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Journal articleSimader FA, Rajkumar CA, Foley MJ, et al., 2026,
Association Between Age and PCI Effectiveness in Stable CAD: Secondary Analysis of ORBITA-2.
, J Am Coll Cardiol, Vol: 87, Pages: 253-265BACKGROUND: ORBITA-2 (Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) was the first randomized placebo-controlled trial to show the efficacy of percutaneous coronary intervention (PCI) in patients with stable angina and single- or multivessel coronary artery disease without background antianginal medication. Whether the effect is consistent across age groups is unknown. OBJECTIVES: The authors sought to evaluate the interaction between age and symptom and stenosis severity, and the efficacy of PCI on the ORBITA-2 primary and secondary endpoints. METHODS: All patients from the primary ORBITA-2 trial contributed data to this post hoc analysis. For daily symptoms, a bayesian longitudinal Markov model was constructed. For treadmill exercise time, stress echocardiography, and questionnaires, a bayesian ordinal proportional odds model was used, including the prerandomization value and treatment arm, which were allowed to interact with age. RESULTS: The mean age was 64 ± 9 years, ranging from 40 to 82 years. There was little relationship between age and symptom and stenosis severity. In older patients, PCI was more effective for symptom relief (OR: 2.03; 95% CrI: 1.67-2.45; Pr > 0.99) than in younger patients (OR: 1.70; 95% CrI: 1.38-2.15; Pr > 0.99; Pr [interaction] = 0.99). In contrast, the effect of PCI on treadmill exercise time was far greater in younger than in older patients (50-year-old: +125 s [95% CrI: 35.8-215.0 s; Pr > 0.99]; 70-year-old: +31.9s [95% CrI: -12.6 to 78.3; Pr = 0.92]; Pr [interaction] = 0.96). CONCLUSIONS: PCI was effective across all ages in reducing angina frequency. Notably, there was limited improvement in treadmill exercise time in the elderly, challenging its role as a primary endpoint in many antianginal trials. These data should inform cardiovascular clinical trial design to ensure applicability across all ages. (Objective Randomized Blinded Investigation With Optimal
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Journal articleConstantinescu-Bercu A, Smith KE, Wong SY, et al., 2026,
Von Willebrand Factor Deficiency Impairs Angiogenesis via Angiopoietin-2: Relevance for Gut Angiodysplasia.
, BloodManagement of recurrent gastrointestinal (GI) bleeding is a clinical unmet need for patients with Von Willebrand disease (VWD) and is linked to the presence of gut vascular malformations (angiodysplasia). We previously demonstrated that von Willebrand factor (VWF) regulates angiogenesis and vascular integrity. VWF controls the storage of the angiogenesis regulator Angiopoietin-2 (Angpt-2) in endothelial cells (EC), suggesting a candidate for the genesis of angiodysplasia; however, no direct evidence of the role of Angpt-2 in VWF-dependent angiogenesis is available. Using VWF-deficient Human Umbilical Vein Endothelial Cells (HUVEC) and endothelial colony forming cells (ECFCs) from severe VWD patients, we find that loss of VWF results in increased Angpt-2 expression through the positive feedback loop Angpt-2-TIE2-AKT-FOXO1-Angpt-2. In the gut of VWF-deficient mice, Angpt-2 expression is increased whilst Angpt-1 expression is decreased, suggesting that VWF regulates the Angpt/Tie2 balance in the gut. Moreover, the intestinal vasculature in the jejunum of VWF-deficient mice appears abnormal, with hyper-sprouting and lumen formation defects. The findings reveal VWF-deficient mice as a model to study gut angiodysplasia. We investigate sprouting angiogenesis in vitro using a fibrin bead assay and find increased sprouting in VWF-deficient EC. We develop a 3D-microfluidic model of angiogenesis and find that ECFCs from severe VWD patients exhibit defective remodeling and abnormal lumen formation, reminiscent of the defects in the gut of VWF KO mice. Importantly, inhibition of Angpt-2 reduces sprouting in VWF-deficient HUVEC and normalises vascular remodeling in VWD ECFCs, suggesting that Angpt-2 inhibitors may be effective in VWD patients with GI bleeding and angiodysplasia.
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Journal articleMeena D, Huang J, Smith A, et al., 2026,
Blood pressure, plasma proteins and cardiovascular diseases: a network Mendelian randomisation and observational study
, European Heart Journal, Vol: 47, Pages: 331-342, ISSN: 0195-668XBackground and AimsThe biological pathways leading to elevated blood pressure (BP) and subsequent cardiovascular diseases (CVDs) remain incompletely understood. Investigating the proteomic landscape of BP and its overlap with CVD could provide critical insights into the molecular determinants and pathways involved in BP regulation and its subsequent effect on CVD.MethodsA proteome-wide Mendelian randomization (MR) study was conducted by leveraging genetic instruments from 2007 plasma proteins to assess their causal effects on BP (systolic and diastolic BP). Proteins showing strong associations with BP were further analyzed for potential causal effects on coronary artery disease (CAD) and stroke subtypes. Network MR was performed to estimate the proportion of CVD risk mediated through BP. Bayesian colocalization was applied to determine whether identified associations share common causal variants. Observational associations were examined in UK Biobank participants to assess associations between proteins, BP, and incident CVD events using linear regression and Cox proportional hazard models.ResultsProteome-wide MR identified 242 proteins associated with BP, of which 48 were also linked to CAD or stroke, with four (ACOX1, FGF5, FURIN, MST1) also supported by genetic colocalization analyses (FDR 5% and PP ≥70%). Genetically predicted FURIN and FGF5 were strongly associated with BP and stroke risk, while ACOX1, FGF5, and MST1 exhibited potential causal effects on CAD. Network MR suggested that a substantial proportion of their effect on CAD and stroke (30.5%–77.2%) was mediated through BP regulation. Observational analyses further supported these findings.ConclusionsThis study identifies key plasma proteins with potential causal roles in BP regulation and CVD risk, highlighting BP as a major mediator of their effects on CAD and stroke. These findings provide novel insights into the molecular mechanisms underlying hypertension-related CVD and identify promising p
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Journal articleSingh B, Karpov OA, Mayr M, 2026,
Clinical proteomics in cardiovascular medicine: Current capabilities, limitations, and future directions.
, Atherosclerosis, Vol: 413BACKGROUND AND AIMS: Commercial high-throughput proteomics platforms, such as Olink and SomaLogic, enable large-scale epidemiological studies with integrated multi-omics measurements. While these proteomics approaches have been widely applied in biobanks, issues of data quality remain underappreciated. In this review, we discuss these limitations and outline a way forward for realizing the clinical translation of proteomics as a comprehensive 'liquid health check'. METHODS: We reviewed the recent literature for artificial intelligence (AI) and multi-omics, particularly proteomics in atherosclerotic cardiovascular disease (ASCVD). RESULTS: AI-driven multi-omics analyses have the potential to advance our understanding of multifactorial causes of ASCVD, including aging. Emerging concepts such as "ageotypes" suggest the potential for personalized intervention to slow aging processes. Commercial proteomics platforms have accelerated biomarker discovery in ASCVD, but challenges remain in clinical translation. Limited correlation between Olink and SomaLogic necessitates orthogonal validation of findings. Platform-specific issues, such as epitope effects and cross-reactivity, can yield divergent protein quantitative trait loci for the same protein, complicating causal inference. While tissue proteomics provides complementary insights to plasma proteomics, reliance on autopsy samples raises concerns about protein degradation and measurement reliability. Increasingly, single-cell and spatial proteomics are being explored to better capture plaque heterogeneity, complementing bulk proteomics in larger cohorts. CONCLUSION: Beyond risk prediction, proteomics offers opportunities to elucidate disease mechanisms and enable drug repurposing. To realize the clinical potential of plasma proteomics, absolute or reliably recalibratable relative quantification will be required to guide patient care. Ultimately, the clinical value of proteomics will be determined by the quality
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Journal articleVon Koch S, Sharma T, Khamis R, et al., 2026,
Long-acting nitrate use before and after revascularization to evaluate angina in chronic coronary syndrome: a case-crossover study from SCAAR
, LANCET REGIONAL HEALTH-EUROPE, Vol: 60, ISSN: 2666-7762 -
Journal articleHada M, Collet C, Storozhenko T, et al., 2026,
Rationale and design of European microcirculatory resistance and absolute flow team: The Euro-CRAFT registry
, AMERICAN HEART JOURNAL, Vol: 291, Pages: 136-143, ISSN: 0002-8703 -
Journal articleYogeswaran A, Annis JS, Funderich M, et al., 2026,
Male survival disadvantage in pulmonary hypertension: independent of aetiology, age, disease severity, comorbidities and treatment
, EBIOMEDICINE, Vol: 123, ISSN: 2352-3964 -
Journal articleZiotti SDV, Dourado LOC, Silva RD, et al., 2026,
Coronary Sinus Reduction for the Treatment of Refractory Angina: What Have We Learned after 70 Years of the Beck Surgery?
, Arq Bras Cardiol, Vol: 122With the increasing prevalence of chronic coronary syndromes, many patients with extensive atherosclerosis experience uncontrolled angina, even while receiving optimal medical therapy. This is especially true for patients who are not suitable candidates for surgical or percutaneous revascularization. Numerous treatments have been investigated for managing angina pectoris, and in this context, the coronary sinus reducer has emerged as a promising therapeutic option. Since the 1950s, beginning with Beck's surgery, the coronary venous sinus has been a focal point of research in anti-ischemic therapies. Significant scientific advances have been made in narrowing the venous sinus in the past two decades. Thanks to technological improvements in minimally invasive procedures and better methods for assessing myocardial blood flow, a new therapeutic option has become available for patients suffering from refractory angina and, possibly, for microvascular dysfunction. In this review, we aim to examine key concepts related to angina pectoris and myocardial ischemia, highlighting the historical background, pathophysiological rationale, and technical aspects of coronary sinus reduction as a therapy for refractory angina. Additionally, we will explore the scientific evidence from recent decades, as well as identify existing gaps and outline future research directions concerning this emerging treatment.
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Journal articleKhawaja AA, Whitlock G, Fidler S, et al., 2025,
Evaluation of the effect of 48 weeks of BIC/F/TAF and DRV/c/F/TAF on platelet function in the context of rapid ART start
, HIV Research & Clinical Practice, Vol: 26, ISSN: 2578-7470IntroductionThe BIC-T&T study aimed to determine the efficacy of bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF) at suppressing viral load in a two-arm, open-label, multi-centre, randomised trial under a UK test-and-treat setting. This sub-study aimed to evaluate potential off-target cardiovascular impact by examining ex vivo platelet function.MethodsPlatelets were isolated by centrifugation of citrated blood from participants attending Chelsea and Westminster Hospital or St Mary’s Hospital at Week 48 following enrolment. Platelet activation was assessed by real-time flow cytometry to examine integrin activation and granule release and platelet aggregation was evaluated by light transmission aggregometry. Statistical significance was determined by 2-way ANOVA with a Šidák’s multiple comparisons post-test.ResultsAn analysis of 21 participants was performed at Week 48 (96% male and 48% white; mean (range) age was 37 (23–78) years). No difference between arms was observed in ADP-, collagen- or thrombin receptor activator for peptide (TRAP)-6-evoked platelet αIIbβ3 integrin activation, granule release or platelet aggregation in response to any of the agonists tested. Despite differences in the demographics between treatment arms, the presence of an unboosted integrase inhibitor or boosted protease inhibitor in a test-and-treat setting did not impact platelet function.ConclusionsOur study provides no evidence of differences in downstream platelet responses between participants taking BIC/F/TAF compared to DRV/c/F/TAF following 48 wk of treatment. Further data are required to explore whether there are biologically significant off-target effects, including effects on platelets and other components of the cardiovascular system between these two test-and-treat regimens.
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Journal articleGuo J, Kostrzyńska K, Kamzolas I, et al., 2025,
Endoglin as a BMP9 co-receptor in vascular endothelial cells: prodomain displacement and TGFBRII recruitment.
, Nat Commun, Vol: 17Endoglin (ENG) is a single-pass transmembrane protein highly expressed in vascular endothelial cells (ECs), where it plays fundamental roles in EC functions. ENG is implicated in several cardiovascular disorders including hereditary haemorrhagic telangiectasia, pulmonary arterial hypertension (PAH) and preeclampsia. However, molecular mechanisms underlying ENG function are not fully understood. Initially identified as a co-receptor for TGF-β signalling, ENG's extracellular domain was later found to only bind BMP9 and BMP10 with high affinity. The relationship between these two observations is unclear. Here, we provide evidence for two primary functions of co-receptor ENG. First, ENG efficiently displaces prodomains from BMP9 and BMP10, enabling effective capturing of both ligands from the circulation. Second, ENG binds to and recruits TGFBRII into the BMP9 signalling complex, thereby explaining ENG's involvement in both TGF-β and BMP9 pathways. We identify BMP9 target genes NOG and ADAMTSL2 as preferentially dependent on ENG and show that their transcript levels have strong positive correlation with ENG in human lung tissues; the expression levels of all three genes are significantly reduced in PAH. Our findings address an important gap in our understanding on ENG biology and provide crucial insight for therapeutic targeting these pathways in vascular diseases.
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Journal articleXiao S, Liu B, Argentieri MA, et al., 2025,
Proteomic signatures of smoking and their associations with risk of incident diseases and mortality in diverse populations.
, Nat CommunSmoking is the most important behavioural determinant of morbidity and mortality. Using machine learning on plasma levels of 2,917 proteins in the UK Biobank (n = 43,914), we develop a proteomic Smoking Index (pSIN) comprising 51 proteins that accurately distinguish current from never smokers (AUC = 0.95; 95% CI 0.94-0.95). Validation in the China Kadoorie Biobank (n = 3,977) shows similar accuracy (AUC = 0.91; 95% CI 0.89-0.92). pSIN is significantly associated with the risk of all-cause mortality and 18 major chronic diseases, including cardiovascular, renal, pulmonary, neurodegenerative, and cancer outcomes. Among current and former smokers, pSIN predicts death and 11 diseases independently of self-reported smoking history and lifestyle factors. Genome-wide analysis identifies 125 genes (e.g., ALPP, CST5, IL12B) associated with pSIN, while exposome analysis highlights maternal smoking, diet, physical activity, and air pollution as key modifiers. Notably, pSIN tracks recovery among former smokers and identifies those whose disease risks remain comparable to current smokers. These findings demonstrate that plasma proteomics effectively capture the biological imprint of smoking and predict smoking-related morbidity and mortality, offering a more nuanced, molecularly grounded assessment of individual variation in biological response to smoking.
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Journal articleHarbaum L, Klose H, Lund J, et al., 2025,
Metabolomic signature of right ventricular-pulmonary arterial coupling differentiates hemodynamic response to imatinib therapy in pulmonary arterial hypertension.
, J Heart Lung TransplantBACKGROUND: Right ventricular (RV) dysfunction is the leading cause of mortality in pulmonary arterial hypertension (PAH). Although RV metabolic remodeling in chronic pressure overload is recognized, the circulating metabolic signatures of RV-pulmonary arterial (PA) coupling and their clinical relevance remain poorly defined. METHODS: We first integrated pressure-volume-derived RV/PA metrics with untargeted plasma metabolomics in 33 PAH patients, using both network-based and single-metabolite analyses. Findings were replicated in 14 patients using echocardiographic surrogates. In 16 participants from the phase 2 PIPAH trial of imatinib, we examined longitudinal metabolite changes in relation to hemodynamic responses obtained from implanted devices. RESULTS: The end-systolic to arterial elastance ratio (Ees/Ea), a load-independent measure of RV contractility and RV-PA coupling, emerged as a central node in the metabolic network, while metrics related to afterload and RV stiffness were more peripherally located. In individual metabolite analyses, 9 metabolites were significantly associated with Ees/Ea and its echocardiographic surrogate, independent of potential confounders, including kidney and liver function. Pathway enrichment analysis confirmed a predominance of fatty acid metabolism, particularly acylcarnitines. In the PIPAH study cohort, individual-level analyses showed that reductions in acylcarnitine levels at 4 and 24 weeks of imatinib therapy discriminated patients with improved cardiac output (area under the curves 0.89 and 0.84). CONCLUSIONS: We identify a distinct circulating metabolomic signature, enriched in fatty acid metabolites, associated with RV-PA coupling in PAH. These metabolites may inform on the risk and trajectory of RV maladaptation during treatment and guide therapeutic decisions to optimize the benefit-harm ratio.
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Journal articleAl-Ansari D, Hu Y, Negrini NC, et al., 2025,
Three-dimensional modelling of lymphangiogenesis in-vitro using bioorthogonal click-crosslinked gelatin hydrogels
, Materials Today Bio, Vol: 35, ISSN: 2590-0064Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vessels, is crucial for maintaining tissue homeostasis and immune function. Despite recent advances in understanding the molecular mechanisms regulating lymphangiogenesis, most in vitro studies rely on traditional two-dimensional (2D) cell cultures, with limited replication of the complex microenvironment that governs lymphangiogenesis in vivo. Here, we present a three-dimensional (3D) lymphangiogenesis model using gelatin hydrogels modified with click-chemistry motifs (tetrazine and norbornene, GelTN), providing a biomimetic and mechanically tunable extracellular matrix (ECM) for lymphatic endothelial cells. By encapsulating human dermal lymphatic endothelial cells (HDLEC) spheroids in GelTN, we established a robust and reliable in vitro sprouting assay (<48 h duration) to investigate the effects of GelTN stiffness on lymphangiogenesis. HDLEC encapsulated in low GelTN concentrations exhibited enhanced sprouting in response to vascular endothelial growth factor (VEGF)-C stimulation, compared to HDLEC encapsulated in higher GelTN concentrations. We also provide evidence for the involvement of β3 integrin in lymphangiogenesis. The reduced sprout length upon β3 integrin inhibition further decreased with combined inhibition of α5β1, suggesting a synergistic interaction of the integrin subunits in controlling HDLEC-ECM mechanotransduction. GelTN hydrogels were also evaluated for their translational potential, demonstrating sustained release of VEGF-C in vitro and supporting cellular infiltration and neo-vessel formation following subcutaneous injection in an in vivo mouse model. Overall, these findings highlight the versatility of GelTN hydrogels as a platform for studying lymphangiogenesis and their potential use for therapeutic applications that require controlled growth factor delivery in tissue engineering and regenerative medicine.
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Journal articleSajjad N, Zhang H, Ng F, et al., 2025,
Improving medical students' research skills: a study on confidence and performance through in-course assessments [version 1; peer review: awaiting peer review]
, MedEdPublish, Vol: 15, ISSN: 2312-7996IntroductionResearch skills account for a core part of competent medical practice to improve patient outcome. Studies have highlighted the significance of supporting students learning experience during a research skills course by stimulating a research-oriented mindset and offering timely feedback. In this study, we aimed to evaluate the effectiveness of our research skills curriculum consisting of three in-course assessments (ICA), workshops and formative tutorials, on enhancing students’ confidence and performance in clinical research tasks.MethodStudents (n=26) completed an anonymised end-of-module survey on their self-perceived confidence rating before and after interventions. We aimed to quantify the relationship between the effectiveness of our in-course interventions, comprising workshops and tutorials, and students’ confidence rating (CR) and research proficiency (formative and summative assessment scores) using Likert scales. Within each teaching block, we compared students’ CR before and after each intervention, as well as the formative and summative assessment scores in each ICA using difference tests. We also performed univariate correlation tests between CR or student engagement and formative or summative ICA scores.ResultsStatistically significant increases in self-perceived CR after each intervention were observed in all ICAs. For each ICA, students obtained a significant score increase between formative and summative assessment. There was a gradual increase in students’ CR during the three ICAs. Post-workshop and post-tutorial CR levels were always higher compared to before the sessions. In ICA1, the formative score was positively correlated with pre-tutorial CR. Performance in the ICA 2 formative assessment was positively linked with pre-workshop CR. In ICA 3, the pre-abstract workshop CR was positively associated with formative lay summary and scientific abstract scores.ConclusionHere we demonstrate the effectiveness of educ
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Journal articleKeles M, Lawrie A, 2025,
Revisiting prostaglandin biology in pulmonary arterial hypertension: targeting the EP4/ANXA2 axis
, EUROPEAN HEART JOURNAL, ISSN: 0195-668X -
Journal articleDunmore BJ, Moore S, Jones RJ, et al., 2025,
BMP9 knockout impairs pulmonary vessel muscularisation and confers aberrant tamoxifen sensitivity
, Angiogenesis, Vol: 29, ISSN: 0969-6970Deleterious mutations in the GDF2 gene, encoding BMP9, are causative of pulmonary arterial hypertension and hereditary haemorrhagic telangiectasia. Paradoxically, BMP9 germ-line knockout (Gdf2−/−; Bmp9 KO) and double Bmp9 KO/conditional Bmp10 cKO (dKO) mice exhibit an attenuated response to PAH-inducing stimuli. We asked whether this contradiction is due to the pathological, physiological, or genetic consequences of BMP9 knockout. In Bmp9 KO mice we observed reduced pulmonary vascular smooth muscle cell (SMC) coverage and using RNA-seq analysis of Bmp9 KO mouse lungs identified two novel genes, COLQ and ITGA6, which were differentially regulated in a human PAH RNA-seq dataset. In order to study BMP10 loss, postnatal tamoxifen treatment was required to induce Bmp10 cKO. As previously reported, in dKO mice we observed cardiomegaly and splenomegaly, as well as hyperplasia and hemosiderosis in the pulmonary vasculature. Surprisingly, tamoxifen treated Bmp9 KO control mice phenocopied these pathological changes in dKO mice and downregulated SMC marker gene transcription. Loss of BMP10 is not critical for severe tissue remodelling in the lung, heart, and spleen, rather Bmp9 KO mice appear sensitive to tamoxifen and BMP9 loss is the primary cause of mild vessel remodelling due to a basal reduction of smooth muscle cell coverage. This study suggests that interaction of the BMP pathway with tamoxifen needs to be carefully considered when studying Bmp9 KO mice and urges caution in the context of tamoxifen use when studying cardiovascular and pulmonary disease models.
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Journal articleTaniguchi Y, Khamis R, Joner M, 2025,
Clinical needs and translational prospects of cardiovascular nanomedicine: Focus on intravascular and molecular imaging of atherosclerosis
, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 788, ISSN: 0006-291X -
Conference paperFoley M, Mohsin M, Ahmed-Jushuf F, et al., 2025,
Endocardial to epicardial blood flow ratio predicts the placebo-controlled efficacy of the coronary sinus reducer
, American-Heart-Association Scientific Sessions / American-Heart-Association Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322 -
Journal articleHartley A, Williams MC, Kaura A, et al., 2025,
Anti-Malondialdehyde Low-Density Lipoprotein Antibodies and Valvular Calcification: A Substudy of the SCOT-HEART Trial
, JOURNAL OF THE AMERICAN HEART ASSOCIATION, Vol: 14 -
Journal articleFicany A, Del Alamo M, Bernabeu C, et al., 2025,
Epistaxis Prevention, Treatment, and Future Perspectives for Hereditary Hemorrhagic Telangiectasia
, JOURNAL OF CLINICAL MEDICINE, Vol: 14
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