss als auch die Lückenöffnung durchführt [9]. MN: Wie erklärt sich diese unterschiedliche Sichtweise? Ihr seid doch alle aktive Mitglieder der Angle Society (ASE), die 2012 ein White Paper zum Thema der Aplasien von oberen seitlichen Schneidezähnen herausgegeben haben [10]. Seid ihr euch also doch nicht so einig? U&L: Wie du weißt, lieber Manuel, denn du bist ja auch ein ASE-Mitglied, beinhaltet das ASE Consensus Paper kein Einheitscredo zum Lückenschluss unter allen Umständen. Unsere Experten haben nach kritischer Evaluation der bestehenden evidenzbasierten Literatur lediglich festgestellt, dass es bei bestimmten Patienten, nämlich jugendlichen (und zwar besonders bei weiblichen) Erwachsenen mit einer hohen Lachlinie besser ist, auf Lückenöffnung mit prothetischer Rehabilitation zu verzichten, da diese ein erhöhtes Risiko für ästhetische Komplikationen aufweisen, zu denen sich unter Umständen noch parodontale Probleme hinzugesellen können. Diese Probleme müssen nicht zwangsläufig auftreten, doch sie stellen natürlich ein unvorhersagbares, aber mögliches Langzeitproblem dar. MN: Welche modernen prothetischen Möglichkeiten stehen für den Ersatz von fehlenden Zähnen im Oberkieferfrontzahnbereich zur Verfügung? Hat sich da in den letzten Jahren eine neue Möglichkeit aufgetan? U&L: Grundsätzlich gibt es 2 Möglichkeiten Lücken im Frontzahnbereich zu versorgen: mit einer einarmigen Klebebrücke („cantilever resin-bonded bridge“) oder einer implantatgetragenen Keramikkrone. Der Vorteil der modernen Klebebrücke im Vergleich zur sogenannten Marylandbrücke ist, dass diese sofort nach Abschluss der kieferorthopädischen Behandlung – also auch beim jugendlichen Patienten – nur an einem Zahn (entweder am mittleren Schneidezahn oder am Eckzahn) palatinal angeklebt wird, sodass sich der Ankerzahn genau wie die anderen natürlichen Zähne den kontinuierlichen Veränderungen der Dentition anpassen kann. Studien von Kern et al. haben gezeigt, dass diese einarmigen Klebebrücken eine ausgezeichnete Langzeitprognose haben und daher heute nicht mehr nur als Langzeitprovisorium, sondern als Dauerlösungen angesehen werden [11] [12] [13]. Natürlich ist es sehr wichtig, dass bereits bei der kieferorthopädischen Lückenöffnung ausreichend Platz für den Aufleger geschaffen wird, damit der Ankerzahn nicht präpariert werden muss. Eine gute interdisziplinäre Kommunikation ist also auch bei dieser sehr konservativen Behandlungsstrategie unerlässlich ([Abb. 3]). Implantatgetragene Kronen hingegen können erst nach Abschluss der Wachstumsphase mit einem längeren Sicherheitsabstand (bei Frauen etwa ab 19 Jahren, bei Männern ab 22 Jahren) eingebracht werden und müssen häufig mit einem zusätzlichem Knochen- und/oder Weichteilaufbau (bone bzw. soft tissue graft) zur Optimierung des Implantatbetts kombiniert werden ([Abb. 4]). Die faziale Knochenwand ist meist zu dünn, um ein jahrzehntelang parodontal und ästhetisch voll befriedigendes Ergebnis zu gewährleisten. Auch hier ist die intensive und gut koordinierte Zusammenarbeit des kieferorthopädisch-implantologisch-prothetischen Teams unerlässlich, um das bestmögliche Langzeitergebnis zu erreichen. Wenn so ein Team gut eingespielt ist und von Tag 1 an zusammenspielt, können heute exzellente Resultate von Einzelzahnimplantaten in dem ästhetisch sensiblen Oberkieferfrontzahnbereich auch langfristig erreicht werden [14] [15] [16] [17] [18] [19] [20]. MN: Also gibt es, laut euch, eigentlich keine Kontraindikationen für Implantate in der ästhetischen Zone? U&L: Doch, die gibt es schon: nämlich genau die, die im White Paper der ASE aufgelistet wurden: Vor allem weibliche Long-Face-Patienten mit einer hohen Lachlinie, die eben viel marginale Gingiva exponieren [10]. Da fallen ja schon minimale Symmetrieunterschiede des Gingivalrands und leichte Einsenkungen des Knochens als Farbunterschiede unschön auf, und es ist manchmal schwer, ein optimales Ergebnis zu bekommen. Zudem ist bei diesen Patienten eine höhere Neigung zum Auftreten einer späteren Infraokklusion beschrieben, die jedoch häufig mehr durch eine Versteilerung der Frontzahnneigung als eine Elongation der Zähne zustande kommt. Allgemein bekannt ist, dass die Rezidivneigung beim...
Published: 11 March 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.635371

Abstract:
The magnitude of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted the repurposing of several drugs to quickly stop the morbidity, mortality, and spread of this new disease. Repurposed drugs tested to fight COVID-19 have been chosen mainly on the basis of promising in vitro efficacy against SARS-CoV-2 or on previous therapeutic results with other human coronavirus diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) (1). Numerous clinical trials have already been completed, but no repurposed drug evaluated to date has been found that could significantly impact the course of COVID-19 pandemic (2). Our experience with previous viral pandemics, such as human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV), has taught us that precise design and target specificity will be essential to obtaining potent and successful antivirals against SARS-CoV-2. Repurposed drugs that have been explored more thoroughly since the beginning of the COVID-19 pandemic include remdesivir, favipiravir, lopinavir-ritonavir, ribavirin, interferon, and hydroxychloroquine (1). Favipiravir, a purine nucleoside analog broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp), approved for treatment of influenza virus infection in Japan, was chosen due to its in vitro activity against SARS-CoV-2, nevertheless, there is no evidence of its clinical efficacy. A prospective, randomized, open-label trial of early vs. late favipiravir in hospitalized patients with COVID-19 has shown that favipiravir did not significantly improve viral clearance (3). Lopinavir-ritonavir, a HIV-1 protease inhibitor, was investigated due to its SARS-CoV antiviral activity in tissue culture and infected patients. However, the lopinavir-ritonavir combination exhibited no clinical benefit against SARS-CoV-2 (4). From the very beginning of the COVID-19 pandemic, remdesivir has been the most promising drug against SARS-CoV-2. This adenosine nucleotide analog prodrug, a potentially inhibitor of RdRp, was initially developed by Gilead Sciences to treat filoviruses, such as the Ebola virus, and was explored due to its broad-spectrum antiviral activity in tissue culture and animal models against filoviruses, paramyxoviruses, pneumoviruses, and pathogenic coronaviruses, including SARS-CoV and MERS-CoV. Randomized controlled trials (RCTs) have found no effect of remdesivir on mortality (5). This drug has been approved to treat COVID-19 in the USA and Europe, but conclusive results to support the use of remdesivir are lacking (6, 7). The use of aminoquinoline drugs chloroquine and hydroxychloroquine is paradigmatic of the failure of repurposed drugs to treat COVID-19. These cheap drugs are generic antimalarials used to treat amoebic liver abscess and rheumatic disease. The early promising results with these two drugs showing antiviral activity against SARS-CoV-2 at micromolar concentrations in tissue culture and their clinical benefit in dubious observational trials of a few patients positioned them at the forefront of possible treatments for COVID-19. However, large observational clinical trials and RCTs have shown no effect of hydroxychloroquine in reducing mortality and/or mobility (2). Moreover, in some studies, a worse infection course was observed in hospitalized patients treated with these aminoquinolines (8). Importantly, recent studies have demonstrated that chloroquine does not inhibit infection of human lung cells with SARS-CoV-2 (9). Previous studies have shown that chloroquine and hydroxychloroquine inhibit the ability of SARS-CoV-2 to infect African green monkey kidney-derived Vero cells. However, when Vero cells were engineered to express TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells rendered SARS-CoV-2-infected Vero cells insensitive to chloroquine (9). Furthermore, chloroquine does not block infection with SARS-CoV-2 in TMPRSS2-expressing human lung Calu-3 cells, indicating that chloroquine targets a pathway for viral activation that is not active in lung cells and is unlikely to protect against the spread of SARS-CoV-2. These results emphasize the necessity of being cautious with observed drug inhibition of viral replication in tissue culture. Ivermectin, another cheap antiparasitic drug with in vitro efficacy against SARS-CoV-2, is being prescribed as a preventative against COVID-19. However, the evidence that ivermectin protects people from COVID-19 is limited (10). We should be prudent using ivermectin, or other potential drugs, outside clinical trials. In some countries, ivermectin is being also administered to SARS-CoV-2 infected patients. Different doses and posology have been used and confounding results have been reported. A recent pilot clinical trial found no significant differences in detection of SARS-CoV-2 RNA from nasopharyngeal swabs at days four and seven after treating with a single oral dose of 400 mcrg/Kg of ivermectin (11). Virus target specificity (e.g., isolation or drug-resistant viruses) should be tested and demonstrated before initiating treatments in virus-infected patients. As hydroxychloroquine showed no effect in SARS-CoV-2 infection in non-human primates (12), testing animal models will be preferable before translating these drugs to humans. In addition to drugs specifically aimed to inhibit SARS-CoV-2 replication, therapeutics that modulate inflammation have also been tested and, in this case, they seem to be a more effective therapeutic strategy for treating COVID-19 morbidity and mortality. Immunomodulators are being tested in several clinical trials for the treatment of SARS-CoV-2-generated cytokine storm. However, data to support the use of one of the most explored compounds to modulate inflammation, tocilizumab, a monoclonal antibody against interleukin-6 receptors, come largely from observational studies (13). Large RCTs with tocilizumab should provide answers regarding its clinical benefit. Immunomodulators that appear to work are corticosteroids. A recent RTC performed with dexamethasone showed that, in patients with moderate or severe COVID-19, dexamethasone plus standard care significantly increases survival and reduces morbidity (14, 15). Other drugs that could offer clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens, statins, N-acetyl cysteine, ACE2 inhibitors, angiotensin receptor blockers, and direct TMPRSS-2 inhibitors (16). Although immunomodulators may be an excellent clinical tool, it is desirable to potently and specifically stop SARS-CoV-2 replication after the onset of the first COVID-19 symptoms to avoid the pathogenic course of the disease. Ideally, we should stop SARS-CoV-2 in the first days of the infection. For example, neuraminidase inhibitors may not produce any detectable effect in a patient hospitalized with severe influenza virus infection, but can be useful in preventing the development of severe disease. The most appropriate therapy goal of an acute viral infection is therefore not to cure severe disease, but to keep the disease from becoming severe, and prevent hospitalization. Treatment early in the course of illness could also limit person-to-person transmission. A way to stop the early spread of SARS-CoV-2 will be through a sterilizing vaccine. SARS-CoV-2-neutralizing antibodies have been associated with protection (17). This is not surprising as natural infection induces both mucosal antibody responses (secretory IgA) and systemic antibody responses (IgG). The upper respiratory tract is mostly protected by secretory IgA, whereas the lower respiratory tract is mostly protected by IgG. Because most vaccines currently in development will be administered intramuscularly or intradermally, they will induce mostly IgG, but no secretory IgA (18). Therefore, these vaccines would probably prevent disease but not generate sterilizing immunity; that is, they may still allow for transmission of the virus (18). In this scenario, the current pandemic will require different strategies utilized in concert, including an effective vaccine and competent antivirals. HIV therapy is arguably among the most successful in treating any single human disease. The success of HIV therapeutics is illustrated by the number of antiretroviral agents and unique drug classes available (19). To date, the Food and Drug Administration (FDA) has approved 23 drugs to treat HIV infection. Based on their molecular mechanism and drug-resistance profile, antiretrovirals are classified into eight different classes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors that block HIV entering CD4+ cells, CCR5 antagonists that block the CCR5 co-receptor that HIV needs to enter the cells, integrase inhibitors, attachment inhibitors that bind HIV glycoprotein 120, and post-attachment inhibitors that block cellular CD4 receptor. In addition to antiretrovirals, one pharmacokinetic enhancer has been approved to increase antiretroviral effectiveness. In contrast to the diffuse viral targets of most of the repurposed drugs mentioned above, antiretroviral target specificity was defined through the in vitro or in vivo selection of HIV-resistant variants for the different drugs. No antiretroviral has been approved in the absence of a specific viral target. Although the virus was discovered in 1983, few antiretroviral treatment options existed for HIV infection before 1996. HIV therapeutics consisted mainly of prophylaxis against common opportunistic pathogens and managing AIDS-related illnesses. The development of HIV reverse transcriptase and protease inhibitors in the mid-1990s, and the introduction of drug regimens that combined these two classes of inhibitors to increase their efficacy, completely revolutionized the clinical approach to HIV. These combination treatments transformed HIV infection from a life-threatening disease to a manageable chronic disease. The success of antiretroviral therapies has strongly impacted the development of therapies against other viral infections. The best example is HCV, another pandemic, life-threatening, human viral infection discovered in 1989. The first generation of FDA-approved HCV drugs included interferon alfacon-1 (approval year: 1997, discontinued in 2013 due to severe adverse events), ribavirin (1998), pegylated interferon alfa-2b (2001), and pegylated interferon alfa-2a (2002) (20). Although these drugs had low cure rates, a treatment duration of 48 weeks, and may cause severe adverse events, they were the only standard-of-care treatments over a decade. Interferons and ribavirin were chosen because they exhibited a certain inhibitory capacity against other viral infections, and their low effectivity is largely due to their low specificity against HCV. Fortunately, the development of direct-acting antivirals (DAAs) targeting the two main HCV enzymes, NS3 protease and RdRp (20), has decreased treatment duration to 8 weeks and increased the cure rate to nearly 100%. DAA therapy is among the best examples of success in the fight against viral infections. DAAs have transformed HCV management and opened the door to the global eradication of HCV. Patients infected with HIV or HCV have a prolonged course of infection measured in months or years, during which they are asymptomatic or only mildly ill, providing ample opportunity to intervene with an antiviral drug. Because viremia is prolonged and relatively steady, a patient can serve as his own control to measure a drug effect. Although the situation is quite different for patients who have developed COVID-19, a rapidly progressive disease in whom might be more difficult to expect an antiviral to provide detectable benefit and more difficult to diagnose in its earlier stages when antiviral approaches would be more likely to be effective, HIV-1 and HCV examples should be mirrors in which we should look for antiviral solutions. It can be argue that a repurposed drug that has not shown any benefit in hospitalized COVID-19 patients might still be useful in slowing the development of illness, preventing severe disease and making hospitalization unnecessary. In the absence of vaccines, a repurposed drug with limited antiviral activity might be given to persons who have been exposed to an infected individual, or are in a situation in which exposure is likely to occur (post- or pre-exposure prophylaxis). However, such benefit would be more difficult to demonstrate than a standard RCT, but could still be tested. A combinatorial approach of repurposing drugs targeting both the virus and host target mechanisms has been also proposed for the management of COVID-19 severity (21). The recent resolution of the crystal structures of the three most likely SARS-CoV-2 targetable proteins (spike, RdRp, and the main protease) is allowing the identification of first-generation SARS-CoV-2-specific antivirals (22–24). Even if the benefits of SARS-CoV-2-specific antivirals remain to be elucidated, we should quickly move these first-generation specific and potent antivirals to the clinic. Antiviral drugs approved for the treatment of human virus infectious diseases have saved tens of millions of human beings over the last decades. It is a challenge to pursue effective, low-toxicity, and well-tolerated drugs that enhance patient compliance and drug administration. Nevertheless, effective antivirals will positively impact COVID-19 therapy, and SARS-CoV-2 transmission and eradication. The success of antiretroviral and antiviral therapies developed against HIV and HCV should provide a point of reference for SARS-CoV-2 drug development and a roadmap for the development of novel COVOD-19 prevention strategies. MM designed and wrote this manuscript. This work was supported by the Spanish Ministry of Science and Innovation (PID2019-103955RB-100). 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. Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother. (2020) 64:e00399–20. doi: 10.1128/AAC.00399-20 PubMed Abstract | CrossRef Full Text | Google Scholar 2. Martinez MA. Clinical trials of repurposed antivirals for SARS-CoV-2. Antimicrob Agents Chemother. (2020) 64:e01101–20. doi: 10.1128/AAC.01101-20 PubMed Abstract | CrossRef Full Text | Google Scholar 3. 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(2020) 368:409–12. doi: 10.1126/science.abb3405 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: COVID-19, repurposed drugs, treatment efficacy, HIV, HCV Citation: Martinez MA (2021) Lack of Effectiveness of Repurposed Drugs for COVID-19 Treatment. Front. Immunol. 12:635371. doi: 10.3389/fimmu.2021.635371 Received: 01 December 2020; Accepted: 19 February 2021; Published: 11 March 2021. Edited by: Reviewed by: Copyright © 2021 Martinez. 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: Miguel Angel Martinez, [email protected]
, , Delaney Benoit
Published: 4 March 2021
Abstract:
<p>The characteristics of waves breaking on a beach can have significant impacts on how water infiltrates and influences coastal groundwater flows. The effects of continuous wave action on groundwater in coastal aquifers is important to understand to predict subsurface flows in beaches. This investigation will study how coastal wave dynamics in the swash zone impact the groundwater table using physical laboratory modelling and detailed image analysis that allows for high density spatial and temporal resolution degree of saturation measurements using unsaturated transparent soil as illustrated in Figure 1. Transparent soil methods will be applied to observe simulated wavedriven subsurface flows in a cross-section of a sandy beach. The objective of this study is to extend the current knowledge of how waves drive groundwater fluctuations by experimentally quantifying the time and length scales of flow within a beach.</p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gnp.37e54696a70064314111161/sdaolpUECMynit/12UGE&app=m&a=0&c=abbe0b116f2bfbac393fa27b5fbd2c00&ct=x&pn=gnp.elif&d=1" alt=""></p><p>Figure 1.</p><p>Transparent soil can be used to experimentally measure subsurface fluid/air flow and is used to quantify spatial and temporal saturation conditions every few seconds during an experiment. Digital image analysis allows for millimeter spatial resolution throughout the domain. Transparent soil is formed are applied by using crushed quartz rock in place of sand and an oil mixture with an identical refractive index to the grains (Peters et al. 2011). When the pores of the crushed quartz are saturated with the oil, the mixture appears transparent. When dry, the crushed quartz appears opaque. Change in colour is quantified, through digital image analysis, to measure degree of saturation throughout the domain (Sills et al. 2017)</p><p>This study applied transparent soil techniques in its first application to understand coastal processes by observing how incident waves infiltrate beaches and induce groundwater table fluctuations. Four tests are reported with variations in beach slope and wave properties, and the images are processed to quantify spatial and temporal degree of saturation variation. In each test, the swash interacted with the groundwater table by forming a partially saturated zone above the saturated zone of the beach. This partially saturated mound followed a consistent shape, that varied in size and rate of change primarily due to beach slope. The partially saturated zone is formed by a combination of capillary forces and downward infiltration, forming a continuously dampened zone in the beach. Finally, the results show a strong inverse correlation between the wetting front formed in a beach and the slope of the swash zone. Steeper slopes displayed much larger partially saturated mounds and were observed to do so in a slower manner compared to flatter slopes.</p><p>&#160;</p><p>Peters, S. B., Siemens, G., and Take, W. A. (2011). &#8220;Characterization of Transparent Soil for Unsaturated Applications.&#8221; Geotechnical Testing Journal, 34(5).</p><p>Sills, L.-A. K., Mumford, K. G., and Siemens, G. A. (2017). &#8220;Quantification of Fluid Saturations in Transparent Porous Media.&#8221; Vadose Zone Journal, 16(2), 1&#8211;9.</p>
, Andrea Balboni, Luigi Bertolotti, Piera Anna Martino, Maurizio Mazzei, Francesco Mira, Ugo Pagnini
Published: 10 February 2021
Frontiers in Veterinary Science, Volume 8; https://doi.org/10.3389/fvets.2021.619207

Abstract:
The recent pandemic caused by the novel human coronavirus (CoV), currently referred to as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which is responsible for COronaVIrus Disease 2019 (COVID-19), is leading to alarmism among pet owners as a consequence of few case reports of SARS-CoV-2 infection in dogs and cats. COVID-19 emerged in December 2019 in Wuhan City, Hubei Province, China, in humans exposed to wildlife at the Huanan seafood wholesale market, the largest seafood market in central China. This is a typical Asian wet market, where different species of farm and wild animals are commonly sold dead and live. The blood and other body fluids originating from these animals represent an exceptional source for the spillover of animal viruses (1). SARS-CoV-2 recognizes a probable zoonotic origin, since the virus likely descends from a bat betacoronavirus, strictly related to the one responsible for the 2002–2003 SARS epidemic (SARS-CoV), which was transmitted to humans directly or through previous adaptation to a not yet identified intermediate host (1, 2). After this adaptation to the new host, the virus was able to spread to the human population through a human-to-human transmission, without any further role of animals in the epidemiological chain. However, pets have been alternatively brought into play as a possible source of infection for humans, intermediate hosts for SARS-CoV-2 transmission to humans or hosts of animal CoVs that may cross-protect humans against the highly pathogenic CoV. The aim of this opinion article is to define the role of dogs and cats in the SARS-CoV-2 epidemiology in the light of current knowledge. To date, sporadic cases of SARS-CoV-2 infection have been reported in dogs and cats. The first animal cases involved 2 dogs, a 17-year-old Pomeranian dog and a 2-year-old German shepherd, living in Hong Kong and in close contact with SARS-CoV-2 infected human patients (3). The animals did not display any clinical signs related to the infection and they shed, in their respiratory secretions, low SARS-CoV-2 loads as measured by real-time RT-PCR, a molecular tool able to detect even traces of viral RNA. Accordingly, a mixed breed dog living with the infected German shepherd (that also developed antibodies against SARS-CoV-2) has remained uninfected. Unfortunately, the Pomeranian dog died a few days after repeatedly testing negative for SARS-CoV-2 and the owner declined any necropsy, but the cause of death was clearly associated to the previous heart and kidney disease affecting this old animal. A third SARS-CoV-2 positive dog was later reported in North Carolina, USA. The infected pug displayed mild respiratory signs (sneeze and cough) and was living in a highly contaminated household, where 3 family members tested positive for SARS-CoV-2. The family participated in a study at Duke University that involved testing family members and their pets for COVID-191. However, the United States Department of Agriculture's National Veterinary Services Laboratories were unable to confirm the positive testing of this pug. The first confirmed case of SARS-CoV-2 infection in a pet dog in the United States was then reported in a German shepherd in the State of New York2. A greater concern was, on the other hand, generated by the involvement of cats. The first case occurred in a cat in Brussels whose owner had just returned from a vacation in Italy (4). The cat developed a gastroenteric disease. It shed discrete SARS-CoV-2 titres in the vomit and, to a lesser extent in the feces. To date, whether the observed clinical signs were associated with SARS-CoV-2 infection is unknown. Another SARS-CoV-2 infected cat was reported in Hong Kong. The pet was living with an infected human patient and did not display any clinical signs, but the virus was detected in its respiratory secretions and feces3. Two cats living in two separate areas of the State of New York and having mild respiratory illness tested SARS-CoV-2 positive. The first cat was tested after it showed mild respiratory signs, but no individuals in the household were confirmed to be ill with COVID-19. The source of infection of the cat might have been the contact with an infected human inside or outside its household. The second cat showed signs of respiratory illness after its owner tested positive for COVID-19. Both animals fully recovered from the respiratory disease (5). Sporadic cases of SARS-CoV-2 natural infection in dogs and cats were reported throughout the world (6). A high prevalence of PCR positive testing was reported in cats in Hong Kong, with 6 cases (out of 50 quarantined animals from COVID-19 positive households) of apparent human-to-feline transmission involving healthy cats (7). To date, despite these few reports of SARS-CoV-2 infections in pets, there is some evidence that cats may be more susceptible than dogs to this highly pathogenic human CoV. SARS-CoV-2 is strictly related to SARS-CoV at genetic and biological levels, being included in the same viral species, Severe acute respiratory syndrome-related coronavirus (subgenus Sarbecovirus, genus Betacoronavirus) and sharing the same cellular receptor, the angiotensin converting enzyme type 2 (ACE2) (8). SARS-CoV-2 infected cats both through the natural and the experimental routes. Several cats of the Amoy Gardens in Hong Kong, where more than 100 infected people were living, were found to be positive for SARS-CoV4 and the experimental administration of this virus resulted in a productive infection with shedding of high viral loads and virus transmission to in-contact cats (9). In-silico analysis of the feline and ferret ACE2 has shown that SARS-CoV-2 can bind with high efficiency to the receptors of these animals (10). Dogs experimentally inoculated with SARS-CoV-2 developed a mild infection and shed low titres of viral RNA. In contrast, experimentally-infected cats and ferrets appeared to be highly susceptible to SARS-CoV-2, shedding high amounts of virus and infecting (few) in-contact animals (11). A serological survey was conducted in cats in Wuhan (China), the epicenter of the CoV pandemic, between January and March 2020. Fifteen out of 102 cats tested positive by an ELISA using the receptor-binding domain (RBD) of the spike protein, and 11 of these positivities were confirmed by virus neutralization. Most of the seropositive animals had been in close contact with SARS-CoV-2 infected humans (12). In a large-scale study assessing SARS-CoV-2 infection in 919 companion animals living in northern Italy, sampled at a time of frequent human infection, none of these pets tested PCR positive. However, 3.3% of dogs and 5.8% of cats had measurable SARS-CoV-2 neutralizing antibody titres; dogs from COVID-19 positive households were significantly more likely to test positive than those from COVID-19 negative households (13). Higher seroprevalence rates for SARS-CoV-2, ranging from 21 to 53% depending of the test used, were observed in domestic carnivores from COVID-19 positive household in two French regions (14). On the contrary, no SARS-CoV-2 antibodies nor viral RNA were detected in 21 domestic pets (9 cats and 12 dogs) living in close contact with a veterinary community with some COVID-19 positive students (15). A recent paper has suggested the dog as an intermediate host for SARS-CoV-2 adaptation and transmission to humans (16). The hypothesis is based on the low frequency of CG dinucleotides (CpG) in the SARS-CoV-2 genome, which was much lower with respect to other betacoronaviruses, but similar to that observed in the canine alphacoronavirus (CCoV), with particular regards to that of a hypervirulent strain (pantropic CCoV) first detected in Italy (17, 18), and later reported in other countries (19, 20). The reduced number of CpGs may represent a pathogenicity marker, since these dinucleotides are the target for a cellular antiviral protein, the zinc finger antiviral protein (ZAP). ZAP binds specifically to CpG dinucleotides in viral RNA genomes via its RNA-binding domain, thus inhibiting viral replication and mediating viral genome degradation. As a consequence, a lower CpG content in the viral genome is associated with a greater ZAP resistance and higher virulence. A further hypothesis of the same study is that SARS-CoV-2 was originally an enteric virus, since the enteric environment seems to be more favorable to the selection of viruses with low CpG content and indeed CCoV, the canine low CpG content alphacoronavirus, replicates in the gut mucosa (21). Accordingly, a number of human patients with COVID-19 display intestinal symptoms (22). Certainly, the possible role of dogs as intermediate hosts is a fascinating hypothesis, but at the moment it appears just a speculation lacking any robust scientific evidence. A snake origin of the virus was suggested on the basis of the codon usage bias of SARS-CoV-2 that seemed to be more suitable for the transcription machinery of reptiles (23). However, this hypothesis was subsequently rebutted due to the lack of robust data (8). Dogs and cats have their own CoVs, which are genetically and biologically divergent from SARS-CoV-2 and do not infect humans (8). Two CoVs are currently circulating in dogs. The enteric alphacoronavirus CCoV forms a unique viral species along with transmissible gastroenteritis virus of swine (TGEV) and feline coronavirus (FCoV). The betacoronavirus canine respiratory coronavirus (CRCoV) is closely related to bovine coronavirus (BCoV) and to a low-pathogenic betacoronavirus of humans, HCoV-OC43 (8). CCoV includes two genotypes, CCoV-I and II. The latter consists of two subgenotypes, CCoV-IIa and IIb, which are represented by classical and recombinant TGEV-like strains, respectively (24, 25). Hypervirulent strains belong to subtype CCoV-IIa (6). In cats two genotypes (FCoV-I and FCoV-II) are known, both including two different pathotypes, namely the feline enteric coronavirus and the feline infectious peritonitis virus. The former is responsible for asymptomatic infections or mild, self-limiting enteritis while the latter causes a systemic, fatal disease known as feline infectious peritonitis (8). An Italian study, based on computational analysis of full-length CoV genomes, has recently identified some immunorelevant epitopes in the RBD of the spike protein, which seem to be conserved between SARS-CoV-2 and some animal betacoronaviruses, mainly BCoV and CRCoV (26). According to the authors' hypothesis, repeated exposure to these animal CoVs may have partially immunized people against SARS-CoV-2. This hypothesis is fascinating but needs to be further investigated. A recent study has demonstrated that humans previously exposed to other antigenically distinct common seasonal HCoVs could have non-neutralizing antibodies that cross-reacted with SARS-CoV-2. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but paradoxically they were boosted upon SARS-CoV-2 infection (27). However, the presence of poorly cross-reacting antibodies may instead trigger an antibody-dependent enhancement favoring the entry into the host cells of viral particles bound to cytophilic antibodies (28). Similar protection against or exacerbation of COVID-19 should have been elicited by HCoV-OC43, a low pathogenic betacoronavirus that has been circulating in humans for more than a century (8). Therefore, in this case also, stronger scientific evidence is needed to confirm the hypothesis suggested on the basis of a raw bioinformatics analysis. To date (December 14, 2020), no pet-to-human transmission of the virus has been reported during this phase of the pandemic and although more than 71 million humans in the world tested positive for SARS-CoV-2 (https://www.ecdc.europa.eu/en/geographical-distribution-2019-ncov-cases), there are only sporadic cases of natural infections known in dogs and cats. Therefore, according to the present knowledge, the fact that SARS-CoV-2 can sporadically infect some domestic carnivores does not imply that pets play an active role in the virus transmission to humans. However, there is increasing evidence that, albeit with different ranges of susceptibility, dogs and cats can be infected as a consequence of close contact with SARS-CoV-2 positive people. In this scenario, dogs and cats act as (often asymptomatic) victims of a human-to-pet transmission rather than the source of infection for human beings. In addition, studies that rely only on bioinformatic and computational analyses of viral genomes, mRNAs and proteins may outline interesting scenarios about SARS-CoV origin, epidemiology and pathobiology, but they need to be supported by more comprehensive in-vitro and in-vivo investigations. Accordingly, taking into account the scientific evidence supporting the current knowledge, dogs and cats are unlikely to play any role in the emergence and/or transmission to humans of this pandemic virus. Only extensive epidemiological investigations in dogs and cats living in geographic areas with high prevalence of SARS-CoV-2 in humans can definitively clarify their role in the transmission of the virus. In addition, more comprehensive seroepidemiological studies in veterinarians, pet owners and breeders should assess whether these population groups are either (partially) protected from COVID-19 or susceptible to a more severe course of SARS-CoV-2 infection. ND wrote the article. 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Emerg Infect Dis. (2010) 16:41–7. doi: 10.3201/eid1601.090726 PubMed Abstract | CrossRef Full Text | Google Scholar 26. Tilocca B, Soggiu A, Musella V, Britti D, Sanguinetti M, Urbani A, et al. Molecular basis of COVID-19 relationships in different species: a one health perspective. Microbes Infect. (2020) 22:218–20. doi: 10.1016/j.micinf.2020.03.002 PubMed Abstract | CrossRef Full Text | Google Scholar 27. Anderson EM, Goodwin EC, Verma A, Arevalo CP, Bolton MJ, Weirick ME, et al. Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection. medRxiv. (2020). doi: 10.1101/2020.11.06.20227215 PubMed Abstract | CrossRef Full Text | Google Scholar 28. Decaro N, Martella V, Saif LJ, Buonavoglia C. COVID-19 from veterinary medicine and one health perspectives: what animal coronaviruses have taught us. Res Vet Sci. (2020) 131:21–3. doi: 10.1016/j.rvsc.2020.04.009 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: SARS-CoV-2, cats, dogs, facts, speculations Citation: Decaro N, Balboni A, Bertolotti L, Martino PA, Mazzei M, Mira F and Pagnini U (2021) SARS-CoV-2 Infection in Dogs and Cats: Facts and Speculations. Front. Vet. Sci. 8:619207. doi: 10.3389/fvets.2021.619207 Received: 19 October 2020; Accepted: 19 January 2021; Published: 10 February 2021. Edited by: Reviewed by: Copyright © 2021 Decaro, Balboni, Bertolotti, Martino, Mazzei, Mira and Pagnini. 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: Nicola Decaro, [email protected]
, Matthias David
Geburtshilfe und Frauenheilkunde, Volume 81, pp 135-138; https://doi.org/10.1055/a-1302-1100

Abstract:
Im Januarheft 2019 berichteten die Herausgeber des „American Journal of Obstetrics & Gynecology“, Roberto Romero und Catherine S. Bradley, dass das „oldest journal in the discipline“ seinen 150. Jahrestag feierte, was eventuell für die spezielle US-Wissenschaftsgeschichte richtig sein mag [1], [2]. Interessant ist jedoch ein Blick auf die ersten Herausgeber der heute wichtigsten amerikanischen Zeitschrift unseres Fachgebietes, die bis 1920 noch „American Journal of Obstetrics and Diseases of Women and Children“ hieß [3]. Editoren waren 1869 B. F. Dawson, „Lecturer on Uterine Pathology“ an der Universität New York, und Emil Noeggerath, „Late Professor of Obstetrics and Diseases of Women and Children“ am New York Medical College ([Abb. 1]). Publication Date:08 February 2021 (online) © 2021. Thieme. All rights reserved. Georg Thieme Verlag KGRüdigerstraße 14, 70469 Stuttgart, Germany
, Huiqin Yang, Segun Bello, , , , Sophie Dodman, Andriy Kharechko, Richard C Haigh, , et al.
Health Technology Assessment, Volume 25, pp 1-248; https://doi.org/10.3310/hta25080

Abstract:
Background Rheumatoid arthritis is a chronic autoimmune disease that primarily causes inflammation, pain and stiffness in the joints. People with severe disease may be treated with biological disease-modifying anti-rheumatic drugs, including tumour necrosis factor-α inhibitors, but the efficacy of these drugs is hampered by the presence of anti-drug antibodies. Monitoring the response to these treatments typically involves clinical assessment using response criteria, such as Disease Activity Score in 28 joints or European League Against Rheumatism. Enzyme-linked immunosorbent assays can also be used to measure drug and antibody levels in the blood. These tests may inform whether or not adjustments to treatment are required or help clinicians to understand the reasons for treatment non-response or a loss of response. Methods Systematic reviews were conducted to identify studies reporting on the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assays to measure drug and anti-drug antibody levels to monitor the response to tumour necrosis factor-α inhibitors [adalimumab (Humira®; AbbVie, Inc., North Chicago, IL, USA), etanercept (Enbrel®; Pfizer, Inc., New York, NY, USA), infliximab (Remicade®, Merck Sharp & Dohme Limited, Hoddesdon, UK), certolizumab pegol (Cimzia®; UCB Pharma Limited, Slough, UK) and golimumab (Simponi®; Merck Sharp & Dohme Limited)] in people with rheumatoid arthritis who had either achieved treatment target (remission or low disease activity) or shown primary or secondary non-response to treatment. A range of bibliographic databases, including MEDLINE, EMBASE and CENTRAL (Cochrane Central Register of Controlled Trials), were searched from inception to November 2018. The risk of bias was assessed using the Cochrane ROBINS-1 (Risk Of Bias In Non-randomised Studies – of Interventions) tool for non-randomised studies, with adaptations as appropriate. Threshold and cost–utility analyses that were based on a decision tree model were conducted to estimate the economic outcomes of adding therapeutic drug monitoring to standard care. The costs and resource use were considered from the perspective of the NHS and Personal Social Services. No discounting was applied to the costs and effects owing to the short-term time horizon of 18 months that was adopted in the economic analysis. The impact on the results of variations in testing and treatment strategies was explored in numerous clinically plausible sensitivity analyses. Results Two studies were identified: (1) a non-randomised controlled trial, INGEBIO, that compared standard care with therapeutic drug monitoring using Promonitor® assays [Progenika Biopharma SA (a Grifols–Progenika company), Derio, Spain] in Spanish patients receiving adalimumab who had achieved remission or low disease activity; and (2) a historical control study. The economic analyses were informed by INGEBIO. Different outcomes from INGEBIO produced inconsistent results in both threshold and cost–utility analyses. The cost-effectiveness of therapeutic drug monitoring varied, from the intervention being dominant to the incremental cost-effectiveness ratio of £164,009 per quality-adjusted life-year gained. However, when the frequency of testing was assumed to be once per year and the cost of phlebotomy appointments was excluded, therapeutic drug monitoring dominated standard care. Limitations There is limited relevant research evidence and much uncertainty about the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assay-based testing for therapeutic drug monitoring in rheumatoid arthritis patients. INGEBIO had serious limitations in relation to the National Institute for Health and Care Excellence scope: only one-third of participants had rheumatoid arthritis, the analyses were mostly not by intention to treat and the follow-up was 18 months only. Moreover, the outcomes might not be generalisable to the NHS. Conclusions Based on the available evidence, no firm conclusions could be made about the cost-effectiveness of therapeutic drug monitoring in England and Wales. Future work Further controlled trials are required to assess the impact of using enzyme-linked immunosorbent assays for monitoring the anti-tumour necrosis factors in people with rheumatoid arthritis. Study registration This study is registered as PROSPERO CRD42018105195. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 8. See the NIHR Journals Library website for further project information.
Published: 28 January 2021
Sportphysio, Volume 9, pp 51-51; https://doi.org/10.1055/a-1256-2097

Abstract:
Traditionell veranstaltet der Schweizer Verband Sportphysiotherapie (SVSP) sein jährliches Symposium im November in Bern. Das Symposium ist dafür bekannt, jedes Jahr renommierte Referenten aus aller Welt zu einem ausgewählten Thema der Sportphysiotherapie aufzubieten. „Knee & Sports“ war das Thema der diesjährigen Edition. Aufgrund der anhaltenden Covid-19-Pandemie entschieden sich die Organisatoren um Dr. Mario Bizzini, das international ausgerichtete Symposium am geplanten Datum 13.11.2020 digital im Webinar-Format stattfinden zu lassen ([ Abb. 1 ]). Trotz hochkarätigem Programm mit dem Schwerpunkt „Kreuzbandrehabilitation“ verzichteten die Veranstalter dieses Jahr sogar auf eine Teilnahmegebühr. Mit 2000 Anmeldungen aus 88 Ländern stieß dieses Angebot weltweit auf großes Interesse. Vorab veröffentlichte der SVSP (Sportfisio) in Zusammenarbeit mit dem Journal of Orthopaedic & Sports Physical Therapy (JOSPT) bereits ein Webinar mit dem Titel „Quality ACL Rehabilitation – Training the Quadriceps” auf YouTube. Das Webinar beschäftigt sich mit dem optimalem Krafttraining in der Rehabilitation nach Kreuzbandverletzungen und geht dabei explizit auf die biomechanischen Aspekte verschiedener Übungen ein. Im Livestream am 13. November gewährten die Referenten den Teilnehmern dann weitere spannende Einblicke in ihre Spezialgebiete. In der Gesamtheit entstand so ein umfassendes Bild von aktuell diskutierten Aspekten rund um die physiotherapeutische Versorgung von Kreuzbandverletzungen. Im Laufe des Tages wurde wiederholt auf die Bedeutung von intensivem Krafttraining, sportartspezifischem Training, psychosozialen Fragestellungen und Präventionsprogrammen hingewiesen. Das Programm enthielt sowohl Exkurse in Spezialgebiete wie Motorisches Lernen, Biomechanik und Psychologie als auch konkrete Beispiele aus der Rehabilitation im Spitzensport (Fußball und Handball). Aus den Vorträgen und den präsentierten Daten ging deutlich hervor, welchen Unterschied eine qualitativ hochwertige Rehabilitation für verletzte Sportler machen kann. Die Datenlage macht aber auch klar, dass derzeit viele Menschen nach Rekonstruktion des Kreuzbands keine optimale, evidenzbasierte Rehabilitation erhalten. Oft wird z. B. zu kurz oder zu wenig intensiv behandelt. Hier leistete die Konferenz des SVSP einen wertvollen Beitrag, aktuelles Wissen aus der Forschung praxisnah einem breiten Fachpublikum zur Verfügung zu stellen. Zudem haben die Organisatoren die Vorträge des Symposiums auf dem YouTube-Channel des SVSP als Playlist mit dem Titel „2020 – Knee & Sports“ verfügbar gemacht (Link). Die jeweils zum Symposium erscheinende Ausgabe des Magazins [email protected], das jedes Jahr eine andere Sportart aus sportphysiotherapeutischer Sicht unter die Lupe nimmt, widmet sich diesmal dem Thema Freeskiing ([ Abb. 2 ]). Das Magazin ist ebenfalls umsonst über die Homepage des SVSP (sportfisio.ch) in digitaler Form verfügbar (Link). Benjamin Thiesmeyer Publication Date:28 January 2021 (online) © 2021. Thieme. All rights reserved. Georg Thieme Verlag KGRüdigerstraße 14, 70469 Stuttgart, Germany
Chung-Yang Yen, Sheng-Jie Yu, Kuo-Lung Lai, Ching-Liang Hsieh
Published: 1 January 2021
SSRN Electronic Journal; https://doi.org/10.2139/ssrn.3839412

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Robert Shapiro, Victor J. Gallardo, Edoardo Caronna, Patricia Pozo-Rosich
Published: 1 January 2021
SSRN Electronic Journal; https://doi.org/10.2139/ssrn.3781652

The publisher has not yet granted permission to display this abstract.
Published: 16 December 2020
manuelletherapie, Volume 24, pp 212-213; https://doi.org/10.1055/a-1293-5967

Abstract:
Liebe Rosi, wenn der Kapitän das Schiff verlässt, dann ist das keine kleine Veränderung, sondern ein Erdbeben. Gut, der Großteil der Crew ist noch an Bord, aber Du wirst schon jetzt vermisst. Du hast uns mit Souveränität, Gelassenheit, einem großen Maß an Fachwissen und Professionalität, aber vor allem Menschlichkeit und Empathie über den Ozean befördert. Manchmal war das Fahrwasser unruhig und geprägt von Veränderungen, aber Du hast uns immer auf Kurs gehalten. Als ich 2002 meinen ersten Artikel in der Zeitschrift manuelletherapie veröffentlicht habe, warst Du als Gründungsmitglied 1997 schon mehr als 5 Jahre an Bord. Du hast die Zeitschrift geprägt und weiterentwickelt und warst für uns Herausgeber immer erste Ansprechpartnerin. Bevorstehende Veränderungen, wie der Relaunch im Jahr 2012 und die neue Namensgebung der Fachzeitschrift im Jahr 2021, hast Du in professioneller Weise mit dem Team kommuniziert und federführend umgesetzt. Deinem Engagement ist auch zu verdanken, dass wir Herausgebersitzungen nicht nur im Verlagshaus in Stuttgart abgehalten haben, sondern auch in Städten wie Basel, Ulm, Heidelberg, München oder Freiburg, wir also die Arbeit mit Gastronomie und Kultur verbinden konnten [ Abb. 1 ] und [ Abb. 2 ]. Diese Zusammentreffen bleiben uns, neben vielem anderen, in bester Erinnerung und sind eng mit Deinem Namen verbunden. Du bist eine Wegbereiterin und Botschafterin für unseren Beruf sowie für das Journal manuelletherapie und wir wissen, dass Du Wichtiges geleistet hast. Hoffentlich weißt Du das auch. Du hast den Erfolg meist im Stillen genossen, nie damit geprahlt. Die große Bühne war nicht Dein Ding. Getreu dem Sprichwort: Reden ist Silber, Schweigen ist Gold. Heute ist allerdings zu konstatieren: Du hast einen maßgeblichen Anteil daran gehabt, dass die Physiotherapie in den letzten 20 Jahren aus ihrem Schatten herausgetreten ist und die Gesundheitsberufe eine Stimme bekommen haben, und dies geht eben auch nicht lautlos. Anlässlich der Verleihung des „Stein der Weisen“ im Jahr 2016 für besonderes Engagement innerhalb der Physiotherapie hat Dich eine Kollegin so beschrieben: „Sie ist unkonventionell, potenzialorientiert und im wahrsten Sinne des Wortes ‚neu-gierig’-offen, reflektiert, engagiert und konsequent. Sie ist motiviert und motivierend und immer lern- und aufnahmebereit.“ Dem ist nichts hinzuzufügen. Jetzt gibst Du das Ruder aus der Hand bzw. weiter an Joachim Schwarz. Du hast Dir diesen (Un-)Ruhestand mehr als verdient. Genieße es – gemeinsam mit Deinem Mann und Deiner Familie. Bleib so wie Du bist – lass Dich nicht verbiegen – und das Allerwichtigste: Glück und Gesundheit! Es war eine Freude, mit Dir zusammenarbeiten zu dürfen. Wir sagen Danke für ALLES! Claus Beyerlein, im Namen aller Herausgeber Publication Date:16 December 2020 (online) © 2020. Thieme. All rights reserved. Georg Thieme Verlag KGRüdigerstraße 14, 70469 Stuttgart, Germany
, G D Adamson, E Benson, S Bhattacharya, M Bofill, K Brian, B Collura, C Curtis, J L H Evers, R G Farquharson, et al.
Published: 30 November 2020
Human Reproduction, Volume 35, pp 2715-2724; https://doi.org/10.1093/humrep/deaa242

Abstract:
STUDY QUESTION Can the priorities for future research in infertility be identified? SUMMARY ANSWER The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY Many fundamental questions regarding the prevention, management and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS Healthcare professionals, people with fertility problems and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties was entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI and IVF) and ethics, access and organization of care were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research and population science. LIMITATIONS, REASONS FOR CAUTION We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgment and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand and Maurice and Phyllis Paykel Trust. G.D.A. reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. A.W.H. reports research sponsorship from the Chief Scientist’s Office, Ferring, Medical Research Council, National Institute for Health Research and Wellbeing of Women and consultancy fees from AbbVie, Ferring, Nordic Pharma and Roche Diagnostics. M.L.H. reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. N.P.J. reports research sponsorship from AbbVie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics and Vifor Pharma. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from AbbVie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. E.H.Y.N. reports research sponsorship from Merck. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring and retains a financial interest in NexHand. J.S. reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring and being a clinical subeditor of Human Fertility. A.S. reports consultancy fees from...
, G.D. Adamson, E. Benson, S. Bhattacharya, M. Bofill, K. Brian, B. Collura, C. Curtis, J.L.H. Evers, R.G. Farquharson, et al.
Published: 29 November 2020
Fertility and Sterility, Volume 115, pp 180-190; https://doi.org/10.1016/j.fertnstert.2020.11.014

Abstract:
Study Question Can the priorities for future research in infertility be identified? Summary Answer The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care for people with fertility problems were identified. What is Known Already Many fundamental questions regarding the prevention, management, and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. Study Design, Size, Duration Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines, and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care. Participants/Materials, Setting, Methods Healthcare professionals, people with fertility problems, and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. Main Results and the Role of Chance The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties were entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities, and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI, and IVF), and ethics, access, and organization of care, were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment, and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings, and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research, and population science. Limitations, Reasons for Caution We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgement, and arbitrary consensus definitions. Wider Implications of the Findings We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems, and others, will help research funding organizations and researchers to develop their future research agenda. Study Funding/ Competing Interest(s) The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand, and Maurice and Phyllis Paykel Trust. Geoffrey Adamson reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies, and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. Hans Evers reports being the Editor Emeritus of Human Reproduction. Andrew Horne reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research, and Wellbeing of Women and consultancy fees from Abbvie, Ferring, Nordic Pharma, and Roche Diagnostics. M. Louise Hull reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. Neil Johnson reports research sponsorship from Abb-Vie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics, and Vifor Pharma. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Ernest Ng reports research sponsorship from Merck. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Jane Stewart reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from...
Adrian Minson, Nada Hamad, Jason P Butler, David Alan Westerman, David Ritchie, Piers Blombery, John F. Seymour, Constantine S. Tam, Michael Dickinson
Published: 5 November 2020
Blood, Volume 136, pp 34-35; https://doi.org/10.1182/blood-2020-138946

Abstract:
Background Mantle cell lymphoma (MCL) is a clinically and pathogenetically distinct B-cell non-Hodgkin lymphoma that presents at a median age of 65 years and typically at an advanced stage. High dose chemotherapy and stem cell transplantation can achieve durable responses, but disease eventually relapses in most patients. Allogeneic transplantation can achieve a cure in some but is only suitable for a minority of younger, fitter patients who achieve remission to salvage but carries risks of GVHD. Bruton tyrosine kinase inhibitors (BTKi) are active in relapsed MCL but the median PFS is generally less than 2 years and ibrutinib failure is associated with particularly poor outcomes (Cheah et al., Ann Oncol 2015). Mutations of TP53 are associated with refractoriness to both chemotherapy and novel agents (Eskelund et al., Blood 2017), and patients with disease harboring these mutations are in particular need of more effective therapies. Promising activity has recently been demonstrated with chimeric antigen receptor T-cells (CAR T), albeit with significant rates of cytokine release syndrome (CRS) and neurotoxicity (Wang et al., New England Journal of Medicine 2020), resulting in FDA approval of brexucabtagene autoleucel in MCL. Rationale Tisagenlecleucel (Novartis) is a CAR T-cell product directed against CD19 that is approved in many countries for the treatment of relapsed DLBCL and ALL. MCL consistently expresses CD19 at diagnosis and relapse and is therefore a promising target. Pre-clinical data suggests synergistic effects if tisagenlecleucel is combined with the BTKi ibrutinib. The proposed mechanism includes enhancing T cell activation and expansion (Fraietta et al., Blood 2016), disrupting the MCL nodal environment (Long et al., The Journal of Clinical Investigation 2017) and mitigating CRS (Ruella et al., Clin Cancer Res 2016). Clinical trials in CLL show that the combination is safe and effective, including deep minimal residual disease negative responses (Gill et al., Blood 2018, Gauthier et al., Hematological Oncology 2019). We hypothesise that combination treatment will be tolerable and improve outcomes in a poor risk MCL population. Combination, time-limited therapy would also avoid the burdens of continuous treatment. Study Design and Methods 20 adult patients with MCL that has relapsed following front-line therapy, or those patients with MCL with TP53 aberrations who have achieved less than complete response on PET imaging after 2 cycles of induction will be enrolled (See Fig 1. for inclusion and exclusion criteria). Treatment consists of 560mg oral ibrutinib followed by a single infusion of tisagenlecleucel. Autologous lymphocytes for CAR T manufacture will be collected after a minimum of 7 days of continuous ibrutinib therapy. Ibrutinib will be continued during CAR T manufacture and for 6 months after infusion (see Fig 2.) Patient characteristics will be presented using descriptive statistics, response rates will be calculated as percentages using exact methods from the binomial distribution, and progression-free survival, duration of response and overall survival will be described using the Kaplan-Meier method. The primary objective is to estimate the complete response (CR) rate at month 4 following tisagenlecleucel infusion in combination with ibrutinib with the primary endpoint being CR rates at month 4 post tisagenlecleucel using the Lugano criteria. Secondary objectives include estimating MRD negative response rates, response rates according to TP53 status, and safety of the combination. Exploratory translational studies include studies of T cell repertoire and phenotype during ibrutinib exposure and after tisagenlecleucel infusion. The role of circulating tumour DNA monitoring in the management of MCL is also being evaluated. The trial is investigator led, sponsored by the Peter MacCallum Cancer Centre, with additional sites throughout Australia. The study was initiated in April 2020 and is actively recruiting patients. The trial is registered at ClinicalTrials.gov: NCT04234061. Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. Blombery:Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria; Novartis: Consultancy. Seymour:Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Pharmacyclics LLC, an AbbVie Company: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Dickinson:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy. OffLabel Disclosure: Tisagenlecleucel is not currently approved for use in MCL.
Mbbs Abhay Singh, Nuria Mencia-Trinchant, Elizabeth A. Griffiths, Matthew Gravina, Rutaba Tajammal, Do Mark G. Faber, Annmarie Nowak, Marc S. Ernstoff, Lunbiao Yan, Megan M. Herr, et al.
Published: 5 November 2020
Blood, Volume 136, pp 15-16; https://doi.org/10.1182/blood-2020-141617

Abstract:
Background. Clonal hematopoiesis (CH) is an aging associated phenomenon with potential to transform to overt myeloid disease at a rate of 1% per year. CH is hypothesized to represent a precursor state for leukemogenesis. CH is detected in 10% of healthy, elderly (>70 years) individuals at variant allele frequencies (VAFs) above 2%, but prevalence is higher in patients (pts) with malignancies (~25%). We recently demonstrated in a large population database study that recent changes in therapy for melanoma and non-small lung cancer (NSCLC) are associated with a decreased incidence of therapy-related myeloid neoplasms (tMNs).1 This trend may reflect declining utilization of chemo-radiotherapies or even regression of CH clones in the context of immune checkpoint inhibitor therapy (ICI). To improve our understanding of the evolving clonal architecture in patients with CH receiving ICI we analyzed blood samples from pts with melanoma and NSCLC at baseline and after exposure to ICIs. We aimed to characterize (i) baseline prevalence of CH in pts with melanoma and NSCLC (ii) alterations in clonal architecture associated with ICI treatment in serial blood samples from these pts. Methods. In this retrospective analysis, stored blood samples from pts with melanoma (N=32) and NSCLC (N= 109) treated with ICIs were analyzed. To detect CH, genomic DNA collected before treatment initiation and serially on ICI were analyzed using a custom panel targeting 93 genes. A 1% VAF cutoff was used to define CH. Relationships among clinical, laboratory and mutational variables were examined using chi-square test, at a significance level of 0.05. Results. We present preliminary results on 25 pts with melanoma (Table 1). Median age was 61 years. 52% (13/25) were men. One/25 pts had previously received chemotherapy and 4/25 had prior radiation therapy exposure. 64% (16/25) had stage IV disease and 36% (9/25) had stage III disease. 20% (5/25) had a history of autoimmune disease. CH was present in 32% of cohort, consistent with prior reports in solid tumor pts. Mutations in DNMT3A (36%) were most common, followed by TET2 (18%). Mutations in PPM1D, ARID1A, SF3B1, LPA and TGFBR2 accounted for 46% of the mutations (Figure 1). The mutational pattern was similar to prior reports in other cancer cohorts. DNMT3A mutations were most common in this cohort, with only one patient harboring a mutation in the R882 AML/MDS hotspot, previously described in CH. Most common mutation type was single nucleotide variants (55%), followed by frameshift (27%), and splice site mutations and truncations. The mean VAF for somatic mutations was 9%, much higher than the usual VAF cutoff for CH. Mutations were more common in smokers (40% vs 26.7%), and in individuals older than 60 years (37.5% vs 22%). Pts with autoimmune disease did not demonstrate CH mutations (0/5), whereas 40% (8/20) of pts without autoimmune diseases harbored mutations, (p=0.08). Conclusions. Our findings demonstrate a high baseline prevalence of putative CH mutations and high mean VAFs in a cohort of melanoma patients, even in the setting of minimal prior chemotherapy and radiation exposure. Despite this high CH prevalence, risk of tMN development after melanoma is declining with the use of newer therapies, suggesting a possible immune clearance or halt in progression of clonal hematopoiesis with newer therapies (ICI). Lack of CH mutations in individuals with autoimmune disease is an interesting finding and warrants further investigation. Ongoing serial sample analysis of the melanoma cohort after exposure to ICI will provide insight into the impact of ICI on the underlying clonal architecture. These findings are also being tested in the NSCLC validation cohort. References Singh A, Mrad C, Faber MG, et al. Evolving risk of therapy-related myelodysplastic syndromes and acute myeloid leukemia (tMDS/AML) following modern cancer therapies. Journal of Clinical Oncology. 2020;38(15_suppl):7516-7516. Acknowledgement: Data and samples for this study were provided by the Data Bank and BioRepository (DBBR), which is funded by the National Cancer Institute (P30 CA016056) and is a Roswell Park Cancer Institute Cancer Center Support Grant shared resource. Disclosures Griffiths: Persimmune: Research Funding; Boston Biomedical: Honoraria; Genentech Inc: Research Funding; Astex Pharmceuticals: Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; AbbVie Inc: Honoraria; Novartis: Honoraria, Research Funding. Guzman:Cellectis: Research Funding; SeqRx: Honoraria. Wang:Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Genentech: Consultancy.
Sujan Piya, Marla Weetall, Bs Josephine Sheedy, Balmiki Ray, Ms Huaxian Ma, Md Kensuke Kojima, Ms Vivian Ruvolo, Bs Mahesh Basyal, Md Marina Konopleva, Md Michael Andreeff, et al.
Published: 5 November 2020
Blood, Volume 136, pp 8-9; https://doi.org/10.1182/blood-2020-139940

Abstract:
Introduction: Acute myeloid leukemia (AML) is characterized by both aberrant proliferation and differentiation arrest at hematopoietic progenitor stages 1,2. AML relies upon de novo nucleotide synthesis to meet a dynamic metabolic landscape and to provide a sufficient supply of nucleotides and other macromolecules 3,4. Hence, we hypothesized that inhibition of de novo nucleotide synthesis would lead to depletion of the nucleotide pool and pyrimidine starvation in leukemic cells compared to their non-malignant counterparts and impact proliferative and differentiation inhibition pathways. PTC299 is an inhibitor of dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for de novo pyrimidine nucleotide synthesis that is currently in a clinical trial for the treatment of AML. Aim: We investigated the pre-clinical activity of PTC299 against AML in primary AML blasts and cytarabine-resistant cell lines. To confirm that PTC299 effects are due to inhibition of de novo pyrimidine nucleotide synthesis for leukemic growth, we specifically tested the impact of uridine and orotate rescue. In addition, a comprehensive analysis of alteration of metabolic signaling in PI3K/AKT pathways, apoptotic signatures and DNA damage responses were analyzed by Mass cytometry based proteomic analysis (CyTOF) and immunoblotting. The potential clinical relevance of DHODH inhibition was confirmed in an AML-PDX model. Results: The IC50s for all tested cell lines (at 3 day) and primary blasts (at 5-7 day) were in a very low nanomolar range: OCI-AML3 -4.43 nM, HL60 -59.7 nM and primary samples -18-90 nM. Treatment of AML in cytarabine-resistant cells demonstrated that PTC299 induced apoptosis, differentiation, and reduced proliferation with corresponding increase in Annexin V and CD14 positive cells (Fig.1). PTC299-induced apoptosis and inhibition of proliferation was rescued by uridine and orotate. To gain more mechanistic insights, we used an immunoblotting and mass cytometry (CyTOF) based approach to analyze changes in apoptotic and cell signaling proteins in OCI-AML3 cells. Apoptotic pathways were induced (cleaved PARP, cleaved Caspase-3) and DNA damage responses (TP53, γH2AX) and the PI3/AKT pathway were downregulated in response to PTC299. In isogenic cell lines, p53-wildtype cells were sustained and an increased DNA damage response with corresponding increase in apoptosis in comparison to p53-deficient cells was shown. (Fig.2) In a PDX mouse model of human AML, PTC299 treatment improved survival compared to mice treated with vehicle (median survival 40 days vs. 30 days, P=0.0002) (Fig.3). This corresponded with a reduction in the bone marrow burden of leukemia with increased expression of differentiation markers in mice treated with PTC299 (Fig.3). Conclusion: PTC299 is a novel dihydroorotate dehydrogenase (DHODH) inhibitor that triggers differentiation, apoptosis and/or inhibition of proliferation in AML and is being tested in a clinical trials for the treatment of acute myeloid malignancies. Reference: 1. Thomas D, Majeti R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 2017; 129(12): 1577-1585. e-pub ahead of print 2017/02/06; doi: 10.1182/blood-2016-10-696054 2. Quek L, Otto GW, Garnett C, Lhermitte L, Karamitros D, Stoilova B et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. The Journal of experimental medicine 2016; 213(8): 1513-1535. e-pub ahead of print 2016/07/06; doi: 10.1084/jem.20151775 3. Villa E, Ali ES, Sahu U, Ben-Sahra I. Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides. Cancers (Basel) 2019; 11(5). e-pub ahead of print 2019/05/22; doi: 10.3390/cancers11050688 4. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv 2016; 2(5): e1600200. e-pub ahead of print 2016/07/08; doi: 10.1126/sciadv.1600200 Disclosures Weetall: PTC Therapeutic: Current Employment. Sheedy:PTC therapeutics: Current Employment. Ray:PTC Therapeutics Inc.: Current Employment. Konopleva:Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Ablynx: Research Funding; Ascentage: Research Funding; Agios: Research Funding; Kisoji: Consultancy; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AbbVie: Consultancy, Research Funding; Calithera: Research Funding; Cellectis: Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Sanofi: Research Funding. Andreeff:Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Borthakur:BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; Oncoceutics: Research Funding.
Paul Koller, Karine Harutyunyan, Msc Antonio Cavazos, PhDMD Natalia Baran, Dvm Saradhi Mallampati, Renee Chin, Zhou Jiang, Heng-Huan Lee, Michael Curran, Mien-Chie Hung, et al.
Published: 5 November 2020
Blood, Volume 136, pp 44-44; https://doi.org/10.1182/blood-2020-141654

Abstract:
Anti-PD1 therapy in hematologic malignancies has shown clinically inferior effects when compared to solid tumors.1 However, immunotherapy has been part of the standard of care in the treatment of acute leukemia for over 40 years. Recently, loss of MHCII was shown to be a mechanism of Immune escape in patients with acute myeloid leukemia after stem cell transplantation.2 Here we demonstrate, in pre-clinical models, that responses to anti-PD1 can be enhanced by increased antigen presentation through induction of MHCII. We used a Philadelphia chromosome positive (Ph+) Acute Lymphoblastic Leukemia (ALL) syngeneic mouse model and treated 4 cohorts of mice with the following regimens: 1) vehicle 2) single agent Dasatinib; 3) single agent anti-PD1; 4) combination anti-PD1 + Dasatinib (Figure 1a). Single agent Dasatinib, was highly active against this model compared to vehicle. Although anti-PD1 therapy showed little or no activity as a single agent, when combined with sub-therapeutic doses of Dasatinib, we observed significantly enhanced survival of mice compared to single agent anti-PD1 or to single agent Dasatinib. (Figure 1b) In our mouse model, Dasatinib increased the MHCII on the surface of the antigen presenting cells in the tumor microenvironment, most notably in dendritic cells (CD11c+ cells) from mouse tumor-infiltrating lymphocytes collected from the mice bone marrow after treatment (Fig 1c). To prove whether Dasatinib-induced MHCII expression can occur independently of a tumor microenvironment, we treated antigen presenting cell lines (KG1) with Dasatinib and were able to confirm an increased MHCII expression by flow cytometry and by western blotting. (Fig 1d) Since Dasatinib is approved for the treatment of Philadelphia chromosome positive ALL, CML, and has been used in a variety of other settings in the treatment of both malignant hematology and solid tumors, this data has immediate translational potential. In fact, Dasatinib in combination with anti-PD1 therapy is currently being tested in a variety of phase I/II trials in various kinds of malignancies (NCT04284202, NCT03516279). Here we show that induction of MHCII by Dasatinib may serve as a biomarker and could predict the potential benefit from the combination treatment. Additionally, targeting anti-PD1 following Dasatinib administration may increase response rates of patients treated with Dasatinib, providing a rationale for sequential treatment design in patients with persistent minimal residual disease. Figure 1. (a) C57BL/6J mice were injected via tail vein injection with a transplantable, immunocompetent BCR-ABL+ B-ALL model and treated with vehicle/Dasatinib/or anti-PD1 as described in the schema. (b) Overall survival of the mice treated in the previous experiment. (c) MHCII cell surface expression on dendritic cells (CD11+ cells) from the bone marrow of treated mice. (d) relative Cell surface expression of MHCII in the KG1 cell line (APC cell line) treated with Dasatinib vs. vehicle. (e) protein expression of MHCII in the KG1 cell line (APC cell line) treated with Dasatinib vs. vehicle. 1. Masarova L, Kantarjian H, Ravandi F, Sharma P, Garcia-Manero G, Daver N. Update on Immunotherapy in AML and MDS: Monoclonal Antibodies and Checkpoint Inhibitors Paving the Road for Clinical Practice. Adv Exp Med Biol 2018;995:97-116. W2. Christopher MJ, Petti AA, Rettig MP, et al. Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. New England Journal of Medicine 2018;379:2330-41. Figure Disclosures Koller: Jazz Pharmaceuticals, Inc.: Consultancy. Konopleva:Stemline Therapeutics: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Sanofi: Research Funding; Genentech: Consultancy, Research Funding; Ablynx: Research Funding; Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AstraZeneca: Research Funding; Amgen: Consultancy; Calithera: Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding. OffLabel Disclosure: anti-pd1 therapy in acute lymphoid leukemia
Ekin Kircali, Guldane Cengiz, Sevgi Çolak, Mehmet Gunduz, Pinar Ataca Atilla, Erden Atilla, Mehmet Özen, Muhit Ozcan, Meral Beksac
Published: 5 November 2020
Blood, Volume 136, pp 13-14; https://doi.org/10.1182/blood-2020-137486

Abstract:
Introduction: Bendamustine is a synthetic alkylating agent made of both mustard and benzimidazole groups. It is used mainly in myeloma patients who have run out of classical treatment options and yet, have eligible performance status. Although data is still accumulating, there is not enough information to recommend a certain standard bendamustine dose or regimen in multiple myeloma. Melflufen is also an alkylator that is activated once metabolized by peptidases [1]. The logic this molecule selects and exterminates myeloma tumor cells by is that, myeloma cells overexpress aminopeptidases. Here, we have compared our and published bendamustine combination with melfufen data. Methods: We retrospectively analyzed our relapsed or refractory multiple myeloma patients who received bendamustine between 2002 and 2020 at Ankara University Medical School. All statistical analyses were performed via SPSS statistics version 20.0 software. After Pubmed search, all published bendamustine combination and melflufen clinical data among relapse refractory myeloma patients were included in the analysis. Results: Female/ male ratio was 14/ 18 (43.7 % / 56.3 %). Median age was 62 (36- 77) years. 22 (68.7 %) patients had Ig G myeloma, 6 (18.7 %) had Ig A myeloma and 4 (12.6 %) had light chain myeloma. ISS scores were as follows: I/ II/ III: 8 (25 %)/ 17 (53.1 %)/ 7 (21.9 %). FISH defined cytogenetics were available for 18 patients; 8 of them had normal chromosome analysis, 3 had only del13q, 1 had tri7. High risk cytogenetics was observed among 6 (33.3 %). R-ISS scores were as follows: I/ II/ III: 4 (22.2 %)/ 12 (66.7 %)/ 2 (11.1 %). Median prior lines of therapy was 3 (1- 6). 30 (93.8 %) patients had a history of bortezomib, 21 (65.6 %) had lenalidomide, 9 (28.1 %) had thalidomide. 21 (65.6 %) patients had undergone high-dose chemotherapy supported by autologous stem cell transplantation before bendamustine. 15 (46.9 %) patients were in treatment- refractory status at bendamustin initiation while 17 (53.1 %) used it for disease progression. Bendamustin was given either with Dexa (n= 13, 40.6 %) Bortezomib+ Dexa (n=6, 18.8 %), Lenalidomide+ Dexa (n=6, 18.8 %), Pomalidomide+ Dexa (n=5, 15.6 %) or Thalidomide+ Dexa (n= 2, 6.3 %). Bendamustine dose was 100- 120 mg/ m2/ day, 2 days monthly. 32 patients were followed up for median 26 months. Response to bendamustine treatment were as follows: Complete remission 4 (12.5 %), very good partial response 12 (37.5 %), partial response 8 (25 %), unresponsive 8 (25 %). Median progression free survival (PFS) was 5.6 (1- 40.6) months and overall survival (OS) was 17.3 (2- 79) months with bendamustine based treatment protocols. 15 (46.9 %) patients suffered grade ≥3 myelosuppression. Febrile neutropenia was experienced by 7 (21.9 %) patients, and 6 (18.7 %) had CMV reactivation during bendamustine treatment. There was no drug related mortality. Conclusion: Although bendamustine is effective among highly refractory myeloma patients, toxicity profile and immune plus myelosuppression prevents long term use. Bendamustine in our experience in combination has provided efficacy comparable to earlier publications. Current single agent Melflufen data in advanced stages may be even more promising if combined with proteasome inhibitors or IMIDs. References 1. Richardson, P.G., et al., Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, phase 1-2 study. The Lancet Haematology, 2020. 2. Knop, S., et al., The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high-dose chemotherapy. haematologica, 2005. 90(9): p. 1287-1288. 3. Grey-Davies, E., et al., Bendamustine, thalidomide and dexamethasone is an effective salvage regimen for advanced stage multiple myeloma. British journal of haematology, 2012. 156(4): p. 552-555. 4. Damaj, G., et al., Efficacy of bendamustine in relapsed/refractory myeloma patients: results from the French compassionate use program. Leukemia & lymphoma, 2012. 53(4): p. 632-634. 5. Ludwig, H., et al., Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood, The Journal of the American Society of Hematology, 2014. 123(7): p. 985-991. Disclosures Ozcan: Abdi Ibrahim: Other; Archigen Biotech: Research Funding; Amgen: Honoraria, Other: Travel support; Bristol Myers Squibb: Other: Travel support; Jazz Pharmaceuticals: Other; Sanofi: Other; F. Hoffmann-La Roche Ltd: Other: Travel support, Research Funding; Celgene: Research Funding; MSD: Research Funding; Janssen: Other: Travel support, Research Funding; AbbVie: Other: Travel support, Research Funding; Bayer: Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding.
Corrigendum
, Irene Iglesias, Ana De La Torre
Frontiers in Veterinary Science, Volume 7; https://doi.org/10.3389/fvets.2020.581766

Abstract:
A Corrigendum onEvolution of the ASF Infection Stage in Wild Boar Within the EU (2014–2018) by Martínez-Avilés, M., Iglesias, I., and De La Torre, A. (2020). Front. Vet. Sci. 7:155. doi: 10.3389/fvets.2020.00155 In the original article, there was a mistake in Table 1 as published. In the third column of the table, first row, under Stage 2 it should be stated in brackets (PCR+, AB+)b. The corrected Table 1 appears below. Table 1. Annual distribution of ASF notifications in wild boar by diagnostic test/s used and estimated stage of infection. 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: antibodies, epidemiology, surveillance, moderately virulent virus, survivor, African Swine fever, wild boar Citation: Martínez-Avilés M, Iglesias I and De La Torre A (2020) Corrigendum: Evolution of the ASF Infection Stage in Wild Boar Within the EU (2014–2018). Front. Vet. Sci. 7:581766. doi: 10.3389/fvets.2020.581766 Received: 09 July 2020; Accepted: 14 August 2020;Published: 26 October 2020. Edited and reviewed by: Andrew William Byrne, Department of Agriculture Food and the Marine, Ireland Copyright © 2020 Martínez-Avilés, Iglesias and De La Torre. 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: Marta Martínez-Avilés, [email protected]
Francisco M Marty, Prashant Malhotra, Robert L Gottlieb, Karen T Tashima, Massimo Galli, Louis Yi Ann Chai, Devi Sengupta, Robert H Hyland, Hongyuan Wang, Lijie Zhong, et al.
Open Forum Infectious Diseases, Volume 7; https://doi.org/10.1093/ofid/ofaa439.382

Abstract:
Background Remdesivir (RDV) shortens time to recovery time in patients with severe COVID-19. Its effect in patients with moderate COVID-19 remains unclear. Methods We conducted an open-label, phase 3 trial (NCT04252664) involving hospitalized patients with confirmed SARS-CoV-2 infection, evidence of pulmonary infiltrates, and oxygen saturation >94% on room air. Patients were randomly assigned 1:1:1 to receive up to 5d or 10d of RDV with standard of care (SoC), or SoC alone; patients could be discharged prior to completing per-protocol assigned treatment duration. RDV was dosed intravenously at 200 mg on d1, 100 mg daily thereafter. Patients were evaluated daily while hospitalized, and via telephone if discharged. The primary endpoint was clinical status on d11 assessed on a 7-point ordinal scale. Results regarding the primary endpoint are expected to be published before IDWeek 2020; we plan to present d28 results at the meeting. Results In total, 584 patients underwent randomization and started their assigned treatment (191, 5d RDV; 193, 10d RDV; 200, SoC). By d11, ³ 2 point improvement on the ordinal scale occurred in 70% of patients in the 5d arm, 65% in the 10d arm, and 61% in the SoC arm. Patients in the 5d RDV arm were significantly more likely to have an improvement in clinical status than those receiving SoC (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.09–2.48; P=0.017); OR of improvement for the 10d RDV arm compared to SoC was 1.31 (95% CI, 0.88–1.95]; p=0.183). This improvement in the 5-day arm over the SOC arm was noted from d6 through d11. We observed a peak of discharges corresponding with the assigned treatment duration of RDV, with increased discharges at d6 in the 5-day arm and at d11 in the 10-day arm. A worsening of clinical status of ≥ 1 point in the ordinal scale was observed more commonly in the SoC am (n=19, 10%) versus the 5d RDV (n=7, 4%) and 10d RDV (n=9, 5%). Conclusion RDV for up to 5 days was superior to SoC in improving the clinical status of patients with moderate COVID-19 by d11. We will report d28 outcomes at the meeting. Disclosures Francisco M. Marty, MD, Allovir (Consultant)Amplyx (Consultant)Ansun (Scientific Research Study Investigator)Avir (Consultant)Cidara (Scientific Research Study Investigator)F2G (Consultant, Scientific Research Study Investigator)Kyorin (Consultant)Merck (Consultant, Grant/Research Support, Scientific Research Study Investigator)New England Journal of Medicine (Other Financial or Material Support, Honorarium for Video)Regeneron (Consultant, Scientific Research Study Investigator)ReViral (Consultant)Scynexis (Scientific Research Study Investigator)Symbio (Consultant)Takeda (Scientific Research Study Investigator)United Medical (Consultant)WHISCON (Scientific Research Study Investigator) Prashant Malhotra, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Robert L. Gottlieb, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Karen T. Tashima, MD, Bristol-Myers Squibb (Research Grant or Support)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator)GlaxoSmithKline (Research Grant or Support)Merck (Research Grant or Support)Tibotec (Research Grant or Support)Viiv Healthcare (Research Grant or Support) Massimo Galli, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Personal fees) Louis Yi Ann Chai, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Devi SenGupta, MD, Gilead Sciences Inc. (Employee, Shareholder) Robert H. Hyland, MD, Gilead Sciences Inc. (Employee, Shareholder) Hongyuan Wang, PhD, Gilead Sciences Inc. (Employee, Shareholder) Lijie Zhong, PhD, Gilead Sciences Inc. (Employee, Shareholder) Huyen Cao, MD, Gilead Sciences Inc. (Employee, Shareholder) Anand Chokkalingam, PhD, Gilead Sciences (Employee) Anu Osinusi, MD, Gilead Sciences (Employee) Diana M. Brainard, MD, Gilead Sciences (Employee) Michael Brown, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Ane Josune Goikoetxea, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Mamta Jain, MD, Gilead Sciences Inc. (Scientific Research Study Investigator, Research Grant or Support)GlaxoSmithKline (Advisor or Review Panel member)Janssen (Research Grant or Support)Merck (Research Grant or Support) David Shu Cheong Hui, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Enos Bernasconi, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Christoph Spinner, MD, AbbVie (Advisor or Review Panel member, Other Financial or Material Support, Travel)Bristol-Myers Squibb (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Travel)Janssen (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)MSD (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)Viiv Healthcare (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)
, , Bernardo Dell'Osso, Matteo Cesari, Mauro Porta, Fabrizia Lattanzio, Giuseppe Banfi, Giuseppe M. Peretti
Published: 28 September 2020
Frontiers in Psychology, Volume 11; https://doi.org/10.3389/fpsyg.2020.565052

Abstract:
Older adults rank in the most at-risk segment of the population because the basal functional resilience, meant as the ability to cope with physical trauma and psychological stressors, is fading (Cesari et al., 2017). Aging is physiologically associated with cognitive decline and impaired stress response (Bishop et al., 2010), with the spinal circuitry degeneration leading to progressive alterations of motor performance (Borzuola et al., 2020). This reduced resilience and cognitive impairment intimately coexist in the rampant -definitely endemics- frailty syndrome (Ofori-Asenso et al., 2019), which is known to be associated with disability, traumatic falls, and hospital admission (Eeles et al., 2012). Regrettably, the wearisome settings of hospital wards provide poor incitements to the oldest minds and often oversee the abilities of individuals, who cope with progressive restlessness, dietary impoverishment, and nutrition-related or activity-related sarcopenia (Eeles et al., 2012; Ligthart-Melis et al., 2020). Multidisciplinary interventions, such as the HEPAS approach (Healthy Eating, Physical Activity, and Sleep), are models for dealing with multiple issues simultaneously (Briguglio et al., 2020c). Despite this knowledge, contemporary society, and health services put the older adults in the background. From the most complex digitization of services to the simplest use of public transport, there is “No Country for Old Men” (Ethan and Joel Coen, 2007). It is therefore not surprising that when the new strain coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus of 2019) spilled out to infect humans found not only fertile ground -a population of old people- but also countries ready to choose treating people with more life expectancy. After the outbreak of viral pneumonia in Wuhan, China, (December 2019), SARS-CoV-2 spread rapidly in Europe. Italy resulted among the worst-hit countries with 214.457 infected and 29.684 deaths (May 7, 2020, WHO situation report 108). The northern region of Lombardy accounted for the overall 52.3% of the deaths (May 7, 2020, Italian SARS-CoV-2 Surveillance Group), with the older adults suffering from chronic cardiovascular diseases and malnutrition counting the highest case-fatality ratio (Briguglio et al., 2020b). Considering that the region counted 128.528 subjects over 60 years of age at the beginning of the past year (Annual Italian Census of 2019), we can say that the north of Italy lost over 10% of its older population. This rapid increase of infected severe cases led to a rapid saturation of health facilities in March-April 2020 and public health interventions focused on social isolation, travel restraints, and at-home confinement. Containment measures have been applied with different degrees of restriction in different Italian regions, but the northern regions -the worst-hit- have suffered the most severe lockdown measures. In Lombardy, almost 100.000 older adult residents locked themselves up in the house. Leaving the house was permitted, but only for proven health or job reasons. Interregional travel was also banned. Most commercial activities were shut down, few have been minimized. Buying necessities was allowed, but only one individual per family wearing masks and gloves. To respect social distancing, supermarkets regulated the entrances eventually forming long queues, with people possibly waiting for hours. Priority tickets could be booked online, as well as masks that were sold out by pharmacies but available on various web sites at inflated prices. Eventually, these measures contributed to reduce the impact on health services and the risk of severe illness (Steffens, 2020). Although reasonable and essential, the social lockdown has affected both the bourgeois and the less well-off classes of the population. However, are the vulnerable groups -the older adults- who will be carrying the worse future debt of disability? In the pre-COVID-19 era, over 50% of older adults were known to be at risk of loneliness (with associated morbid events) (Fakoya et al., 2020) and this feature fused with reduced health care capacity during the pandemic. In the COVID-19 era, most medical clinics closed or adhered to special hours and the reorganization of the health system led to a significant reduction in clinical and surgical assistance. These restrictions prevented the older adults from having a continuity of care for their co-existing chronic conditions. The decline in social relations combined with reduced support increase the disability debt, with the reaching of the “social frailty.” Results from a Chinese -another worst-hit country- online survey proved over 50% of respondents rating the psychological impact of COVID-19 moderate-to-severe, with depressive and anxiety symptoms being prevalent (Wang et al., 2020). Dramatic events, such as the loss of a kin, but also anxiety from the fear of being infected and the inability to do something can further compromise the mental health. On one hand, the Italian daily newscast informed the public about the disease severity, reporting hundreds of daily deaths. On the other hand, the indirect fear inherent in those who were watching has been a major side effect. Frailty therefore acquired a mental nature, becoming “psychological frailty” (Gobbens et al., 2012). Older adults require increasing cognitive demand to perform any motor task (Seidler et al., 2010). The COVID-19 restrictions have been not only associated with psychological derangements, but also with an increasing “bed-kitchen-sofa” lifestyle. Low environmental information-processing was consequently prevalent during daytime, with further impairment of age-associated spatial disorientation, proprioception, disequilibrium, and incoordination (Dunsky, 2019). At-home confinement easily led to sarcopenia. The sedentary lifestyle associated with constant stress that decreased the desire to eat. Either reduced food security or food supply reduced energy intake, leading to nutritional deficits (Briguglio et al., 2020b). Sarcopenia easily became osteosarcopenia. After 2 months (end of March, April, and early May) of confinement, the perceived loss of balance inherits the fear of falling. The “physical frailty” reaches its peak. The easing of COVID-19 lockdown on the older population has possibly brought effects comparable to the hospital-associated deconditioning. The disability debt earned during the lockdown will require an augmented need for care for older individuals suffering from the abovementioned geriatric conditions -functional disability- and psychosocial disorders, mainly isolation. The surviving older individuals who have not been infected with SARS-CoV-2 are definitely more fragile, malnourished, and more ill than the pre-COVID-19 era. Those who have been infected will encounter permanent disabilities, such as pulmonary fibrosis and impaired liver function. Indeed, reduced respiratory capacity has been observed for the survivors after SARS-CoV-1 (Ngai et al., 2010). Permanent affections could be also mental, with long-term neuropsychiatric consequences being characteristics of neurotrophic coronaviruses (Briguglio et al., 2020a; De Felice et al., 2020). We expect the frail older adults to be exposed to an increased risk of traumatic events amid restrictions (Clegg et al., 2013). This worsening of the three-dimension frailty may therefore transduce into more hospital admissions. Frail older adults encounter a 1.2- to 2.8-fold risk for falls and fractures and 1.2- to 1.8-fold risk for hospitalization (Vermeiren et al., 2016). Even though COVID-19-associated admissions are known to be flattening, it is also known that most fractures occur in the home and the prolonged restrictions may expose orthopedic hospitals to a different kind of saturation post-COVID-19. During the pandemic, the choice of operating older adult subjects who have suffered a falling trauma was a matter of debate. In the worst-hit countries, the experience of Chinese (Mi et al., 2020) and Spanish (Munoz Vives et al., 2020) authors would suggest delaying the surgical treatment of fractured patients with SARS-CoV-2 as they have observed excessive mortality rates. The Italian experience would suggest instead to treating the fracture as soon as possible in order to stabilize the patient (Catellani et al., 2020). Anyhow, it is a fact that elective orthopedic surgery has been delayed, but there may be also a debt of traumatic fractures that must be bridged. It is also possible that many lonely seniors who fell into the house during the restricted period have not yet been established: fall not reported? While there was over a halving of emergency room accesses for high energy fractures in Italy during the pandemic (Fojut, 2020; Magro et al., 2020), on the other hand, low energy/fragility fractures did not substantially reduce (Benazzo et al., 2020; Jain et al., 2020). This highlights the lack of home prevention measures for the elderly that certainly has exposed them to an increased risk of risk of hospital-acquired SARS-CoV-2 infection. In the post-COVID-19 era, the saturation of health services may only be the tip of the iceberg in relation to the restriction-derived burden of frailty. During confinement, the diminished state of resilience in elderly people may have worsened all age-associated conditions, such as a mild high blood pressure, glucose intolerance, basal immune dysfunction, inflammaging, and mental liability with anxiety-depressive traits. The dynamics of “frailty” renders its transition to a worse level more common than improvement (Morley et al., 2013), and this COVID-19 pandemic may have spin the loop of a decline of decreasing functional ability, increasing frailty, greater risk of traumatic falls, and higher hospital admissions for fragility fractures in the near future (Figure 1). Since it is difficult to predict when SARS-CoV-2 will become a secondary problem, it is also important to ponder the possibility of a second wave of infections since this prolonged social isolation has created a population with fewer anti-viral immune defenses (Cole et al., 2015). Homeless and people with disabilities should also be a matter of concern (Mesa Vieira et al., 2020). It is therefore mandatory to get prepared for pandemic consequences with appropriate interventions, being both public health-oriented and patient-oriented. This pandemic has not only underlined the public health challenges to guarantee that older population can access the services they need, but it has also shown new opportunities to be seized, such as an expanded workforce specialized in aging (Morrow-Howell et al., 2020), a promotion of intergenerational solidarity (Brooke and Jackson, 2020), or practical community participations, such as the dropping off of groceries (Fraser et al., 2020). In clinical settings, the confronting with a fast-growing geriatric population suffering from multiple comorbidities needs a multidisciplinary approach like the orthogeriatric co-management model of care, with orthopedic doctors and geriatricians prioritizing the patients' needs and aiming at clinical as well as cost-benefit advantages for older adults (Gosch et al., 2016). Valuable and tailored patient-oriented solutions have been proposed after COVID-19 pandemic restriction-associated isolation to cope with social, psychological, and physical frailty. Both the procurement of health care assistance and the reduction of loneliness to older adults that who have suffered from isolation should be a priority for social frailty handling. For instance, remote interventions via online systems may be valuable (Patel and Clark-Ginsberg, 2020) but an appropriate utility assessment and training in the use of technological services should be provided. Psychological frailty should be counteracted through older adult engagement and motivation, possibly via phone contact with health professionals (Armitage and Nellums, 2020) or by broadcasting television entertaining with premeditated programs (Jawaid, 2020). Also, symptoms such as fear and sleeping disturbances should be properly identified and addressed (Berg-Weger and Morley, 2020). Physical frailty can be resolved through educational videos and recorded physical activity sessions (Angulo et al., 2020). Actually, online technologies are the most valuable support systems, but have to be appropriately planned for older minds (Meinert et al., 2020). Of note, prioritized interventions should be established for low and middle income countries where family dynamics are different, a large number of older adults are illiterate, and proper health care assistance is limited (Lloyd-Sherlock et al., 2020). Figure 1. Tendencies of the consequences of the COVID-19 pandemic on the health of the elderly and the risk of hospital admissions after lockdown easing. The severe acute respiratory syndrome coronavirus that was discovered in Hubei province, China at the end of December 2019 (SARS-CoV-2) burst a pandemic that shut down the world. Under normal circumstances, the older adults must deal with a diminished functional ability and progressive establishment of geriatric fragility. If a healthy status is present, recovery from any trauma is discreet even if it is not associated with full pre-trauma functionality. Although restrictive measures were necessary for public health during the pandemic, they have exposed older individuals to confinement that has worsened their physical and mental health. Upon easing of the lockdown, the older person will suffer a disability debt, which will make him highly vulnerable to the risk of falling. Orthopedic hospitals that recorded a halving of traumatic admissions could contrariwise encounter a surge in accesses for traumas amid lockdown easing. To conclude, we can say that: • The new coronavirus SARS-CoV-2 met a population of frail elderly • The restrictions due to the COVID-19 pandemic generated a more fragile class of older adults • The health system should re-organize for efficiently managing the surge of frailty fractures • Long-term psychological consequences amid COVID-19 pandemic and associated restrictions should be considered, especially for the oldest fragile minds. MB formulated the hypothesis and wrote the first draft of the manuscript together with RG. BD, MC, MP, FL, GB, and GMP revised the first draft and contributed to manuscript sections. All authors contributed to manuscript revision, read and approved the submitted version. 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Public Health 17:1729. doi: 10.3390/ijerph17051729 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: frailty syndrome, coronavirus, SARS-CoV-2, COVID-19, infections, nutritional status, sedentary behavior, quality of health care Citation: Briguglio M, Giorgino R, Dell'Osso B, Cesari M, Porta M, Lattanzio F, Banfi G and Peretti GM (2020) Consequences for the Elderly After COVID-19 Isolation: FEaR (Frail Elderly amid Restrictions). Front. Psychol. 11:565052. doi: 10.3389/fpsyg.2020.565052 Received: 26 May 2020; Accepted: 26 August 2020; Published: 28 September 2020. Edited by: Reviewed by: Copyright © 2020 Briguglio, Giorgino, Dell'Osso, Cesari, Porta, Lattanzio, Banfi and Peretti. 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: Riccardo Giorgino, [email protected]
, Hong Gao, Yuhui Luo, Hushan Zheng, Xiang Liao, Donglin Xiong, Lizu Xiao
Published: 24 September 2020
Frontiers in Microbiology, Volume 11; https://doi.org/10.3389/fmicb.2020.572318

Abstract:
Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was identified at the end of 2019, has become a widespread, global public health crisis, raising many concerns (Khan et al., 2020). According to the newest data from the World Health Organization (WHO), global SARS-CoV-2 infection cases have reached 18.6 million, with the reported deaths of more than 700,000 individuals (WHO, 2020). Coronaviruses are enveloped, positive-stranded RNA viruses, with an average diameter of 100 nm. The genome length of most coronaviruses ranges from 26 to 32 kb. Coronaviruses can infect various vertebrate species, including bats, dogs, and humans (Fan et al., 2019; Sit et al., 2020). Since the start of the Twenty one century, humans have encountered coronavirus outbreaks three times: severe acute respiratory syndrome-associated coronavirus (SARS-CoV-1), in 2003 (de Wit et al., 2016), Middle East respiratory syndrome-related coronavirus (MERS-CoV), in 2008 (Hemida et al., 2020), and SARS-CoV-2, in 2019 (Wu F. et al., 2020). Genetic comparisons have indicated 79.5% similarity between SARS-CoV-2 and SARS-CoV, and the similarity is up to 96% between SARS-CoV-2 and a coronavirus strain isolated from bats (Zhou et al., 2020). According to the structural and genome-wide association studies, SARS-CoV-2 can more easily infect and replicate in host cells than other coronaviruses (Gussow et al., 2020; Yan et al., 2020). SARS-CoV-2 infections are responsible for the ongoing, global COVID-19 pandemic, which has a fatality rate between 2 and 4% (Weiss and Murdoch, 2020). SARS-CoV-2 infections result in major impacts on the human respiratory system (Rothan and Byrareddy, 2020), with fever, mild cough, pneumonia, and dyspnoea (Singhal, 2020). COVID-19 patients also experience various neurological symptoms, such as headache, epilepsy, disturbed consciousness (Mao et al., 2020; Wu Y. et al., 2020), smell, vision and taste loss, neuralgia (Jin et al., 2020; Mao et al., 2020), and acute neurological disorders, such as stroke and seizure (Jin et al., 2020) in COVID-19 patients. It has been reported that SARS-CoV-2 infection affected the central and peripheral nervous system manifesting as dysosmia, visual disturbances, and neuralgia after (Mao et al., 2020). Abdelnour et al. has reported a case of SARS-CoV-2 infection manifesting as peripheral neuropathy (Abdelnour et al., 2020). This evidence demonstrates that SARS-CoV-2 can cause serious malfunction and damage to both the central and peripheral nervous systems. It has been reported that SARS-CoV-2 infections in elderly and weak individuals cause more severe syndromes, such as acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), which are associated with lung malfunction and death (Matuschak and Lechner, 2010). Patients with chronic obstructive pulmonary disease (COPD) and smoking history have also been reported to experience worse progression and outcomes when diagnosed with COVID-19 (Zhao et al., 2020). COVID-19 in cancer patients has a 36% lethality, and worse prognosis has been observed among older individuals (Stroppa et al., 2020). Human immunodeficiency virus (HIV)-positive patients may be more vulnerable to COVID-19 due to their immune-compromised status. A recent clinical observation reported that COVID-19 results in a death rate of approximately 9% among patients living with HIV (Harter et al., 2020). Besides, some patients treated with opioids could be more susceptible to SARS-CoV-2 infections because treatments with morphine and fentanyl have been reported to be the most immunosuppressive (Mellon and Bayer, 1998; Shavit et al., 2004). Opioids act on the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system, further suppressing the immune system (Mellon and Bayer, 1998; Shavit et al., 2004; Plein and Rittner, 2018). These studies suggest that hypo-immune individuals might have higher risks and worse outcomes associated with COVID-19. On the other hand, the possibility of SARS-CoV-2 infection in hyper-immune individuals is also worldwide discussed because of their immunological background and therapies. It has been reported that hyper-immunity individuals have received treatment with immunosuppressive or modulatory agents; these approaches may increase the possibility of SARS-CoV-2 infection (Cai et al., 2020). Therefore, individuals with altered immunity (hypo-immune & hyper-immune) may require additional attention to prevent the infection of SARS-CoV-2 during the COVID-19 outbreak. It is known that the induction of a cytokine storm is the basic cause of pathogenic inflammation in COVID-19 (Jose and Manuel, 2020; Mehta et al., 2020). Cytokine storm is an acute hyperinflammatory response responsible for critical illness in many conditions, including viral infections, cancer, sepsis, and multi-organ failure (Bhaskar et al., 2020). The elevation of cytokines in the blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients (Bhaskar et al., 2020). Laboratory results have shown that dysregulation in the immune system has occurred in COVID-19 patients. SARS-CoV-2 infection increases the plasmatic secretion of interleukin 1β, interferon-γ, interferon-γ-induced proteins, monocyte chemoattractant protein-1, IL-4, and IL-10 (Vinciguerra et al., 2020). Moreover, it has been reported that SARS-CoV-2 infection induces the up-regulation of a series of interferon-stimulated genes, indicative of immune and interferon responses to the virus (Blanco-Melo et al., 2020). These results demonstrated that SARS-CoV-2 infection-induced immune alteration in COVID-19 patients. The SARS-CoV-2 infection causes systemic inflammation and dysregulation of immunity, resulting in various delayed neurological complications. Both central and peripheral nervous systems have been reported to be involved in the immune-mediated manifestations in COVID-19 patients (Abdelnour et al., 2020; Mao et al., 2020). It is known that the virus could enter the brain carried by infected immune cells (Bergmann et al., 2006). Several regions in the brain, including vasculature, meninges, and choroid plexus, could be the entry sites for virus-infected immune cells (Engelhardt et al., 2017). Besides, SARS-CoV-2-induced cytokines, IL-6, IL-1β, TNF, and IL-17 could facilitate the entry of the virus into the brain through disrupting the blood-brain barriers (BBB) (Erickson and Banks, 2018). On the other hand, the hypothalamus in the brain also contributes to the dysregulation of immunity. IL-6, IL-1β, and TNF-α have been reported to be robust activators of the HPA axis (Dantzer, 2018). HPA axis plays a central role in regulating systemic immunity and is majorly activated by BBB dysfunction and neurovascular inflammation (Dantzer, 2018). These studies suggested that SARS-CoV-2 infection-induced immune alteration could further result in the concurrence of chronic pain since it affects the nervous system. Chronic pain is a complex and distressing problem, which significantly impacts the life quality of each individual. Chronic pain is not merely an accompanying symptom and can be associated with various underlying causes, including immunity alterations, and viral infections. Patients with chronic pain must be given effective and continuous treatments to manage their long-term pain at an acceptable level. To date, the prevalence of COVID-19 appears to continue increasing exponentially worldwide. Constant exposure risk to COVID-19 is currently expected to become the new normal. In this situation, the management of immunity alteration-induced chronic pain may require additional attention. Here we summarize several types of chronic pain, which are closely related to the alteration of immunity in individuals, and give some recommendations from a clinical view. HZ is an acute, cutaneous viral infection caused by the reactivation of the VZV (Saguil et al., 2017). The incidence of HZ has been estimated to be 7.7% in China, with a lifetime risk of 30% in each individual (Yang et al., 2019). The risk factors associated with the reactivation of VZV have not yet been clarified; however, malignancies, immune deficiencies, solid organ, and bone marrow transplantations, autoimmune diseases, psychological conditions, emotional stress, and immunosuppressive therapies have been identified as possible major risk factors (Wei et al., 2019). In hypo-immune conditions, especially those associated with decreased cell-mediated immune status, the risk of VZV reactivation is 100-fold higher than in healthy subjects (Singh et al., 2020). It has been reported that SARS-CoV-2 infected individuals have also developed severe acute herpetic neuralgia despite the early initiation of antiviral therapy (Saati et al., 2020; Shors, 2020). Herpes zoster (HZ) might be an indicator of latent SARS-CoV-2 infection because the clinical presentation of HZ even in patients having mild or no upper respiratory symptoms should be considered as an alarming sign for SARS-CoV-2 infection (Elsaie et al., 2020), which highlights the possibility of COVID-19-induced HZ. Postherpetic neuralgia (PHN) is the most common complication in approximately one-fifth of HZ patients, especially among elderly individuals (Gershon et al., 2010). PHN is defined as skin-distributed pain that persists for at least 3 months after acute HZ (Salvetti et al., 2019). The treatment for PHN focuses on symptom control, including the use of topical lidocaine or capsaicin and oral gabapentin, pregabalin, or tricyclic antidepressants (Hempstead et al., 2020; Kopel and Brower, 2020), as well as the improvement of immunity and antiviral treatments (Huning et al., 2019; Hunter et al., 2020). The analgesic effects of traditional treatments have not been reported to have good efficacy among PHN patients with older age, serious skin lesions, or long disease courses. Neuromodulation, such as spinal cord stimulation, may represent a new approach for pain relief among these patients (Huang et al., 2020). Acquired immune deficiency syndrome (AIDS) is associated with various infection symptoms, and peripheral neuropathic pain is the most common and severe neurological manifestation that has been reported in HIV-positive, immunocompromised individuals (Amaniti et al., 2019). Statistical analysis has revealed that up to one-third of HIV-infected individuals suffer from neuropathic pain, which presents as distal, symmetrical, axonal, and peripheral sensory neuropathic pain, accompanied by a burning sensation and paraesthesia, which primarily affects the legs and hands (Gabbai et al., 2013). The possible pathogenesis of HIV infection-induced neuropathic pain includes tumor necrosis factor-α (TNF-α) (Zheng et al., 2011), CCAAT/Enhancer Binding Protein β (CEBPβ) phosphorylation (Yi et al., 2018), and mitochondrial oxidative stress (Kanda et al., 2016). The current clinical treatment for HIV-induced neuropathic pain includes nonopioid pain relievers, opioid analgesics, adjuvant medications, and psychosocial therapies (Krashin et al., 2012). Reactive arthritis (RA), an autoimmune disease, is the most common chronic inflammatory disease. RA is characterized by the progressive, symmetric inflammation of affected joints and tendon (tenosynovitis), resulting in both cartilage destruction and bone erosion (Lin et al., 2020). The clinical manifestations of RA vary greatly among individuals and can become more severe without medical intervention. The prevalence of RA has been reported to range from 4 to 13 per 1,000 individuals, and the risk factors include age, gender, genetics, smoking, obesity, exposure to ultraviolet (UV) light, drugs, changes in the microbiome of the gut, mouth, and lungs, periodontal disease (periodontitis), and infections (Deane et al., 2017). Besides, SARS-CoV-2 infection also causes RA (Ono et al., 2020). Joint inflammation in RA is mediated by T-cells, B-cells, macrophages, fibroblasts, and inflammatory cytokines (Lin et al., 2020). Currently available therapeutic drugs include the administration of non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressive glucocorticoids (Hajialilo et al., 2016), and disease-modifying anti-rheumatic drugs (DMARDs) (Fries, 2000). Ankylosing spondylitis (AS) is both an autoimmune rheumatological arthritis and a chronic inflammatory disease. AS is reported to be highly correlated with the presence of human leukocyte antigen (HLA)-B27 (Hill et al., 1976). Moreover, genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) related to AS susceptibilities, such as those in IL-23R, IL-17A, RUNX3, and BCL11B (Liu et al., 2020). AS is caused by chronic inflammatory disorders, manifested as structural damage to the spinal and sacroiliac joints, which subsequently develops into ankylosis, due to new osteogenesis (Sieper and Poddubnyy, 2017). The clinical symptoms of AS include chronic back pain, morning stiffness, fatigue, and the loss of spinal mobility (Sieper and Poddubnyy, 2017). The clinical treatment of AS typically involves suppressing immunity and anti-inflammatory medications (Yang et al., 2018). NSAIDs are the first-line drugs used clinically and are considered the most effective therapeutic approach, according to current management recommendations (Ward et al., 2019). Chronic pain involves complex brain circuits, which include sensory, emotional, cognitive, and interoceptive processing (Simons et al., 2014). An association exists between psychosocial factors and the severity of chronic pain. Psychosocial factors have been reported to affect the development of chronic pain, as well as pain treatment outcomes. The severity of chronic pain can be evaluated by pain-related distress. COVID-19 has caused an international public health emergency and poses a tremendous challenge to psychological resilience. These adverse psychological impacts and psychiatric symptoms include depression, anxiety, panic, somatic symptoms, self-blame, guilt, post-traumatic stress disorder (PTSD), delirium, psychosis, and even suicide (Steenblock et al., 2020). A recent survey has revealed that 12.5, 37.8, and 36.4% of participants reported sleep difficulties, paranoia regarding the acquisition of COVID-19 infection, and distress related to social media. A perceived mental healthcare need was reported for more than 80% of participants (Roy et al., 2020). These phycological challenges could affect the management of chronic pain. Abnormal psychological status results in more severe chronic pain and increased difficulty experiencing clinical relief. Moreover, the reasons for adverse psychological outcomes among patients ranged from inadequate access to personal protective equipment, shocking news media, feeling not supported, helpless and hopeless, experiencing insomnia, undergoing complicated medical procedures and environments, and the relatively high infection rate among medical staff and patients (Spoorthy et al., 2020). Therefore, phycological counseling became critical for the management of chronic pain during the COVID-19 outbreak. Cognitive-behavioral therapy is recommended as a psychological intervention for patients with chronic pain. Strengthening the patient's confidence could be necessary to relieve psychological stress in chronic pain patients during the COVID-19 outbreak. 1. Postpone immunosuppressive therapy for patients with immunity alteration-induced chronic pain. The postponement or stoppage of immunosuppressive therapy, such as immunosuppressive glucocorticoids, should be considered unless the pain condition does not allow these options. This suggestion is as same as the international psoriasis council (IPC) statement on the Coronavirus (COVID-19) Outbreak. Patients using steroids, azathioprine, methotrexate, and cyclosporine should pay additional attention to the proper use of personal protective equipment. 2. Psychological counseling for patients with chronic pain Psychological evaluations are necessary for patients with chronic pain, especially during the COVID-19 outbreak. Cognitive-behavioral therapy is recommended as a psychological intervention for patients with chronic pain. Strengthening the patient's confidence is recommended to relieve psychological stress in chronic pain patients during the COVID-19 outbreak. 3. Remote pain management, telemedicine, and medical quarantine for patients with chronic pain Blood tests and instrumental examination interventions, such as functional MRI (fMRI), electroencephalogram (EEG), nerve block, and spinal cord stimulation (SCS), should be avoided unless critically necessary during the COVID-19 outbreak. Patients should medically quarantine themselves, and avoid contact with other individuals, except in cases of emergency. Clinical investigations and medical interventions that require repeated access to hospitals or medical staff may increase the susceptibility to SARS-CoV-2 infection. Outpatient visits and patient treatments should be performed with care to avoid potential infections within the hospital setting. If possible, patients' pain conditions should be monitored remotely or through telemedicine, to minimize the risks of SARS-CoV-2 infection. Therefore, clinical investigations and medical interventions should be suspended or postponed. 4. Monitoring body temperature, wearing masks, and avoid contact with outside individuals for inpatients should be given during the COVID-19 outbreak For inpatients, a body temperature monitor strategy could avoid the internal infection of SARS-CoV-2 in the hospital. Wearing masks is the basic prerequisite for inpatients. A medical staff has the right to reject patients who do not wear a mask and ask inpatients to follow the local instructions and guidelines to avoid contact with outside individuals during the COVID-19 outbreak. 5. Special care for inpatient should be given to prevent the infection of SARS-CoV-2 Patients in an emergency or eager for treatment in the hospital have to receive SARS-CoV-2 nuclear acid assay and CT image check before entering into the hospital. For those suspected COVID-19 patients, if medical treatment is critically necessary, medical staff has to make adequate preparation to protect themselves and patients. Besides, disposable materials, including masks and gloves, should not be used repeatedly, and particular attention should be paid to cleaning and sterilization. All procedures must follow local instructions and guidelines. The pandemic of COVID-19 has made great challenges to the social, medical system, particularly in light of the redistribution of medical staff, beds, equipment, and resources against SARS-CoV-2 infection. Chronic pain is suffering, significantly impacts the quality of life. Chronic pain patients have received limited treatment and discounted services during the COVID-19 outbreak due to limit the spread of SARS-CoV-2 infection. Chronic pain patients may also have increased infection risks to SARS-CoV-2 due to complicated reasons. Therefore, professional management of immune modulation-induced chronic pain during the COVID-19 outbreak is critical. In this opinion, we provide several recommendations, which represent the best available strategy and expert opinion at present, to aid the healthcare of those with chronic pain. However, our recommendations may need an update to adapting the local instructions and guidelines. WS, HG, YL, HZ, XL, DX, and LX were responsible for the concept and design of the study. WS, DX, and LX performed writing of the manuscript. WS obtained funding. All authors contributed to the article and approved the submitted version. 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PubMed Abstract | Google Scholar Keywords: COVID-19, chronic pain, neuropathic pain, SARS-CoV-2, pain management, coronavirus Citation: Sun W, Gao H, Luo Y, Zheng H, Liao X, Xiong D and Xiao L (2020) Management of Immunity Alteration-Induced Chronic Pain During the Coronavirus Disease-2019 (COVID-19) Pandemic. Front. Microbiol. 11:572318. doi: 10.3389/fmicb.2020.572318 Received: 02 July 2020; Accepted: 03 September 2020; Published: 24 September 2020. Edited by: Reviewed by: Copyright © 2020 Sun, Gao, Luo, Zheng, Liao, Xiong and Xiao. 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: Wuping Sun, [email protected]; Lizu Xiao, [email protected]
Hélène Faury, Camille Courboulès, Mathilde Payen, Aude Jary, Pierre Hausfater, CharlesEdouard Luyt, Martin Dres, Valérie Pourcher, Basma Abdi, Marc Wirden, et al.
Published: 13 August 2020
Journal of Infection, Volume 82; https://doi.org/10.1016/j.jinf.2020.08.017

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Addendum
, Werner A. Scherbaum
Published: 12 August 2020
Der Diabetologe, Volume 16, pp 1-5; https://doi.org/10.1007/s11428-020-00669-w

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Published: 11 August 2020
Der Nervenarzt, Volume 91, pp 1146-1148; https://doi.org/10.1007/s00115-020-00979-w

Abstract:
Das bekannteste Bild aus seinem Münchner Labor zeigt Aloys Alzheimer selbst und die junge, internationale Elite der Hirnforschung, nämlich Nicolas Achúcarro, Rudolf Allers, Francesco Bonfiglio, Ugo Cerletti, Friedrich Heinrich Lewy, Fritz Lotmar, Gaetano Perusini, Stefan Rosenthal und links vorne Adele Grombach (Abb. 1). Wer aber ist die selbstbewusst in der Mitte sitzende und von den Herren umringte Dame im dunklen Kleid, die auf der Fotografie üblicherweise mit einem Fragenzeichen oder als „unbekannt“ bezeichnet wird? Sie war die Koleiterin des Anatomischen Labors, Emma Wilson Mooers, geboren 1858 in Greendale, Wisconsin. Gruppenfoto: sitzend von links nach rechts: Frau Grombach, U. Cerletti, E.W. Mooers, F. Bonfiglio, G. Perusini; stehend von links nach rechts: F. Lotmar, NN, St. Rosenthal, R. Allers, N.N., A. Alzheimer, M. Achúcarro, F.H. Lewy. (Quelle: Wikimedia Commons [12]) Im Jahr 1884 schloss Emma W. Mooers das Medizinstudium an der University of Michigan in Ann Arbor ab. Sie war eine von mehreren Ärztinnen deren Namen zwei Jahre später in einem launigen Bericht der New York Tribune und des Ann Arbor Couriers Erwähnung finden: „Mehr als 50 Alumni der University of Michigan nahmen letzte Nacht am Dinner der New York Association … teil. Ein neuer, aber nichtsdestoweniger angenehmer Zug war die Teilnahme von Absolventinnen, zehn Damen … aus Ann Arbor, welche mit der Anmut femininer Vollendung und Errungenschaften zum Glanz des Ereignisses beitrugen“ [1]. Dies schien offensichtlich noch der Erwähnung wert, obwohl Frauen das Medizinstudium an einigen US-amerikanischen Lehreinrichtungen bereits seit Mitte des 19. Jahrhunderts möglich war und damit 50 Jahre früher als an Universitäten in Deutschland [2]. Danach ist Dr. Emma D. Mooers als Mitglied in den Berichten der American Public Health Association aufgeführt. 1888 wohnt sie in Arlington, Massachusetts. 1898 wird sie Assistenzärztin am Northampton Insane Hospital. 1899 wird sie in die American Medico-Psychological Association aufgenommen. Im Jahr 1902 taucht der Name Emma Wilson Mooers im Zusammenhang mit einem Skandal im Journal of the American Medical Association auf [11]: Eine Betrügerin hatte sich mit der Behauptung, sie sei Dr. Emma W. Mooers und ihre Unterlagen wären verbrannt, beim Sekretär der University of Michigan falsche Dokumente erschlichen. Die falsche Dr. Mooers praktizierte zunächst im nördlichen Michigan, danach in Chicago und schließlich in Colorado, wo sie gefasst werden konnte. Ein Kollege hatte sich bei der University of Michigan über sie beschwert. Dort aber war bekannt, dass die richtige Dr. Mooers zu der Zeit als Pathologin am McLean Hospital, der psychiatrischen Klinik von Harvard, in Waverley, Mass., arbeitete. „Der ganze Vorgang belastete die richtige Dr. Mooers erheblich, deren Arbeit stets von höchster Qualität und deren Verhalten äußerst professionell war“ [11]. Im Jahr 1903 veröffentlichte Emma W. Mooers eine ausführliche Studie im Boston Medical and Surgical Journal über eine vermutlich bakterielle Meningoenzephalomyelitis mit makropathologischen und histologischen Abbildungen, in der sie auch mehrere deutschsprachige Arbeiten zitierte [6]. 1904 erschien ihre Arbeit über den amnestischen Symptomenkomplex bei Neurosyphilis. Sie war die erste Forscherin am McLean Hospital [7]. Der Jahresbericht Michigan Alumnus vermerkt 1904 Emma Mooers sei nach Übersee gegangen und nun über die Adresse c/o Brown, Shipley & Co, 123 Pall Mall, London, zu erreichen. Im Wintersemester 1905/1906 ist sie im Gasthörerverzeichnis der Münchner Universität verzeichnet; sie beschäftige sich mit Psychiatrie und Anatomie. Im ausführlichen Jahresbericht 1906/1907 der Königlich Psychiatrischen Klinik in München schreibt Kraepelin auf der ersten Seite „in die Reihe der wissenschaftlichen Assistenten trat zunächst Dr. Plaut, dann die Herren Rüdin und Isserlin, endlich Frau Dr. Mooers … Frau Dr. Mooers unterstützte Dr. Alzheimer in der Leitung des anatomischen Laboratoriums“ [4]. Kraepelin akzeptierte keine Mitarbeiter, die nicht ausreichend Deutsch sprachen. Zwei bedeutende kanadische Psychiater besuchten die Münchner Klinik im Sommer 1907 und erstatteten ausführlich Bericht im American Journal of Insanity. C.K Clarke, Professor für Psychiatrie an der Universität Toronto, erwähnt „Drs. Gudden, Moers (!), Plaut, Weiler und andere haben bereits wohlverdienten Ruhm erworben und die Arbeiten dieser enthusiastischen Bande haben die psychiatrische Wissenschaft auf bemerkenswerte Weise bereichert und Licht auf die verzwicktesten Probleme geworfen, mit denen wir uns beschäftigen müssen“ [3]. Dr. Ryan aus Kingston, Ontario, schrieb: „Dr. Mooers, eine ÄRZTIN (‚a lady physician‘) aus Amerika, ist eine bekannte Dozentin und Meisterin der Technik“ [8]. Auf der ersten Seite des Jahresberichts 1908/1909 erwähnt Kraepelin, von den wissenschaftlichen Assistenten sei Frau Mooers ausgeschieden, um nach Amerika zurückzugehen [5]. Ein Vergleich der Zeiten, zu denen die fotografierten Forscher in München arbeiteten und die Sitzordnung der Kollegen um Emma W. Mooers herum, legen den Schluss nahe, es könne sich um Mooers’ Abschiedsfoto aus Alzheimers Labor handeln (Abb. 1). Die Abb. 2 zeigt Emma W. Mooers in den USA, würdevoll und noch besser gekleidet als kurz davor in München. Am 20.07.1910 wurde sie zur „Kuratorin“ („Custodian“) der Neuropathologischen Sammlung ernannt und war damit die zweite Frau an der Harvard Medical School, wenngleich ohne richtige Fakultätszugehörigkeit [9]. Wiederholte Hinweise, dass sie einen Doktortitel...
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