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Mechanotherapy is a groundbreaking approach to impact carcinogenesis. Cells sense and respond to mechanical stimuli, trans-lating them into biochemical signals in a process known as mechanotransduction. The impact of stress on tumor growth has been studied in the last three decades, and many papers highlight the role of mechanics as a critical self-inducer of tumor fate at the in vitro and in vivo biological levels. Meanwhile, mathematical models attempt to determine laws to reproduce tumor dynamics. This review discusses biological mechanotransduction mechanisms and mathematical-biomechanical models together. The aim is to provide a common framework for the different approaches that have emerged in the literature from the perspective of tumor avascularity and to provide insight into emerging mechanotherapies that have attracted interest in recent years., the MINECO-FEDER (Spain) research grant number EQC2018-004508-P, PID2019-106947RA-C22 RTI2018-098850-B-I00, Ministry of Science, Innovation and Universities of Spain, project numbers PID2020-115372RB-I00, Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía P18-RT-1653 PY18-RT-2422 & B-FQM-580-UGR20, Consejería de Universidad, Investigación e Innovación from Junta de Andalucía, P21.00182, Ministry of Science, Innovation and Univer-sities of Spain, FPU2017/01415, Universidad de Granada / CBUA

Anthropology has traditionally studied the origin and processes of violence worldwide. Violent death has been one of the manifestations of these processes, where the violated body contains a strong load of meanings when they are not culturally catered to. A type of applied anthropology linked to the forensic context, human rights, and humanitarian action has been contributing to the direct documentation of millions of bloody episodes. Peru has not been the exception; after a period of armed violence (1980–2000), there are tens of thousands of people dead, and people reported missing. Today, the aftermath is widely notorious. On the one hand, relatives continue to search for missing loved ones. On the other hand, there are landscapes and rural communities where there are still sites of clandestine deposits of dead bodies and body parts. A cultural, social, and humanitarian breakdown has been faced, where the bad death persists in the social imaginary of the communities, contaminating the cultural landscape of the populations. Forensic anthropology has been able to identify, register, and systematize these deathscapes, which still persist in liminality. New challenges must be conducted to tackle this issue.

The dichotomous behavior of superoxide dismutase-2 (SOD2) in cancer biology has long been acknowledged and more recently linked to different posttranslational forms of the enzyme. However, a distinctive activity underlying its tumor-promoting function is yet to be described. Here, we report that acetylation, one of such posttranslational modifications (PTMs), increases SOD2 affinity for iron, effectively changing the biochemical function of this enzyme from that of an antioxidant to a demethylase. Acetylated, iron-bound SOD2 localizes to the nucleus, promoting stem cell gene expression via removal of suppressive epigenetic marks such as H3K9me3 and H3K927me3. Particularly, H3K9me3 was specifically removed from regulatory regions upstream of Nanog and Oct-4, two pluripotency factors involved in cancer stem cell reprogramming. Phenotypically, cells expressing nucleus-targeted SOD2 (NLS-SOD2) have increased clonogenicity and metastatic potential. FeSOD2 operating as H3 demethylase requires H 2 O 2 as substrate, which unlike cofactors of canonical demethylases (i.e., oxygen and 2-oxoglutarate), is more abundant in tumor cells than in normal tissue. Therefore, our results indicate that FeSOD2 is a demethylase with unique activities and functions in the promotion of cancer evolution toward metastatic phenotypes.

Transcription stability enforces cellular identity and is tightly controlled by restrictions imposed on both transcription factor function and target gene accessibility. Progression of cancer to metastasis and multi-drug resistance requires fluid transcriptional programs that can explore different genomic landscapes to enable clonal expansion of aggressive and treatment resistant phenotypes. Here, we show that increased levels of H2O2produced in mitochondria leads to H3.1 oxidation at Cys96, a distinctive redox sensitive amino acid residue restricted to this histone variant, in the nucleus. The oxidation of Cys96 promotes the eviction of H3.1 from chromatin and its exchange with H3.3, thereby opening silenced portions of the chromatin. Mutation of Cys96 by an oxidation-resistant serine residue or quenching nuclear H2O2reversed chemotherapy resistance and drove established metastatic disease into remission. Together, these results show that increased mitochondrial H2O2production, characteristic of metabolic dysfunction, promotes transcriptional plasticity by removing structural chromatin restrictions imposed by the redox sensitive histone variant H3.1. We suggest that this new regulatory nexus between cancer metabolism and chromatin remodeling controls chromatin states that enable cancer progression and drug resistance acquisition.

Breast cancer survivors frequently present cardiac autonomic dysfunction. Physical activity (PA) has been associated with better cardiac autonomic modulation (CAM) in breast cancer survivors.This study aimed to analyze the association between CAM and PA levels performed in different domains (work and occupation, sport and exercise, and leisure time and commuting) in breast cancer survivors.This is a cross-sectional study with 99 breast cancer survivors (age, 55.3 ± 10.4 years). Cardiac autonomic modulation was assessed by heart rate variability, and PA levels at work and occupation, sport and exercise, and leisure time and commuting were assessed using the Baecke PA questionnaire. The sum of these 3 domains provided the total PA. The Mann-Whitney test was used to compare CAM between active and inactive women in different domains of PA.Cardiac autonomic modulation was similar between active and inactive women in the different domains (P.05). However, when considering the total PA, active breast cancer survivors presented higher SDNN (average standard deviation of all normal RR intervals) (20.0 ± 13.4 vs 28.8 ± 14.0; P = .008) and SD2 (standard deviation of the long-term intervals between consecutive heartbeats) indices (29.2 ± 17.3 vs 38.7 ± 19.9; P = .005) compared with their inactive counterparts.Breast cancer survivors with higher total PA presented better CAM compared with their less active peers.The results of this study are promising and show the importance of increasing PA levels in different domains for the maintenance of cardiovascular health among breast cancer survivors.

Introduction Lipoprotein(a) [Lp(a)] is an LDL-like molecule composed of a part of apolipoprotein(a) bounding covalently to apolipoprotein B-100. High plasma Lp(a) levels were associated with MACE in stable CAD patients. Recent research shows contradictory results in stable CAD patients with high Lp(a) plasmatic levels and impaired glucose metabolism in MACE occurrence. Purpose Investigate whether high Lp(a) levels were associated with MACE in CAD patients with impaired glucose metabolism, at an extended follow-up. Methods A prospective cohort of 1,127 CAD patients with impaired glucose metabolism (pre-diabetes and diabetes) was observed during 4.9±3.4 years. Pre-diabetes was considered when fasting plasma glucose ranged from 5.6 to 6.9 mmol/L, or hemoglobin A1c levels ranging from 5.7 to 6.4%. Lp(a) levels ≥30 mg/dL were considered high. Bivariate and multivariate Cox regression analysis evaluated the risk of Lp(a) ≥30 mg/dL for MACE occurrence. Kaplan-Meier curves estimated the survival probability for high and low Lp(a) levels. Results Of the patients with Lp(a) levels ≥30, 44.4% presented MACE and 32.0% had no MACE (p Conclusion Our study demonstrated that high Lp(a) levels were an independent predictor of MACE and cardiovascular mortality in a CAD population with impaired glucose metabolism. Lp(a) measurement may help further risk stratification for diabetes and pre-diabetes patients suffering CAD. With the recent development of drugs that selectively lower Lp(a) levels, this marker can become a clinical target for reducing CVD risk. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Introduction Coronary artery disease (CAD) is a dynamic inflammatory disease caused by atherosclerosis. GWAS showed that ZNF259 rs964184 encoding zinc finger protein (ZPR1) was associated with dyslipidemia and CAD. Recent research found that ZPR1 transcription is up-regulated in the brain of mice fed a high-fat diet, influencing the cell cycle, apoptosis, and RNA metabolism in neurons. This process at the heart vessels may increase oxidative stress and CAD. Purpose Study the association between the ZNF259 rs964184 C>G polymorphism with dyslipidemia and CAD susceptibility in a Portuguese population. Methods A case-control study was performed with 3,160 individuals, namely 1,723 CAD patients (mean age 53.3±7.9; 78.7% male) and 1,437 controls (mean age 52.8±7.8; 76.3% male). Participants were stratified into two age groups (55 years). ZNF259 rs964184 C>G was genotyped and analysed using the dominant model (CG+GG vs CC). Multivariate logistic regression was performed in both age groups to investigate whether rs964184 polymorphism was associated with dyslipidemia and CAD susceptibility. Results The dominant model of ZNF259 was associated with dyslipidemia (OR=1.85; 95% CI: 1.22–2.79; p=0.003) and CAD (OR=1.46; 95% CI: 1.02–2.09; p=0.036) in the younger population under 45 years. In the >55 years group, this model was associated with dyslipidemia (OR 1.46; 95% CI: 1.06–2.01; p=0.020) but not with CAD. After multivariate logistic regression, the CG+GG remained an independent risk factor for CAD susceptibility only in the population Conclusion ZNF259 rs964184 is a risk factor for dyslipidemia in the whole population. Dyslipidemia may up-regulate ZPR1 transcription, enhancing the vulnerability of coronary endothelial cells to both oxidative stress and inflammatory response, increasing CAD susceptibility. This mechanism seems more relevant at the cellular level in young patients representing a possible prophylactic and therapeutic target, especially in this age group. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Introduction The European Systematic Coronary Risk Evaluation (SCORE) has predicted a 10-year risk of CVD since 1986. It included only fatal CVD outcomes, underestimating the total CVD burden, especially for younger people. To counteract this issue, a new score was created (SCORE2) to estimate 10-year fatal and non-fatal CVD risk in Europeans without previous CVD or diabetes aged 40–69 years. Purpose Establish a comparison between SCORE and SCORE2 in terms of CV outcomes in a moderate-risk population. Methods A population of 1,178 individuals without CVD (mean age 53.3±6.9 years; 73.9 male) was stratified into three risk categories for SCORE and SCORE2: low, moderate and high-risk. Using t-test and Chi-square, we compared the two scores in terms of means and risk categories. Kaplan-Meier estimator evaluated MACE occurrence for each category of the two scores during an extended follow-up (mean of 5.2±3.4 years). MACE discriminative capacity of SCORE and SCORE2 was evaluated through C-index methodology. Results The means of the two scores were significantly different (p Conclusion SCORE2 enhanced the identification of individuals at higher risk of developing CVD and better discriminated MACE occurrence relatively to SCORE. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Introduction Coronary artery calcium (CAC) score has emerged as the most predictive cardiovascular risk marker in asymptomatic individuals, capable of adding prognostic information beyond the traditional risk factors (TRF). Genetic risk score (GRS) significantly improves cardiovascular genetic risk assessment at the individual level providing a more personalized measure of disease risk. Purpose We intend to evaluate which tool, added to TRF, is more valuable in predicting and discriminating cardiovascular events and death (MACE) - GRS or CAC score? Methods We performed a prospective study with 1153 participants without CAD history at baseline (74.2% male, age 51.7±8.3 years) during a mean follow-up of 5.4±3.4 years. We selected 14 SNPs previously associated with CAD presenting a risk (HR) for cardiovascular events ≥1. A weighted GRS was calculated, as the sum of these 14 risk alleles weighted by the corresponding effect size in prognostic (HR), and subsequently, subdivided into tertiles. CAC (Agatson) score was calculated in all participants and categorized into: low CAC (0≤CAC75). Two models were created with TRF baseline (hypertension, smoking, body mass index, dyslipidemia, diabetes, chronic kidney disease, physical inactivity): 1) plus wGRS and 2) plus CAC score categories. Cox Regression Analyses and C-statistic assessed the predictive and discriminative capacity of both models. Results For model 1, Cox regression presented an HR of 4.292 for TRF (p=0.007) and 2.713 for 3rd tertile of wGRS (0.036). A modest but statistically significant improvement in MACE discriminative capacity was verified by adding wGRS to TRF, increasing the C-statistic from 0.617 to 0.687 (ΔC=0.070; p=0.013). On the other hand, model 2 better discriminated MACE when the CAC score (C-statistic = 0.765) was added to TRF (ΔC=0.148; p=0.001). Cox regression displayed an HR of 4.42 for TRF (p=0.015) and an HR of 4.55 for high-risk CAC score (p=0.001). Conclusion Our results suggest that adding a polygenic risk score to conventional risk factors provides a modest improvement in the discrimination of first-onset MACE. However, the CAC score added to the traditional model allows better discrimination of MACE compared to wGRS. CAC score could be helpful for MACE prediction, at least in individuals belonging to the higher genetic risk group. However, further investigation is required before clinical implementation. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Genome-wide association studies have identified several loci linked to coronary artery disease, and coronary atherosclerosis progression. However, the impact of the genetic contribution to MACE occurrence in sub-clinical atherosclerosis is unknown. Purpose This study intended to assess the relationship between a set of single nucleotide popymorphism (SNP) associated with CAD by GWAS and the MACE occurrence in an asymptomatic population. After that evaluate whether a wGRS englobing these variants is useful to estimate the prognostic. Methods Prospective study performed in an asymptomatic cohort from GENEMACOR population-based sample of 1114 subjects aged 51.7±8.3, 74.2 male, without prior coronary artery disease. Coronary Artery Calcium (CAC) score was assessed by coronary computed tomography (Agatston method), and two categories were considered 1–99 and >100. 33 SNP were evaluate to assess the significantly associated with prognostic. A weighted (wGRS) was constructed as the sum of the risk alleles weighted by the corresponding effect size (HR). Cox regression analysis adjusted for the main risk factors, calcium score (CAC) and wGRS to assess the risk of MACE during follow-up. Kaplan Meier assessed the survival. Results Of the studied 33 SNPs previously associated with CAD (GWAS), only 4 presented the significant association with MACE occurrence: CDKN2B-AS1 rs4977574, HNF4A rs1884613, APOE rs7412/rs429358A and GJA4A rs 618675. After Cox regression analysis the wGRS remained in the equation (HR=2.834); p=0.012, together with CAC score (HR 3.35); p=0.012; diabetes (HR=2.398); p=0.032 and age (HR=1.056; p=0.049. WGRS above the median presented a worst survival rate (p=0.006). Conclusion The wGRS englobing: CDKN2B-AS1 rs4977574, HNF4A rs1884613, APOE rs7412/rs429358A and GJA4A rs 618675 is independently associated with cardiovascular events in an asymptomatic population. CDKN2B-AS1 rs4977574 gene expression modulates the progression and severity of vascular calcification in vascular smooth muscle cells (VSMCs), HNF1α-AS1 is an important regulatory molecule in cancer biology and cardiovascular disease (its expression may regulate VSMCs, and high expression promotes atheroprotection). More research is crucial for understand prognosis in asymptomatic population. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPE

Introduction TCF21 is a member of the basic helix-loop-helix (bHLH) transcriptor factor family, being critical for embryogenesis of the heart. It regulates epicardium-derived cells differentiation into smooth muscle (SMC) and fibroblast lineages. The biological roles of TCF21 in epicardial fate determination and the progression of atherosclerosis remains a controversial issue. Purpose Investigate the impact of the TCF21 rs12190287 G>C variant on the prognosis of a coronary artery disease (CAD) cohort. Methods A prospective study was performed with 1,713 CAD patients (mean age 53.3±7.8; 78.7% male) surveyed in terms of MACE occurrence in an extended follow-up of 5.0±4.3. TCF21 rs12190287 was genotyped and analysed using the dominant model (GC+CC) and, subsequently, compared with the wild-type GG to evaluate the survival probability by Kaplan-Meier. A Cox regression analysis with all the risk factors and genetic models was performed to assess the independent variables associated with the prognosis of CAD patients. Results GG wild genotype was present in 9.5% of the population, GC in 43.2% and the risk genotype CC accounted for 47.3% of the CAD patients. The dominant model GC+CC showed a worse survival throughout the follow-up period. After multivariate Cox regression analysis, this model remained in the equation as an independent risk factor for MACE occurrence with an HR of 1.41 (p=0.033) together with multivessel disease, physical inactivity, chronic kidney disease (CKD) and diabetes. Conclusion TCF21 rs12190287 is a risk factor for prognosis in our population. The role of this gene may influence fundamental SMC processes in response to vascular stress, accelerating atherosclerosis progression and may represent a target for future therapies. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Introduction The new SCORE2 provides risk estimates for the combined outcome of fatal and non-fatal cardiovascular disease (CVD) events, in contrast with SCORE's use for CVD mortality only. Genetic predisposition to CVD is not considered in SCORE2 for prevention and treatment. Purpose Evaluate the impact of adding a Genetic Risk Score (GRS) to the new European SCORE2 in MACE prediction and estimate the additional value in cardiovascular risk stratification in an asymptomatic Portuguese population. Methods A prospective study was performed in a population-based cohort of 1,100 individuals without known CVD and diabetes (mean age 53.3±6.9 years). For all included participants, SCORE2 was calculated and three risk categories were considered: low-, moderate- and high-risk. A 33-SNP GRS was constructed and two groups were analyzed: lower and higher than the GRS median. Kaplan-Meier survival curves were created and a Cox regression model was performed with the two scores to assess MACE risk. C-statistic methodology compared the model between SCORE2 solely and SCORE2 plus GRS. Results After Kaplan-Meier analysis for MACE occurrence, the high categories of SCORE 2 and GRS showed worst survival when compared to the lower categories (p Conclusions In this work, combining SCORE2 with multiple genetic loci gathered into a GRS, improved the identification of patients with the worst prognosis. This new tool may be of great utility in risk stratification in primary prevention. Larger prospective multicenter cohorts with longer follow-up should reproduce and validate these findings. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Introduction The new European SCORE2 estimates the combined risk of fatal and non-fatal cardiovascular (CV) events, in contrast with SCORE's use for CV mortality only. Although controversial, several studies point out that Coronary Artery Calcification (CAC) scoring could improve CV risk stratification in primary prevention. Purpose Assess the impact of including CAC score to the new SCORE2 in MACE prediction and CV risk stratification in an asymptomatic Portuguese population. Methods The new SCORE2 was calculated in a population-based cohort of 1,014 individuals (mean age 58.6±8.5 years) without known CV disease and diabetes. Population was stratified into three SCORE2 risk categories (low-, moderate- and high-risk). According to the Hoff's nomogram, CAC score was categorized into: low CAC (0≤CAC75). Kaplan-Meier survival curves were estimated and a multivariate regression analysis predicted the MACE risk for both scores. C-statistic methodology evaluated the ability of CAC when added to the SCORE2 model in MACE prediction. Results Kaplan-Meier curves showed that the highest categories of both scores presented a worst survival. Cox regression analysis showed that the highest categories of both CAC and SCORE2 remained in the equation with an increased MACE risk (HR) of 3.69 (p=0.008) and 9.87 (p=0.005), respectively, when compared with the lowest categories. C-statistic demonstrated that the predictive value for MACE increased from 0.668 (SCORE2 model) to 0.787 when CAC was included (p=0.012), showing a better predictive and discriminative capacity for MACE. Conclusions Our results highlight the importance of adding CAC score to SCORE2 in primary prevention to improve cardiovascular risk stratification and MACE risk prediction. Larger prospective multicenter cohorts with longer follow-up should reproduce and validate these findings. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Customer churn prediction is a valuable task in many industries. In telecommunications it presents great challenges, given the high dimensionality of the data, and how difficult it is to identify underlying frustration signatures, which may represent an important driver regarding future churn behaviour. Here, we propose a novel Bayesian hierarchical joint model that is able to characterise customer profiles based on how many events take place within different television watching journeys, and how long it takes between events. The model drastically reduces the dimensionality of the data from thousands of observations per customer to 11 customer-level parameter estimates and random effects. We test our methodology using data from 40 BT customers (20 active and 20 who eventually cancelled their subscription) whose TV watching behaviours were recorded from October to December 2019, totalling approximately half a million observations. Employing different machine learning techniques using the parameter estimates and random effects from the Bayesian hierarchical model as features yielded up to 92\% accuracy predicting churn, associated with 100\% true positive rates and false positive rates as low as 14\% on a validation set. Our proposed methodology represents an efficient way of reducing the dimensionality of the data, while at the same time maintaining high descriptive and predictive capabilities. We provide code to implement the Bayesian model at https://github.com/rafamoral/profiling_tv_watching_behaviour., 10 pages, 5 figures

Suppressor of cytokine signaling-1 (SOCS1) exerts control over inflammation by targeting p65 nuclear factor-κB (NF-κB) for degradation in addition to its canonical role regulating cytokine signaling. We report here that SOCS1 does not operate on all p65 targets equally, instead localizing to a select subset of pro-inflammatory genes. Promoter-specific interactions of SOCS1 and p65 determine the subset of genes activated by NF-κB during systemic inflammation, with profound consequences for cytokine responses, immune cell mobilization, and tissue injury. Nitric oxide synthase-1 (NOS1)-derived nitric oxide (NO) is required and sufficient for the displacement of SOCS1 from chromatin, permitting full inflammatory transcription. Single-cell transcriptomic analysis of NOS1-deficient animals led to detection of a regulatory macrophage subset that exerts potent suppression on inflammatory cytokine responses and tissue remodeling. These results provide the first example of a redox-sensitive, gene-specific mechanism for converting macrophages from regulating inflammation to cells licensed to promote aggressive and potentially injurious inflammation.

Background and Aims Incidence of endoscopic retrograde cholangiopancreatography (ERCP)-related adverse events varies between endoscopy units. We aimed to identify factors related to successful bile duct (BD) cannulation and to determine the incidence and predictive factors of post-ERCP adverse events. Methods About 1103 ERCPs were evaluated from a prospective database over a 4-year period and 57 were excluded: age Results Out of 1046 ERCPs analyzed, successful cannulation rate of native papilla of Vater was 91.3% (n = 639). Guidewire-assisted BD cannulation and choledocholithiasis were associated with higher native papilla cannulation rates (P = 0.02 and P Conclusion Choledocholithiasis is associated with a higher cannulation rate while malignant biliary stricture and acute gallstone pancreatitis are associated with a lower BD cannulation rate. Patients with native papilla have a significantly higher risk of PEP with the only factor associated with PEP being 2 or more unintentional pancreatic duct cannulations.

Dextrocardia with situs inversus totalis is a rare congenital abnormality. Most coronary artery bypass grafting surgeries in patients with dextrocardia were performed with anastomosis, using the right internal thoracic artery to revascularize the left anterior descending. It should be noted that in the literature there are few reports of coronary artery bypass grafting surgery, in a patient with this abnormality, its anatomical complexity constitutes a challenge in planning the surgical technique and the grafts to be used. We present an unusual case of a patient with situs inversus totalis and coronary artery disease who underwent coronary artery bypass grafting surgery making it a more technically complex procedure for surgeons, in addition to the difficulty in choosing grafts.

Significance: Reactive oxygen species (ROS) are now widely recognized as central mediators of cell signaling. Mitochondria are major sources of ROS. Recent Advances: It is now clear that mitochondrial ROS are essential to activate responses to cellular microenvironmental stressors. Mediators of these responses reside in large part in the cytosol. Critical Issues: The primary form of ROS produced by mitochondria is the superoxide radical anion. As a charged radical anion, superoxide is restricted in its capacity to diffuse and convey redox messages outside of mitochondria. In addition, superoxide is a reductant and not particularly efficient at oxidizing targets. Because there are many opportunities for superoxide to be neutralized in mitochondria, it is not completely clear how redox cues generated in mitochondria are converted into diffusible signals that produce transient oxidative modifications in the cytosol or nucleus. Future Directions: To efficiently intervene at the level of cellular redox signaling, it seems that understanding how the generation of superoxide radicals in mitochondria is coupled with the propagation of redox messages is essential. We propose that mitochondrial superoxide dismutase (SOD2) is a major system converting diffusion-restricted superoxide radicals derived from the electron transport chain into highly diffusible hydrogen peroxide (H(2)O(2)). This enables the coupling of metabolic changes resulting in increased superoxide to the production of H(2)O(2), a diffusible secondary messenger. As such, to determine whether there are other systems coupling metabolic changes to redox messaging in mitochondria as well as how these systems are regulated is essential.

Primary biliary cholangitis is an autoimmune disease that mostly affects women. It is uncommon in women of childbearing age and the diagnosis during pregnancy is rare and can be challenging. Described here is a case of primary biliary cholangitis first manifesting during pregnancy, with the onset of pruritus, jaundice, biochemical liver abnormalities and positive antimitochondrial antibodies. Although treatment with ursodeoxycholic acid was started at the time of diagnosis, there was a progressive worsening of cholestatic biochemical markers throughout pregnancy. In addition, fasting hyperglycemia with polyhydramnios was diagnosed, consistent with gestational diabetes. She had a spontaneous preterm delivery at 31 weeks of gestation, of a newborn who was admitted to the neonatal intensive care unit but who subsequently had no long-term sequelae of preterm delivery. A maternal postpartum flare occurred. Treatment with ursodeoxycholic acid was well tolerated during pregnancy and lactation. info:eu-repo/semantics/publishedVersion

Introduction Coronary Heart Disease (CAD) is a multifactorial disease, including environmental and genetic risk factors. Current smoking, dyslipidemia and diabetes have a significant impact in long- term mortality and morbidity. However, several genetic variants associated with CAD but not with traditional risk factors (TRFs) has been reported to improve prediction of events and extended mortality, in younger CAD people. Aim To evaluate the clinical utility of a GRS composed by variants from GWAS associated to CAD but not with TRF to predict life-long residual risk in patients under 55 years old and a low level of TRFs. Methods We conducted a prospective study with 573 consecutive patients aged 150 mg/ml). We analysed several biochemical markers and performed a GRS with variants not associated with TRFs (TCF21 rs12190287, CDKN2B-AS1 rs1333049, CDKN2B rs4977574, PHACTR1 rs1332844, MIA3 rs17465637, ADAMTS7 rs3825807, ZC3HC1 rs11556924, SMAD3 rs17228212 and GJA4 rs618675). We studied the GRS association with a primary composite endpoint of all-cause vascular morbidity and mortality including recurrent acute coronary syndrome (myocardial infarct and unstable angina), coronary revascularization (coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), re-hospitalization for heart failure, ischemic stroke and cardiovascular dead. Results A total of 573 patients were studied and followed up for a mean of 4.7±4.0 years. There were 169 recurrent cardiovascular events. The GRS was sub-divided into terciles, verifying that patients in the third tercile (high risk) had a higher number of risk alleles. Compared with the low-risk GRS tercile, the multivariate-adjusted HR for recurrences was 1.520 (95% CI 1.011–2.286); p=0.044 for the intermediate-risk group and was 2.051 (95% CI 1.382–3.044); p Conclusions A multilocus GRS may identify young coronary disease patients with a low level of TRFs but at significant risk of long-term events recurrence. The genetic information may improve prediction discrimination, and reclassification over the conventional risk factors alone, providing better cost-effective therapeutic strategies. Funding Acknowledgement Type of funding sources: None. Figure 1

Introduction Epicardial adipose tissue (EAT) volume can be noninvasively detected by CT and has been suggested to predict major adverse cardiovascular events (MACE). Framingham Risk Score is one of a number of scoring systems used to determine an individual's chances of developing cardiovascular disease, hence identifying who is most likely to benefit from prevention. Objectives The purpose of this study was to determine net reclassification improvement (NRI) and improved risk prediction based on EAT volume, in comparison to a traditionally known cardiovascular risk score, such as the Framingham. Methods 895 asymptomatic volunteers were prospectively enrolled in a single Portuguese center (mean age 51.9±7.7, 78.5% male) and underwent a median follow-up time of 3.7 years (IQR 5.0). EAT volume was measured by Cardiac Computed Tomography (CCT) using a modified simplified method. For NRI assessment, EAT volume as a continuous variable was added to the Framingham Risk Score. Results After 3.7 median years of follow-up, 27 patients developed a MACE. Using NRI, the net proportion of events (netNRIe) that assigned a higher risk was 33.3% (better reclassified), and the net ratio of non-events (netNRIne) was 24.7%, resulting in a net reclassification index (netNRI) of 58.0%. When the new marker was included in the model, 58.0% of patients were better reclassified. In our work, a total of 33.3% of patients who suffered events (n=27) were correctly reclassified and assigned a higher risk. Conclusion EAT volume results in a high reclassification rate in an asymptomatic, low-risk population, demonstrating the benefit of this marker beyond traditional risk assessment models. Our study supports its application, especially in carefully selected individuals. Funding Acknowledgement Type of funding sources: None. Figure 1

Introduction Epicardial adipose tissue (EAT) is an emerging cardiovascular risk marker. It has been suggested to be an inflammatory mediator with a role in subclinical atherosclerosis and coronary artery disease. However, its prognostic relevance in hard clinical outcomes remains thoroughly unexplored in the literature. Purpose Evaluate the prognostic relevance of EAT, regarding the occurrence of major adverse cardiovascular events (MACE) in an asymptomatic population. Methods 895 asymptomatic volunteers were prospectively enrolled in a single Portuguese center (mean age 51.9±7.7, 78.5% male) and underwent a median follow-up time of 3.7 years (IQR 5.0). EAT volume was measured by Cardiac Computed Tomography (CCT) using a modified simplified method. Participants were distributed into two groups, above and below the EAT-volume median. We compared both groups regarding the occurrence of MACE through univariate analysis, Kaplan-Meier Survival curves and log-rank test. Association to subclinical atherosclerosis was addressed using correlation between EAT volume and calcium score (Agatson). Results There is a strong correlation between EAT volume and calcium score (r=0.205, p Conclusion In an asymptomatic population, EAT volume seems to be related to subclinical atherosclerosis and to the occurrence of adverse cardiovascular events on long-term follow-up. Our study addresses some unanswered questions, such as the prognostic relevance of EAT as an emerging cardiovascular risk marker. Funding Acknowledgement Type of funding sources: None.

Background Hepatocyte nuclear factor4 A (HNF4A) gene was considered by GWAS associated with atherosclerosis and CAD susceptibility. Loss-of-function mutations in human hepatocyte nuclear factor 4α (HNF4α), a transcriptor factor encoded by the HNF4A gene, are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. Aim We propose identifying the genetic predisposition to atherosclerosis progression and events occurrence or regression and better prognosis, through a cohort study from GENEMACOR population. Methods We investigated a cohort of 1,712 patients who underwent coronary angiography with more than 70% stenosis of at least one main coronary vessel. 33 SNPs associated with the risk of CAD in previous GWAS were genotyped by TaqMan assays methodology. We evaluated the best genetic model associated with CAD prognosis (events) with a 95% CI in bivariate analysis. The hazard function was performed by a Cox survival regression model adjusted for age, sex, type 2 diabetes, hypertension, and hypercholesterolemia, to evaluate their relationship with the event's incidence. Finally, we constructed Kaplan–Meier cumulative-event curves for the significant genetic variants. Results Our evaluation revealed a SNP paradoxically associated with protection from atherosclerosis progression and events occurrence: rs1884613 C>G in the HNF4A gene on chromosome 20 dominant model [OR=0.653; 95% CI (0.522–0.817); p=0.0002]. Cox survival regression model showed a CAD protective effect of HNF4A with a Hazard ratio (HR) of 0.771; p=0.007. The Kaplan-Meier cumulative event analysis disclosed that the CG+GG vs CC genotype of rs1884613 HNF4α was associated with a better prognosis (Breslow test, p=0.004) at the end of the follow-up. Conclusion We identified, in this study, one SNPs paradoxically associated with a better CAD prognosis rs1884613 in HNF4A. The HNF4A gene variants could induce loss of HNF4α function, modifying and modulating hepatic lipase and lipid metabolism conferring a beneficial effect on atherosclerosis progression and events occurrence. Funding Acknowledgement Type of funding sources: None.

Background Metabolic syndrome (MetS) is a clinical condition composed of metabolic and cardiovascular risk factors, such as abdominal obesity, hyperglycemia, dyslipidemia and hypertension. Many patients with MetS suffer major adverse cardiovascular events (MACE) that are not adequately identified by traditional risk assessment, suggesting the need for early detection of subclinical coronary heart disease to identify those at high-risk. Coronary artery calcification (CAC) screening has added utility in categorizing patients with low, intermediate and high cardiovascular risk. Purpose Evaluate the prognostic role of CAC score in asymptomatic population patients with metabolic syndrome in cardiovascular events risk prediction. Methods A total of 1,122 asymptomatic individuals without known coronary heart disease, enrolled from GENEMACOR study, were followed for a mean of 5.3±3.4 years for the primary endpoint of all-cause of cardiovascular events. All were referred for computed tomography for the CAC scoring assessment. According to the Hoff's nomogram, 3 categories were created: low CAC (0≤CAC75). In a subgroup of 507 individuals with MetS and 615 controls, CAC values were compared by T-student and association of CAC severity with events occurrence was evaluated. Finally, a logistic regression model adjusted for CAC severity was performed in patients with MetS. Results Among our population, the extent of CAC differs significantly between men and women in the same age group. Patients with Mets (23.2%, n=115) had higher CAC scores than controls (219.0±486.0 vs 115.8±370.8, p Conclusion Our results point to the importance of the inclusion of CAC screening in patients with MetS to further stratify those patients that, despite tight control of cardiovascular risk factors, may benefit from more intensive therapies. This tool is a useful and straightforward method that could have a significant impact on the prognosis of future cardiovascular disease in patients with MetS. Funding Acknowledgement Type of funding sources: None.

Introduction TCF21 is expressed in cells that migrate into the developing plaque facilitating the repair of the vessel wall. However, the rs12190287 risk allele (C) of TCF21 can lead to reduced TCF21 expression being a risk factor for CAD. Purpose Investigate whether the variant rs12190287 G>C of TCF21 gene represents a risk factor for CAD in a Southern European population. Methods Case-control with 3139 individuals, 1723 CAD patients and 1416 controls, adjusted for age and gender. Genotyping of TCF21 rs12190287 G>C was performed by TaqMan Real-Time PCR. CAD association of each genetic model was evaluated. Multivariate logistic regression analysis adjusted for confound variables: smoking status, dyslipidemia, diabetes, physical inactivity, and hypertension, was made. Results TCF21 rs12190287 G>C has shown significant genotypic differences between cases and controls: GG 9.5% vs 11.9%; GC 43.2% vs 46.5% and CC 47.3% vs 41.6%. CAD risk was significant in all models: dominant (OR 1.28; 95% CI: 1.02–1.61; p=0.033); recessive (OR 1.26; 95% CI: 1.09–1.45; p=0.001); additive (OR 1.20; 95% CI: 1.08–1.34; p=0.001). After multivariate analysis, TCF21 variant was independently associated with CAD. Conclusion TCF21 variant rs12190287 G>C may be a risk factor for CAD. It is plausible that TCF21 loci exert its protective effect by promoting infiltration of fibromyocytes in the coronary wall lesion and fibrous layer and loss of TCF21 expression can result in fewer fibromyocytes to fibrous cap increasing vulnerability of the plaque. Funding Acknowledgement Type of funding sources: None. Variables associated with CAD risk