Genome wide association study of uric acid in Indian population and interaction of identified variants with type 2 diabetes

Abnormal level of Serum Uric Acid (SUA) is an important marker and risk factor for complex diseases including Type 2 diabetes. Since genetic determinant of uric acid in Indians is totally unexplored, we tried to identify common variants associated with SUA in Indians using Genome Wide Association Study (GWAS). Association of five known variants in SLC2A9 and SLC22A11 genes with SUA level in 4,834 normoglycemics (1,109 in discovery and 3,725 in validation phase) was revealed with different effect size in Indians compared to other major ethnic population of the world. Combined analysis of 1,077 T2DM subjects (772 in discovery and 305 in validation phase) and normoglycemics revealed additional GWAS signal in ABCG2 gene. Differences in effect sizes of ABCG2 and SLC2A9 gene variants were observed between normoglycemics and T2DM patients. We identified two novel variants near long non-coding RNA genes AL356739.1 and AC064865.1 with nearly genome wide significance level. Meta-analysis and in silico replication in 11,745 individuals from AUSTWIN consortium improved association for rs12206002 in AL356739.1 gene to sub-genome wide association level. Our results extends association of SLC2A9, SLC22A11 and ABCG2 genes with SUA level in Indians and enrich the assemblages of evidence for SUA level and T2DM interrelationship

The incidence and risk factors of acute pain after preoperative needle localization of pulmonary nodules: a cross-sectional study

Background: The incidence, severity and associated risk factors of acute pain after preoperative needle localization of pulmonary nodules are poorly characterized. We therefore conducted a cross-sectional study to quantify the acute pain induced by preoperative needle localization of small pulmonary nodules before video-assisted thoracoscopic surgery (VATS). Methods: We conducted this study at Shanghai Chest Hospital from September 2021 through December 2021. Eligible patients were between 18 and 75 years old and had small pulmonary nodules requiring preoperative CT-guided needle localization. The intensity of acute pain was assessed using the visual analogue scale (VAS) after preoperative needle localization. A VAS score ≥4 cm indicated moderate to severe pain. Patient demographics and CT-guided localization factors were collected to identify significant predictors associated with moderate to severe pain. Results: A total of 300 patients were included in the final analysis, with a mean (SD) age of 51 (SD =12) years old; 63% were female. Moderate to severe pain occurred in 50.8% of patients during deep breathing and 45.7% of patients during movement. Multivariate logistic regression analysis showed that multiple localization needles [multiple needle localizations vs. single needle localization, odds ratio (OR): 2.363, 95% confidence interval (CI): 1.157–4.825, P=0.018] and the specific location of needle puncture on the chest wall were significant predictors of moderate to severe pain after CT-guided needle localization (lateral chest wall vs. anterior chest wall OR: 2.235, 95% CI: 1.106–4.518, P=0.025; posterior chest wall vs. anterior chest wall OR: 1.198, 95% CI: 0.611–2.349, P=0.599). Conclusions: In adult patients receiving hookwire CT-guided localization, moderate to severe pain was common. Avoiding the localization route through lateral chest wall may be helpful and pharmacological medications or regional blockade is necessitated in high-risk population

Common variants in CLDN2 and MORC4 genes confer disease susceptibility in patients with chronic pancreatitis

A recent Genome-wide Association Study (GWAS) identified association with variants in X-linked CLDN2 and MORC4 and PRSS1-PRSS2 loci with Chronic Pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10-09; rs12008279—OR 1.56, P = 1.53 x 10-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10-09; rs6622126—OR 1.75, P = 4.04x10-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Development and validation of the artificial intelligence (AI)-based diagnostic model for bronchial lumen identification

Background: Bronchoscopy is a key step in the diagnosis and treatment of respiratory diseases. However, the level of expertise varies among different bronchoscopists. Artificial intelligence (AI) may help them identify bronchial lumens. Thus, a bronchoscopy quality-control system based on AI was built to improve the performance of bronchoscopists. Methods: This single-center observational study consecutively collected bronchoscopy videos from Shanghai Chest Hospital and segmented each video into 31 different anatomical locations to develop an AI-assisted system based on a convolutional neural network (CNN) model. We then designed a single-center trial to compare the accuracy of lumen recognition by bronchoscopists with and without the assistance of the AI system. Results: A total of 28,441 qualified images of bronchial lumen were used to train the CNNs. In the cross-validation set, the optimal accuracy of the six models was between 91.83% and 96.62%. In the test set, the visual geometry group 16 (VGG-16) achieved optimal performance with an accuracy of 91.88%, and an area under the curve of 0.995. In the clinical evaluation, the accuracy rate of the AI system alone was 54.30% (202/372). For the identification of bronchi except for segmental bronchi, the accuracy was 82.69% (129/156). In group 1, the recognition accuracy rates of doctors A, B, a and b alone were 42.47%, 34.68%, 28.76%, and 29.57%, respectively, but increased to 57.53%, 54.57%, 54.57%, and 46.24% respectively when combined with the AI system. Similarly, in group 2, the recognition accuracy rates of doctors C, D, c, and d were 37.90%, 41.40%, 30.91%, and 33.60% respectively, but increased to 51.61%, 47.85%, 53.49%, and 54.30% respectively, when combined with the AI system. Except for doctor D, the accuracy of doctors in recognizing lumen was significantly higher with AI assistance than without AI assistance, regardless of their experience (P<0.001). Conclusions: Our AI system could better recognize bronchial lumen and reduce differences in the operation levels of different bronchoscopists. It could be used to improve the quality of everyday bronchoscopies

Imaging of the Left Atrial Appendage Before Occluder Device Placement: Evaluation of Virtual Monoenergetic Images in a Single-Bolus Dual-Phase Protocol

Purpose Preimplantation cardiac computed tomography (CT) for assessment of the left atrial appendage (LAA) enables correct sizing of the device and the detection of contraindications, such as thrombi. In the arterial phase, distinction between false filling defects and true thrombi can be hampered by insufficient contrast medium distribution. A delayed scan can be used to further differentiate both conditions, but contrast in these acquisitions is relatively lower. In this study, we investigated whether virtual monoenergetic images (VMI) from dual-energy spectral detector CT (SDCT) can be used to enhance contrast and visualization in the delayed phase. Materials and Methods Forty-nine patients receiving SDCT imaging of the LAA were retrospectively enrolled. The imaging protocol comprised dual-phase acquisitions with single-bolus contrast injection. Conventional images (CI) from both phases and 40-keV VMI from the delayed phase were reconstructed. Attenuation, signal-, and contrast-to-noise ratios (SNR/CNR) were calculated by placing regions-of-interest in the LAA, left atrium, and muscular portion of interventricular septum. Two radiologists subjectively evaluated conspicuity and homogeneity of contrast distribution within the LAA. Results Contrast of the LAA decreased significantly in the delayed phase but was significantly improved by VMI, showing comparable attenuation, SNR, and CNR to CI from the arterial phase (attenuation/SNR/CNR, CI arterial phase: 266.0 +/- 117.0 HU/14.2 +/- 7.2/6.6 +/- 3.9; CI-delayed phase: 107.6 +/- 35.0 HU/5.9 +/- 3.0/1.0 +/- 1.0; VMI delayed phase: 260.3 +/- 108.6 HU/18.2 +/- 10.6/4.8 +/- 3.4). The subjective reading confirmed the objective findings showing improved conspicuity and homogeneity in the delayed phase. Conclusions The investigated single-bolus dual-phase acquisition protocol provided improved visualization of the LAA. Homogeneity of contrast media was higher in the delayed phase, while VMI maintained high contrast

Implementation of artificial intelligence in the histological assessment of pulmonary subsolid nodules

BACKGROUND: Clinical management of subsolid nodules (SSNs) is defined by the suspicion of tumor invasiveness. We sought to develop an artificial intelligent (AI) algorithm for invasiveness assessment of lung adenocarcinoma manifesting as radiological SSNs. We investigated the performance of this algorithm in classification of SSNs related to invasiveness. METHODS: A retrospective chest computed tomography (CT) dataset of 1,589 SSNs was constructed to develop (85%) and internally test (15%) the proposed AI diagnostic tool, SSNet. Diagnostic performance was evaluated in the hold-out test set and was further tested in an external cohort of 102 SSNs. Three thoracic surgeons and three radiologists were required to evaluate the invasiveness of SSNs on both test datasets to investigate the clinical utility of the proposed SSNet. RESULTS: In the differentiation of invasive adenocarcinoma (IA), SSNet achieved a similar area under the curve [AUC; 0.914, 95% confidence interval (CI): 0.813–0.987] with that of the 6 doctors (0.900, 95% CI: 0.867–0.922). When interpreting with the assistance of SSNet, the sensitivity of junior doctors, specificity of senior doctor, and their accuracy were significantly improved. In the external test, SSNet (AUC: 0.949, 95% CI: 0.884–1.000) achieved a better AUC than doctors (AUC: 0.883, 95% CI: 0.826–0.939) whose AUC increased (AUC: 0.908, 95% CI: 0.847–0.982) with SSNet assistance. In the histological subtype classifications, SSNet achieved better performance than practicing doctors. The AUCs of doctors were significantly improved with the assistance of SSNet in both 4-category and 3-category classifications to 0.836 (95% CI: 0.811–0.862) and 0.852 (95% CI: 0.825–0.882), respectively. CONCLUSIONS: The AI diagnostic system achieved non-inferior performance to doctors, and will potentially improve diagnostic performance and efficiency in SSN evaluation