Background Long-COVID syndrome is a public health issue, affecting millions of individuals worldwide. However, the pathophysiological mechanisms underlying the syndrome’s sequelae are still under investigation. Adiponectin has been implicated with acute SARS-CoV2 infection, while its role in Long-COVID remains obscure. The aim of this study is to investigate the potential association of adiponectin and SNPs of adiponectin pathway with Long-COVID.Materials and methods A single-center cross-sectional observational study was conducted, investigating the potential association of adiponectin and SNPs of adiponectin pathway with Long-COVID in 159 individuals, who were presented at the COVID-19 outpatient re-evaluation office. Adiponectin blood levels and detection of SNPs ADIPOQ rs1501299, ADIPOQ rs2241766, ADIPOR2 rs16928751, PPARA rs1800206 and PPARG rs1801282 were measured 3 months after acute COVID-19.Results ADIPOQ rs1501299 was the only SNP significantly associated with the progression of symptoms after the acute SARS-CoV2 infection and the development of Long-COVID syndrome. Homozygous GG genotype individuals exhibited increased risk for sequelae of Long-COVID (OR 2.0, 95% CI 1.1, 3.7, p = 0.023), particularly fatigue (OR 2.4, 95% CI 1.2, 5.0, p = 0.014), compared to the T allele carriers, independently of age, sex, BMI, waist to hip ratio, comorbidities and severity of acute infection (OR 2.2, 95% CI 1.2, 4.3, p = 0.013 and OR 3.1, 95% CI 1.4, 6.7, p = 0.004 respectively). Adiponectin levels were correlated with obesity and severity of acute SARS-CoV2 infection, but not with Long-COVID symptoms.Conclusion ADIPOQ rs1501299 could potentially serve as a genetic marker, contributing to risk stratification of developing Long-COVID syndrome.

The management of high-bleeding risk (HBR) patients undergoing percutaneous coronary intervention (PCI) for an acute coronary syndrome (ACS) remains a significant challenge, requiring careful balancing of ischemic prevention and bleeding avoidance. Bleeding risk reduction in patients with HBR treated with newer-generation drug-eluting stents includes P2Y12 inhibitor intensity de-escalation, shortening of the dual antiplatelet therapy (DAPT) duration and monotherapy with a P2Y12 inhibitor. Although data for HBR patients are limited, an individualized approach is required. Preference for a short DAPT duration and use of clopidogrel where indicated may reduce bleeding incidence without incurring ischemic risk. Pharmacogenomic testing for CYP2C19 helps personalize antiplatelet therapy in specific patient subgroups. We herein discuss current data and limitations of DAPT strategies in the understudied HBR patient population with ACS undergoing PCI. A literature search of PubMed/MEDLINE and Embase (inception-January 2026) identified randomized trials, meta-analyses, registries, and major guidelines (ESC, ACC/AHA, JCS) on ACS, high-bleeding risk, CYP2C19-guided antiplatelet strategies, de-escalation, and monotherapy. Individualized antiplatelet therapy, genetic characteristics and clinical parameters, should be integrated in the management of such patients. Clopidogrel pharmacogenomics and modern monotherapy or short DAPT strategies promise improved safety and efficacy, with the patient at the center of the therapeutic decision.

Background/Objectives: Among other substrates, the a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) protease degrades thrombospondin-5 (the cartilage oligomeric protein, COMP), thrombospondin-1 (TSP-1) and the tissue inhibitor of metalloproteinases-1 (TIMP-1) indicating a potential role of ADAMTS7 expression on coagulation cascade, tissue remodeling and wound healing. We analyzed the potential effect of direct oral anticoagulant (DOAC) treatment on ADAMTS7 promoter methylation and followed it over time to assess whether DOACs epigenetically modulate ADAMTS7 and induce pathways associated with coagulation or endothelium repair machinery. Methods: Eighty-four DOAC-treated atrial fibrillation (AF) patients followed-up from baseline (t0) to 7 days (t1, n = 70) and 28 days of treatment (t2, n = 62) and 19 non-AF controls were included in the study. Genomic DNA was extracted from blood at all timepoints and was bisulfite-converted prior to methylation analysis. ADAMTS7 promoter DNA methylation was analyzed with MIP-qMSP-PCR. Results: A total of 16 minor bleeding events occurred. The baseline percentage of ADAMTS7 methylation did not differ between AF patients and controls (15.8% vs. 16.1%, p = 0.908). In the patient cohort, DOAC therapy marginally decreased ADAMTS7 methylation from t0 to t2 (15.2% vs. 14.0%, p = 0.044). This ADAMTS7 demethylation from t0 to t2 was statistically significant only in patients experiencing bleeding (17.1%. vs. 13.4%, p = 0.010 in bleedings, 14.5% vs. 14.2%, p = 0.561 in non-bleedings). No other differences were observed. Conclusions: ADAMTS7 is demethylated during DOAC-related bleedings, a mechanism potentially leading to COMP degradation and thus thrombin-induced platelet aggregation, as well as the induction of endothelium repair through different ADAMTS7-dependent pathways.

miR-27a-3p targets several proteins on the coagulation cascade. The potential effect of direct oral anticoagulants (DOACs) treatment on miR-27a-3p expression and their broader regulative effect on anticoagulation is unknown. Fifty-nine atrial fibrillation patients treated with rivaroxaban ( n = 19), apixaban ( n = 27) or dabigatran ( n = 13), were included in the study. miR-27a-3p expression was analyzed at baseline and after 7 days of DOAC therapy by using a predesigned TaqMan assay. Relative quantitation of miR-27a-3p expression was calculated and compared in pooled population and in different sample groups. DOAC therapy did not alter miR-27a-3p expression (0.80 fold-change, p = 0.486, pooled population; 0.839 fold-change, p = 0.706, rivaroxaban; 0.921 fold-change, p = 0.800, apixaban; 0.733 fold-change, p = 0.540, dabigatran). miR-27a-3p expression did not differ between controls and bleeding cases (0.833 fold-change, p = 0.588, baseline). Female patients had a trend towards increased baseline expression (1.564 fold-change, p = 0.177) and reduced expression after DOAC treatment (0.683 fold-change, p = 0.243) compared to male patients. Despite the regulatory role of miR-27a-3p on coagulation cascade, treatment with DOACs did not alter its expression. However, additional studies in different ethnic groups are necessary to fully elucidate the effect, if any, of DOACs on miR-27a-3p expression. Graphical Abstract

Background/Objectives: Identification, monitoring, and modulation of biochemical markers that increase risk of severe illness and death from COVID-19 are crucial for effective disease treatment. This study aims to investigate the prognostic value of baseline troponin, D-dimers, fibrinogen, and D-dimers/fibrinogen ratio (DFR) as biomarkers for mortality in remdesivir-treated patients, and additionally, to investigate the impact of remdesivir treatment on troponin, D-dimers, fibrinogen, and DFR levels during disease course. Methods: We retrospectively analyzed the demographic, biochemical, and clinical characteristics of 549 (47.5% male, mean age 69.6 ± 14.7) hospitalized COVID-19 patients, all treated with remdesivir. Results: A total of 106 patients (19.3%) died during hospitalization. Elevated baseline troponin levels and D-dimers increased risk of death (HR 2.374, 95% CI 1.343–4.197; p = 0.003, adjusted for comorbidities and HR 1.862, 95% CI 1.127–3.076, p = 0.015, unadjusted, respectively). After remdesivir treatment, death risk was increased by elevated troponin (HR 2.010, 95% CI 1.219–3.316, p = 0.006), D-dimers (HR 2.207, 95% CI 1.254–3.882, p = 0.006) and DFR (HR, 3.816, 95% CI 1.567–9.291, p = 0.003) levels, in models adjusted for age, sex, and comorbidities. Remdesivir treatment decreased fibrinogen levels both in survivors (p < 0.001) and non-survivors (p < 0.001). In survivors, remdesivir treatment significantly decreased troponin levels (p < 0.001) and D-dimers (p < 0.001), whereas in non-survivors, it increased DFR (p < 0.001) and D-dimers (p < 0.001). Conclusions: In addition to its antiviral action, remdesivir treatment was associated with changes in coagulation biomarkers, potentially preventing patients from the COVID-19-provoked hypercoagulable state. Troponin, D-dimers, and DFR hold a critical role in predicting mortality risk among COVID-19 patients treated with remdesivir and can aid in identifying individuals at increased risk of death.

To investigate the genotype frequencies of club cell secretory protein (CC16) polymorphisms in preterm neonates and explore their association with respiratory distress syndrome (RDS), and bronchopulmonary dysplasia (BPD). A prospective cohort study was conducted including 187 preterm neonates of ≤ 34 weeks of gestational age. Genotype frequencies of rs4963506, rs12270961, and rs3741240 CC16 polymorphisms were detected, comparing the CC16 polymorphisms between neonates with versus without RDS, and with versus without BPD. Serum CC16 was measured, when available, on the first and fourteenth postnatal days. A significant association of increased risk of RDS was detected for the homozygous GG rs4963506 variant (OR 3.03, 95

Abstract Introduction Atrial fibrillation (AF) and Type 2 Diabetes Mellitus (T2DM) are two closely interconnected conditions, sharing a complex relationship within cardiac pathophysiology. Common risk factors such as obesity, hypertension, inflammation, and endothelial dysfunction contribute to their coexistence. T2DM is known to drive cardiac fibrosis and promote electrical and structural remodeling of the heart, creating a substrate conducive to AF onset, while AF in T2DM patients increases the risk of adverse cardiovascular outcomes, such as stroke. Understanding this complex relationship is pivotal for improving the therapeutic and preventive strategies for these patients. This study aims to examine the proteomic differences between AF patients with and without T2DM, providing novel insights into pathophysiological mechanisms and identifying novel therapeutic targets and biomarkers. Methods In total, 14 AF patients undergoing open-heart surgery, comprising of 6 T2DM individuals and 8 non-T2DM individuals have been included. The mean age of the T2DM patients was 69.5 ± 10 years, while the non-T2DM was 69.3 ± 8.2 and BMI was 29.2 ± 2.9 and 29.5 ± 3 respectively. Right atrial appendages (RAA) from these patients were obtained in an RNA stabilization solution during open-heart surgery and processed using the phenol-based method for protein extraction. The proteins were digested with trypsin to generate peptides, followed by an additional clean-up step using C18 pipette tips. The prepared peptide samples were analyzed by employing a label-free-based quantitative (LFQ) approach, using a C18 (75cmx75cm) column. Proteomic analysis was performed using a Nano liquid chromatography system coupled to tandem mass spectrometer (nano LC-MS/MS), followed by a comprehensive bioinformatics analysis, using appropriate software. Results A total of 1548 proteins were identified, of which 899 could be quantified using LFQ analysis. Applying strict significance criteria, including FDR <0.1 and Abundance ratio (AR)>2 or <0.5, we identified 100 differential expressed proteins, with 21 upregulated and 79 downregulated in T2DM (Fig.1). Most notably, DPP9 and ATP1A2 were overexpressed in hearts of AF patients with T2DM (AR=100), while INPPL1 and ARID5A were underexpressed (AR=0.01), thereby representing attractive therapeutic targets. In pathway enrichment analysis (Fig.2), the dysregulated proteins participate in noteworthy pathways, including Non-alcoholic fatty liver disease (NAFLD), Type II diabetes mellitus, and Insulin signaling pathway. Conclusion Given the increased morbidity associated with the coexistence of AF and T2DM, there is a pressing need for novel therapeutic strategies tailored to this patient population. While AF and T2DM share certain molecular characteristics in the heart, this study emphasizes the necessity for further evaluation and validation of the distinct proteomic signatures identified.Fig.1:Volcano PlotFig.2:Protein Enrichment Network

Direct oral anticoagulants (DOACs) are the standard treatment for thromboembolic protection in atrial fibrillation (AF) patients. Epigenetic modifications, such as DNA methylation and microRNAs, have emerged as potential biomarkers of AF. The epigenetics of DOACs is still an understudied field. It is largely unknown whether epigenetic modifications interfere with DOAC response or whether DOAC treatment induces epigenetic modifications. To fill this gap, we started the miR-CRAFT (Circulating microRNAs and DNA methylation as regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation) research study. In miR-CRAFT, we follow, over time, changes in DNA methylation and microRNAs expression in naïve AF patients starting DOAC treatment. The ultimate goal of miR-CRAFT is to identify the molecular pathways epigenetically affected by DOACs, beyond the coagulation cascade, that are potentially mediating DOAC pleiotropic actions and to propose specific microRNAs as novel circulating biomarkers for DOAC therapy monitoring. We herein describe the study design and briefly present the progress in participant enrolment.

Aim: MicroRNA 27a (miR-27a) regulates post-transcriptionally DPD activity. We have analyzed the association of MIR27A rs895819T>C variation, that modulates miR-27a expression, with fluropyrimidine-induced toxicity. Materials & methods: MIR27A rs895819T>C genotyping was conducted by TaqMan® allelic discrimination assay in 313 FP-treated cancer patients. Results: In overdominance (TC vs TT + CC), TC genotype was associated with grade 3-4 toxicity (p = 0.002), any grade toxicity (p = 0.052), and delayed drug administration or therapy discontinuation (p = 0.038). Odds of grade 3-4 toxicity were increased by both DPYD deficiency (OR: 8.923; p = 0.006) and MIR27A rs895819 TC genotype (OR: 3.865; p = 0.002). Conclusion: MIR27A rs895819 TC genotype is an independent risk factor for fluoropyrimidine-associated toxicity in the Greek population. Thus, MIR27A rs895819TC patients can be closely monitored for fluoropyrimidine-induced severe toxicity.

Background/Objectives: MIR27A rs895819 polymorphism has emerged as a potential additional pharmacogenomic marker of fluoropyrimidine response. Current evidence on its potential effect on miR-27a expression, which represses DPD activity, leading to DPD deficiency and increased fluoropyrimidine-associated toxicity risk, is scarce and inconsistent. We have analyzed the effect of MIR27A rs895819 polymorphism on miR-27a-3p plasma expression levels under different models of inheritance to contribute further evidence on its plausible biological role in miR-27a expression. Methods: A total of 59 individuals with no medical history of cancer were included in this study. MIR27A rs895819 genotyping and miR-27a-3p expression were analyzed by using predesigned TaqMan assays. Results: The frequency of TT, TC, and CC genotypes was present at a prevalence of 50.8%, 44.1%, and 5.1%, respectively. Individuals carrying the CC genotype presented with decreased miR-27a-3p expression (0.422 fold-change versus TT, p = 0.041; 0.461 fold-change versus TC, p = 0.064), whereas no differences were present between TT and TC individuals (1.092 fold-change, p = 0.718). miR-27a-3p expression was decreased in CC individuals under a recessive model of inheritance (0.440 fold-change, p = 0.047). No differences were found in dominant (TT vs. TC+CC, 0.845 fold-change, p = 0.471) or over dominant (TT+CC vs. TC, 0.990 fold-change, p = 0.996) models of inheritance. Conclusions: MIR27A rs895819CC genotype leads to severely reduced miR-27a-3p expression in plasma. Further study of this association is warranted in cancer patients to apply MIR27A genotyping in therapeutics to identify fluoropyrimidine-treated patients who are at a decreased risk of experiencing fluoropyrimidine-induced severe toxicity.

Aim: We herein inferred the genetic diversity of CYP450 isoenzymes to predict the percentage of patients who need dose adjustment in drugs used in psychiatry.Materials & methods: Data of 784 Greek patients receiving psychiatric care who were genotyped for CYP2D6, CYP2C19, CYP1A2, CYP3A5 and CYP2C9 isoenzymes were inferred to gene-drug pairs according to the US FDA, Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group annotations and published literature.Results: Atypical metabolism was found for 36.8% of patients in CYP2D6, 49.2% in CYP2C19, 45% in CYP1A2, 16.7% in CYP3A5 and 41.8% in CYP2C9. Dosage adjustment need was estimated for 10.2% of venlafaxine, 10.0% of paroxetine, 6.4% of sertraline, 30.8% of citalopram, 52.1% of escitalopram, 18.2% of fluvoxamine, 54.1% of tricyclic antidepressants, 16.7% of zuclopenthixol, 10.6% of haloperidol and 13.3% of risperidone treated patients.Conclusion: Clinical psychiatric pharmacogenomic implementation holds promise to improve drug effectiveness and safety.

BACKGROUND:Fluoropyrimidine-induced toxicity is a main limitation of therapy. Currently, polymorphisms in the DPYD gene, which encodes the 5-FU activation enzyme dihydropyrimidine dehydrogenase (DPD), are used to adjust the dosage and prevent toxicity. Despite the predictive value of DPYD genotyping, a great proportion of fluoropyrimidine toxicity cannot be solely explained by DPYD variations. OBJECTIVE:We herein summarize additional sources of DPD enzyme activity variability, spanning from epigenetic regulation of DPYD expression, factors potentially inducing protein modifications, as well as drug-enzyme interactions that contribute to fluoropyrimidine toxicity. RESULTS:While seminal in vitro studies provided evidence that DPYD promoter methylation downregulates DPD expression, the association of DPYD methylation with fluoropyrimidine toxicity was not replicated in clinical studies. Different non-coding RNA molecules, such as microRNA, piwi-RNAs, circular-RNAs and long non-coding RNAs, are involved in post-transcriptional DPYD regulation. DPD protein modifications and environmental factors affecting enzyme activity may also add a proportion to the pooled variability of DPD enzyme activity. Lastly, DPD-drug interactions are common in therapeutics, with the most well-characterized paradigm the withdrawal of sorivudine due to fluoropyrimidine toxicity deaths in 5-FU treated cancer patients; a mechanism involving DPD severe inhibition. CONCLUSIONS:DPYD polymorphisms are the main source of DPD variability. A study on DPYD epigenetics (both transcriptionally and post-transcriptionally) holds promise to provide insights into molecular pathways of fluoropyrimidine toxicity. Additional post-translational DPD modifications, as well as DPD inhibition by other drugs, may explain a proportion of enzyme activity variability. Therefore, there is still a lot we can learn about the DPYD/DPD fluoropyrimidine-induced toxicity machinery.

Purpose Vitamin D deficiency has been associated with the occurrence of obstructive sleep apnea syndrome (OSAS). Megalin ( LRP2 ) and cubilin ( CUBN) are implicated in vitamin D metabolism, whereas LRP2 and CUBN polymorphisms have been previously associated with variable serum vitamin D levels. The present study aimed to evaluate the role of LRP2 rs2228171 c.8614C > T and CUBN rs1801222 c.758A > G polymorphisms in OSAS susceptibility, independently or in synergy with vitamin D levels. Methods Vitamin D serum concentration of consecutive individuals was measured. PCR–RFLP was used for LRP2 rs2228171 and CUBN rs1801222 genotyping. Results A total of 176 individuals was enrolled, including 144 patients with OSAS and 32 controls. Frequency of LRP2 rs2228171 c.8614 T and CUBN rs1801222 c.758G alleles was estimated at 22.4% and 79.8%, respectively. LRP2 and CUBN polymorphisms were not associated with OSAS occurrence (rs2228171Τ allele: 22.9% in OSAS group vs. 20.3% in controls, p = 0.651; rs1801222A allele 19.4% in OSAS group vs. 23.4% in controls, p = 0.471). Frequency of CUBN rs1801222A allele carriers was increased in patients with moderate or severe OSAS compared to mild OSAS ( p = 0.028). Patients with OSAS homozygous for LRP2 CC and CUBN GG genotypes had lower vitamin D serum concentration compared to controls carrying the same genotype (18.0 vs 27.0 ng/mL, p = 0.006 and 19.0 vs 27.5 ng/mL, p = 0.007, respectively). Conclusion CUBN rs1801222 polymorphism may affect OSAS severity. Among other factors, low vitamin D concentration is associated with OSAS occurrence, irrespectively of LRP2 and CUBN polymorphisms.

Abstract Introduction Direct Oral Anticoagulants (DOACs) are recommended as first-line treatment in atrial fibrillation (AF) patients. Despite their benefits and effectiveness, several patients experience bleeding events. No studies have addressed how epigenetic modifications may affect DOAC treatment. To fill this gap, we are conducting a study aiming to follow in time changes of DNA methylation patterns in naïve AF patients starting DOAC therapy. Herein, we present our findings regarding DNA methylation analysis of ADAM Metallopeptidase with Thrombospondin Type 1 Motif 7 (ADAMTS7), a protease that acts on the cardiovascular system. Methods A total of 76 AF patients treated with dabigatran, rivaroxaban, or apixaban and 22 non-AF controls were included. Genomic DNA has been isolated at baseline (t0, controls and patients), and for patients at 7 (t1) and 28 (t2) days of DOAC treatment. Blood genomic DNA was isolated and bisulfite converted prior to methylation analysis. Promoter DNA methylation of ADAMTS7 was analyzed with qMSP-PCR. Results In our study, no major bleeding or thrombotic events were recorded. A total of 16 minor bleeding events occurred. The percentage of ADAMTS7 methylation at baseline did not differ between patients and controls (16,8% vs. 14,8%, p=0,138). In patient cohort, DOAC therapy did not alter ADAMTS7 methylation at different timepoints (16,8% at t0, 15,7% at t1 and 14,3% at t2, p=0,293 from t0 to t1, p=0,06 from t0 to t2 and p=0,205 from t0 to t1). When patients were categorized into experiencing bleeding events (cases) or not (controls), ADAMTS7 was demethylated from t0 to t2 (-3,7% in cases vs. -1.2% in controls, p=0.015) and from t1 to t2 (-2,1% in cases vs. -1,1% in controls, p=0.034). In adjusted regression analysis, bleeding was associated with ADAMTS7 demethylation (β=-2,973, 95%CI -5,481, -0,466, p=0,021). Conclusion This is the first study of DNA methylation on DOACs. Our findings suggest that the methylation of the promoter of ADAMTS7 is reduced when DOAC-related bleeding occurs, increasing its expression levels, and may subsequently promote hemostasis and endothelium remodeling through different pathways.

Direct Oral Anticoagulants (DOACs) have simplified the treatment of thromboembolic disease. In addition to their established anticoagulant effects, there are indications from clinical and preclinical studies that DOACs exhibit also non-anticoagulant actions, such as anti-inflammatory and anti-oxidant actions, advocating overall cardiovascular protection. In the present study, we provide a comprehensive overview of the existing knowledge on the pleiotropic effects of DOACs on endothelial cells (ECs) in vitro and their underlying mechanisms, while also identifying potential differences among DOACs. DOACs exhibit pleiotropic actions on ECs, such as anti-inflammatory, anti-atherosclerotic, and anti-fibrotic effects, as well as preservation of endothelial integrity. These effects appear to be mediated through inhibition of the proteinase-activated receptor signaling pathway. Furthermore, we discuss the potential differences among the four drugs in this class. Further research is needed to fully understand the pleiotropic effects of DOACs on ECs, their underlying mechanisms, as well as the heterogeneity between various DOACs. Such studies can pave the way for identifying biomarkers that can help personalize pharmacotherapy with this valuable class of drugs.

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia worldwide and is characterized by a high risk of thromboembolism, ischemic stroke, and fatality. The precise molecular mechanisms of AF pathogenesis remain unclear. The purpose of this study was to use bioinformatics tools to identify novel key genes in AF, provide deeper insights into the molecular pathogenesis of AF, and uncover potential therapeutic targets. Four publicly available raw RNA-Seq datasets obtained through the ENA Browser, as well as proteomic analysis results, both derived from atrial tissues, were used in this analysis. Differential gene expression analysis was performed and cross-validated with proteomics results to identify common genes/proteins between them. A functional enrichment pathway analysis was performed. Cross-validation analysis revealed five differentially expressed genes, namely FGL2, IGFBP5, NNMT, PLA2G2A, and TNC, in patients with AF compared with those with sinus rhythm (SR). These genes play crucial roles in various cardiovascular functions and may be part of the molecular signature of AF. Furthermore, functional enrichment analysis revealed several pathways related to the extracellular matrix, inflammation, and structural remodeling. This study highlighted five key genes that constitute promising candidates for further experimental exploration as biomarkers as well as therapeutic targets for AF.

Introduction:Heart failure (HF) is a complex clinical syndrome leading to high morbidity. In this study, we aimed to identify the gene expression and protein signature of HF main causes, namely dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM).Methods:Omics data were accessed through GEO repository for transcriptomic and PRIDE repository for proteomic datasets. Sets of differentially expressed genes and proteins comprising DCM (DiSig) and ICM (IsSig) signatures were analyzed by a multilayered bioinformatics approach. Enrichment analysis via the Gene Ontology was performed through the Metascape platform to explore biological pathways. Protein-protein interaction networks were analyzed via STRING db and Network Analyst.Results:Intersection of transcriptomic and proteomic analysis showed 10 differentially expressed genes/proteins in DiSig (AEBP1, CA3, HBA2, HBB, HSPA2, MYH6, SERPINA3, SOD3, THBS4, UCHL1) and 15 differentially expressed genes/proteins in IsSig (AEBP1, APOA1, BGN, CA3, CFH, COL14A1, HBA2, HBB, HSPA2, LTBP2, LUM, MFAP4, SOD3, THBS4, UCHL1). Common and distinct biological pathways between DiSig and IsSig were retrieved, allowing for their molecular characterization. Extracellular matrix organization, cellular response to stress and transforming growth factor-beta were common between two subphenotypes. Muscle tissue development was dysregulated solely in DiSig, while immune cells activation and migration in IsSig.Discussion:Our bioinformatics approach sheds light on the molecular background of HF etiopathology showing molecular similarities as well as distinct expression differences between DCM and ICM. DiSig and IsSig encompass an array of "cross-validated" genes at both transcriptomic and proteomic level, which can serve as novel pharmacological targets and possible diagnostic biomarkers.

Therapeutic drug monitoring (TDM) is the clinical practice of measuring drug concentrations. TDM can be used to determine treatment efficacy and to prevent the occurrence or reduce the risk of drug-induced side effects, being, thus, a tool of personalized medicine. Drugs for which TDM is applied should have a narrow therapeutic range and exhibit both significant pharmacokinetic variability and a predefined target concentration range. The aim of our study was to assess the current status of TDM in Greek public hospitals and estimate its progress over the last 20 years. All Greek public hospitals were contacted to provide data and details on the clinical uptake of TDM in Greece for the years 2003 and 2021 through a structured questionnaire. Data from 113 out of 132 Greek hospitals were collected in 2003, whereas for 2021, we have collected data from 98 out of 122 hospitals. Among these, in 2003 and 2021, 64 and 51 hospitals, respectively, performed TDM. Antiepileptics and antibiotics were the most common drug categories monitored in both years. The total number of drug measurement assays decreased from 2003 to 2021 (153,313 ± 7794 vs. 90,065 ± 5698; p = 0.043). In direct comparisons between hospitals where TDM was performed both in 2003 and 2021 (n = 35), the mean number of measurements was found to decrease for most drugs, including carbamazepine (198.8 ± 46.6 vs. 46.6 ± 10.1, p < 0.001), phenytoin (253.6 ± 59 vs. 120 ± 34.3; p = 0.001), amikacin (147.3 ± 65.2 vs. 91.1 ± 71.4; p = 0.033), digoxin (783.2 ± 226.70 vs. 165.9 ± 28.9; p < 0.001), and theophylline (71.5 ± 28.7 vs. 11.9 ± 6.4; p = 0.004). Only for vancomycin, a significant increase in measurements was recorded (206.1 ± 96.1 vs. 789.1 ± 282.8; p = 0.012). In conclusion, our findings show that TDM clinical implementation is losing ground in Greek hospitals. Efforts and initiatives to reverse this trend are urgently needed.