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Please confirm that an ethics committee approval has been applied for or granted: Not relevant (see information at the bottom of this page) Application for ESRA Abstract Prizes: I apply as an Anesthesiologist (Aged 35 years old or less)Background and AimsIPAH corresponds to sporadic disease without any family history of PH or known triggering factor with mPAP > 25 mm Hg or more at rest after excluding left sided heart disease and certain other disorders[1].Pregnancy in IPAH patients is associated with very high peri-partum mortality and conception is not advised and if detected early in pregnancy, then termination is advised[2].MethodsParturient,37years,at 35 weeks gestation,in premature labour was referred to us being diagnosed as IPAH;NYHA Class III,on Tab.Sildenafil 12.5mg BD and Inj.Enoxaparin 40mg s.c. Post high risk consent,LSCS done under lumbar epidural anaesthesia with 0.25% Bupivacaine+Fentanyl,with standard monitoring and intra arterial line,maintaining hemodynamic stability.Intra-op BP decreased twice,treated with Phenylephrine 50mcg iv bolus & rest was uneventful.Patient monitored in CCU for 48hours;on continuous epidural 0.125% Bupivacaine infusion,with uneventful post operative period.ResultsDuring pregnancy the circulatory and haematological changes which occur can lead to increased peri-op mortality and morbidity in patients of IPAH.The anaesthetic goals are Maintenance of adequate Systemic Vascular Resistance (SVR);Maintenance of intra-vascular volume and venous return;Avoidance of aorto-caval compression;Prevention of pain, hypoxemia,hypercarbia and acidosis which may increase Pulmonary Vascular Resistance(PVR) and avoidance of myocardial depression.The choice of anaesthesia for LSCS in patients with IPAH is controversial as there is no established anaesthetic protocols to manage such patients and varied reports make it difficult to come to a well-established decision.ConclusionsEpidural anesthesia can be safely administered during LSCS in a selected group of patients with IPAH,using a multi-disciplinary team approach and extreme vigilance leading to a good maternal and fetal outcome.

Abstract Background Quantitative polymerase chain reaction (qPCR) targeting ipaH has been proven to be highly efficient in detecting Shigella in clinical samples compared to culture-based methods, which underestimate Shigella burden by 2- to 3-fold. qPCR assays have also been developed for Shigella speciation and serotyping, which is critical for both vaccine development and evaluation. Methods The Enterics for Global Health (EFGH) Shigella surveillance study will utilize a customized real-time PCR–based TaqMan Array Card (TAC) interrogating 82 targets, for the detection and differentiation of Shigella spp, Shigella sonnei, Shigella flexneri serotypes, other diarrhea-associated enteropathogens, and antimicrobial resistance (AMR) genes. Total nucleic acid will be extracted from rectal swabs or stool samples, and assayed on TAC. Quantitative analysis will be performed to determine the likely attribution of Shigella and other particular etiologies of diarrhea using the quantification cycle cutoffs derived from previous studies. The qPCR results will be compared to conventional culture, serotyping, and phenotypic susceptibility approaches in EFGH. Conclusions TAC enables simultaneous detection of diarrheal etiologies, the principal pathogen subtypes, and AMR genes. The high sensitivity of the assay enables more accurate estimation of Shigella-attributed disease burden, which is critical to informing policy and in the design of future clinical trials. Shigella spp, Shigella flexneri serotypes, and other diarrhea-associated enteropathogens are detected and quantified with a customized real-time polymerase chain reaction–based TaqMan Array Card in the Enterics for Global Health: Shigella surveillance study. Shigella burden will be estimated with a quantitative methodology.

IpaH enzymes are secreted bacterial effectors that function within host cells as E3 ubiquitin (Ub) ligases. Catalytic activity is imparted by a conserved novel E3 ligase (NEL) domain that is unique to Gram-negative pathogens and whose activity is repressed by a flanking substrate-binding leucine-rich repeat (LRR) domain when substrate is absent. How the NEL domain catalyzes the conjugation of Ub onto substrates, recognizes host E2s, and maintains its autoinhibited state remain poorly understood. Here we used mutagenesis and enzyme kinetic analyses to address these gaps in knowledge. Mutagenesis of conserved residues on two remote surfaces of the NEL domain identified functional clusters proximal to and distal to the active site cysteine. By analyzing the kinetics of Ub charging and discharging, we identified proximal active site residues that function as either the catalytic acid or catalytic base for aminolysis. Further analysis revealed that distal site residues mediate the direct binding of E2. In studying the full-length protein, we also have uncovered that IpaH family autoinhibition is achieved by a short-circuiting mechanism wherein the LRR domain selectively blocks productive aminolysis, but not the nonproductive discharge of Ub from the E3 to solvent. This mode of autoinhibition, which is not shared by the HECT domain ligase Smurf2, leads to the unanticipated depletion of E2∼Ub and thus a concomitant dominant-negative effect on other E3s in vitro, raising the possibility that short circuiting also may serve to restrict the function of host E3s in cells.

Background Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. Methods Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. Results Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. Conclusions Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.

An enteroinvasive Escherichia coli (EIEC) outbreak affecting 154 individuals was identified among attendees at a wedding in Loei Province, Thailand. The median time to symptom onset was 18 h (range: 7–72 h). The epidemiological evidence suggested that larb-neua-dib ( spicy minced raw beef salad) was the probable source of the outbreak. The O8:H19 isolates identified in this study closely resemble the O8:H19 strains from the United States and the United Kingdom, but not the O96:H19 strains from Europe. This is the first EIEC outbreak documented in Thailand. Complexities in identifying EIEC contribute to its underreporting.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease observed in a small proportion of patients after acute pulmonary embolism (PE). CTEPH has a high morbidity and mortality rate, related to the PH severity, and a poor prognosis, which mirrors the right ventricular dysfunction involvement. Pulmonary endarterectomy (PEA) reduces pulmonary vascular resistance, making it the treatment of choice and should be offered to operable CTEPH patients, as significant symptomatic and prognostic improvement has been observed. Moreover, these patients may also benefit from the advances made in surgical techniques and pulmonary hypertension-specific medication. However, not all patients are eligible for PEA surgery, as some have either distal pulmonary vascular obstruction and/or significant comorbidities. Therefore, surgical candidates should be carefully selected by an interprofessional team in expert centers. This review aims at making an overview of the risk factors and latest developments in diagnostic tools and treatment options for CTEPH.

BackgroundFibroblast growth factor 23 (FGF-23) has been associated with left ventricular hypertrophy (LVH) and heart failure. However, its role in right ventricular (RV) remodeling and RV failure is unknown. This study analyzed the utility of FGF-23 as a biomarker of RV function in patients with pulmonary hypertension (PH).MethodsIn this observational study, FGF-23 was measured in the plasma of patients with PH (n = 627), dilated cardiomyopathy (DCM, n = 59), or LVH with severe aortic stenosis (n = 35). Participants without LV or RV abnormalities served as controls (n = 36).ResultsMedian FGF-23 plasma levels were higher in PH patients than in healthy controls (p < 0.001). There were no significant differences between PH, DCM, and LVH patients. Analysis across tertiles of FGF-23 levels in PH patients revealed an association between higher FGF-23 levels and higher levels of NT-proBNP and worse renal function. Furthermore, patients in the high-FGF-23 tertile had a higher pulmonary vascular resistance (PVR), mean pulmonary artery pressure, and right atrial pressure and a lower cardiac index (CI) than patients in the low tertile (p < 0.001 for all comparisons). Higher FGF-23 levels were associated with higher RV end-diastolic diameter and lower tricuspid annular plane systolic excursions (TAPSE) and TAPSE/PASP. Receiver operating characteristic analysis revealed FGF-23 as a good predictor of RV maladaptation, defined as TAPSE < 17 mm and CI < 2.5 L/min/m2. Association of FGF-23 with parameters of RV function was independent of the glomerular filtration rate in regression analysis.ConclusionFGF-23 may serve as a biomarker for maladaptive RV remodeling in patients with PH.Graphic abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive vascular disease with high mortality and heritability. Pyroptosis is a novel form of programmed cell death, and it is closely associated with IPAH. However, the roles of pyroptosis-related genes (PRGs) in IPAH are still largely unknown. In this study, we identified KIF23 as the most relevant gene for IPAH and pyroptosis, and its expression was significantly increased in pulmonary arterial smooth muscle cells (PASMCs) of IPAH. Besides, the pyroptosis level of PASMCs was also considerably upregulated in IPAH. Knockdown of KIF23 in PASMCs could significantly suppress the PASMCs’ pyroptosis and proliferation and then alleviate the increase in pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary vascular resistance in IPAH. KIF23 regulated the expression of Caspase3, NLRP3, and HMGB1, and they were all involved in the PI3K/AKT and MAPK pathways, indicating that PI3K/AKT and MAPK pathways might participate in regulating PASMCs pyroptosis by KIF23. In conclusion, our study suggests that KIF23 may be a new therapeutic target for IPAH, which can alleviate the symptoms of IPAH by inhibiting the pyroptosis and proliferation of PASMCs.

Background Abnormal glycolytic metabolism plays a significant role in pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH), yet the specific mechanisms remain unclear. The primary objective of this study is to investigate the key regulatory mechanisms of glycolysis in IPAH. Methods Bulk and single-cell sequencing data obtained from IPAH patient tissue samples were downloaded from the GEO database. scMetabolism and AUCcell analyses of the IPAH single-cell sequencing data were carried out to quantify the glycolytic metabolic activity and identify the main cell types regulating glycolysis, respectively. The ssGSEA method was used to assess the glycolytic activity in each bulk sample within the bulk sequencing data. Differential analysis, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network analysis were conducted to identify key genes associated with glycolysis in IPAH samples. Single-cell sequencing and a monocrotaline (MCT)-induced model of PH in rats were utilized to validate the expression of these key genes. Results Single-cell sequencing data indicated that IPAH patients displayed increased glycolytic activity, which was primarily regulated by fibroblasts. Similarly, bulk transcriptomic data revealed a significant increase in glycolytic activity in IPAH patients. Differential analysis, WGCNA, PPI network analysis, and integrated single-cell analysis further identified insulin-like growth factor-1 (IGF1), lysyl-tRNA synthetase (KARS), caspase-3 (CASP3), and cyclin-dependent kinase inhibitor 2 A (CDKN2A) as key genes associated with fibroblast-mediated glycolysis in IPAH patients. Differential expression of IGF1, KARS, CASP3, and CDKN2A was also observed in our in vivo model of PH. Conclusion Our study identifies IGF1, KARS, CASP3, and CDKN2A as key regulatory genes in glycolysis in IPAH, which provides the basis for the development of targeted therapies.

The immunopathogenesis of end-stage chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) remains poorly understood. Emerging evidence suggests that distinct T cell subpopulations may play critical roles in the progression of both diseases. A better understanding of these roles could provide important insights into underlying mechanisms and guide the development of targeted therapies. We performed flow cytometric analysis of explanted lung tissue from patients with advanced COPD (n = 9), IPF (n = 9), and idiopathic pulmonary arterial hypertension (IPAH, n = 3) undergoing lung transplantation. Healthy donor lung tissue (n = 7) served as controls. Both COPD and IPF lungs demonstrated an increased frequency of Th1 (CXCR3 CCR4 CCR6 ) lymphocytes compared to controls. In contrast, Tc17 cells were significantly reduced. No notable differences were observed in Th2, Th17, or Tc1 cell populations. Activated CD4 T cells (CD69 CD25 HLA-DR ) were significantly enriched in IPF compared to COPD and donor lungs. COPD lungs exhibited a marked expansion of terminally differentiated cytotoxic CD8 CD28 CD27 T cells. In double-negative (DN; CD3 CD4 CD8 ) T cell compartment, CD25 T cells were increased in COPD, whereas DN tissue-resident memory (TRM; CD69 CD25 HLA-DR ) cells were reduced in both COPD and IPF. Invariant natural killer T (iNKT; Vα24 Vβ11 ) cell levels were uniformly low without intergroup differences. Our findings identify disease-specific immune signatures in end-stage COPD and IPF. Th1 cell expansion together with a reduction in Tc17 and DN TRM subsets represented shared features of COPD and IPF, whereas accumulation of terminally differentiated cytotoxic CD8 T cells and CD25 DN T cells was specific to COPD. These findings enhance our understanding of adaptive immune dysregulation in COPD and IPF and may support the development of immunomodulatory strategies.