Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. Methods: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS). Findings: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles. Interpretation: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. Funding: Funded by Roche Sequencing Solutions, Inc

Detailed stratified GWAS analysis for severe COVID-19 in four European populations

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.S.E.H. and C.A.S. partially supported genotyping through a philanthropic donation. A.F. and D.E. were supported by a grant from the German Federal Ministry of Education and COVID-19 grant Research (BMBF; ID:01KI20197); A.F., D.E. and F.D. were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). D.E. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). D.E., K.B. and S.B. acknowledge the Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). T.L.L., A.T. and O.Ö. were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. M.W. and H.E. are supported by the German Research Foundation (DFG) through the Research Training Group 1743, ‘Genes, Environment and Inflammation’. L.V. received funding from: Ricerca Finalizzata Ministero della Salute (RF-2016-02364358), Italian Ministry of Health ‘CV PREVITAL’—strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ‘REVEAL’; Fondazione IRCCS Ca’ Granda ‘Ricerca corrente’, Fondazione Sviluppo Ca’ Granda ‘Liver-BIBLE’ (PR-0391), Fondazione IRCCS Ca’ Granda ‘5permille’ ‘COVID-19 Biobank’ (RC100017A). A.B. was supported by a grant from Fondazione Cariplo to Fondazione Tettamanti: ‘Bio-banking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by an MIUR grant to the Department of Medical Sciences, under the program ‘Dipartimenti di Eccellenza 2018–2022’. This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP (The Institute for Health Science Research Germans Trias i Pujol) IGTP is part of the CERCA Program/Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIII-MINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). M.M. received research funding from grant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (European Regional Development Fund (FEDER)-Una manera de hacer Europa’). B.C. is supported by national grants PI18/01512. X.F. is supported by the VEIS project (001-P-001647) (co-funded by the European Regional Development Fund (ERDF), ‘A way to build Europe’). Additional data included in this study were obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, European Institute of Innovation & Technology (EIT), a body of the European Union, COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. A.J. and S.M. were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). A.J. was also supported by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the European Regional Development Fund (FEDER). The Basque Biobank, a hospital-related platform that also involves all Osakidetza health centres, the Basque government’s Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. M.C. received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). M.R.G., J.A.H., R.G.D. and D.M.M. are supported by the ‘Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III’ (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100) and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón’s team is supported by CIBER of Epidemiology and Public Health (CIBERESP), ‘Instituto de Salud Carlos III’. J.C.H. reports grants from Research Council of Norway grant no 312780 during the conduct of the study. E.S. reports grants from Research Council of Norway grant no. 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). P.K. Bergisch Gladbach, Germany and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF). O.A.C. is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—CECAD, EXC 2030–390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. K.U.L. is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. F.H. was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to A.R. from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme—Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to A.R. P.R. is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). F.T. is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). C.L. and J.H. are supported by the German Center for Infection Research (DZIF). T.B., M.M.B., O.W. und A.H. are supported by the Stiftung Universitätsmedizin Essen. M.A.-H. was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. E.C.S. is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).Peer reviewe

Detailed stratified GWAS analysis for severe COVID-19 in four European populations

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ∼0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.Andre Franke and David Ellinghaus were supported by a grant from the German Federal Ministry of Education and Research (01KI20197), Andre Franke, David Ellinghaus and Frauke Degenhardt were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). David Ellinghaus was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). David Ellinghaus, Karina Banasik and Søren Brunak acknowledge the Novo Nordisk Foundation (grant NNF14CC0001 and NNF17OC0027594). Tobias L. Lenz, Ana Teles and Onur Özer were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. Mareike Wendorff and Hesham ElAbd are supported by the German Research Foundation (DFG) through the Research Training Group 1743, "Genes, Environment and Inflammation". This project was supported by a Covid-19 grant from the German Federal Ministry of Education and Research (BMBF; ID: 01KI20197). Luca Valenti received funding from: Ricerca Finalizzata Ministero della Salute RF2016-02364358, Italian Ministry of Health ""CV PREVITAL – strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ""REVEAL""; Fondazione IRCCS Ca' Granda ""Ricerca corrente"", Fondazione Sviluppo Ca' Granda ""Liver-BIBLE"" (PR-0391), Fondazione IRCCS Ca' Granda ""5permille"" ""COVID-19 Biobank"" (RC100017A). Andrea Biondi was supported by the grant from Fondazione Cariplo to Fondazione Tettamanti: "Biobanking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by a MIUR grant to the Department of Medical Sciences, under the program "Dipartimenti di Eccellenza 2018–2022". This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP. IGTP is part of the CERCA Program / Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIIIMINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). Marta Marquié received research funding from ant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIIISubdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa").Beatriz Cortes is supported by national grants PI18/01512. Xavier Farre is supported by VEIS project (001-P-001647) (cofunded by European Regional Development Fund (ERDF), “A way to build Europe”). Additional data included in this study was obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, EIT COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. Antonio Julià and Sara Marsal were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). Antonio Julià was also supported the by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the FEDER. The Basque Biobank is a hospitalrelated platform that also involves all Osakidetza health centres, the Basque government's Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. Mario Cáceres received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). Manuel Romero Gómez, Javier Ampuero Herrojo, Rocío Gallego Durán and Douglas Maya Miles are supported by the “Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III” (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100), and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón's team is supported by CIBER of Epidemiology and Public Health (CIBERESP), "Instituto de Salud Carlos III". Jan Cato Holter reports grants from Research Council of Norway grant no 312780 during the conduct of the study. Dr. Solligård: reports grants from Research Council of Norway grant no 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). Philipp Koehler has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF).Oliver A. Cornely is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping was performed by the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. Kerstin U. Ludwig is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. Frank Hanses was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to Alfredo Ramirez from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme – Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Philip Rosenstiel is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). Florian Tran is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). Christoph Lange and Jan Heyckendorf are supported by the German Center for Infection Research (DZIF). Thorsen Brenner, Marc M Berger, Oliver Witzke und Anke Hinney are supported by the Stiftung Universitätsmedizin Essen. Marialbert Acosta-Herrera was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. Eva C Schulte is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).N

İlköğretim Öğretmenlerinin BT Okuryazarlık Düzeyleri ve BT’yi Öğretim ve Mesleki Gelişim Amaçlı Kullanımlarının İncelenmesi

    This study examines primary school teachers’ Information Technology (IT) literacy level with regard to the Dynamic IT Literacy model and the use of IT for instruction and professional development purposes. 459 teachers from 22 primary schools in Ankara were involved in this survey study. Teachers’ IT literacy was defined with regard to the Dynamic IT Literacy model which has 6 factors: problem solving, analysis and production with IT, communication and metacognition, basic IT capabilities, information and internet-related capabilities, sustainability and transferability of IT capacities. The questionnaire was adapted to Turkish by performing validity and reliability analysis. The results of the study revealed that most of the primary school teachers have been using IT for 1-3 years and have been using IT frequently for professional development purposes. In addition, teachers who have been using IT for a long time and use IT frequently for professional development have higher IT literacy level.         Araştırmada, ilköğretim okullarında görev yapan öğretmenlerin Dinamik BT Okuryazarlık Modeline göre bilgi teknoloji­leri (BT) okuryazarlık düzeyleri ve BT’yi öğretim ve mesleki gelişim amaçlı kullanımları  incelenmiştir. Tarama modeli ile gerçekleştirilen bu araştırmaya Ankara ilinde 22 okulda görev yapmakta olan 459 öğretmen katılmıştır. Öğretmenlerin BT okuryazarlıkları, Dinamik BT Okuryazarlık Modelindeki 6 faktör olan problem çözme, analiz ve üretim, iletişim ve metabilişsel, temel bilgi teknoloji­leri, bilgi ve internet, sürdürebilme ve transfer edebilme becerilerini kapsayan bir ölçek ile belirlenmiştir. Bu ölçek geçerlik ve güvenirlik ça­lışmaları yapılarak ilk defa Türkçe’ye uyarlanmıştır. Araştırma sonucunda ilköğretim öğretmenlerinin çoğunluğunun BT’yi öğretim amaçlı 1-3 yıldır kullandıkları ve BT’den mesleki gelişim sağlama amacıyla sıklıkla yararlandıkları belirlenmiştir. Aynı zamanda BT’yi öğretim amacıyla uzun süredir ve mesleki gelişim amaçlı sıklıkla kullanan öğretmenlerin, BT okuryazarlık düzeylerinin anlamlı bir biçimde daha yüksek olduğu da belirlenmiştir.   &nbsp

15-29 Aralık 1931 Tarihli Âli İktisat Meclisi Raporuna Göre 1930'lu Yılların Başında Türkiye'deki Limanların Durumu

1927 yılında liberal ve milli ekonomi anlayışının bir sonucu olarak faaliyete geçirilen Âli İktisat Meclisi'nin 15-29 Aralık 1931 tarihli toplantısı sonucunda yayınlanan raporunun bir bölümü, Türk limanlarının geliştirilmesi için alınması gereken tedbirlere dair tekliflerin incelenmesini içermektedir. Türkiye'nin liman hizmetleri ve bu hizmetlerin geliştirilmesi için alınması gereken tedbirlerle ilgili teklifler, Türkiye'deki limanların durumu ve ticari faaliyetleri raporun limanlarla ilgili kısmının ana başlıklarını oluşturmaktadır. Raporun içeriğinde İstanbul, Mersin, Samsun, Trabzon, İzmir ve Ereğli limanlarının genel durumları ile ticari faaliyetler yer almaktadır. Genel durumlarla ilgili verilen bilgilere göre 1931 yılının sonuna gelindiğinde Türk limanlarının haiz olduğu şartlar yetersizdir. İşleyişteki problemler, yüksek gümrük vergileri, formalitelerin fazlalığı ve limanların sıhhi bakımlardan yetersiz oluşları gibi birçok sebep ticaret gemilerinin Türk limanlarını mecburi bir durum olmadıkça tercih etmemeleri sonucunu doğurmuştur. Ayrıca hırsızlık, kaçakçılık gibi olaylara rastlanmakta ve mevcut kanunlar ve uygulamalar bu olayları engellemekte yetersiz kalmaktaydı. 1932 yılı ile II. Dünya Savaşı'nın başlangıcına kadar olan süreçte 1935 yılında lağvedilmesine rağmen Âli İktisat Meclisi'nin önerileri olumsuzluklar giderilmeye çalışılmıştır. Bu çalışma, danışma meclisi hüviyetindeki Âli İktisat Meclisi'nin 1931 yılına ait raporu doğrultusunda 1930'lu yılların başında Türkiye'deki limanların genel durumunu değerlendirmek amacıyla 1931 yılı Âli İktisat Meclisi Raporu, arşiv belgeleri ve resmi yayınlardan yararlanılarak hazırlanmıştırA section of a report published at the end of the meeting dated as 15-29 December 1931 by Higher Council of Economy, which was founded as required by liberal and national economy in 1927, was devoted to an analysis of proposals regarding the measures for improving Turkish ports. Proposals regarding the measures for Turkish port services and improving these services, the situation of ports in Turkey and their commercial activities constitute the main titles of the section of the report in relation to ports. The content of the report contains general situations of İstanbul, Mersin, Samsun, Trabzon, İzmir and Ereğli ports as well as commercial activities. According to information provided in relation to general situation, the conditions that Turkish ports have at the end of 1931 were inadequate. Many reasons such as problems of administration, high customs duty, abundance of formalities and inadequate health conditions of ports led to the result that commercial ships avoided Turkish ports when non-obligatory. Besides, thefts and smuggling were common and laws and practices of that time were not deterrent enough to prevent these incidents. Though it was dissolved in 1935, some arrangements were made according to the recommendations of Higher Council of Economy during the period starting from 1932 until the beginning of II. World War and these negativities were tried to be eradicated. This study was based on report of Higher Council of Economy belonging to year 1931, archive documents and official publications to evaluate general situation of the ports in Turkey in early 1930

Metformin Attenuates ROS via FOXO3 Activation in Immune Cells

Forkhead box O 3 (FOXO3) is a transcription factor involved in cell metabolism, inflammation and longevity. Here, we investigated if metformin can activate FOXO3 in human immune cells and affects the subsequent level of reactive oxygen/nitrogen species (ROS/RNS) in immune cells. AMP-activated protein kinase (AMPK) and FOXO3 activation were investigated by immunoblot or flow cytometry (FC) analysis, respectively. FOXO3 target gene expression was quantified by real-time PCR. ROS/RNS measurement using dichlorodihydrofluorescein diacetate (DCFH-DA) dye was investigated by FC. The role of the FOXO3 single nucleotide polymorphisms (SNPs) rs12212067, rs2802292 and rs12206094 on ROS/RNS production was studied using allelic discrimination PCR. Metformin induced activation of AMPK (pT172) and FOXO3 (pS413). ROS/RNS level was reduced in immune cells after metformin stimulation accompanied by induction of the FOXO3 targets mitochondrial superoxide dismutase and cytochrome c. Studies in Foxo3 deficient (Foxo3(-/-) ) mouse splenocytes confirmed that metformin mediates its effects via Foxo3 as it attenuates ROS/RNS in myeloid cells of wildtype (WT) but not of Foxo3(-/-) mice. Our results suggest that FOXO3 can be activated by metformin leading to reduced ROS/RNS level in immune cells. This may add to the beneficial clinical effects of metformin observed in large cohort studies on longevity, cardiovascular and cancer risk

First effectiveness data of lenvatinib and pembrolizumab as first-line therapy in advanced anaplastic thyroid cancer: a retrospective cohort study

Abstract Background Anaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC. Methods In a retrospective analysis, we investigated the activity and tolerability of combined lenvatinib (starting dose 14 to 24 mg daily) and pembrolizumab (200 mg every three weeks) as first-line therapy in an institutional cohort of ATC patients. Results Five patients with metastatic ATC received lenvatinib and pembrolizumab as systemic first-line therapy. The median progression-free survival was 4.7 (range 0.8–5.9) months, and the median overall survival was 6.3 (range 0.8-not reached) months. At the first follow-up, one patient had partial response, three patients had stable disease, and one patient was formally not evaluable due to interference of assessment by concomitant acute infectious thyroiditis. This patient was then stable for more than one year and was still on therapy at the data cutoff without disease progression. Further analyses revealed deficient DNA mismatch repair, high CD8+ lymphocyte infiltration, and low macrophage infiltration in this patient. Of the other patients, two had progressive disease after adverse drug reactions and therapy de-escalation, and two died after the first staging. For all patients, the PD-L1 combined positive score ranged from 12 to 100%. Conclusions The combination of lenvatinib and pembrolizumab was effective and moderately tolerated in treatment-naïve ATC patients with occasional long-lasting response. However, we could not confirm the exceptional responses for this combination therapy reported before in pretreated patients

Additional file 1 of First effectiveness data of lenvatinib and pembrolizumab as first-line therapy in advanced anaplastic thyroid cancer: a retrospective cohort study

Supplementary material 1

Incidence of Type 1 diabetes in children aged below 18 years during 2013-2015 in Northwest Turkey

Azizoglu, Mehmet (Trakya author) Dilek, Emine (Trakya author)Objective: To assess the incidence of type I diabetes mellitus (T1DM) in children under 18 years of age in the northwest region of Turkey during 2013-2015. Methods: All newly diagnosed T1DM cases were recorded prospectively during 2013-2015. Total, as well as gender and age group specific (0-4, 5-9. 10-14 and 15-17 age) mean incidences per 100,000 per year were calculated. Results: There were 1,773 patients diagnosed during 2013-2015 (588 cases in 2013, 592 cases in 2014, 593 cases in 2015). Of these, 862 (48.6 %) were girls and 911 (51.4%)were boys. The mean age at diagnosis was 9.2 +/- 4.2 years and it was not significantly different between girls (9.0 +/- 4.1 years) and boys (9.4 +/- 4.4 years) (p = 0.052). The crude mean incidence was 8.99/100.000 confidence interval (CI) (95% CI: 8.58-9.42). Although mean incidence was similar between boys [8.98/100.000 (CI: 8.40 to 9.58)] and girls [9.01/100.000 (CI: 8.42 to 9.63)], there was male predominance in all groups except for 5-9 year age group. The standardized mean incidence was 9.02/100.000 according to the World Health Organization standard population. The mean incidence for the 0-4, 5-9, 10-14 and 15-17 age groups was 6.13, 11.68, 11.7 and 5.04/1 00.000 respectively. The incidence of T1DM was similar over the course of three years (p = 0.95). A significant increase in the proportion of cases diagnosed was observed in the autumn-winter seasons. Conclusion: The northwest region of Turkey experienced an intermediate incidence of T1DM over the period of the study