AB0171 THE IMMUNOMODULATORY AND ANTI-INFLAMMATORY EFFECTS OF BOSENTAN IN SYSTEMIC SCLEROSIS

Background:Plasma endothelin-1 (ET-1) levels are increased in patients with systemic sclerosis (SSc), playing a central role in the development of fibrosis, vasoconstriction and inflammation1. While the beneficial effect of Bosentan, the endothelin receptor antagonists, have been demonstrated on vasoconstriction and fibrosis, its potential anti-inflammatory and immunomodulatory activity needs to be further investigated.Objectives:To assess whether Bosentan can modulate the gene expression profile of immune cells in sample of patients with limited and diffuse SSc and active digital ulcers.Methods:We enrolled 34 patients affected by SSc. Twenty-four patients were affected by limited SSc and 12 by diffuse SSc. Blood samples were collected from patients before and after 24 weeks of treatment with Bosentan, in the absence of immunosuppressive therapies. All patients received Bosentan 125 mg twice a day for 24 weeks. Gene expression profiles were assessed by GeneChip® Human Transcriptome Array 2.0 microarray technology. Significantly (p-value1.5) expressed genes pre/post treatment were obtained by paired t-statistics, as implemented in Partek Genomics Suite ver. 6.6. These genes were subjected to functional enrichment analysis by Ingenuity Pathway Analysis. The effect of Bosentan on patients was studied on the "diffuse" and "limited" sub-cohorts, individually, as well as on the whole cohort.Results:Contrary to the limited cohort where differentially expressed genes resulted to be all non-coding genes which are almost all over-expressed before treatment, the diffuse cohort was characterized by 19 differentially expressed genes that enrich biological functions and pathways related to the immune system and its organic response (in particular T-cells). Comparing the limited to the diffuse cohort, pre- and post- treatment, a distinct genetic fingerprint emerges, that characterizes the response to Bosentan by the latter cohort as increased apoptosis of lymphocytes (z-score=3.28) and a decreased quantity of antigen presenting cells (from z-score=1.06 (pre) to -0.75 (post)).Conclusion:The presence of an inflammatory microenvironment, as occur in SSc, influence the relative expression of ET-1 receptors on immune cells, which in turn further contribute to the amplification of cellular responses to inflammation. The observed difference response to therapy between the two cohorts of patients was attributed to influence of ET-1 levels on the relative expression of ET-1 receptors on immune cells surface. Interestingly Bosentan, beside the already-known effect on promoting antigen presenting cells apoptosis, seem to exert its immunomodulatory activity also by deregulating functions that mainly involves the T cells and by promoting their apoptosis, which in turn reflect also its anti-inflammatory proprieties.References:[1]Tinazzi E, Puccetti A, Patuzzo G, et al. Endothelin receptors expressed by immune cells are involved in modulation of inflammation and in fibrosis: relevance to the pathogenesis of systemic sclerosis. J Immunol Res. 2015;2015:147616.Disclosure of Interests:None declare

Mortality and pulmonary complications in patients undergoing surgery with perioperative sars-cov-2 infection: An international cohort study

Background The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (740%) had emergency surgery and 280 (248%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (261%) patients. 30-day mortality was 238% (268 of 1128). Pulmonary complications occurred in 577 (512%) of 1128 patients; 30-day mortality in these patients was 380% (219 of 577), accounting for 817% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 175 [95% CI 128-240], p<00001), age 70 years or older versus younger than 70 years (230 [165-322], p<00001), American Society of Anesthesiologists grades 3-5 versus grades 1-2 (235 [157-353], p<00001), malignant versus benign or obstetric diagnosis (155 [101-239], p=0046), emergency versus elective surgery (167 [106-263], p=0026), and major versus minor surgery (152 [101-231], p=0047). Interpretation Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Isolation and cloning by a polymerase chain reaction of a genomic DNA fragment of the human slow skeletal troponin (TNNT1) gene

The genomic 3' structure of the gene coding for the human slow skeletal troponin T (TNNT1) gene, is reported. An intron of 912 nucleotides containing an Alu-element has been identified and characterized. The complexity of the sequenced region suggests an alternative exon use. The present results may be valuable for further studies on the gene structure of TNNT1 and the related troponin gene family