Journal articles on the topic 'Hua xue'

This article focuses on female editorship and sexual politics in late Ming and early Qing China, using Hua suo shi, an anthology edited by the courtesan poet Xue Susu, as a case study. It traces textual production and transmission, and reconstructs the literary and cultural contexts of this work to explore the courtesan’s editorial gaze and representation of gender through a close reading of it. The analysis of its two main themes—women as commodities, and women as agents—shows how the courtesan editor re-imagined China’s cultural landscape from her point of view. New examples of female agency are discovered in analyzing the cultural process of editing as a “web of discourses,” providing a window on the emergence of a new female editorial voice in early modern China’s cultural discourse. Cet article se concentre sur le rôle éditorial des femmes et sur les politiques sexuelles en Chine à la fin des Ming et au début des Qing. Une anthologie éditée par la courtisane et poétesse Xue Susu, le Hua suo shi, sert d’étude de cas. Le processus de production et de transmission textuelle est examiné et le contexte littéraire et culturel de l’ouvrage restitué, permettant d’explorer le regard éditorial et le jeu de genre de la courtisane à travers une lecture serrée du texte. L’analyse des deux thèmes dominants — la femme comme marchandise, la femme comme agent — démontre la façon dont la courtisane éditrice ré-imagine le paysage culturel chinois de son propre point de vue. D’autres exemples d’intervention féminine se révèlent lorsqu’on analyse le processus culturel d’édition en tant que “réseau de discours”. Ainsi s’ouvre une fenêtre sur l’émergence d’une nouvelle voix éditoriale féminine au sein du discours culturel chinois au début des temps modernes.

Though it would be almost impossible to trace who first applied the term ‘Avant-Garde fiction’ (Xianfeng Xiaoshuo ) to a recent trend in Chinese fiction since 1985, it is an appropriate name in many respects. All the previous schools of fiction in modern China—Wound fiction (Shangheng Xiaoshuo ), Reform fiction (Gaige Xiaoshuo ), Re-thinking fiction (Fansi Xiaowen ), or Roots-Seeking fiction (Xungen Xiaoshuo )—received their names after their respective subject matters. The naming of Avant-Garde fiction itself seems to indicate that Chinese fiction has grown out of its thematic age to enter a new phase of life beyond themes.The earliest authors of Chinese Avant-Garde fiction—Can Xue , Ma Yuan , Hong Feng , Zhaxi Dawa , Mo Yan and others—are all based in remote areas far from the centres of modern Chinese civilization. This led some critics to the conclusion that literary modernity was at odds with modern urbanized culture. Hardly had such an argument been put forward when, towards the end of 1987, there appeared a new group of Avant-Garde writers—Su Tong with The escape of 1934 (Yijiu sansi nian de taowang— :), Sun Ganlu with The letter from the postman (Xinshi zhi han Ge Fei with The lost boat (Mizhou) and Yu Hua with One kind of reality (Xianshi yizhong)— all of them based in the Yangtze Delta, the most prosperous area of modern China. This would suggest, at least, that Chinese avant-gardism is not entirely dependent on economic-geographical conditions.

Abstract Introduction: The effect of trastuzumab in targeted therapy for HER2-positive gastric cancer (GC) is limited by the eventual development of resistance within patients. Although numerous studies have been published on this topic, both the mechanism of innate and acquired trastuzumab resistance are still not fully understood. In this study, we compare the mutational landscape of paired solid tumor samples before and after treatment in an effort to identify acquired events associated with resistance. Methods: We performed whole-exome sequencing on 46 tumor and 23 whole blood samples from patients with stage IV gastric cancer were obtained from before treatment (n = 23) and at disease progression (PD) (n = 23). HER2 status was checked using immunohistochemistry and validated with florescence in situ hybridization (FISH). Correlation analysis was then conducted between the mutational profile and clinical data of patients. Results: Comparisons between innate resistance samples and acquired resistance samples at baseline revealed three copy number variation events (CDK12 amplification, ERBB2 amplification, MECOM amplification) that occurs in significantly different proportions (p < 0.05). In addition, for baseline samples, MECOM was shown to be associated with poor progression-free survival (PFS) (Hazard Ratio (HR), 12; 95% CI, 1.6 - 85; p = 0.027). Commonly acquired events (i.e., lacking in before treatment samples and present at PD) within patients include TP53 mutation, MYC amplification, MCL1 amplification, CDKN2A/2B deletion, and CCNE1 amplification. Of these, patients with MCL1 gene amplification had worse survival (HR, 4.8; 95% CI, 1.2 - 20; p = 0.050) than patients with wild-type MCL1. In addition, the NOTCH pathway acquired mutations in 4 of 23 patients and was found to be correlated with a worse PFS (HR, 5.1; 95% CI, 1.4 - 19; p = 0.023), indicating that this pathway is possibly involved with trastuzumab resistance to some degree. Conclusion: Overall, our results show that comparisons of samples obtained before treatment and at PD can give insight about innate and acquired resistance mechanisms to trastuzumab in stage IV, HER2-positive GC patients. Citation Format: Qi Xu, Jingjing Li, Haimeng Tang, Hua Bao, Junrong Yan, Xue Wu, Yang Shao, Jianying Jin, Cong Luo, Haimin Weng, Jieer Ying. Dissecting the molecular mechanism of trastuzumab resistance in stage IV HER2-positive gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5336.

Abstract Objective: To identify genetic and clinicopathological factors that affect the response of patients with esophageal squamous cell carcinoma (ESCC) to neoadjuvant chemoradiotherapy (nCRT), profile the genomic and transcriptomic alterations after nCRT and relate the alterations to patient’s prognosis. Methods: A total of 137 samples from 57 ESCC patients undergoing nCRT were collected. 82 samples including 54 pre-treatment samples and 28 post-treatment samples were subjected to whole-exome sequencing, and 55 samples including 26 pre-treatment samples and 29 post-treatment samples were subjected to RNA-seq analysis. Genetic and clinicopathological factors associated with patient’s response to nCRT were identified by comparing baseline features of patients achieving pathological response (pCR) and patients not achieving pCR. Genomic and transcriptomic profiles before and after nCRT were compared to identify features acquired during nCRT and the association of identified features with patient’s recurrence-free survival (RFS) and overall survival (OS) were investigated. Results: Co-deficiency of DDR and HIPPO pathway at baseline synergistically sensitized ESCC to nCRT. The arachidonic acid metabolism pathway was upregulated at baseline in patients with pCR. The proportion of small deletion and insertion (INDEL %) significantly increased in acquired mutations (p<0.001) and was positively correlated with focal chromosomal loss (Spearman's ρ=0.52, p=0.005) and negatively correlated with broad chromosomal gain (Spearman's ρ=-0.61, p<0.001) after nCRT. Acquired INDEL% was associated with tumor regression grade (TRG) (p=0.06) and predicted the worse RFS (p=0.16) and OS (p=0.067). The degree of clonal expansion during nCRT was associated with patient’s RFS (p=0.0087) and OS (p=0.023), and negative correlated with acquired INDEL % (Spearman's ρ=-0.45, p=0.02). The expression profile of tumor tissue was changed after nCRT and displayed upregulation of cell adhesion and stromal related pathways and downregulation of DNA replication and cell cycle pathways, and the alteration of expression profile was associated with patient’s prognosis. Conclusions: nCRT remodels the genome and transcriptome of ESCC. Small deletion/insertion and focal chromosomal loss may be characteristic genomic alterations imposed by radiation. Acquired INDEL proportion is a biomarker to indicate the efficacy of nCRT and predict patient’s prognosis. The degree of clonal expansion during nCRT reflects the treatment resistance and associated with patient’s prognosis. Citation Format: Yang Yang, TingTing Feng, Xiaojun Fan, Xia Zhou, Wu'an Bao, Danhong Zhang, Hua Bao, Junrong Yan, Xue Wu, Yang Shao, Guoqin Qiu, Dan Su, Qixun Chen. Genomic and transcriptomic remodeling of esophageal squamous cell carcinoma by neo-adjuvant radiochemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6054.

Introdução: Lesões endoperiodontais são lesões originadas de produtos inflamatórios encontrados tanto em periodonto quanto em polpa. Tais lesões podem se originar devido a uma infecção pulpar ou periodontal. Visando o prognóstico favorável, é imprescindível o conhecimento da etiologia, realização do correto diagnóstico e elaboração do plano de tratamento que envolve o tratamento endodôntico precedido do tratamento periodontal. Objetivo: O propósito do presente trabalho foi de relatar um caso clínico de lesão endoperiodontal e o tratamento realizado. Relato de caso clínico: Paciente gênero feminino, 51 anos, compareceu à clínica com uma fístula na região do dente 46, procedeu-se com exame radiográfico, rastreamento de fístula, testes endodônticos e avaliação periodontal. Foi diagnosticada lesão endoperiodontal. Executou-se, então, o tratamento endodôntico em sessões múltiplas, utilizando hidróxido de cálcio como medicação intracanal e o tratamento periodontal concomitante; finalizou-se endodontia obturando-se os canais radiculares. Conclusão: Observou-se, no controle, que a associação de tratamentos foi eficaz e houve melhora significativa do quadro, constatando-se silêncio clínico e sucesso do tratamento. Realizar o tratamento conservador a despeito da exodontia foi a melhor escolha para a paciente. Descritores: Endodontia; Periodontia; Polpa Dentária; Periodonto. Referências Sunitha VR, Emmadi P, Namasivayam A, Thyegarajan R, Rajaraman V. The periodontal - endodontic continuum A review. J Conserv Dent. 2008;11(2):54-62. Betancourt P, Elgueta R, Fuentes R. Treatment of endo-periodontal lesion using leukocyte-platelet-rich fibrin - a case report. Colomb Med. 2017;48(4):204-7. Lopes HP, Siqueira JF. Endodontia: Biologia e Técnica. Rio de Janeiro: Medsi-Guanabara Koogan; 2015. Lindhe J, Karring T, Lang NP. Tratado de periodontia clínica e implantologia oral. Rio de Janeiro: Guanabara Koogan; 2010. Anand V, Govila V, Gulati M. Endo-perio lesion part II (the treatment) - a review. 2012;3(1):10-6. Rotstein I, Simon JH. Diagnosis, prognosis and decision-making in the treatment of combined periodontal-endodontic lesions. J Periodontol. 2004;34:165-203. Parolia A, Gait TC, Porto ICCM, Mala K. Endo-perio lesion: a dilemma from 19th until 21st century. J Interdisp Dent. 2013;3(1):2-11. Kim E, Song JS, Jung IY, Lee SJ, Kim S. Prospective clinical study evaluating endodontic microsurgery outcomes for cases with lesions of endodontic origin compared with cases with lesions of combined periodontal-endodontic origin. J Endod. 2008;34(5):546-51. Heasman PA. An endodontic conundrum: the association between pulpal infection and periodontal disease. Br Dent J. 2014;216(6):275-9. Schmidt JC, Walter C, Amato M, Weiger R. Treatment of periodontal-endodontic lesions--a systematic review. J Clin Periodontol. 2014; 41(8):779-90. Jivoinovici R, Suciu I, Dimitriu B, Perlea P, Bartok R, Malita M, Ionescu C. Endo-periodontal lesion--endodontic approach. J Med Life. 2014;7(4):542-44. Estrela C. Endodontia laboratorial e clínica, Série Abeno: Odontologia Essencial - Parte Clínica. São Paulo: Artes Médicas; 2013. Vera J, Siqueira JF Jr, Ricucci D, Loghin S, Fernández N, Flores B et al. One-versus two-visit endodontic treatment of teeth with apical periodontitis: a histobacteriologic study. J Endod. 2012;38(8):1040-52. Mohammadi Z, Dummer PMH. Properties and applications of calcium hydroxide in endodontics and dental traumatology. Inter Endod J. 2011;44(8):697-730. Batista VES, Olian DA, Mori GG. Diffusion of hydroxyl ions from calcium hydroxide and aloe vera pastes. Braz Dent J. 2014;25(3):212-16. Pereira TC, da Silva Munhoz Vasconcelos LR, Graeff MSZ, Ribeiro MCM, Duarte MAH, de Andrade FB. Intratubular decontamination ability and physicochemical properties of calcium hydroxidepastes. Clin Oral Investig. 2019;23(3):1253-62. Andolfatto C, da Silva GF, Cornélio AL, Guerreiro-Tanomaru JM, Tanomaru-Filho M, Faria G, Bonetti-Filho I, Cerri PS. Biocompatibility of intracanal medications based on calcium hydroxide. ISRN Dent. 2012;2012:904963. Duque TM, Prado M, Herrera DR, Gomes BPFA. Periodontal and endodontic infectious/inflammatory profile in primary periodontal lesions with secondary endodontic involvement after a calcium hydroxide-based intracanal medication. Clin Oral Investig. 2019;23(1):53-63. Kim D, Kim E. Antimicrobial effect of calcium hydroxide as an intracanal medicament in root canal treatment: a literature review - Part I. In vitro studies. Restor Dent Endod. 2014; 39(4):241-52. Adl A, Motamedifar M, Shams MS, Mirzaie A. Clinical investigation of the effect of calcium hydroxide intracanal dressing on bacterial lipopolysaccharide reduction from infected root canals. Aust Endod J. 2015;41(1):12-6. Hilton TJ, Ferracane JL, Mancl L; Northwest Practice-based Research Collaborative in Evidence-based Dentistry (NWP). Comparison of CaOH with MTA for direct pulp capping: a PBRN randomized clinical trial. J Dent Res. 2013;92(7 Suppl):16S-22S. Labban N, Yassen GH, Windsor LJ, Platt JA. The direct cytotoxic effects of medicaments used in endodontic regeneration on human dental pulp cells. Dent Traumatol. 2014;30(6):429-34. McIntyre PW, Wu JL, Kolte R, Zhang R, Gregory RL, Bruzzaniti A, Yassen GH. The antimicrobial properties, cytotoxicity, and differentiation potential of double antibiotic intracanal medicaments loaded into hydrogel system. Clin Oral Investig. 2019;23(3):1051-59. Bergenholtz, G., Hasselgren, G. Endodontics and periodontics. In: Lindhe, K., Karring, T., Lang, N. Clinical periodontology and implant dentistry. Copenhagen:Munksgaard; 2015. Harrington GW, Steiner DR, Ammons WF. The periodontal-endodontic controversy. Periodontol 2000. 2002;30:123-30. Fernandes LA, Martins TM, Almeida JM, Nagata MJ, Theodoro LH, Garcia VG, Bosco AF. Experimental periodontal disease treatment by subgingival irrigation with tetracycline hydrochloride in rats. J Appl Oral Sci. 2010;18(6):635-40. Storrer CM, Bordin GM, Pereira TT. How to diagnose and treat periodontal endodontic lesions? 2012;9(4):427-33. Verma PK, Srivastava R, Gupta KK, Srivastava A. Combined endodontic periodontal lesions: A clinical dilema. J Interdiscip Dent. 2011;1(2):119-24. Oh SL, Fouad AF, Park SH. Treatment strategy for guided tissue regeneration in combined endodontic-periodontal lesions: case report and review. J Endod. 2009;35(10):1331-36. Malli R, Lele P, Vishakha. Guided tissue regeneration in communicating periodontal and endodontic lesions - a hope for the hopeless. J Indian Soc Periodontol. 2011;15(4):410-13. Ghezzi C, Virzì M, Schupbach P, Broccaioli A, Simion M. Treatment of combined endodontic-periodontic lesions using guided tissue regeneration: clinical case and histology. Int J Periodontics Restorative Dent. 2012;32(4):433-9. Sun J, Liu Q. [Bio-Oss collagen bone grafting in the treatment of endodontic-periodontic lesion]. Nan Fang Yi Ke Da Xue Xue Bao. 2009;29(9):1905-6. Sharma R, Hegde V, Siddharth M, Hegde R, Manchanda G, Agarwal P. Endodontic-periodontal microsurgery for combined endodontic-periodontal lesions: An overview. J Conserv Dent. 2014;17(6):510-16. Li Y, Wang X, Xu J, Zhou X, Xie K. [The clinical study on the use of diode laser irradiation in the treatment of periodontal-endodontic combined lesions]. Hua Xi Kou Qiang Yi Xue Za Zhi. 2012;30(2):161-64, 168. Narang S, Narang A, Gupta R. A sequential approach in treatment of perio-endo lesion. J Indian Soc Periodontol. 2011;15(2):177-80. Pereira AL, Orzechowski PR, Filho SB, Cortelli JR. Subepithelial connective tissue graft: an alternative application for treating endoperiodontal lesions. Gen Dent. 2013;61(2):50-3. Yoneda M, Motooka N, Naito T, Maeda K, Hirofuji T. Resolution of furcation bone loss after non-surgical root canal treatment: application of a peptidase-detection kit for treatment of type I endoperiodontal lesion. J Oral Sci. 2005; 47(3):143-47. Shenoy N, Shenoy A. Endo-perio lesions: diagnosis and clinical considerations. Indian J Dent Res. 2010;21(4):579-85. Gerritsen AE, Allen PF, Witter DJ, Bronkhorst EM, Creugers NH. Tooth loss and oral health-related quality of life: a systematic review and meta-analysis. Health Qual Life Outcomes. 2010;8:126.

<b><i>Introduction:</i></b> The prevalence of hyperuricemia (HUA) is increasing worldwide; understanding of population attributable fraction of modifiable risk factors (MRFs) is important for disease prevention. Given the sparse evidence on how MRFs influence HUA in mainland China, we aimed to explore the effect of excess body weight and alcohol consumption and their population attributable fractions of HUA based on a national survey in mainland China. <b><i>Methods:</i></b> Using data from the China National Health Survey which included 31,746 Han Chinese of 20–80 years of age from 10 provinces, we estimated the prevalence and MRFs (overweight/obesity and alcohol consumption) of HUA. HUA was defined as serum uric acid &#x3e;417 μmol/L in men and &#x3e;340 μmol/L in women. Restricted cubic-spline models were used to demonstrate the linear and nonlinear associations between exposures and HUA. The adjusted population attributable risk (PAR) was calculated to understand the relative importance of each MRF. <b><i>Results:</i></b> The prevalence of HUA was 25.1% in men and 15.9% in women. The population fraction of HUA cases that could be avoided by weight loss was 20.6% (19.3%–22.0%) in men and 18.1% (17.1%–19.0%) in women. The PAR of alcohol consumption was 12.8% (8.5%–17.1%) in men. Participants from Southwest China (Yunnan) had the highest HUA prevalence (47.9% in men and 29.9% in women) but with lower PAR of MRFs, especially in men (16.7%). Subjects in North China had lower HUA prevalence but higher PAR of MRFs. Around 44.8% male HUA cases in Inner Mongolia (26.9% of HUA prevalence) and 37.7% cases in Heilongjiang (34.4% of HUA prevalence) were attributable to overweight/obesity and alcohol consumption. <b><i>Conclusion:</i></b> There are significant sex and geographic difference on PAR of HUA due to MRFs. More tailored prevention strategies are needed to prevent HUA through weight loss and reduction of alcohol consumption.

<p>1949年後北京故宮輾轉播遷至臺灣，落腳於臺中霧峰北溝(1950-1965)十六年。守護者莊嚴全家也落腳於此，此地乃當時臺中最重要的文化及旅遊勝地。然1965年北溝故宮北遷後，空餘庫房山洞供人憑弔。當時曾出現一批「故宮文學家」，他們與「北溝故宮」有或深或淺的關係，曾留下相關記憶的書寫，這些文本正是本論文考察的對象。職是，本論文以文化空間與文學記憶為論述概念，首論偏安北溝的「回憶空間」，莊嚴父子大半生與故宮文物流離至北溝所構建的回憶空間。其次則論在此文化空間的文人對傳統文化的傳承，即孔德成與臺靜農等人至北溝故宮清點文物的記憶。第三則論及個體記憶的再現，以臺靜農與林文月、凌叔華與蘇雪林的北溝旅行為主。第四則論及集體記憶中的文化旅遊勝地，兼論齊邦媛的英譯暨陪訪史。透過以上討論，可在集體的歷史大敘述外，呈現個體的文學記憶，豐富北溝故宮之文化記憶。</p> <p>&nbsp;</p><p>After 1949, the Palace Museum from Beijing relocated to Taiwan and settled in Beigou北溝 of Taichung (1950-1965) for 16 years. Zhuang Yan莊嚴 and his family who guard the Palace Museum in Beigou北溝故宮 is also setteled here, this place also was the most important cultural tourist attraction in Taichung.However, after the Palace Museum in Beigou北溝故宮 moved northward in 1965, the empty warehouse caves in this area were for people to hang. At that time, a group of &quot; the Palace Museum writers故宮文學家&quot; appeared. They had a deep or shallow relationship with the &quot; the Palace Museum in Beigou北溝故宮&quot;,they had left relevant memory writing,these texts are the objects of this paper. In this paper, the concept of cultural space and literary memory is discussed in this dissertation. Firstly, discussion is about the &ldquo;memory space&rdquo; in Beigou北溝,the memory space constructed by the Zhuang Yan莊嚴 father and son for most of his life and the Palace Museum 故宮’s cultural relics moved to Beigou北溝. Secondly, it discusses the inheritance of traditional culture by the literati in this cultural space, that is, the memory of Kung Te-Cheng孔德成 and Tai Jing-nong臺靜農 and others to the Palace Museum in Beigou北溝故宮 to count the cultural relics. Thirdly, on the reappearance of personal memory, mainly on the the Palace Museum in Beigou北溝故宮 trip of Tai Jing-nong臺靜農 and Lin Wen-yue林文月, Ling Shu-hua凌叔華and Su Xue-lin蘇雪林. Fourthly, the cultural tourism resort in the collective memory, as well as the history of Qi Bang-yuan’s齊邦媛English translation and accompanying visits. Through the above-mentioned discussion, the individual’s literary memory can be presented in addition to the collective grand historical narrative, especially enrich the cultural memory of the Palace Museum in Beigou北溝故宮.</p> <p>&nbsp;</p>

Objetivo: Esse estudo objetivou investigar percepções de estudantes de Odontologia quanto ao medo e à ansiedade em relação ao manejo de pacientes e ao risco de infecção por COVID-19. Materiais e métodos: Esse estudo transversal envolveu todos os alunos regularmente matriculados em Odontologia, no primeiro semestre de 2020, da Universidade Federal de Pelotas. Um questionário foi aplicado, coletando dados demográficos, nível de formação e perguntas relacionadas ao medo e ansiedade frente à pandemia de COVID-19. Quatro comparações de acordo com a fase da graduação (fase pré-clínica ou clínica), nível de graduação e pós-graduação e de acordo com os sexos foram feitas. Análises independentes para as comparações entre os sexos foram realizadas para os alunos de graduação e de pós-graduação (α<5%). Resultados: Foram incluídos 408 estudantes. Na graduação, mulheres relataram sentirem-se mais ansiosas ao realizar tratamento em pacientes com suspeita de COVID-19 (54%) e sentem mais medo ao ouvir que a infecção tem causado mortes (92,4%), na pós-graduação, responderam ser mais nervosas para conversar com pacientes em ambientes fechados em comparações com homens (P<0,05). Alunos em fase pré-clínica possuem significativamente menor receio (65,5%), ansiedade (32,3%) e nervosismo (28,3%) do contágio do COVID-19 quando comparados com aqueles na fase clínica. Conclusões: Mulheres e alunos na fase clínica apresentam maior ansiedade e nervosismo. Descritores: Ansiedade; Estudantes de Odontologia; Medo; Infecções por Coronavírus. Referências Chang J, Yuan Y, Wang D. [Mental health status and its influencing factors among college students during the epidemic of COVID-19]. Nan Fang Yi Ke Da Xue Xue Bao. 2020;40(2):171-176. World Health Organization. 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Ahmed MA, Jouhar R, Ahmed N, Adnan S, Aftab M, Zafar MS, Khurshid Z. Fear and Practice Modifications among Dentists to Combat Novel Coronavirus Disease (COVID-19) Outbreak. Int J Environ Res Public Health. 2020;17(8):2821. Talevi D, Socci V, Carai M, Carnaghi G, Faleri S, Trebbi E, di Bernardo A, Capelli F, Pacitti F. Mental health outcomes of the CoViD-19 pandemic. Riv Psichiatr. 2020;55(3):137-44. Mijiritsky E, Hamama-Raz Y, Liu F, Datarkar AN, Mangani L, Caplan J, Shacham A, Kolerman R, Mijiritsky O, Ben-Ezra M, Shacham M. Subjective Overload and Psychological Distress among Dentists during COVID-19. Int J Environ Res Public Health. 2020;17:5074. Rymarowicz J, Stefura T, Major P, Szeliga J, Wallner G, Nowakowski M, Pędziwiatr M. General surgeons' attitudes towards COVID-19: A national survey during the SARS-CoV-2 virus outbreak. Eur Surg. 2020;1-6. Adams JG, Walls RM. Supporting the Health Care Workforce During the COVID-19 Global Epidemic. JAMA. 2020;323(15):1439-40. Naz N, Iqbal S, Mahmood A. Stress, anxiety and depression among the dental students of university college of medicine and dentistry Lahore; Pakistan. Pak J Med Health Sci. 2017;11(4):1277-81. Waqas A, Iftikhar A, Malik Z, Aedma KK, Meraj H, Naveed S. Association of severity of depressive symptoms with sleep quality, social support and stress among Pakistani medical and dental students: A cross-sectional study. Global Psychiatry. 2019;2(2):211-20. Wang Y, Di Y, Ye J, Wei W. Study on the public psychological states and its related factors during the outbreak of coronavirus disease 2019 (COVID-19) in some regions of China. Psychol Health Med. 2020;1-10. Xiong J, Lipsitz O, Nasri F, Lui LMW, Gill H, Phan L, Chen-Li D, Iacobucci M, Ho R, Majeed A, McIntyre RS. Impact of COVID-19 pandemic on mental health in the general population: A systematic review. J Affect Disord. 2020;277:55-64. Liu N, Zhang F, Wei C, Jia Y, Shang Z, Sun L, Wu L, Sun Z, Zhou Y, Wang Y, Liu W. Prevalence and predictors of PTSS during COVID-19 outbreak in China hardest-hit areas: Gender differences matter. Psychiatry Res. 2020;287;112921. Terán E, Mayta-Tovalino F. Risk Factors, Self-perceived Stress, and Clinical Training among Dentistry Students in Peru: A Cross-sectional Study. J Contemp Dent Pract. 2019;20(5):561-5. Uraz A, Tocak YS, Yozgatligil C, Cetiner S, Bal B. Psychological well-being, health, and stress sources in Turkish dental students. J Dent Educ. 2013:77(10):1345-55. Agius AM, Gatt G, Vento Zahra E, Busuttil A, Gainza-Cirauqui ML, Cortes ARG et al. Self-reported dental student stressors and experiences during the COVID-19 pandemic. J Dent Educ. 2020. doi: 10.1002/jdd.12409. Hu J, Zou H, Dai Y, Feng Z. How to keep students engaged in oral health education during the COVID-19 pandemic. J Dent Educ. 2020. doi: 10.1002/jdd.12420. Liu S, Yang L, Zhang C, Xiang YT, Liu Z, Hu S, Zhang B. Online mental health services in China during the COVID-19 outbreak. Lancet Psychiatry. 2020;7(4):e17-8. Maia BR, Dias PC. Anxiety, depression and stress in university students: the impact of COVID-19. Estudos de Psicologia (Campinas). 2020;37:e200067.

A new species, Anoplophora siderea Bi, Chen & N. Ohbayashi, sp. nov. (繁星星天牛, Fán xîng xîng tiân niú), is described from Guangxi and Guangdong, China. Unknown males of Anoplophora cheni Bi & N. Ohbayashi, 2015, A. chiangi Hua & Zhang, 1991, A. flavomaculata (Gressitt, 1933) and A. multimaculata (Xie & Wang, 2015) are recorded for the first time. The endophalli of those species and A. ankangensis (Chiang, 1981) are described. New localities, habitus, endophallic structure and major diagnostic features of them are provided.

<b><i>Objective:</i></b> Serum uric acid (SUA) has been linked with development and progression of diabetic kidney disease (DKD). In this study, we intend to compare the effects of hyperuricemia (HUA) on beta-cell function, renal function, and lipid panels of patients with DKD. <b><i>Methods:</i></b> A total of 492 patients with DKD were included for data collection and analysis. Males and females have different standard SUA levels; thus, we analyzed these 2 groups separately. Normouricemia (NUA) for men (<i>n</i> = 253) was ≤428 μmol/L and for women (<i>n</i> = 83) was ≤357 μmol/L, whereas HUA for men (<i>n</i> = 94) was &#x3e;428 μmol/L and for women (<i>n</i> = 62) was &#x3e;357 μmol/L. Clinical characteristics of patients were analyzed based on gender-specific NUA and HUA. The Spearman rank correlation test was used to evaluate the correlation between SUA and other clinical variables. Finally, stepwise multinomial logistic regression test was performed to identify the factors that are independently associated with HUA. <b><i>Results:</i></b> A total of 492 patients were included in this study. The regression analysis showed that there was a significant association between HUA and decreased estimated glomerular filtration rate (eGFR) in both male and female patients (odds ratio (OR) [95% confidence interval (CI)] = 4.73 [2.19–10.24], <i>p</i> value ≤0.01 in male patients and OR [95% CI] = 3.07 [], <i>p</i> value = 0.04 in female patients). FBG, 2hPBG, and HbA1c were negatively correlated with SUA in male patients (<i>r =</i> −0.182, <i>p</i> value ≤0.01; <i>r =</i> −0.168, <i>p</i> value ≤0.01; and <i>r</i> = −0.187, <i>p</i> value ≤0.01, respectively), whereas fasting insulin was positively correlated in male patients (<i>r =</i> 0.131, <i>p</i> value = 0.023) and female patients (<i>r =</i> 0.192, <i>p</i> value = 0.041). The atherogenic index of plasma was significantly high in patients with HUA (OR [95% CI] = 5.75 [2.32–14.23], <i>p</i> value ≤0.01 in male patients and OR [95% CI] = 8.37 [1.96–35.78], <i>p</i> value ≤0.01 in female patients). Other indices of lipid profile such as lipoprotein combine index, atherosclerosis index, and triglyceride/high-density lipoprotein ratio were also independently associated with HUA in both male and female patients. <b><i>Conclusion:</i></b> SUA can affect various clinical parameters in patients with DKD. There is a significant association between HUA and decline in eGFR in both male and female patients. HUA is also associated with dyslipidemia in DKD, increasing the risk of cardiac complications and mortality.

A new species of freshwater red algae, Sheathia jinchengensis, is described based on material collected from rocks in a clean and cold-water stream from the Jincheng region of Shanxi province in North China. Molecular sequences of rbcL and psbA genes were used to evaluate the phylogenetic relationship among samples of S. jinchengensis and other Sheathia species from several regions of the world. The results showed that S. jinchengensis formed an independent branch and separated from the previously published sequence data of other Sheathia taxa. From a morphological point of view, this new species differs also from other species of the genus by the smaller diameter of whorls (167.0–312.5 μm) and larger carpogonium diameter (17.0–29.0 μm). Comparison of sequence variation and thallus morphology with other Sheathia taxa resulted in the proposal of the new species—S. jinchengensis. Additionally, two endemic Batrachospermum species described earlier from China i.e., B. hongdongense and B. longipedicellata are now transferred to the genus Sheathia based on the present study as S. hongdongensis (S.L.Xie & J.Feng) Han, Nan, Feng, Lv, Liu, Kociolek et Xie comb. nov. and S. longipedicellata (Hua & Shi) Han, Nan, Feng, Lv, Liu, Kociolek et Xie comb. nov.

Abstract Background: Morpho-physiological alternations of platelets provided a rationale to harness RNA sequencing of tumor-educated platelets (TEPs) for preoperative diagnosis of cancer. Timely, accurate, and non-invasive detection of ovarian cancer in women with adnexal masses presents a significant clinical challenge. Patients and Methods: This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n=3; Netherlands, n=5; Poland, n=1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. Results: The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. Analysis of public datasets suggested that TEPs had potential to detect multiple malignancies (Table 1). Conclusions: TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, early-stage ovarian cancer as well as other malignancies. However, these observations warrant prospective validations in a larger population before clinical utilities. Table 1. Performance for TEPs in public pan-cancer datasets. Disease n Healthy Control AUC, area under the curve (95% CI) Women NSCLC (non-small-cell lung cancer) 126 77 0.758 (0.691-0.825) Breast cancer 38 77 0.817 (0.726-0.909) Colorectal cancer 18 77 0.973 (0.945-1.000) Pancreatic cancer 16 77 0.993 (0.981-1.000) Glioblastoma 10 77 0.923 (0.831-1.000) Men NSCLC 119 82 0.746 (0.677-0.815) Colorectal cancer 25 82 0.933 (0.884-0.982) Pancreatic cancer 22 82 0.993 (0.984-1.000) Glioblastoma 19 82 0.981 (0.959-1.000) All NSCLC 245 159 0.774 (0.728-0.820) Colorectal cancer 40 159 0.978 (0.961-0.996) Breast cancer 38 159 0.821 (0.736-0.906) Pancreatic cancer 35 159 0.987 (0.974-0.999) Glioblastoma 35 159 0.931 (0.890-0.972) Hepatobiliary carcinomas 14 159 0.991 (0.978-1.000) Citation Format: Yue Gao, Chun-Jie Liu, Hua-Yi Li, Xiao-Ming Xiong, Sjors G.j.g. In ‘t Veld, Gui-Ling Li, Jia-Hao Liu, Guang-Yao Cai, Gui-Yan Xie, Shao-Qing Zeng, Yuan Wu, Jian-Hua Chi, Qiong Zhang, Xiao-Fei Jiao, Lin-Li Shi, Wan-Rong Lu, Wei-Guo Lv, Xing-Sheng Yang, Jurgen M.j. Piek, Cornelis D de Kroon, C.a.r. Lok, Anna Supernat, Sylwia Łapińska-Szumczyk, Anna Łojkowska, Anna J. Żaczek, Jacek Jassem, Bakhos A. Tannous, Nik Sol, Edward Post, Myron G. Best, Bei-Hua Kong, Xing Xie, Ding Ma, Thomas Wurdinger, An-Yuan Guo, Qing-Lei Gao. Platelet RNA signature enables early and accurate detection of ovarian cancer: An intercontinental, biomarker identification study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB168.

Background: Human leukocyte antigen (HLA) genes on chromosome 6p21 encode the major histocompatibility complex (MHC). MHC molecules are expressed on all nucleated cells and are essential to the immune system's ability to distinguish healthy native cells from foreign or abnormal ones. Specialized antigen presenting cells display MHC molecules loaded with foreign peptides to initiate T cell responses. HLA sequencing variability is critical to function; studies have shown even single allelic changes can alter the ability of MHC molecules to recognize cognate T cell receptors. Given the role of MHC molecules in identifying cells as "self", associations between HLA sequence variation and autoimmunity is a research focus. Like other autoimmune disorders, association between ITP and HLA genes has been investigated. Prior studies are limited by outdated HLA typing methods, genetically homogenous study populations, and lack of validation studies. Preexisting exome data has historically not been used to provide accurate HLA sequencing information given the polymorphic, highly repetitive sequence in this region. This study applied a novel bioinformatics pipeline, xHLA, to an existing set of whole exome sequencing in a cohort of chronic pediatric ITP patients. xHLA, reported by Xie et al. in 2017, yields high-resolution, two field HLA typing for HLA-A, -B, -C, -DQB1, -DPB1, and -DRB1. A prior genetic analysis of chronic ITP patient whole exome data identified a missense variant in BTNL2, a gene which plays a role in peripheral regulatory T cell induction. This variant (rs143211074) is upregulated in chronic ITP versus healthy controls (minor allele frequency= 4.17% in ITP v. 0.54% in controls, p=1.43x10-4). Linkage of rs143211074 and HLA alleles was examined in this study. Methods: Whole exome sequencing data for a cohort of 272 chronic ITP patients was processed using the xHLA method. In order to eliminate sequencing variability related to ethnicity alone, initial analyses were focused on Caucasians only (n=170), using Eigenvectors for principle components analysis. The frequency of individual HLA alleles and HLA haplotypes for Caucasians from the National Marrow Donor Program (NMDP) Be The Match Registry® were compared to the ITP cohort. HLA haplotypes were inferred using the NMDP HaploStats program. A chi-squared test was utilized to compare nonparametric categorical data using GraphPad Prism version 8.0.1 for Windows, GraphPad Software, San Diego, California, USA, www.graphpad.com. A Bonferroni correction was applied and a p-value of <0.05 was statistically significant. Results: 12 HLA alleles had increased frequency in the chronic ITP cohort versus controls. (Table 1) The BTNL2 variant, rs143211074, was found in linkage disequilibrium with the HLA-DRB1*04:02, HLA-DQB1*03:02 haplotype. Of the 10 patients heterozygous for the variant allele, 80% had the HLA-DRB1*04:02, HLA-DQB1*03:02 haplotype. Both patients homozygous for rs143211074 were also homozygous for the HLA-DRB1*04:02, HLA-DQB1*03:02 haplotype. In the entire cohort, this haplotype was identified in 3.63% of ITP patients, and only in 1.27% of controls. Our group recently published that a positive direct antiglobulin test is associated with chronic ITP and need for second line treatments. Of the patients with the HLA-DRB1*04:02, HLA-DQB1*03:02 haplotype with DAT testing performed (n=9), 66% had a positive DAT test and 33% had a negative DAT result. Of those without the HLA-DRB1*04:02, HLA-DQB1*03:02 haplotype who had DAT testing, 17.2% had a positive DAT and 82.8% had a negative test (p=0.0026). Conclusions: HLA alleles are seen at increased frequency in a cohort of Caucasian chronic ITP patients. The HLA-DRB1*04:02, HLA-DQB1*03:02 haplotype is linked to a variant previously identified in BTNL2. Coupled with prior data suggesting that a positive DAT result is associated with chronic disease and use of second line agents, this presence of the HLA-DRB1*04:02, HLA-DQB1*03:02 haplotype may also be linked to refractory disease. Confirmation of the accuracy of the xHLA method in a cohort of patients with both exome data and traditional HLA typing is underway. In the future, a separate cohort of chronic and acute ITP patients will undergo next generation sequencing and have similar HLA typing performed as an independent validation set. Table 1 Disclosures Despotovic: Novartis: Research Funding; Amgen: Research Funding; Dova: Honoraria.

Background:Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease and increases the risk of developing osteoporosis. Incidence of fracture is higher in this group of patients compared to the general population and can lead to increased morbidity (1). Bone strength of the proximal femur is not only linked to bone mineral density; it also depends on the geometric properties of the bone mass (2). Hip structural analysis (HSA) is a technique used to assess hip bone structure that takes geometric measurements of the femur from dual-energy X-ray absorptiometry (DEXA) images (3).Objectives:To determine whether HSA measurements help predict fracture in patients with RA.Methods:Data were collected from June 2004 to August 2017 from RA patients who underwent a DEXA scan at a District General Hospital. This included hip axis length (HAL), cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), distance from centre of femoral head to centre of femoral neck (D1) and to inter-trochanteric line (D2), mean femoral neck diameter (D3), shaft angle (A) neck/shaft angle (Θ) and proximal femur strength index (SI) and distance from centre of mass of femoral neck to superior neck margin (Y). Fracture was predicted by a series of binomial logistic regression models, adjusted for sex, age and bone mineral density (BMD). Odds ratios with 95% confidence intervals and area under the receiver operating characteristic curve (AUC) were calculated.Results:2077 patients with RA were identified, 1632 were female and the mean age was 66.7. HAL, D1, D2, D3, A, Θ and Y were not significant predictors of fracture in regression models; odds ratios are included in table 1. CSA, CSMI and SI predicted fracture risk. The AUC for CSA, CSMI and SI regression models were 0.632, 0.609 and 0.625 respectively.Table 1.Odds ratios of fracture for different HSA parameters in RA patientsHSA ParameterOdds Ratio (95% Confidence Interval)HAL1.01410 (0.99958 - 1.02883)CSMI0.99994 (0.99990 - 0.99998)CSA0.98523 (0.98065 - 0.98982)D11.01683 (0.98925 - 1.04518)D21.01286 (0.99886 - 1.02705)D31.00664 (0.96958 - 1.04511)Y1.04580 (0.98633 - 1.10886)A1.00898 (0.98878 - 1.02959)Θ1.00276 (0.98672 - 1.01906)SI0.56769 (0.43400 - 0.74258)Figure 1.Receiver operating characteristic curves for CSA (red), CSMI (green) and SI (blue). AUC for CSA was 0.632, CSMI-0.609 and SI-0.625.Conclusion:These data suggest that CSA, CSMI and SI help predict the fracture risk in patients with RA. HAL, D1, D2, D3, A, Θ and Y do not predict risk of fracture. The CSA regression model was the strongest predictor of fracture. HSA measurements can therefore help predict risk of fracture in conjunction with other factors. Limitations of the study are that it was retrospective and only studied patients who had a DEXA scan.References:[1]Xue A, Wu S, Jiang L, Feng A, Guo H, Zhao P. Bone fracture risk in patients with rheumatoid arthritis: A meta-analysis. Medicine. 2017; 96 (36): e6983. Available from: doi: 10.1097/MD.0000000000006983.[2]Faulkner KG, Wacker WK, Barden HS, Simonelli C, Burke PK, Ragi S, Del Rio L. Femur strength index predicts hip fracture independent of bone density and hip axis length. Osteoporos Int. 2006;17(4):593-9. doi: 10.1007/s00198-005-0019-4.[3]Kaptoge S, Beck TJ, Reeve J, Stone KL, Hillier TA, Cauley JA, et al. Prediction of Incident Hip Fracture Risk by Femur Geometry Variables Measured by Hip Structural Analysis in the Study of Osteoporotic Fractures. Journal of Bone and Mineral Research. 2008; 23 (12): 1892-1904. Available from: doi: https://doi.org/10.1359/jbmr.080802.Disclosure of Interests:None declared

<b><i>Introduction:</i></b> Nitisinone used in alkaptonuria (AKU) can result in keratopathy due to strongly increased tyrosine levels. <b><i>Methods:</i></b> This study aimed to investigate nutritional status and changes in plasma tyrosine and phenylalanine and urinary homogentisic acid (u-HGA) levels in 8 adult AKU patients (mean age, 56.3 ± 4.7 years) who were on tyrosine/phenylalanine-restricted diet together with 2 mg/day nitisinone. <b><i>Results:</i></b> The treatment period was 23.4 ± 6.9 months. Daily dietary protein intake was restricted to 0.8–1.0 g/kg/day. Daily tyrosine intake was restricted to 260–450 mg/day for females and 330–550 mg/day for males. Tyrosine/phenylalanine-free amino acid supplements accounted for an average of 56.1% of daily protein intake. The following assessments were performed: anthropometric and plasma tyrosine level measurements every 2 months; ophthalmological examination every 6 months, and nutritional laboratory analyses and measurements of plasma amino acids and u-HGA once in a year. It was targeted to keep the plasma tyrosine level &#x3c;500 μmol/L. The plasma tyrosine level was &#x3c;100 μmol/L before the treatment in all patients and around a mean of 582.5 ± 194.8 μmol/L during the treatment. The diet was rearranged if a plasma tyrosine level of &#x3e;700 μmol/L was detected. The u-HGA level before and after the 1st year of treatment was 1,429.3 ± 1,073.4 mmol/mol creatinine and 33.6 ± 9.5 mmol/mol creatinine, respectively. None of the patients developed keratopathy or experienced weight loss and protein or micronutrient deficiency. <b><i>Conclusion:</i></b> AKU patients should receive tyrosine/phenylalanine-restricted diet for reducing plasma tyrosine level to the safe range. Tyrosine/phenylalanine-free amino acid supplements can be safely used to enhance dietary compliance. Keratopathy and nutrient deficiency should be frequently monitored.

Abstract Background: Bone is one of the most frequent sites for breast cancer metastasis. Breast cancer bone metastasis leads to skeletal morbidity including pain, fractures, spinal compression, and impact quality of life. Immunotherapy is a promising therapy for advanced cancer patients. Thus, a better understanding of the immune microenvironment for breast cancer and its bone metastasis sites may prompt new therapy strategies. This study aimed to investigate immune parameters change between breast cancer and its bone metastasis site. Methods: 63 patients with breast cancer bone metastasis including 31 paired primary sites with bone metastasis were included in our study. The percentage of stroma and stromal tumor infiltrated lymphocytes (TILs) was evaluated through hematoxylin and eosin stained tumor slides. The quantification of stromal TILs (CD4, CD8) and macrophages (CD68, HLA-DR), programmed cell death protein 1(PD-1), and programmed cell death protein ligand 1(PD-L1, SP142) were evaluated through immunohistochemical staining. Statistical analysis was performed with paired t-test, Wilcoxon test, spearman correlation test, univariate and multivariate cox regression. Results: Median survival after breast cancer bone metastasis was pathologically diagnosed was 20.5 months (3-95 months). None of the immune parameters was found correlated with survival after bone metastasis. Compared to the primary site, bone metastases exhibited more stroma (mean: 58.5% vs 28.87%, p&lt;0.001) and less TILs (mean: 8.45% vs 14.03%, p=0.042). The quantification of CD4 (23.95/mm2 vs 51.69/mm2, p=0.026) and CD8 (18.15/mm2 vs 58.95/mm2, p=0.004) positive TILs also followed this tendency. The number of macrophages (CD68 and HLA-DR) showed no significant difference between primary sites and bone metastases. PD-1 expression was present in 87.1% of the primary sites and 74.19% of the bone metastasis. PD-L1 expression was present in 25.81% of the primary sites and 7.94% of the bone metastasis. Conclusions: Our findings suggest that compared with the primary site, bone metastasis obtain a less active immune microenvironment. Positive expression of PD1 and PD-L1 in bone metastasis indicates potential therapeutic effects of immune checkpoint inhibitors in some cases. Table 1.Patient CharacteristicsVariableN%Bone metastasis leisions63Primary tumor and matched bone metastasis3149.21Primary tumor histologyDuctal , non-special type5180.95Ductal, micropapillary11.59Ductal, mucinous23.17Ductal and lobular23.17Uncertain711.11Primary tumor grade111.5921523.8134063.49Uncertain711.11Primary tumor phenotypesLuminal A1117.46Luminal B2946.03HER2 amplification1523.81Triple negative46.35Uncertain46.35Primary tumor size≤2 cm1117.462-5 cm2438.10&gt;5cm23.17Uncertain2641.27Nodes statusNegative1015.871-3 nodes2031.754-9 nodes46.35&gt;101320.63Uncertain1625.40SurgeryMastectomy4469.84Breast conserving surgery57.94None57.94Uncertain914.29Chemotherapyadjuvant5485.71neoadjuvant11.59None812.70Radiotherapyadjuvant2641.27None3758.73Trastuzumab/pertuzumab application in Her-2 positive patients7/15Endocrine therapyYes4063.49No2336.51Bone metastasis at first diagnosis57.94Bone metastasis sitesIlium57.94Sternum711.11Rib11.59Vertebra4368.25Femur34.76Humerus11.59Skull11.59Treatment after bone metastasisRadiotherapy812.70Chemotherapy2742.86Endocrine therapy4266.67Trastuzumab/pertuzumab46.35Alive at last follow-up4368.25 Table 2.Assessment of tumor microenviroment of breast cancer bone metastasisVariable MedianIQRStroma (%)7040-80Stromal TILs(%)55-10Stromal CD4+ TILs (/mm2)12.51-27.5Stromal CD8+ TILs (/mm2)51-35CD4/CD8 ratio10.53-5.18Stromal HLA-DR+ macrophages (/mm2)8560-120Stromal CD68+ macrophages (/mm2)37.512.5-57.5HLA-DR/CD68 ratio2.271.44-5PD-1 expression43/6368.25(%)PD-L1 expression5/637.94(%)Osteoclasts(/mm2)0.330-3 Citation Format: Xue Chao, Ying Zhang, Jiabin Lu, Peng Sun, Jiehua He. Immune microenvironment change of breast cancer and bone metastasis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-20-01.

Introdução: O manejo no atendimento odontológico infantil torna-se fatigante quando não há cooperação por parte da criança e/ou dos responsáveis. A fim de minimizar esses quadros, quando não existe sucesso das técnicas de abordagem comportamental tradicionais, métodos terapêuticos alternativos têm sido amplamente estudados, em especial a sedação consciente com óxido nitroso associada ou não a fármacos sedativos. Objetivo: Dessa forma, objetivou-se realizar uma revisão crítica da literatura norteando o cirurgião-dentista sobre o uso do óxido nitroso e sua associação a fármacos, esclarecendo suas indicações, vantagens e desvantagens. Métodos: Foi realizada uma busca integrativa da literatura nacional e internacional, entre 2004 a 2019, nas bases Bireme e PubMed, utilizando os descritores: sedação consciente, ansiedade no tratamento odontológico e óxido nitroso. Resultados: No total, 43 artigos foram incluídos nesse estudo. O óxido nitroso tem sido bastante utilizado na odontologia, especialmente na odontopediatria. Este atua no sistema nervoso, promovendo uma leve depressão do córtex cerebral e não deprime o centro respiratório, sendo considerado seguro. A técnica pode ser combinada a outros fármacos, como Midazolam e Prometazina, sendo que cada abordagem medicamentosa apresenta suas indicações e vantagens específicas. Conclusão: A sedação consciente mostra-se como um método viável, e quando bem indicada é considerada segura. Seu papel na Odontologia vem sendo consolidado com o tempo, em decorrência dos inúmeros benefícios encontrados. No entanto, ainda existe certa resistência na utilização da mesma, tanto por parte dos responsáveis como também de alguns profissionais. Descritores: Sedação Consciente; Ansiedade ao Tratamento Odontológico; Óxido Nitroso. Referências Jain S. Sedation: A Primerfor Pediatricians. Pediatr Ann. 2018;47(6):254-58. Ashley PF, Chaudhary M, Lourenço-Matharu L. Sedation of children undergoing dental treatment. Cochrane Database Syst Rev.2018;12:1-152 Mozafar S, Bargrizan M, Golpayegani MV, Shayeghi S, Ahmadi R . Comparison of nitrous oxide/midazolam and nitrous oxide/promethazine for pediatric dental sedation: A randomized, cross-over, clinical trial. Use of nitrous oxide for pediatric patients. Dent Res J (Isfahan). 2018;15(6):411-19. Johnson C, Weber-Gasparoni K, Slayton RL, Qian F. Conscious sedation attitudes and perceptions: a survey of american academy of pediatric dentistry members. Pediatr Dent. 2012;34(2):132-37. Hand D, Averley P, Lyne J, Girdler N. Advanced paediatric conscious sedation: an alternative to dental general anaesthetic in the U.K. SAAD Dig. 201;27:24-9. Holroyd I. Conscious sedation in pediatric dentistry. A short review of the current UK guidelines and the technique of inhalational sedation with nitrous oxide. Paediatr Anaesth. 2008;18(1):13-7. Naudi AB, Campbell C, Holt J, Hosey MT. An inhalation sedation patient profile at a specialist paediatric dentistry unit: a retrospective survey. Eur Arch Paediatr Dent. 2006;7(2):106-9, Blumer S, Iraqui R, Bercovich R, Peretz B. Oxygen saturation and pulserate change in children during sedation with oral midazolam and nitrous oxide. J Clin Pediatr Dent. 2018;42(6):461-64. Choi SC, Yang Y, Yoo S, Kim J, Jeong T, Shin TJ. Decelopment of a web-based nationwide Korean pediatric dental sedation registry. J Clin Pediatr Dent. 2017;41(6):478-81. Wilson S, Houpt M . Project USAP 2010: use of sedative agents in pediatric dentistry- a 25- yar follow up survey. J Pediatr Dent.2016;38(2):127-33. Wilson S, Gosnell ES. Survey of American academy of pediatric dentistry on nitrous oxide and sedation: 20 years later. J Pediatr Dent. 2016;38(5):385-92. White J, Wells M, Arheart KL, Donaldson M, Woods MA. A questionnaire of parental perceptions of conscious sedation in pediatric dentistry. J Pediatr. Dent. 2016;38(2):116-21. Nelson TM, Xu Z. Pediatric dental sedation: challenges and opportunities. Clin Cosmet Investig Dent. 2015;7:97-106. Czlusniak GD, Rehbein M, Regattieri LR. Sedação consciente com oxido nitroso e oxigênio (NO2/O2): avaliação clínica pela oxime Publ. UEPG Ci Biol Saúde. 2007;13(4):23-8. Bham F, Perrie H, Scribante J, Lee CA. Paediatric dental chair sedation: An audit of current practice in Gauteng, South Africa. S Afr Med J. 2015;105(6):461-64. Diedericks BJ. Paediatric dental sedation: Will your child return home unharmed? S Afr Med J. 2015;105(6):453. Wilson S, Gosnell ES. Survey of American Academy of Pediatric Dentistry on Nitrous Oxide and Sedation: 20 Years Later. J Pediatr Dent. 2016;38(5):385-92. Levering NJ, Welie JVM. Current status of nitrous oxide as a behavior management practice routine in pediatric dentistry. J Dent Child (Chic). 2011;78(1):24-30. Ashley PF, Chaudhary M, Lourenço-Matharu L. Sedation of children undergoing dental treatment. Cochrane Database Syst Rev. 2018;12:3877. Hariharan S, Hosey MT, Bernabe E . Comparing the profile of child patients attending dental general anaesthesia and conscioussedation services. Br Dent J. 2017;222(9):683-87. Miranda-Remijo D, Orsini MR, Corrêa-Faria P, Costa LR. Mother-child interactions and young child behavior during procedural conscious sedation. BMC Pediatr. 2016;16(1):201. Morin A, Ocanto R, Drukteinis L, Hardigan PC . Survey of Current Clinical and Curriculum Practices of Postgraduate Pediatric Dentistry Programs in Nonintravenous Conscious Sedation in the United States. J Pediatr Dent. 2016;38(5):398-405. Woolley SM, Hingston EJ, Shah J, Chadwick BL. Paediatric conscious sedation: views and experience of specialists in paediatric dentistry. Br Dent J. 2009;207(6):280-81. Hosey MT, Makin A, Jones RM, Gilchrist F, Carruthers M. Propofol intravenous conscious sedation for anxius children in a specialist pediatric dentistry unit. Int J Pediatr Dent. 2004;14:2-8 Nathan JE .Effective and safe pediatric oral conscious sedation: philosophy and practical considerations. Alpha Omegan. 2006;99(2):78-82. Wilson S, Houpt M. Project USAP 2010: Use of Sedative Agents in Pediatric Dentistry-a 25-year Follow-up Survey. Amer Acad of Ped Dent. 2016;38(2):127-33. Paterson SA, Tahmassebi JF. Paediatric dentistry in the new millennium: 3. Use of inhalation sedation in paediatric dentistry. Dent Update. 2003;30(7):350-58. Wilson S. A survey of the American Academy of Pediatric Dentistry membership: nitrous oxide and sedation. Pediatr Dent. 1996;18(4):287-93. Zhong T, Hu D. Technology of nitrous oxide/oxygen inhalation sedation and its clinical application in pediatric dentistry. Hua Xi Kou Qiang Yi Xue Za Zhi. 2014;32(1):101-4. Levering NJ, Welie JVM. Ethical considerations in the use of nitrous oxide in pediatric dentistry. J Am Coll Dent;77(2):40-7 American academy of pediatric dentistry: recommendations- best practices. Reference manual. 2018;40(6):281-86. American academy of pediatric dentistry. Guideline on use of nitrous oxide for pediatric dental patients. 2011;33(6):181-84. Wilson KE. Overview of paediatric dental sedation: 2. Nitrous oxide/oxygen inhalation sedation. Dent Update. 2013;40(10):822-29. Foley J. A prospective study of the use of nitrous oxide inhalation sedation for dental treatment in anxious children. Eur J Paediatr Dent. 2005;6(3):121-28. Paterson SA, Tahmassebi JF. Paediatric dentistry in the new millennium: 3. Use of inhalation sedation in paediatric dentistry.Dent Update. 2003;30(7):350- Veerkamp JS, Gruythuysen RJ, Van Amerongen WE, Hoogstraten J. Dental treatment of fearful children using nitrous oxide. Part 2: The parent's point of view. ASDC J Dent Child.1992;59(2):115-19. Veerkamp JS, Van Amerongen WE, Hoogstraten J, Groen HJ. Dental treatment of fearful children, using nitrous oxide. Part I: Treatment times. ASDC J Dent Child.1991;58(6): 453-457. 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Background:The shared epitope (SE) is the strongest known genetic risk factor for rheumatoid arthritis (RA) and is associated with an amino acid motif at positions 70-74 in HLA-DRB1. It is linked to anti-citrullinated protein antibody (ACPA) positivity, a specific serological marker for RA. In 2005, a new classification of HLA-DRB1 alleles was proposed, in which each allele is sorted into one of five classes (S1, S2, S3P, S3D, or X).1 The method was subsequently validated for predicting risk of developing RA2 and was described as “a major advance and a template for future studies.”3 However, there have been relatively few studies utilizing this classification.Objectives:To characterize the prevalence of each SE genotype from the 2005 classification and their association with ACPA positivity in a cohort of individuals with RA.Methods:Participants in FORWARD, The National Databank for Rheumatic Diseases, with RA and donated serum (collected 2010-2019) were analyzed to obtain ACPA status and high-resolution HLA-DRB1 type. Alleles were classified based on the presence (S2, S3P) or absence (S1, S3D, X; collectively L) of the SE motif, and individuals were classified by allele pair. Logistic regression models (adjusted for age, sex, and race/ethnicity) to determine risk of ACPA positivity by class were generated using L/L as the reference.Results:Characteristics of the 855 participants at the time of sample collection are presented in Table 1. Overall, 67% of participants were SE positive and 51% were ACPA positive. Of the 1,710 total alleles, X was the most common (29%) followed by S3P (24%), S1 (18%), S2 (18%), and S3D (9%). Adjusted models showed that the risk of ACPA positivity was highest among those with the genotype S2/S3P, followed by S2/S2, S2/S3D, S2/X, S3P/S3D, S1/S2, S3P/S3P, S3P/X, and S1/S3P (Figure 1).Table 1.Characteristics of study population by SE status and allele count (mean [SD] or n [%]). Significance was assessed by Student’s t-test or Χ2 test, as appropriate.SE negativeSE positiveP (SE- vs SE+)0 allelesAll1 allele2 allelesn=286n=569n=407n=162Age, years57.4 (12.3)58.1 (11.8)58.0 (11.9)58.5 (11.5)0.42RA duration, years15.2 (12.8)17.0 (13.9)16.8 (14.1)17.6 (13.4)0.07Female259 (90.6)500 (87.9)359 (88.2)141 (87.0)0.24White260 (90.9)525 (92.3)372 (91.4)153 (94.4)0.49History of smoking117 (40.9)223 (39.2)166 (40.8)57 (35.2)0.63RDCI, 0-92.4 (1.8)2.0 (1.7)2.1 (1.7)1.9 (1.7)<0.01ACPA positive74 (25.9)365 (64.1)241 (59.2)124 (76.5)<0.001RF positive84 (29.4)333 (58.5)219 (53.8)114 (70.4)<0.001Pain VAS, 0-104.2 (2.7)3.6 (2.7)3.7 (2.6)3.5 (2.9)<0.01Patient global severity, 0-104.0 (2.5)3.3 (2.5)3.4 (2.4)3.1 (2.6)<0.001HAQ-II, 0-31.0 (0.7)0.8 (0.6)0.8 (0.6)0.8 (0.6)<0.001csDMARD use204 (71.3)433 (76.1)302 (74.2)131 (80.9)0.13bDMARD use165 (57.7)351 (61.7)244 (59.95)107 (66.0)0.26Corticosteroid use98 (34.3)165 (29.0)121 (29.7)44 (27.2)0.12Figure 1.Risk of ACPA positivity by the motif-based classification and prevalence of SE by binary status, allele count, and class. The area within each circle is proportionate to the sample size of that group.Conclusion:The ranking by risk of ACPA positivity among this RA cohort is similar to the order of risk for developing RA, as determined in the 2006 validation paper for this classification method. A notable trend among the classes with one SE positive allele is the consistent ranking of S3D as higher risk, X in the middle, and S1 as the lowest, suggesting a potential protective effect from S1 alleles. Future work should examine clinical associations with these allele classes, including disease progression and treatment effects.References:[1]du Montcel, ST et al. New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility. Arthritis Rheum52, 1063–1068 (2005).[2]Michou, L et al. Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis. Arthritis Res Ther8, R79 (2006).[3]Winchester, R. Reshaping Cinderella’s slipper: the shared epitope hypothesis. Arthritis Res Ther8, 109 (2006).Acknowledgements:This study was sponsored by Bristol Myers Squibb.Disclosure of Interests:Kristin Wipfler: None declared, Xue Han Employee of: Bristol Myers Squibb, Sarah (Sang Hee) Park Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Keith Wittstock Employee of: Bristol Myers Squibb, Kaleb Michaud: None declared

Bac Giang is a province in the northern midland and mountainous region of Vietnam. Bac Giang has many potentials and advantages in terms of natural conditions and human resources for economic development. However, climate change has been having a great impact on the socio-economic development of the province. The study applied the correlation assessment method and regression analysis to process temperature data at 4 meteorological stations: Bac Giang, Hiep Hoa, Son Dong, and Luc Ngan. The results demonstrate that in 44 years (1970 - 2014) the trend of change in average temperature is from 0.012 oC\year to 0.018 oC\year. On the other hand, the changing trend of the annual absolute maximum temperature is common at a higher level, from 0.028 oC\year to 0.032 oC\year. The variability of extreme temperature values is much broader than that of the average temperature. The trend of temperature variation (average temperature, annual absolute maximum temperature) is highest in the eastern territory of the province, in mountainous districts including Son Dong, Luc Ngan, and lowest in the western lowland areas namely Hiep Hoa district. The research results will be the assisting tool for management agencies to find solutions to develop socio-economic adaptation to climate change.

<b>Introduction:</b> IgA nephropathy (IgAN) can be associated with spondyloarthritis (SpA). The course of SpA-associated IgAN remains largely unknown due to the absence of large cohorts. <b>Methods:</b> This retrospective study included patients with biopsy-proven IgAN and definite SpA. Kidney biopsies were centrally examined and scored according to the IgAN Oxford Classification. Thirty-two patients fulfilled the inclusion criteria, with a male:female ratio of 9:1 and median age of 27 and 37 years at SpA and IgAN diagnosis, respectively. HLA-B27 was positive in 90% of cases, and most patients (60%) presented with ankylosing spondylitis. The mean baseline estimated glomerular filtration rate (eGFR) was 84 ± 26 ml/min per 1.73 m², and the urine protein-to-creatinine ratio was 0.19 g/mmol. <b>Results:</b> Renal biopsy revealed frequent presence of crescents (33%) and interstitial inflammation (18%). Despite almost constant use of renin-angiotensin system inhibitors, combined with steroids in 13 of 32 patients, renal outcome was particularly poor. After a median follow-up of 5.9 years, 4 patients (12.5%) reached end-stage renal disease and 41% of patients experienced a &#x3e;50% decrease of eGFR. The mean annual eGFR decline rate was –4.3 ± 6.7 ml/min per 1.73 m². The risk of reaching class IV or V chronic kidney disease (CKD) stage during follow-up was associated with the presence of hypertension, level of proteinuria, and baseline S- and T-scores of the Oxford. <b>Conclusion:</b> SpA-associated IgAN is associated with a poor renal outcome, despite frequent use of steroids. Tumor necrosis factor (TNF)-α blockade did not appear to influence the rate of eGFR decline in this setting.

Abstract Peptide-HLA (pHLA)- targeting therapeutics, such as T cell receptor-engineered T cells (TCR-T), have had clinical success in treating solid tumors. However, challenges related to safety exist: major concerns remain surrounding the cross-reactivity of T cell receptors (TCRs) as well as the ability of therapeutics to discriminate between on-target vs off-target pHLAs while maintaining high potency. Therefore, approaches that survey the diversity of the T cell repertoire to discover optimal TCRs, as well as platforms to comprehensively identify potential off-target liabilities, are critical to de-risking and accelerating the development of this promising class of pHLA-targeting therapeutics. We have developed a strategy that (1) queries the TCR repertoire to enrich and identify multiple active, sequence-distinct endogenous TCRs; (2) uses 3T-TRACE, a high-diversity pHLA library, to screen for cross-reactivity; and (3) exploits functional selections to simultaneously optimize for TCR potency and specificity. We applied this approach to identify TCRs of optimal specificity and potency targeting a peptide derived from the cancer-testis antigen NY-ESO-1 (SLLMWITQC) displayed by HLA-A2. We profiled 6 sequence-distinct TCRs using 3T-TRACE and validated potential endogenous off-target cross-reactivities. Many of the identified off-targets exhibited little to no sequence homology to the NY-ESO-1 epitope, highlighting the importance of diverse combinatorial libraries in identifying unexpected cross-reactivities. Leveraging the off-target liabilities identified by 3T-TRACE, we designed a functional library and selection scheme that enabled the identification of TCRs with increased potency and specificity. Optimized TCRs exhibited enhanced killing activity and improved safety against an NY-ESO-1-expressing melanoma cell line compared to benchmark TCRs, indicating that this approach has potential to improve clinical safety and efficacy. Using this multi-faceted and comprehensive approach we rapidly identified highly potent and specific TCRs against NY-ESO-1. Identifying cross-reactivities using 3T-TRACE proved to be critical in selecting TCRs suitable for engineering and functional selections. This approach can be extended to any pHLA target to create safe and effective TCR-Ts for clinical development. Citation Format: John D. Leonard, Alejandro Ramirez, Jason Romero, Jake Kleiner, Joanna Dreux, Bindu Hegde, Bryan Xie, Akshay Sharathchandra, Nathan Katz, Venita I. DeAlmeida, Hans-Peter Gerber, Marvin H. Gee, Leah V. Sibener. A functional approach to identifying and engineering TCRs results in highly-potent and specific TCRs for TCR-T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 578.

Abstract Background: The aging marrow stem cell demonstrates more somatic mutations when compared to younger marrow stem cells. These abnormalities have been noted in pts with MDS, as well as in patients with normal peripheral blood counts (Steensma et al, Blood 2015; Jaiswal et al, N Engl J Med 2014). Mutations are rarely detected in people <40 years of age, but increase each decade thereafter (Jaiswal et al, N Engl J Med 2014). Certain mutations (eg, DNMT3A, TET2, ASXL1, and SF3B1) are most prevalent in the oldest pts, and approximately 2% of pts with mutations associated with leukemia or lymphoma have age-related hematopoietic clonal expansion, which increases to 5-6% among patients ≥70 years of age (Xie et al, Nat Med 2014). In another study, 10% of elderly subjects had clonal hematopoiesis with somatic mutations and this number increased with increasing age (Genovese et al, N Engl J Med 2014). In a randomized, Phase III study with intravenous rigosertib (ONTIME) in patients with MDS failing HMA therapy, a much higher proportion of pts with bone marrow mutations was observed. The most frequent mutations were as follows: SRSF2 (28% of pts), TP53 (22%), ASXL1 (19%), SF3B1 (14%), and TET2 (14%) (Mufti et al, Blood 2014). Given that MDS is a disease of the elderly, and the importance of somatic mutations for diagnosis, prognosis, and (potentially) targeted therapy, we explored the correlation between age and type of somatic bone marrow mutation found in pts entered into ONTIME. Methods: We evaluated the bone marrow mutations in patients with MDS who were enrolled in ONTIME after failing to respond to a previous HMA. Bone marrow genomic DNA was isolated from single microscopic slides from 153 pts from ONTIME and subjected to sequence analysis of a "myeloid panel" comprising of 24 selected loci known to be frequently mutated in MDS and AML (Mufti et al, Blood 2014). We investigated these 24 myeloid abnormalities for their frequency in the identified age cohorts prior to study randomization to explore the correlation between age and the somatic mutation identified, specifically looking at pts older or younger than the mean age of pts with MDS in ONTIME (75 years). Results: Approximately 45% of patients had 1 mutation and an equal number had >1 (Figure 1). Table 1 shows the most frequent clonal myeloid mutations in ONTIME, based on age above and below 75 years (the median age in ONTIME).Table 3.Incidence (%) of Patients with Specific Mutations, Age Above and Below 75 YearsMutation< 75 years (N=60)≥ 75 years (N=51)Total (N=111)Fisher's Exact Test P-valueSRSF22729280.83TP532518220.37ASXL12018190.81SF3B11316140.79U2AF11212121.00TET21216140.59RUNX1814110.38DNMT3A812100.75In a separate analysis, the number of months from diagnosis of MDS and duration of prior HMA treatment did not appear to influence the pattern of mutations (Table 2). Table 2.Mutations by Months Since MDS Diagnosis and Duration of Prior HMAMutationNMonths from MDS Diagnosis median (range)Duration of HMA (mo) median (range)All analyzed pts11118.5 (0.1-116)8.9 (1.2-65)TP532414.9 (0.7-116)13.0 (1.2-36)SF3B11629.4 (7.5-63)13.0 (1.2-36)TET21522.6 (0.1-63)11.4 (2.0-36)SRSF23117.2 (6.6-116)6.4 (3.0-35)ASXL12115.7 (4.9-66)8.2 (2.8-44)DNMT3A1115.1 (7.4-36)6.5 (4.2-30)Conclusions: Somatic mutations are common in marrow stem cells from patients with HR-MDS. Over 45% of patients had 1 mutational abnormality, and 44% had >1. Of note, patients under and over the median age of pts with MDS had a similar mutational pattern, which was not influenced by either length of time since diagnosis of MDS or prior treatment with an HMA. In this analysis, the mutational genomic abnormalities in the MDS marrow stem cell were similar among younger and older patients with MDS, suggesting the underlying pathogenic mechanisms causing these abnormalities are also similar irrespective of patient age. Figure 1. Number of Mutations Per Patient Figure 1. Number of Mutations Per Patient Figure 2. Overall Survival in ONTIME by Number of Marrow Stem Cell Mutations Figure 2. Overall Survival in ONTIME by Number of Marrow Stem Cell Mutations Disclosures Mufti: Onconova Therapeutics Inc: Research Funding. Silverman:Onconova Therapeutics Inc: Honoraria, Patents & Royalties: co-patent holder on combination of rigosertib and azacitdine, Research Funding. Best:Onconova Therapeutics Inc: Research Funding. Fructman:Onconova Therapeutics Inc: Employment. Azarnia:Onconova Therapeutics Inc: Employment. Petrone:Onconova Therapeutics Inc: Employment.

Background:The shared epitope (SE) is a significant genetic risk factor for rheumatoid arthritis (RA), and it has been proposed to be associated with T-cell activation and the production of anti-citrullinated protein antibody (ACPA).1-3The results from the Early AMPLE trial, a head-to-head trial comparing the efficacy of abatacept versus adalimumab among early moderate-to-severe RA patients with positive ACPA (ACPA+) and rheumatoid factor (RF), showed that at week 24, patients with SE positivity (SE+) responded better to abatacept compared to adalimumab across all efficacy measures evaluated (ACR20 [American College of Rheumatology], ACR50, ACR70, DAS[disease activity score]28-CRP[C-reactive protein]).4Objectives:To compare the cost per responder (CPR) between abatacept and adalimumab among RA patients with SE+ at week 24 using the Early AMPLE trial data from a United States (US) payer perspective.Methods:A CPR analysis was conducted for RA patients with SE+, ACPA+, and RF. Responders were defined as patients achieving ACR20, ACR50, ACR70, or DAS28-CRP ≤2.6 and efficacy data was sourced from the trial (Figure 1).4Approved product labels were referenced for treatment dosing regimen and wholesale acquisition cost was used to calculate pharmacy cost.5A real-world rebate scenario was considered for adalimumab (30%) to reflect the real-world pricing in the US market. The CPR was calculated as the total pharmacy cost divided by the proportion of responders.Results:The total pharmacy cost at week 24 was $26,273 per patient for abatacept and $21,731 per patient for adalimumab. With achieving ACR70 as the definition of responder, the CPR at 24-week was $46,337 for abatacept and $74,935 for adalimumab, a difference of $28,598 (Table 1). The CPR was consistently lower for abatacept compared to adalimumab across all clinical measures, with difference ranging from $7,099 to $43,609.Table 1.Overall cost per responder resultsAbataceptAdalimumabDifferenceACR20$30,303.74$37,403.06-$7,099.32ACR50$34,254.68$48,077.83-$13,823.15ACR70$46,337.46$74,935.10-$28,597.64DAS28-CRP ≤2.6$52,546.68$96,155.65-$43,608.97Conclusion:While the pharmacy cost was higher for abatacept compared to adalimumab driven by the rebate, due to its higher clinical efficacy, the CPR was consistently lower for SE+ RA patients treated with abatacept. The results may be useful for US healthcare decision makers in understanding how to optimize treatment for SE+ RA patient while minimizing costs in today’s budget constrained environment.References:[1]Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.Arthritis and rheumatism. 1987;30(11):1205-13.[2]Holoshitz J. The rheumatoid arthritis HLA-DRB1 shared epitope.Curr Opin Rheumatol. 2010;22(3):293-8.[3]Sakkas LI, Bogdanos DP, Katsiari C, et al. Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment.Autoimmun Rev. 2014;13(11):1114-20.[4]Fleischmann R, Weinblatt M, Ahmad H, et al. Efficacy of abatacept and adalimumab in patientsn with early rheumatoid arthritis with multiple poor prognostic factors: post hoc analysis of a randomized controlled clinical trial (AMPLE).Rheumatol Ther. 2019;6(4): 559-571.[5]Truven Health Analytics. Redbook online. Accessed October 11, 2019.Disclosure of Interests:Sang Hee Park Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study, Xue Han Employee of: BMS, Francis Lobo Shareholder of: Bristol-Myers Squibb (US), Employee of: Bristol-Myers Squibb (US), Sakina Nanji Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study, Dipen Patel Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study

Abstract Background: Lung cancer is one of the deadliest types of cancer in China. Its 5-year survival rates at early stages are significantly higher than advanced stages. LDCT has been adopted for lung cancer screening in high-risk individuals; however, debate regarding its accuracy is still ongoing. Mutation detection on cell free DNA (cfDNA) has traditionally been used to monitor DNA molecular changes derived from lung cancer cells in blood, while recently fragmentation pattern profiling of cfDNA has been shown as a promising alternative for early cancer detection. We aimed to combine mutation detection and fragmentation pattern analysis on cfDNA to develop a non-invasive assay to screen early lung cancer. Methods: Candidate DNA mutations were curated from literature and public databases, including COSMIC and TCGA. DNA fragmentation markers were collected from literature and whole genome sequencing (WGS) datasets. A panel of 407 primers covering selected mutation and fragmentation markers was developed to distinguish lung adenocarcinoma (ADC) plasma and normal plasma. We enrolled a total of 122 plasma samples (64 normal, 58 ADC) for this study. 49 normal samples and 44 ADC samples were used to construct a mutation-based classification model and a fragmentation-based classification model separately. The tuning parameters and features were determined by inner 4-fold cross validation. For the mutation-based model, baseline was set using normal samples in training set. Maximum allele frequency was calculated for each sample in test data (15 normal, 14 ADC), which was filtered by the background baseline. For the fragmentation-based model, we used the DELFI fragment score to construct fragmentation profiles, which was the ratio between short fragments (100-150bp) and long fragments (151-220bp). After optimization, the two models were integrated by Logistic Regression to create a combined model, which was validated by 4-fold nested cross validation. Results: ADC and normal plasma were sequenced by the aforementioned panel at an average depth of 2,000X to ensure the reliability of model construction and classification results. In classifying normal and ADC plasma, the mutation model alone is only modestly accurate as it produced an AUC of 0.69. But the fragmentation model demonstrated significantly higher accuracy, achieving AUC of 0.85. Furthermore, the combined model performed better than either model along, achieving an elevated AUC of 0.87. Conclusions: We demonstrate that DNA mutation and fragmentation pattern of cfDNA can classify lung cancer and normal plasmas separately, but fragmentation pattern are more accurate than mutation in this task. Combining the two models further improved prediction accuracy, suggesting they complement each other. Although this is a pilot study of limited cases, it demonstrated the potential of combining markers for accurate lung ADC detection in plasma. Citation Format: Zhoufeng Wang, Minjie Xu, Hua Chen, Kehui Xie, Minyang Su, Qiye He, Zhixi Su, Rui Liu, Weimin Li. Plasma cell-free DNA fragmentation patterns combined with tumor mutation detection in diagnosis of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6202.

Sickle cell disease (SCD) results from genetic mutation in the β-globin gene encoding a subunit of the adult form of hemoglobin (HbA), leading to red blood cell (RBC) deformation and disease pathology. It has been demonstrated that reactivation of the fetal ortholog of the hemoglobin beta subunit, HBγ (also referred to as HBG proteins), can prevent or reduce disease-related pathophysiology. In SCD, the presence of HBG protein in hemoglobin tetramers prevents sickle hemoglobin polymerization under deoxygenated conditions and therefore may be of therapeutic benefit in SCD. FTX 6058, a novel orally bioavailable small molecule, is in development for the treatment of sickle cell disease (SCD) by Fulcrum Therapeutics. FTX-6058 was demonstrated to inhibit the novel biological target and elevate the expression of HBγ, resulting in induction of fetal hemoglobin (HbF) tetramer in differentiated human primary CD34+ cells. The in vivo target engagement (TE) and pharmacologic effects of FTX-6058 were characterized in wild-type CD-1 mice and humanized Townes SCD mice, with TE also confirmed in non-human primates. In CD-1 mice, once-daily (QD) FTX-6058 oral administration induced TE in a time- and dose-dependent manner and most markedly in erythroid lineage (Ter119+) cells derived from bone marrow, the putative therapeutic compartment, and increased transcript levels of Hbb-bh1, a murine embryonic hemoglobin surrogate for human HBG gene. Steady state TE in circulating monocytes, following repeated QD FTX-6058 administration, correlated well with that in bone marrow-derived erythroid cells, suggesting peripheral monocytes as a suitable surrogate for assessing erythroid TE activity in Fulcrum's Phase 1 study. In non-human primate cynomolgus monkeys, QD oral dosing of FTX-6058 as early as for 7 days induced robust and comparable TE in bone marrow derived CD34+ erythroid progenitors and circulating monocytes, further supporting the use of monocytes to assess TE in bone marrow. Mouse data also provided evidence of the reversibility of TE effects once dosing is stopped. In repeat-dose studies in the humanized Townes SCD mouse model, FTX-6058 was superior to standard of care hydroxyurea as measured by human HBG1 transgene induction and increased %F-cells and HBG1 protein levels. Furthermore, the induction of %F cells was sustainable for several days after dosing cessation. These in vivo studies have demonstrated that FTX-6058 engages its novel biological target in multiple preclinical models and induces HbF expression at plasma concentrations likely to b e readily achievable in clinic, and peripheral monocytes is a suitable surrogate for assessing TE in bone marrow erythroid cells, which could be beneficial to patients with SCD. Disclosures Xie: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Roth:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Efremov:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Silver:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Thompson:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stickland:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company.

BackgroundBackground: Anti-Melanoma Differentiation-Associated gene 5 (MDA-5) Dermatomyositis (MDA5, DM) is a rare systemic autoimmune disease, characteristically associated with Rapidly Progressive Interstitial Lung Disease (RP-ILD) and cutaneous manifestations. Anti-MDA5 dermatomyositis may develop in genetically predisposed subjects after environmental exposure such as vaccines, infections and neoplasms (1). Myalgia is one of the main symptoms related to SARS-COV2 infection and sometimes may occurs after COVID-19 vaccine administration (2). However, only few cases have reported the occurrence of severe inflammatory myopathies after COVID19 vaccine administration (3)ObjectivesTo describe a case of Anti-MDA5 Dermatomyositis occurred after BNT162b2 vaccine administrationMethodsThis is a case of a 44 year-old-patient affected by Anti-MDA5 Dermatomyositis occurred after BNT162b2 vaccination referred at the Center for Rheumatic Diseases in Venice, ItalyResultsA 44 year-old-woman presented to the Center for Rheumatic Diseases in Venice, suffering from a cutaneus rash on her face, upper limbs, décolleté, gluteus and lower limbs occurred two days after the first dose BNT162b2 vaccination (Figure 1). A few days after the second dose of the vaccine the rash got worse and myalgias, strength deficiency and fatigue occurred. Elevated inflammatory and myocytolysis parameters were detected (Table 1). After chest HRCT a mild ILD was diagnosed. Muscle edema was detected with whole-body short tau inversion recovery (STIR)-MRI (Figure 1).The Skyn biopsy showed features of dermatomyositis with perivascular inflammatory infiltrates. 1 mg/Kg/die of prednisone was administered and then cyclosporine 3mg/kg/die was associated with clinical benefit.Table 1.Clinical and laboratory characteristics of the patientAge (years)44SexFemalePrevious Rheumatological diagnosis-Previous Vaccination reaction-Time to onset COVID 19 vaccination2 daysMMT-8*124/150 (150/150)Blood TestsHb* (12-16 g/dl)11,5 g/dlCRP* (< 5 mg/L)23,4 mg/LAST* (31 U/L)98 U/LALT* (1-34 U/L)63 U/LCPK * (10-145 U/L)1085 U/LAldolase (0-7,6)13,2 U/LSARS-CoV-2 RT PCRnegativeAutoantibodiesANA*1:1280 nucleolarMyositis antibodiesAnti-MDA5HLA- DRB103-04HLA-DQB02-03MMT-8 MANUAL MUSCLE TESTING; Hb Hemoglobin; WBC withe blood cells count; CRP C-reactive proteine; AST Aspartate amino transferase; ALT Alanine amino transferase; CPK creatinine phosphokinase; ANA anti nuclear antibodies, ENA extractable nuclear antigens; HLA HumanLeukocyte AntigenConclusionIn rare cases COVID-19 vaccination could induce inflammatory myopathies (3). COVID-19 vaccine administration may have acted as a trigger for the myopathy driven by an autoimmune-mechanism. In such cases, it could be useful to investigate inflammatory myopathies, requiring blood tests (e.g. myocytolysis indices and anti myositis antibodies) and medical instrumental insights, in patients affected by skin manifestation and muscle pain occurred after vaccine administration. Although the association between vaccination and inflammatory myopathies is presumptive, the temporal proximity of the BNT162b2 vaccine to the onset of the signs and symptoms related to the inflammatory miopathies may suggest a possible relationship between these two events. To the best of our knowledge this is the first case of Anti-MDA5 Dermatomyositis occurred after BNT162b2 vaccination.References[1]Mehta P, Machado P.m, Gupta L. Understanding and managing anti-MDA 5 dermatomyositis, including potential COVID-19 mimicry. Rheumatol Int 2021 Jun;41(6):1021-1036[2]Beatty A.L, Peyser N.D, Butcher X.E, Cocohoba J.M, Lin F, Olgin J.E, Pletcher M.J, Marcus G.M. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study Lancet Infect Dis 2021; 21: 939–49[3]Maramattom B.V, Philips G, Thoas J, Santhamma Nair S.G. Inflammatory myositis after ChAdOx1 vaccination. The Lancet Rheumatology Volume 3, ISSU 11, e747-e749, November 01.2021Disclosure of InterestsNone declared

BackgroundAccording to the recent medical literature, COVID-19 disease can lead to a constellation of clinical syndromes lasting well beyond the first 30 days of infection. The most common post COVID sequalae includes pulmonary, nervous system and neurocognitive, mental, metabolic, cardiovascular, gastrointestinal and several other clinical manifestations. Regarding joint involvement and particularly reactive arthritis (ReA), literature data is limited and describes case reports or series of cases of patients diagnosed with this condition following COVID-19 disease.ObjectivesTo describe the pattern and the management of post-COVID reactive arthritis.MethodsWe have conducted a descriptive study of consecutive adult patients who presented to rheumatology outpatient clinic for joint or peri-articular pain/swelling/stiffness and received a diagnosis of post-COVID 19 reactive arthritis, by excluding other types of rheumatological conditions. The assessed clinical variables were: visual analogue scale (VAS) pain, swollen joint count (SJC), tender joint count (TJC), duration of morning stiffness, presence of enthesitis/tendinitis and axial involvement. Biochemistry and serology was performed: rheumatoid factor, ACPA, ANA, HLA B27, antiChlamydia Trachomatis, Ureaplasma Urealyticum and Mycoplasma Hominis Ab, anti HBs and HBc Ab, and anti HCV. COVID-19 disease prior to diagnosis of ReA was confirmed by PCR test.ResultsIn the study were included 16 patients with confirmed post COVID-19 ReA. The mean age of the study group was 43.5±10.8 (range 21-60), the female: male ratio was 4:1 and the duration of joint symptoms was 10.4±11.8 (range 1-42) weeks. The severity of COVID-19 disease was mild in 68.7% cases, moderate in 18.7% and severe in only 6.2% of the cases. The duration between COVID-19 diagnosis and ReA varied between cases, with a mean value of 4.3±4.2 (range 1-12) weeks. In 43.7% of the cases patients had peripheral joint involvement (synovitis), in 37.5% - periarticular involvement (enthesitis), 6.25% - isolate axial involvement (sacroiliac joints), 6.25% enthesitis and axial involvement (cervical spine) and 6.25% synovitis and enthesitis. In patients with peripheral joint pattern, the distribution of pain was symmetric (71.4%). The pattern of synovitis was determined by a TJC of 6.25±5.2 (range 1-16) joints and SJC 1.6±2.4 (range 0-7) joints. Both TJC and SJC correlated positively with the duration of morning stiffness (r=0.9 and r=0.6), but did not correlate with the VAS pain scale. In most of the cases synovitis affected the hand (wrist, MCP and PIP) 62.5% and the knee, feet and ankles – 50%. Two patients presented with monoarthritis, 1 with oligoarthritis and 5 with polyarthritis, in the majority of cases, involvement being symmetric (75%). Periarticular pattern was determined by enthesitis, affecting the elbow and shoulder (50%), costo-sternal enthesitis (25%) and trochanteritis (25%). From the entire study group, 31.2% had elevated serum inflammatory markers (ESR and/or CRP). Patients responded well to NSAIDs alone in 68.7% cases, local (intra-articular or peri-articular infiltrations) or and systemic corticoids (5 mg Prednisolone equivalent) were administered in 5.3% and 12.5% cases respectively, in 12.5% cases (two patients) Methotrexate was administered.ConclusionReactive arthritis represents a post COVID-19 sequelae. The time of onset of ReA varied between 1 and 12 weeks after COVID-19 diagnosis. The clinical pattern of the disease was expressed by joint or periarticular involvement, mainly affecting the hand, feet and knee symmetrically. Cases of axial manifestations were less common. Most of the patients responded well to NSAIDs, only in a few particular cases, low doses of corticoids and/or Methotrexate were recommended.References[1]Kocyigit, B. F., & Akyol, A. (2021). Reactive arthritis after COVID-19: a case-based review. Rheumatology international, 41(11), 2031–2039.[2]Xie, Y., Bowe, B., & Al-Aly, Z. (2021). Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status. Nature communications, 12(1), 6571.Disclosure of InterestsNone declared

Abstract Aneuploidy causes a proliferative disadvantage, mitotic and proteotoxic stress in non-malignant cells ( Torres et al. Science 2007). Chromosome gain or loss, which is the hallmark of aneuploidy, is a relatively common event in Acute Myeloid Leukemia (AML). About 10% of adult AML display isolated trisomy 8, 11, 13, 21 (Farag et al. IJO 2002), or either an isolated autosomal monosomy or monosomal karyotype (Breems et al. JCO 2008). This evidence suggests that tumor-specific mechanisms cooperate to overcome the unfitness barrier and maintain aneuploidy. However, the molecular bases of aneuploid AML are incompletely understood. We analyzed a cohort of 166 cytogenetically-characterized AML patients (80 aneuploid (A-) and 86 euploid (E-)) treated at Seràgnoli Institute (Bologna). Aneuploidy was significantly associated with poor overall survival (median survival: 13 and 26 months in A-AML and E-AML respectively; p=.006, Fig.1). To identify AML-specific alterations having a causative and/or tolerogenic role towards aneuploidy, we integrated high-throughput genomic and transcriptomic analyses. We performed 100 bp paired-end whole exome sequencing (WES, Illumina Hiseq2000) of 70 samples from our A-AML and E-AML cohort of 166 patients. Variants where called with MuTect or GATK for single nucleotide variant and indels detection, respectively. AML samples were genotyped by CytoScan HD Array (Affymetrix). Gene expression profiling (GEP) was also conducted on bone marrow cells from 24 A-AML, 33 E-AML (≥80% blasts) and 7 healthy controls (HTA 2.0, Affymetrix). We detected a significantly higher mutation load in A-AML compared with E-AML (median number of variants: 31 and 15, p=.04) which was interestingly unrelated to patients' age (median age: 63.5 years in A-AML and 62 years in E-AML, Xie et al, Nat. Med. 2014). C>A and C>T substitutions, which are likely mediated by endogenous 5mCdeamination, were the most frequent alterations (Alexandrov et al. Nat. 2013). However, aneuploidy associated with an increased variability in terms of mutational signatures, with the majority of A-AML displaying 3 or more signatures compared to few E-AML cases (p=.04). WES analysis also revealed a specific pattern of somatic mutations in A-AML. A-AML had a lower number of mutations in signaling genes (p=.04), while being enriched for alterations in cell cycle genes (p=.01) compared with E-AML. The mutated genes were involved in different cell cycle phases, including DNA replication (MCM6, PURB, SSRP1), centrosome dynamics (CEP250, SAC3D1, HEPACAM2, CCP110), chromosome segregation (NUSAP1, ESPL1, TRIOBP), mitotic checkpoint (ANAPC7, FAM64A) and regulation (CDK9, MELK, ZBTB17, FOXN3, PPM1D, USP2). Moreover, genomic deletion of cell cycle-related genes was frequently detected in A-AML. Notably, ESPL1 which associated with aneuploidy, chromosome instability and DNA damage in mammary tumors (Mukherjee et al. Oncogene 2014) was mutated and also upregulated in A-AML compared with E-AML (p=.01), the latter showing expression levels comparable to controls. Among the top-ranked genes differentially expressed between A-AML and E-AML, we identified a specific signature characterized by increased CDC20 and UBE2C and reduced RAD50 and ATR in A-AML (p<.001), which has been previously linked to defects in chromosome number. Additional mutations targeting DNA damage and repair pathways were identified in A-AML, including TP53 mutations, which account for 15% of cases. Moreover, A-AML showed a significant upregulation of a KRAS transcriptional signature and downregulation of FANCL- and TP53-related signatures, irrespective of TP53 mutational status. Our data show a link between aneuploidy and genomic instability in AML. Deregulation of the cell cycle machinery, DNA damage and repair checkpoints either through mutations, copy number and transcriptomic alterations is a hallmark of A-AML. The results define specific genomic and transcriptomic signatures that cooperate with leukemogenic pathways, as KRAS signaling, to the development of the aggressive phenotype of A-AML and suggest that a number of A-AML patients may benefit frompharmacological reactivation of TP53pathway (e.g. MDM2 inhibitor, clinical trial NP28679). Supported by: FP7 NGS-PTL project, ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12 GS & AP: equal contribution Disclosures Soverini: Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Cavo:JANSSEN, CELGENE, AMGEN: Consultancy. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Martinelli:MSD: Consultancy; BMS: Speakers Bureau; Roche: Consultancy; ARIAD: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy.

BackgroundGuselkumab (GUS), a selective IL-23p19 inhibitor, showed greater mean improvements in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores vs placebo (PBO) at Week (W) 24 in patients (pts) with active PsA and investigator-confirmed sacroiliitis in pooled post hoc analyses of data from phase 3 DISCOVER (D)-1&2 trials. Improvements in symptoms of axial involvement were maintained through 1 year.1ObjectivesTo assess maintenance of GUS effect on symptoms of axial involvement in biologic-naïve PsA pts with investigator-confirmed sacroiliitis through 2 years of D-2.MethodsIn D-2, 739 bio-naïve pts with active PsA (≥5 swollen + ≥5 tender joints, CRP ≥0.6 mg/dL despite standard therapies) were randomized 1:1:1 to GUS 100 mg every 4W (Q4W; n=245), GUS 100 mg at W0, W4, then Q8W (n=248), or PBO (n=246) with PBO→GUS 100 mg Q4W at W24. Pts with investigator-identified axial symptoms and sacroiliitis (prior X-ray or MRI, or pelvic X-ray at screening) were evaluated. Efficacy was assessed by changes in BASDAI, modified BASDAI (mBASDAI, excluding Q3 [peripheral joint pain]), and BASDAI Q2 (Spinal Pain) scores, and proportions of pts achieving BASDAI 50, Spinal Pain score ≤2, and AS Disease Activity Score (ASDAS) responses through W100. Through W24, pts who met treatment failure criteria or had missing data were considered nonresponders. After W24, missing data were imputed as nonresponse for binary endpoints or no change from baseline for continuous endpoints (nonresponder imputation [NRI]). Axial-related outcomes were also summarized by HLA-B27 status (+/-).Results246 pts had investigator-confirmed sacroiliitis. Baseline characteristics were similar across treatment groups (62% male; mean age 44.4 years; mean BASDAI scores 6.5-6.6). At W24, LS mean/mean changes in BASDAI (-2.4/-2.6) and ASDAS (-1.3/-1.5) scores were greater in GUS- vs PBO-treated pts. Improvements were maintained through W100 in GUS-treated pts: BASDAI, -3.1; Spinal Pain, -3.1; mBASDAI, -3.1; ASDAS, -1.7. Response patterns were similar for BASDAI 50 response rates in GUS-treated pts (W24 38-40%; W100 49-54%). At W24, GUS-treated pts had higher response rates for achievement of ASDAS inactive disease, major improvement, and clinically important improvement vs PBO; response rates (NRI) were maintained, or in some cases further increased, at 2 years. Results were consistent for achievement of ASDAS LDA and Spinal Pain score ≤2 (data not shown). GUS-related improvements in axial symptoms through W100 were generally consistent in HLA-B27+/- pts (data not shown).ConclusionIn bio-naïve pts with active PsA and investigator-confirmed sacroiliitis, GUS provided durable improvements in axial symptoms through W100, with substantial proportions of pts achieving and maintaining clinically meaningful improvements.References[1]Mease PJ et al. Lancet Rheumatol 2021;3:e715-723Table 1.Axial symptom assessments through W100 in PsA pts with investigator-confirmed sacroiliitis in DISCOVER-2 (NRI)GUS Q4W N=82GUS Q8W N=68PBO→GUS Q4W N=96Change in BASDAI scoreW24, LS mean (95% CI)-2.5 (-2.9, -2.0)-2.4 (-3.0, -1.8)-1.2 (-1.7, -0.7)Mean (SD)-2.5 (2.0)-2.6 (2.4)-1.4 (2.4)W52, mean (SD)-2.9 (2.3)-2.7 (2.5)-2.9 (2.6)W100, mean (SD)-3.0 (2.3)-3.1 (2.6)-3.3 (2.6)Change in mBASDAI (excludes Q3) scoreW24, LS mean (95% CI)-2.4 (-2.9, -1.9)-2.4 (-2.9, -1.8)-1.2 (-1.7, -0.7)Mean (SD)-2.5 (2.1)-2.6 (2.5)-1.3 (2.3)W52, mean (SD)-2.7 (2.6)-2.6 (2.5)-2.9 (2.4)W100, mean (SD)-3.3 (2.6)-3.1 (2.6)-3.0 (2.4)Change in Spinal Pain (BASDAI Q2) scoreW24, LS mean (95% CI)-2.2 (-2.7, -1.7)-2.3 (-2.9, -1.7)-0.9 (-1.5, -0.4)Mean (SD)-2.3 (2.6)-2.5 (2.8)-1.1 (2.5)W52, mean (SD)-2.6 (2.7)-2.5 (2.7)-2.5 (2.7)W100, mean (SD)-2.8 (2.7)-3.1 (2.8)-3.0 (2.8)Change in ASDAS scoreW24, LS mean (95% CI)-1.3 (-1.6, -1.1)-1.3 (-1.6, -1.1)-0.6 (-0.8, -0.4)Mean (SD)-1.4 (1.0)-1.5 (1.2)-0.7 (1.1)W52, mean (SD)-1.5 (1.1)-1.5 (1.3)-1.5 (1.3)W100, mean (SD)-1.6 (1.2)-1.7 (1.2)-1.6 (1.2)Disclosure of InterestsPhilip J Mease Speakers bureau: AbbVie, Aclaris, Amgen, BMS, Celgene, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Novartis, Pfizer, SUN Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, BMS, Celgene, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Novartis, Pfizer, SUN Pharma, and UCB, Grant/research support from: AbbVie, Aclaris, Amgen, BMS, Celgene, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Novartis, Pfizer, SUN Pharma, and UCB, Philip Helliwell Speakers bureau: AbbVie, Janssen, and Novartis, Consultant of: Eli Lilly, Janssen, and Pfizer, Dafna D Gladman Consultant of: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: Abbvie, Amgen, BMS, Celgene, Eli Lilly, Janssen, Novartis, Pfizer and UCB, Denis Poddubnyy Consultant of: AbbVie, Eli Lilly, GlaxoSmithKline, MSD, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Eli Lilly, MDS, Novartis, and Pfizer, Xenofon Baraliakos Speakers bureau: AbbVie, Biocad, Chugai, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, and UCB, Consultant of: AbbVie, Biocad, Chugai, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Biocad, Chugai, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, and UCB, Soumya D Chakravarty Shareholder of: Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC, Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Xie L Xu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Shihong Sheng Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Stephen Xu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB Pharma, Employee of: Imaging Rheumatology BV, Atul Deodhar Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Glaxo Smith & Kline, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Eli Lilly, Glaxo Smith & Kline, Novartis, Pfizer, and UCB

Study of petrological and geochemical characteristics of mantle peridotite xenoliths in Pliocene alkaline basalt in Nghia Dan (West Nghe An) was carried out. Rock-forming clinopyroxenes, the major trace element containers, were separated from the xenoliths to analyze for major, trace element and Sr-Nd isotopic compositions. The data were interpreted for source geochemical characteristics and geodynamic processes of the lithospheric mantle beneath the region. The peridotite xenoliths being mostly spinel-lherzolites in composition, are residual entities having been produced following partial melting events of ultramafic rocks in the asthenosphere. They are depleted in trace element abundance and Sr-Nd isotopic composition. Some are even more depleted as compared to mid-ocean ridge mantle xenoliths. Modelled calculation based on trace element abundances and their corresponding solid/liquid distribution coefficients showed that the Nghia Dan mantle xenoliths may be produced of melting degrees from 8 to 12%. Applying various methods for two-pyroxene temperature- pressure estimates, the Nghia Dan mantle xenoliths show ranges of crystallization temperature and pressure, respectively, of 1010-1044°C and 13-14.2 kbar, roughly about 43km. A geotherm constructed for the mantle xenoliths showed a higher geothermal gradient as compared to that of in the western Highlands (Vietnam) and a conductive model, implying a thermal perturbation under the region. The calculated Sm-Nd model ages for the clinopyroxenes yielded 127 and 122 Ma. 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Introducción: La enfermedad renal crónica asociada a la obesidad (ERC-AO) es una enfermedad con aumento en la prevalencia en las últimas décadas. Se caracteriza por un exceso de desequilibrios hormonales adipocíticos (adipoquinas), desregulación del sistema de equilibrio energético y desequilibrios en la homeostasis metabólica. Propósito de la revisión: El objetivo de la revisión es delinear el papel de los diferentes mecanismos fisiopatológicos para el desarrollo de enfermedad renal funcional o anatómica en pacientes con obesidad. Buscamos reportes actualizados en donde se incluye los resultados de mejor supervivencia para los pacientes con ERC-AO. Recientes hallazgos: Actualmente sabemos la ERC-AO tiene un comportamiento pro inflamatorio crónico. La obesidad y sobrepeso se asocian alteraciones hemodinámicas, estructurales e histopatológicas en el riñón, así como alteraciones metabólicas y bioquímicas que predisponen a la enfermedad renal, aun cuando la función renal y las pruebas convencionales sean normales. Conclusiones: Clasificamos a la ERC-AO en Tipo 1: Obesidad y alteraciones funcionales potencialmente reversibles. Tipo 2: Obesidad y alteraciones estructurales histopatológicas potencialmente no reversibles (Incluye la Glomerulopatía asociada a obesidad y glomeruloesclerosis focal y segmentaria). Tipo 3: Obesidad en relacionada con enfermedades crónicas (Diabetes, Hipertensión, Hipertensión pulmonar. Insuficiencia Cardíaca). Tipo 4: Obesidad en el paciente con terapia sustitutiva de la función renal. Recibido: Agosto 03, 2022 Aceptado: Septiembre 30, 2022 Publicado: Septiembre 30, 2022 Editor: Dr. Franklin Mora Bravo. Introducción La obesidad es una enfermedad en crecimiento con un aumento en su prevalencia en las últimas décadas, asociándose a un elevada carga asistencial y económica para los sistemas sanitaros derivado de su relación con enfermedades cardiovasculares, endocrinas, psicológicas, renales entre otras [1, 2]. El incremento en las tasas de obesidad en distintos grupos etarios, desde niños hasta adultos jóvenes conlleva a asumir que en el futuro veremos más enfermedad renal relacionada con la obesidad (ERC-AO) en la población general, con implicaciones relevantes para los sistemas de atención [3]. Por ello el conocimiento y comprensión de esta interacción podría tener implicaciones en la prevención y tratamiento de las enfermedades renales. Dentro de la población general la obesidad se asocia a incremento en el riesgo de diversas condiciones patológicas, como la hipertensión arterial crónica (HTA), enfermedad renal crónica (ERC), artrosis, infecciones, síndrome de apnea hipopnea obstructiva del sueño (SAHOS) y diabetes mellitus (DM) entre otras [3]. No obstante, en el escenario de la ERC, la obesidad juega un rol dual y paralelo en el desarrollo de la enfermedad, tradicionalmente se ha denominado “paradoja de la obesidad”, donde por un lado actúa como un factor de riesgo modificable para el desarrollo de la enfermedad renal crónica (ERC) y por otro se ha asocia de manera consistente con mejores resultados de supervivencia en pacientes con enfermedad renal terminal [1]. Por lo anterior, en las próximas páginas describimos aspectos fisiopatológicos que involucran la obesidad en el desarrollo de la ERC. Definición y epidemiología La obesidad es una condición que se caracteriza por la acumulación anormal o excesiva de tejido adiposo con consecuencias patológicas adversas e incremento del riesgo cardiovascular [4]. Utilizando para su definición y diagnostico un indicador simple como es la relación entre el peso y la talla denominado índice de masa corporal (IMC), se calcula dividiendo el peso de una persona en kilos por el cuadrado de su talla en metros (kg/m2). Un IMC entre 18.5 y 25 kg/m2 es considerado por la Organización Mundial de la Salud (OMS) como peso normal, un IMC entre 25 y 30 kg/m2 como sobrepeso y un IMC > 30 kg/m2, como obesidad [5-7]. Además, la obesidad puede ser clasificada en tres niveles de severidad: clase I (IMC 30.0 – 34.9), clase II (IMC 35.0 – 39.9) y clase III (IMC > 40) [8]. Durante las últimas tres décadas, la prevalencia de adultos con sobrepeso y obesidad (IMC ≥ 25 kg/m2) en todo el mundo ha aumentado sustancialmente, convirtiendo a la obesidad en una epidemia y se prevé que su prevalencia crezca un 40% en la próxima década [6]. Actualmente, el problema de obesidad se ha visto en mayor aumento debido al incremento en la afectación en niños, lo que ocasiona una mayor prevalencia de patologías a edad temprana. En 2016, según las estimaciones de la OMS unos 41 millones de niños menores de cinco años tenían sobrepeso o eran obesos [7]. Esto afectando a todos los países, independiente de su nivel de ingresos [7]. La prevalencia del sobrepeso y la obesidad en niños y adolescentes (de 5 a 19 años) ha aumentado de forma espectacular, del 4% en 1975 a más del 18% en 2016. Este aumento ha sido similar en ambos sexos: un 18% de niñas y un 19% de niños con sobrepeso en 2016. Mientras que en 1975 había menos de un 1% de niños y adolescentes de 5 a 19 años con obesidad, en 2016 eran 124 millones (un 6% de las niñas y un 8% de los niños) [7]. La creciente prevalencia de la obesidad tiene implicaciones para las enfermedades cardiovasculares (ECV) y también para la ERC. Un IMC alto es uno de los factores de riesgo más fuertes para la ERC de nueva aparición [6]. Epidemiología de la enfermedad renal crónica asociada a obesidad (ERC-AO) La enfermedad renal crónica (ERC) es una condición de interés en salud pública, asociada a una elevada morbilidad y mortalidad a nivel mundial. Las guías KDIGO (Kidney Disease: Improving Global Outcomes), definen la ERC como la presencia de alteraciones en la estructura o función renal durante al menos tres meses y con implicaciones para la salud [9, 10]. Los principales elementos clasificatorios para definir la presencia de ERC son la tasa de filtración glomerular (TFG) estimada (G1 a G5) utilizando como umbral definitorio una TFG 60 ml/min/1,73m2 y la tasa de excreción de albúmina en orina (A1 a A3) según el cociente albúmina/creatinina en una muestra aislada de orina sea < 30, 30-300 o > 300 mg/g, respectivamente [9, 10]. Si bien inicialmente existía cierta controversia sobre el uso de la TFG para el diagnóstico de la ERC en fases iniciales, trabajos recientes han puesto en evidencia que tanto una TFG< 60 ml/min/1.73 m2 como un cociente albúmina/creatinina (CAC) ≥ 1.1 mg/mmol (10 mg/g) son predictores independientes del riesgo de mortalidad e insuficiencia renal terminal (IRT) en población general [11, 12]. En consecuencia, debido a estas categorías podemos determinar el pronóstico de cada paciente. Los datos globales sugieren que la prevalencia de la ERC se encuentra entre el 10 y el 16 %, pero la información sobre la prevalencia de la población por categoría de TFG y ACR es escasa [13]. La ERC es una afección asociada a una elevada carga de morbilidad, mortalidad y enfermedad cardiovascular (ECV). A medida que disminuye la función renal, surgen trastornos metabólicos y hemodinámicos que aumentan las tasas de hospitalización, ECV y muerte [4]. El conjunto de factores de riesgo conocidos para la progresión de la ERC es relativamente pequeño, y las terapias y estrategias efectivas para retrasar la progresión de la ERC son limitadas [14]. Por lo cual resulta necesario conocer y entender los diferentes factores de riesgo y su impacto en el daño renal, en aras de lograr minimizar la progresión del mismo, sobre todo en aquellos en los cuales se puede realizar intervenciones activas, evaluables, controlables y con seguimiento continuo como es la obesidad. A la fecha existe suficiente evidencia para asociar la obesidad con el desarrollo y progresión de la enfermedad renal crónica. Los datos granulares sobre la prevalencia de la obesidad en personas con ERC son limitados pero consistentes en todo el espectro de la enfermedad renal. En la Encuesta Nacional de Examen de Salud y Nutrición de 2011–2014, el 44.1 % de los pacientes con ERC en los Estados Unidos también tenían obesidad (21.9 % con obesidad de clase 1 y 11.1 % con clase 2 y obesidad clase 3, habiéndose incrementado el porcentaje global un 5% en los últimos 12 años [15]. La glomeruloesclerosis focal y segmentaria (GEFS) es el tipo de glomerulonefritis que se asocia con mayor frecuencia a la obesidad [16]. La enfermedad glomerular habitualmente asociada a la obesidad se denomina glomerulopatía relacionada con la obesidad (GRO). Esta condición suele presentarse con síndrome nefrótico y pérdida progresiva de la función renal. Con la epidemia mundial de obesidad, se produjo un aumento progresivo de la GRO del 0.2% entre 1986 y 1990 al 2% entre 1996 y 2000, y se ha convertido en un tema emergente en el ámbito de la nefrología [15]. Etiología y patogénesis de la ERC-AO La obesidad se caracteriza por un exceso de desequilibrios hormonales adipocíticos (adipoquinas), desregulación del sistema de equilibrio energético y desequilibrios en la homeostasis metabólica [12]. Hay dos tipos de tejido adiposo presentes en los humanos: tejido adiposo blanco (WAT) y tejido adiposo marrón (BAT) [17-19]. El depósito de grasa ectópica primariamente ocurre en lugares donde no se almacena fisiológicamente, como el hígado, el páncreas, el corazón y el músculo esquelético; secundariamente hay un cambio en la distribución del tejido adiposo visceral con almacenamiento de tejido adiposo en los espacios intraperitoneal y retroperitoneal; luego se presenta la desregulación inflamatoria y de adipoquinas; y por último la resistencia a la insulina [20]. Tejido adiposo blanco (WAT) El tejido adiposo blanco (WAT) se caracteriza por ser un tejido blanco o amarillo con menor vascularización e inervación que el tejido marrón. Las células grasas tienen un tamaño que oscila entre 20 y 200 µm y contienen una única vacuola lipídica (uniloculares). En dicha vacuola se almacenan lípidos para su uso cuando hay demanda energética. De la totalidad de los lípidos que abarca la vacuola lipídica del adipocito blanco, del 90 al 99% son triacilgliceroles. El tejido adiposo blanco genera una gran cantidad de adipocinas y lipocinas. Las adipocinas son péptidos que actúan como hormonas o mensajeros que regulan el metabolismo. El tejido adiposo blanco se localiza en el tejido omental, mesentérico, retroperitoneal, perirrenal, gonadal y pericárdico [19]. Este tejido al igual que el tejido adiposo de otros sitios, está compuesto por una variedad de células que incluyen macrófagos, neutrófilos, células T CD4 y CD8, células B, neutrófilos, mastocitos, células T reguladoras y células T asesinas naturales (NK) [21, 22]. El tejido adiposo es responsable de la secreción de muchas moléculas de señalización, incluidas adipocinas, hormonas, citocinas y factores de crecimiento, como leptina, adiponectina, resistina, factor de necrosis tumoral-α (TNF-α), interleucina 6 (IL-6), monocito, proteína quimioatrayente-1 (MCP-1), factor de crecimiento transformante-β (TGF-β) y angiotensina II [23]. Tejido adiposo marrón o pardo (BAT) La coloración marrón del tejido adiposo se debe a que está más vascularizado y tiene un alto contenido de mitocondrias, las células grasas que componen el tejido adiposo pardo son multiloculares o tienen varias vacuolas lipídicas. Estas células tienen forma poligonal y miden de 15 a 50 µm. A diferencia del tejido adiposo blanco, el tejido marrón no tiene la función de almacenar energía, sino que la disipa a través de la termogénesis. Para lograr la regulación de la temperatura corporal, el tejido adiposo pardo se localiza en sitios superficiales y profundos [18]. Clasificación de la ERC-AO Se ha establecido que la obesidad es una enfermedad con un comportamiento pro inflamatorio crónico con múltiples comorbilidades asociadas [19]. El tejido adiposo como se describió previamente funciona como un órgano con actividad endocrina y esta infiltrado por diferentes poblaciones celulares que incluyen macrófagos y otras células con actividad inmune como linfocitos T, B y células dendríticas [19]. La mayor parte de la grasa corporal total, se considera como un sistema de órganos endocrinos, la perturbación de este tejido tiene como resultado una respuesta patológica al balance calórico positivo en individuos susceptibles que directa e indirectamente contribuye a la enfermedad cardiovascular y metabólica, se tiene conocimiento de tres principales mecanismos de disfunción del tejido adiposo “adiposopatía” [20]. Estos mecanismos incluyen alteraciones hemodinámicas, metabólicas e inflamatorias, lo que es la base de la clasificación de la ERC-AO propuesta en esta revisión (Tabla 1). ERC-AO tipo 1 La obesidad produce un daño renal de forma directa a través de alteraciones hemodinámicas, inflamatorias, y desregulación de factores de crecimiento y adipocitoquinas, además de aumento de leptina y disminución de adiponectina, aun cuando la función renal y las pruebas convencionales sean normales [16]. La obesidad desencadena una serie de eventos, que incluyen resistencia a la insulina, intolerancia a la glucosa, hiperlipidemia, aterosclerosis e hipertensión, todos los cuales están asociados con un mayor riesgo cardiovascular [4, 16] (Figura 1). La obesidad conduce a un incremento en la reabsorción tubular de sodio, alterando la natriuresis y provocando una expansión de volumen extracelular debido a la activación del sistema nervioso simpático (SNS) y el sistema renina-angiotensina-aldosterona (SRAA)(16). El aumento en la reabsorción tubular de sodio y la consiguiente expansión de volumen extracelular es un evento central en el desarrollo de HTA en la obesidad [4, 16]. Algunos estudios sugieren que se produce un aumento de la reabsorción de sodio en algunos segmentos además del túbulo proximal, posiblemente en el asa de Henle. Además, hay un aumento del flujo sanguíneo renal, la tasa de filtración glomerular (TFG) y la fracción de filtración [16]. La hiperfiltración glomerular, asociada con el aumento de la presión arterial y otras alteraciones metabólicas como la resistencia a la insulina y la DM, finalmente resultan en daño renal y disminución del filtrado glomerular [16]. Por otro lado, la activación del SNS también contribuye a la hipertensión relacionada con la obesidad [4]. Hay evidencia de que la denervación renal reduce la retención de sodio y la hipertensión en la obesidad, lo que sugiere que la activación del SNS inducida por la obesidad aumenta la presión arterial principalmente debido al estímulo de retención de sodio, más que a la vasoconstricción [16]. Los mecanismos que conducen a la activación del SNS en la obesidad aún no se conocen por completo, pero se han propuesto varios factores como desencadenantes de este estímulo, entre ellos la hiperinsulinemia, la hiperleptinemia, el aumento de los niveles de ácidos grasos, los niveles de angiotensina II y las alteraciones del reflejo barorreceptor. El aumento de los niveles de leptina está asociado a la activación del SNS y su efecto sobre el aumento de los niveles de presión arterial incluye también la inhibición de la síntesis de óxido nítrico (potente vasodilatador) [16, 24, 25].También se ha descrito un aumento de la producción de endotelina-1 en sujetos obesos, lo que contribuye aún más a la elevación de los niveles de presión arterial y, en consecuencia, a la disfunción renal. Estudios recientes han demostrado que la endotelina-1 está aumentada en pacientes con hipertensión intradiálisis, lo que sugiere que esta sustancia juega un papel clave en la génesis de la hipertensión en pacientes con ERC y posiblemente esté asociada con la hipertensión en pacientes obesos [16, 25]. Por lo anterior, las alteraciones hemodinámicas en los pacientes con obesidad conllevan a progresión de la ERC e incremento del riesgo cardiovascular derivado del desarrollo de enfermedades adicionales como la HTA, potencialmente estos cambios son reversibles con el control de la obesidad. ERC-AO Tipo 2 Mantener el estado de obesidad más allá de los efectos renales funcionales produce cambios estructurales irreversibles a nivel glomerular [25]. El estudio de pacientes con ERC y obesidad ha permitido identificar la presencia de enfermedad glomerular asociada a la obesidad, denominada glomerulopatía relacionada con la obesidad (GRO). En esta condición la hipertrofia glomerular parece ser la lesión inicial que estimula el borramiento de los podocitos y desencadena la respuesta inflamatoria local [25, 26]. Es relevante mencionar que las señales profibrogénicas inducen la formación de depósitos en la matriz extracelular de las nefronas, que conduce al engrosamiento de la membrana basal glomeruloesclerosis y fibrosis tubulointersticial [26]. Dentro del curso patogénico de la enfermedad la expansión de la superficie glomerular conduce a que los podocitos sean incapaces de cubrirla, esto lleva a disfunción y borramiento de los mismos, generando ruptura de la barrera de filtración glomerular con sobrecarga de las células restantes, lo que finalmente conduce a hiperfiltración y proteinuria [25, 26]. No obstante, no todos los pacientes con obesidad o IMC aumentado desarrollan ERC, lo cual sugiere que el incremento del IMC por sí solo no genera aumento en la incidencia o progresión de la ERC, ameritando alteraciones metabólicas adicionales. En los siguientes apartados se describen algunas de estas vías fisiopatológicas comunes a todos los tipos de ERC-AO. ERC-AO Tipo 3 La obesidad produce daño renal de forma secundaria ya que aumenta el riesgo de diabetes mellitus, hipertensión y daño cardiovascular, estas patologías causan enfermedad renal diabética (ERD), nefroangioesclerosis, y glomerulopatía asociada a hipertensión pulmonar e insuficiencia cardíaca. La mortalidad no solo se ve afectada por la presencia de la obesidad sino por la presencia de diabetes tipo 2, hipertensión arterial, hipertensión pulmonar e insuficiencia cardíaca. Los peores resultados en supervivencia lo padecen los pacientes con falla cardíaca, obesidad e insuficiencia renal. ERC-AO Tipo 4 En pacientes en hemodiálisis los niveles más elevados de adiponectina se asocian paradójicamente con tres veces más riesgo de muerte [24]. La obesidad se asocia a niveles muy bajos adiponectina por lo que la obesidad en el grupo poblacional que se realiza hemodiálisis es un fuerte factor protector con mejores resultados de supervivencia a 3 años comparados con pacientes con índice de masa corporal normal o baja. Mecanismos fisiopatológicos comunes en la ERC-AO Lipotoxicidad derivada del tejido adiposo En pacientes obesos el exceso de energía conduce a un microambiente sometido a estrés crónico, lo cual resulta en hipertrofia del tejido adiposo hasta que los adipocitos alcanzan su límite de crecimiento [25]. En ese momento, el exceso de especies toxicas lipídicas se acumula ectópicamente en diferentes órganos, induciendo un efecto nocivo conocido como lipotoxicidad; especialmente a nivel renal [27]. La lipotoxicidad se asocia a cambios estructurales y funcionales de las células mesangiales, podocitos y células tubulares proximales [28]. En los podocitos, esto interferiría con la vía de la insulina, crítica para la supervivencia y el mantenimiento de la estructura de los podocitos, lo que conduciría a la apoptosis de los podocitos e induciría una respuesta hipertrófica compensatoria en los podocitos restantes [25]. En el riñón, los depósitos de lípidos ectópicos contribuyen tanto a la inflamación local como al estrés oxidativo [27]. En modelos de ERD, la dislipidemia puede favorecer la acumulación de lípidos ectópicos e intermediarios lipídicos, no solo en el riñón sino también en tejidos extrarrenales como hígado, páncreas y corazón [27]. La acumulación de lípidos en el parénquima renal, genera daño en varias poblaciones celulares, incluídos podocitos, células epiteliales tubulares proximales y el tejido tubulointersticial a través de distintos mecanismos descritos en las siguientes apartados, pudiendo general compromiso a largo plazo de la función renal [27]. El tejido adiposo es una fuente importante de producción de diferentes factores proteicos activos, conocidos como adipocitocinas, las cuales participan en diferentes procesos metabólicos. Alteraciones en la secreción y señalización de moléculas derivadas del tejido adiposo durante la obesidad en gran medida puede mediar en la patogenia de los trastornos metabólicos [25]. A continuaciones se describe el rol de las adipocinas en la patogenia de la ERC y obesidad. Adiponectina La adiponectina es una proteína secretada principalmente por los adipocitos WAT, las principales funciones biológicas de la adiponectina incluyen una mayor biosíntesis de ácidos grasos y la inhibición de la gluconeogénesis hepática [17]. Es probablemente la adipocina secretada más abundantemente, forma alrededor del 0.05 % de las proteínas séricas y mide de 3 a 30 mg/ml en humanos, para su activación utiliza dos isoformas del receptor (AdipoR1 y AdipoR2) son receptores de siete transmembranas y tienen una homología del 66.7 % en su estructura [17]. Sin embargo, AdipoR1 y AdipoR2 son estructural y funcionalmente distintos de los receptores acoplados a proteína G porque su terminal N es intracelular, mientras que el terminal C es extracelular [29, 30]. La señalización de adiponectina se basa principalmente en interacciones de tipo receptor-ligando, en las que la adiponectina se une a sus receptores afines e inicia la activación de varias cascadas de señalización intracelular a través de las vías AMPK, mTOR, NF-κB, STAT3 y JNK [17]. La adiponectina inicia la activación de la señalización de AMPK mediada por la proteína adaptadora APPL1, que se une al dominio intracelular de AdipoR. Eso produce la activación de la biosíntesis de moléculas, otras proteínas reguladoras e importantes factores de transcripción. AMPK es un regulador que participa principalmente en la proliferación celular [17]. Hay dos tipos de macrófagos, M1 participan en la estimulación de los factores pro inflamatorios e induce la resistencia a la insulina y M2 bloquean una respuesta inflamatoria y promueve el metabolismo oxidativo; En los macrófagos, la adiponectina promueve la diferenciación celular de monocitos a macrófagos M2 y suprime su diferenciación a macrófagos M1, lo que muestra efectos pro inflamatorios y antiinflamatorios. Además, también activa los factores antiinflamatorios IL-10 pero reduce las citoquinas pro inflamatorias como IFN-γ, IL-6 y TNF-α en los macrófagos humanos [17]. Los pacientes con ERC muestran niveles elevados de proteína C reactiva (PCR), IL-6 y TNF-α y tienen una activación aberrante de receptor tipo toll (TLR)-4 [25]; en un estudio realizado en el año 2005 en 29 pacientes con ERC no diabéticos en etapa 5 y 14 controles sanos, se identificó que los pacientes con ERC tenían una expresión elevada del gen y la proteína TLR4, la estimulación de TLR-4 in vitro indujo la activación de TNF-α y NF-κB en células C2C12. Esto sugiere indirectamente que la activación de TLR-4 podría promover la inflamación muscular de los pacientes con ERC [31]. Los niveles de adiponectina se consideran predictivos de ERC, dado que estos se encuentran aumentados en pacientes con etapa pre diálisis [17, 29, 32]. Adicionalmente, en un estudio prospectivo realizado en el año 2008 en pacientes con ERC primaria no diabética identificó niveles elevados de adiponectina como un predictor novedoso de progresión de la ERC en hombres [33]. En estudios realizados en animales (ratones) muestran que la deficiencia de adiponectina se relaciona con varias alteraciones histológicas, incluida la fusión segmentaria procesos podocitarios, albuminuria y aumento del estrés oxidativo en los riñones [34]. Por otro lado, en pacientes obesos la producción de adiponectina se encuentra disminuida por lo que se cree que puede generar una función protectora sobre el riñón [29]. No obstante, paradójicamente, algunos estudios muestran que los pacientes con ERC y enfermedad renal crónica en diálisis (ERCT) tienen altos niveles de adipocinas, las explicaciones a esta situación son controversiales, se ha planteado podrían corresponder a un mecanismo compensatorio, otras consideraciones sugieren una disminución de la sensibilidad a la adiponectina o una reducción en el aclaramiento de la misma [35]. Leptina En pacientes con ERC independiente de la presencia de obesidad o no, se asocian a niveles elevados de leptina sérica. La leptina es una proteína de 167 aminoácidos, con una masa molecular de aproximadamente 16 kDa que está codificada por el gen LEP [23] secretada principalmente por los adipocitos, es una adipocina pleiotrópica. La leptina circulante llega a los órganos diana, donde se une a receptores específicos (conocidos como ObR, LR o LEPR), se conocen cinco isoformas del receptor de leptina en humanos (ObRa, ObRb, ObRc, ObRd y ObRe), de estas solo la isoforma ObRb (isoforma larga) se considera un receptor completamente activo, ya que es capaz de transducir completamente una señal de activación en la célula. Esta isoforma se encuentra altamente expresada en el sistema nervioso central (SNC), especialmente en el hipotálamo, donde participa en la regulación de la actividad secretora de este órgano. Los efectos de la leptina están mediados por cinco vías principales de señalización. Estas vías incluyen las vías de señalización JAK-STAT, PI3K, MAPK, AMPK y mTOR [23]. Por esta razón la principal función fisiológica de la leptina es transmitir información al hipotálamo sobre la cantidad de energía almacenada, como la masa de tejido adiposo, e influir en el gasto de energía al reducir el apetito. Regula el metabolismo energético, tiene efecto sobre la ingesta de alimentos, procesos de coagulación, angiogénesis, funciones relacionadas con la insulina y la remodelación vascular, además funciona como un pro inflamatorio molecular [36]. La leptina tiene efectos sobre el apetito y se ha demostrado que la hiperleptinemia contribuye a la hipertensión asociada a la obesidad por sobre activación del sistema nervioso simpático [37]. En cuanto al curso de la ERC, la leptina puede modular diferentes vías de señalización en el riñón, debido a que las células endoteliales glomerulares y mesangiales expresan abundantes receptores de leptina [25]. La leptina inducirá un incremento en la expresión de genes profibróticos, como TGF-β1 y citocinas pro inflamatorias [25]. El aumento en la expresión de TGF-β1, también contribuirá al desarrollarlo de la fibrosis renal, al unirse a receptores específicos a nivel renal, estimulara la expresión de factores profibróticos en un ciclo de retroalimentación positiva. Además, TGF-β1 es un potente iniciador de proliferación de células mesangiales renales [25]. Debido a su tamaño relativamente pequeño, la leptina atraviesa libremente el filtro glomerular de los riñones y luego se reabsorbe en la parte proximal de los túbulos contorneados [23]. Por lo que el estado elevado de leptina puede indicar una función renal deficiente [36]. Promueve la inflamación y trastorno de los lípidos, que contribuyen al riesgo de ERC [36]; se considera como “toxina urémica”, estando implicada tanto en la progresión de la enfermedad renal a través de efectos pro-hipertensivos y profibróticos, como en el desarrollo de complicaciones relacionadas con la ERC (inflamación crónica, pérdida de proteínas) [38]. Como se mencionó previamente, la leptina estimula la proliferación de células endoteliales glomerulares renales y aumenta la expresión de TGF-β1, un mediador clave de la hidrogénesis en estas células, el aumento de los niveles de leptina también contribuye al aumento de la expresión de colágeno tipo IV en el riñón, induce la proliferación de células mesangiales glomerulares mediante la activación de la vía PI3K, la hipertrofia de las células mesangiales aumenta la cantidad de proteína filtrada y albúmina que llega a las células del túbulo proximal y, como resultado, activa las vías inflamatorias y la fibrosis [23]. Puede presentarse un aumento en la síntesis del receptor TGFβ-1 secretado por las células endoteliales, este actúa de manera parácrina sobre el mesangio uniéndose a su receptor y activando la síntesis de proteínas de la matriz extracelular (ECM), incluyendo colágeno, fibronectina, tenazina y proteoglicanos; consiguientemente, un aumento en el nivel de TGFβ-1 conduce a la acumulación de MEC y, en consecuencia, a fibrosis glomerular y glomeruloesclerosis. En los podocitos, la leptina contribuye a la disminución de la expresión de las proteínas responsables de la filtración glomerular adecuada, incluidas la podocina, la nefrina, la podoplanina y la podocalixina. En las células del túbulo contorneado proximal (PTC), la leptina reduce la actividad metabólica de las células al activar la vía de señalización de mTOR [23]. Por otro lado, la leptina inhibe el apetito y aumenta el gasto de energía conduciendo a anorexia y desnutrición en pacientes con ERC, particularmente en casos de hemodiálisis de mantenimiento [36]. Por ende, una elevación de la leptina no solo nos indicaría daño renal, sino que además nos indica mayor progresión de complicaciones secundarias [39]. La obesidad aumenta la carga sobre los riñones y es un factor de riesgo de lesión renal, además de contribuir en los trastornos metabólicos asociados. Por lo que, teniendo en cuenta los efectos inhibitorios de la leptina sobre la obesidad, se puede considerar que puede proteger contra la lesión renal [39, 40]. Un estudio experimental publicado en el año 2017 demostró que la leptina disminuyó la ingesta calórica y los niveles de glucosa en ratas diabéticas [41], ese mismo año se publicó un estudio retrospectivo donde demostraron que la metreleptina, una metionil leptina humana recombinante, reduce el peso corporal y la dosis diaria de insulina en la diabetes mellitus tipo 1 [42]. La metreleptina ejerce efectos terapéuticos en la lipodistrofia [43], lo que indica que es probable que la leptina se aplique en los trastornos metabólicos [36]. Otras adipocinas Las principales adipocinas corresponden a la adiponectina y leptina como se ha descrito previamente. Además de estas, se distinguen la actividad de la visfatina y resistina, las cuales muestran propiedades pro-inflamatorias y efectos aterogénicos [25]. La visfatina estimula la expresión de TGF-β1, inhibidor del activador del plasminógeno-1 (PAI-1) y colágeno tipo I, los cuales han demostrado un rol importante como agentes profibróticos. Por otro lado, la resistina estimula la producción de las moléculas de adhesión como la molécula de adhesión intracelular 1 (ICAM-1) y la proteína de adhesión celular vascular 1 (VCAM-1) y promueve la activación del sistema renal simpático. Los niveles de estas adipocinas están marcadamente elevados en la obesidad y ERC correlacionándose con parámetros proinflamatorios y disminución de la tasa de filtración glomerular (TFG) [25, 37]. Durante el curso de la obesidad se presenta una sobre activación del SRAA, el tejido adiposo también estaría involucrado en la producción o estimulación de algunos de los componentes del RAS. Por ello la sobre estimulación del SRAA en obesos, asociado a la glomerulomegalia y desregulación de la reabsorción de sodio/glucosa, generalmente conlleva a hipertensión glomerular e hiperfiltración [25]. Otra adipocina a considerar, es la actividad de la adipocina proinflamatoria lipocalina 2 (LCN2), también denominada lipocalina asociada con la gelatinasa de neutrófilo (NGAL), estudiada como biomarcador funcional tanto para la enfermedad renal aguda como ERC(25). LCN2 es conocido por su papel en la respuesta inmune innata a través de su unión a sideróforos derivados de una infección bacteriana. Sin embargo, LCN2 no es secretada únicamente por neutrófilos sino también por otros tejidos como hígado, pulmones y de interés para este artículo, a nivel renal [25]. Se han informado niveles elevados de LCN2 en suero y orina en la lesión renal, debido a una expresión aumentada de LCN2 en el túbulo distal renal y una reabsorción alterada en el túbulo proximal [44]. El tejido adiposo, también puede producir factores angiogénicos como el factor de crecimiento del endotelio vascular (VEGF). Este elemento podría inducir la formación de novo de capilares glomerulares en gran parte defectuosos dentro del riñón, lo que contribuye a la hipertrofia glomerular característica de GRO [25] (Figura 2). Conclusiones La obesidad y el sobrepeso se asocian a alteraciones hemodinámicas, estructurales e histopatológicas en el riñón, así como alteraciones metabólicas y bioquímicas que predisponen a la enfermedad renal, aun cuando la función renal y las pruebas convencionales sean normales. Por lo tanto, los efectos renales de la obesidad son estructurales y funcionales. Hay varios mecanismos actualmente descritos que involucran a la obesidad como generador de alteraciones renales. Teniendo en cuenta las bases fisiopatológicas, proponemos una clasificación de la ERC-AO basadas en 4 tipos. Abreviaturas ERC: enfermedad renal crónica. ERC-AO: enfermedad renal crónica-asociada a enfermedad. VEGF: factor de crecimiento del endotelio vascular. OR: Odds ratio. Información suplementaria Materiales suplementarios no han sido declarados. Agradecimientos No aplica. Contribuciones de los autores Jorge Rico-Fontalvo: Conceptualización, Curación de datos, Análisis formal, Adquisición de fondos, Investigación, Metodología, Administración de proyecto, Recursos, Software, Escritura – borrador original. Rodrigo Daza-Arnedo: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Tomás Rodríguez-Yanez: Metodología, validación, supervisión, redacción: Revisión y edición. Washington Osorio: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Beatriz Suarez-Romero: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Oscar Soto: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Juan Montejo-Hernandez: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. María Cardona-Blanco: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Juan Camilo Gutiérrez: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Todos los autores leyeron y aprobaron la versión final del manuscrito. Financiamiento Los autores proveyeron los gastos de la investigación. Disponibilidad de datos o materiales Los conjuntos de datos generados y analizados durante el estudio actual no están disponibles públicamente debido a la confidencialidad de los participantes, pero están disponibles a través del autor correspondiente a pedido académico razonable. Declaraciones Aprobación del comité de ética y consentimiento para participar No aplica para revisiones narrativas. Consentimiento para publicación No aplica cuando no se publican imágenes o fotografías del examen físico o radiografías/tomografías/resonancias de pacientes. Conflictos de interés Los autores reportan no tener conflictos de interés. 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The Huo-Xue-Hua-Yu decoction (HXHYD) prescription, which possesses good clinical practice for healing fractures, is made up of 12 kinds of traditional chinese medicines (TCMs). According to the own drug efficacy...

Ethnopharmacology relevance: Yunnan Baiyao (YNBY), a traditional Chinese medicine formulae, has some significant properties including activating blood circulation to dissipate blood stasis (Huo-Xue-Hua-Yu), eliminating swelling and alleviating pain (Xiao-Zhong-Zhi-Tong), and eliminating necrotic tissues and promoting granulation (Qu-Fu-Sheng-Ji).Aim of this study: This paper intends to provide a comprehensive and critical analysis of studies on YNBY, proposing new possible therapeutic directions of this formula.Materials and methods: Relevant data on YNBY were retrieved from available databases and a hand-search by searching the keywords such as “Yunnan Baiyao,” “pharmacology,” “toxicity,” and “clinical applications.”Results: Traditionally, YNBY has been used to cure hemorrhage, bruises, swelling, and pain caused by injuries in the Chinese folk. Modern pharmacological studies show that YNBY possesses pharmacological activities including hemostasis, invigorating the circulation of blood, wound healing, anti-inflammation, analgesia, antibiosis, infection prevention, and other effects. Toxicological studies demonstrate that YNBY has a certain toxicology, which is mainly caused by Aconitum alkaloids from Cao-wu (CW, Aconiti Kusnezoffii Radix). The developmental non-toxic reaction dose (NOAEL) of YNBY for embryos and fetuses is 0.5 g/kg in rats. In addition, the NOAEL for fertility and early embryo development toxicity is 4.0 g/kg in rats. Clinical trials have confirmed the safety of YNBY in a large number of patients, and adverse drug reactions (ADRs) such as abdominal pain, diarrhea, allergy, and others in very few people. YNBY is routinely used in clinic to cure bleeding, pain, swelling, upper digestive tract ulcer, postoperative wound, arthritis, mouth ulcers, ulcerative colitis, etc.Conclusions: Hemostasis is a conspicuous effect of YNBY. Except for this effect, analgesia and anti-infection may be new research directions of this formula. In addition, the in vitro and in vivo pharmacology and mechanisms of action of YNBY are encouraged as well as the pharmacokinetics of this formulae. Furthermore, the material basis of the pharmacological effects of YNBY also needs clear identification.