Search Results (152)

Background: The diagnosis of hypercholesterolemia relies on the laboratory assessment of lipid parameters. This study aimed to evaluate differences in the distribution of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB) concentrations according to the presence and type of lipid-lowering therapy (LLT). Methods: This retrospective analysis included consecutive patients who had at least one measurement of LDL-C, apoB, and non-HDL-C between March and November 2024 in a high-volume tertiary hospital. All lipid fractions were expressed as the percentages of measurements above or below cut-off values established by the recent ESC guidelines. Subgroup analysis based on LLT type was performed, with patients categorized as receiving either single or combined LLT. Results: A total of 5048 patients were included in the analysis. Among patients receiving LLT, most were on statin monotherapy (77.3%), predominantly atorvastatin. Combined therapy, primarily statin plus ezetimibe, was used in 22.7% of treated patients. Discordance between on-target apoB levels and elevated LDL-C concentrations occurred in 26.6% of untreated and 13.6% of all treated patients, and in 15.1% and 8.6% of single and combined-LLT patients, respectively. Similarly, discordance between on-target non-HDL-C and elevated LDL-C levels was observed in 13.5% of untreated and 7.5% of all treated patients, and in 8.4% and 4.8% of single and combined-LLT patients, respectively. Conclusions: Classification of hyperlipidemia based on LDL-C, non-HDL-C, and apoB concentrations reveals significant discrepancies between these markers, especially between LDL-C and apoB. LLT reduces these discrepancies with combined LLT being particularly effective. Full article

Background: While the 2024 ESC Guidelines provide guidance on utilising incidental CAC findings from non-gated CT scans to enhance risk stratification and guide treatment decisions, there remain gaps in detailed protocols for managing such incidental findings, particularly in inpatient settings. An incidental finding of CAC in a patient without known atherosclerosis provides an opportunity to assess cardiac risk, promote risk factor optimisation and evaluate need for further cardiac work up. The aim of this study was to assess the prevalence of incidental coronary artery calcification on non-cardiac dedicated gated CT thorax scans among general medical inpatients and to evaluate the subsequent management of these findings. Methods: This was a single-centre retrospective observational study of consecutive general medical inpatients aged 40–75, who had undergone a non-cardiac gated CT thorax during their admission, between February and March 2025. Data were collected using local electronic health records. Exclusion criteria were patients with known ischaemic heart disease (IHD). Risk factor assessment was noted by documentation of smoking status, hypertension, diabetes and low-density lipoprotein (LDL) values. Results: A total of 186 patients with thoracic CT scans were identified. On review of all CT reports, 53 (28.4%) patients had CAC reported, of whom 17 had known IHD. Therefore 36 (19.4%) patients were identified for further analysis. An exercise stress test was booked in none of the patients. A coronary angiogram was booked in 1 patient. Conclusions: One fifth of medical inpatients in our study had a new finding of CAC on thoracic imaging. Cardiovascular risk factors of LDL and HbA1c were checked in less than half of patients. None of these patients went on to have functional testing. There is a valuable opportunity to optimise cardiac risk factors and evaluate the need for functional testing in a subset of patients with CAC reported on non-cardiac CTs. This can be facilitated by raising awareness and implementing a flowchart tool for hospital physicians to reference. Full article

Objectives: To investigate the characteristics of monoclonal human urine-derived stem cells (hUSCs) obtained through different culture protocols and compare their therapeutic effects on renal ischemia–reperfusion injury in mice. Methods: Monoclones of hUSCs derived from the urine of healthy volunteers were isolated and cultured using two different culture media. Flow cytometry, qRT-PCR and RNA sequencing were employed to characterize each monoclonal clone of multipotent stem cells across multiple passages. To evaluate their therapeutic effects on unilateral renal ischemia–reperfusion injury in BALB/c mice, 5 × 10⁵ hUSCs from each monoclonal clone were intravenously administered to mice via the tail vein, followed by assessments using Masson staining, qRT-PCR and renal tissue transcriptomics analysis. Results: Four monoclonal strains were successfully isolated from four fresh urine samples of a healthy young male volunteer: three cultured in EGM-MV medium and one in our modified medium. All four strains demonstrated stable expression of mesenchymal stem cell-related markers over eight passages of expansion. Bioinformatics analysis of multiple cell transcriptome datasets revealed that these four cell strains are more closely related to kidney tissue than to bone marrow mesenchymal stem cells (BMSCs), adipose-derived mesenchymal stem cells (ADMSCs), induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), and urothelial cells. Additionally, significant differences were observed in the expression of genes associated with kidney development among the four monoclonal strains. Furthermore, the therapeutic effects of different monoclonal clones on renal ischemia–reperfusion injury in mice showed notable variability. Conclusions: The isolated monoclonal urine-derived stem cells in this study were showed closer transcriptomic similarity to renal progenitor cells than to other mesenchymal stem cell types and possessed differential therapeutic effects on acute kidney injury. Full article

Background: Lowering lipid levels after an acute coronary syndrome is critical for preventing recurrent adverse cardiovascular events. Multiple medications are now available, but there is limited evidence comparing how frequently they lead to the achievement of guideline-recommended lipid targets. Methods and Results: This observational study evaluated the impact of novel lipid-lowering therapies (alirocumab, evolocumab, inclisiran, and bempedoic acid) in patients with a history of atherosclerotic cardiovascular disease or familial hypercholesterolaemia treated with maximum-tolerated doses of high-intensity statin therapy with or without ezetimibe. Our primary assessment was the achievement of LDL-C below 1.4 mmol/L as per the European Society of Cardiology guidelines. The study comprised of 256 patients. Reduction in LDL-C was greatest with alirocumab and evolocumab, achieving a reduction of 62% (95% confidence interval [CI], 51 to 93; p < 0.001) and 58% (95% CI, 47 to 88; p < 0.001) after 12 months, respectively. This was followed by inclisiran with a reduction of 47% (95% CI, 37 to 78; p < 0.001) and bempedoic acid with a reduction of 36% (95% CI, 22 to 69; p < 0.001). Patients treated with alirocumab and evolocumab started from a higher baseline LDL-C than inclisiran, due to the higher LDL threshold required for initiation of alirocumab and evolocumab in the UK. Despite this, inclisiran, evolocumab, and alirocumab were all associated with similar proportions of patients achieving LDL targets: 35%, 42%, and 37% of patients achieved a guideline-recommended LDL-C target of <1.4 mmol/L. Patients with a baseline LDL-C > 4 mmol/L were more likely to reach the ESC target when treated with alirocumab or evolocumab compared to inclisiran, with results of 33.3% vs. 24.1% (p = 0.016) and 35.7% vs. 24.1% (p = 0.05). Conclusions: Alirocumab and evolocumab were associated with the greatest reductions in LDL-C, followed by inclisiran and bempedoic acid. Overall, alirocumab, evolocumab, and inclisiran led to approximately 40% of patients reaching ESC targets for LDL-C. In patients with a baseline LDL-C > 4 mmol/L, significantly more patients achieved LDL-C targets when treated with alirocumab or evolocumab compared to inclisiran. Strength and limitations: This was the first study to comprehensively compare the efficacy of novel lipid-lowering therapies in achieving guideline-recommended LDL targets within a high-risk cardiovascular population. The sample size was relatively small, especially for patients treated with bempedoic acid. Full article

Background/Objectives: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease characterized by immune dysregulation, vasculopathy, and fibrosis. Objectives: To evaluate the genetic architecture and autoantibody profile in a Kazakh cohort of patients with SSc. Methods: A total of 26 Kazakh patients with diffuse SSc were examined for disease activity and organ impairment using EScSG and the modified Rodnan skin score (mRSS). Eighteen healthy volunteers were enrolled in the control group. Antinuclear factor (ANF) was estimated on HEp-2 cells, while antibodies to Scl-70, CENP-B, U1-snRNP, SS-A/Ro52, SS-A/Ro60, Sm/RNP, Sm, SS-B, Rib-P0, and nucleosomes were determined by immunoblotting. The level of IL-6 cytokine was detected using ELISA. To investigate the genetic basis of SSc in Kazakh patients, a custom AmpliSeq panel including targeting immune/fibrosis pathways and 120 genes was used on the Ion Proton sequencer. The statistical analysis of categorical variables was conducted using Fisher’s exact test and Chi-square (χ²) test. Results: The examination of SSc patients (mRSS 16 ± 7.2; EScSG 3.54 ± 2.18) revealed a broad range of antibodies to Scl-70, CENP-B, SS-A/Ro60, SS-A/Ro52, U1-snRNP, and RNP/Sm, which were undetectable in the control group. Genetic analysis identified multiple variants across immune regulatory genes, including likely pathogenic changes in SAMD9L, REL, IL6ST, TNFAIP3, ITGA2, ABCC2, AIRE, IL6R, AFF3, and TREX1. Variants of uncertain clinical significance were detected in LY96, IRAK1, RBPJ, IL6ST, ITGA2, AIRE, IL6R, JAZF1, IKZF3, IL18, IL12B, PRKCQ, PXK, and DNASE1L3. Novel variants at the following genomic coordinates were identified and have not been previously reported in association with SSc: LY96 (chr8:74922341 CT/C), PTPN22 (chr1:114381166 CT/C), IRAK1 (indels at chrX:153278833), and SAMD9L (chr7:92761606 GT/G; chr7:92764981 T/TT). Conclusions: The first immunogenetic investigation of SSc in Kazakhstan revealed a polygenic architecture involving immune signalling pathways that partially overlap with international cohorts while exhibiting region-specific variation. Although the limited sample size and lack of functional validation constrain the interpretability of the findings, the results provide a framework for larger research to confirm the pathogenic mechanisms and establish clinical relevance. Full article

Spermatogonial stem cells (SSCs) are unipotent germline cells with emerging pluripotent potential under specific in vitro conditions. Understanding their capacity for reprogramming and the molecular mechanisms involved offers valuable insights into regenerative medicine and fertility preservation. SSCs were isolated from Oct4-GFP C57BL/6 transgenic mice using enzymatic digestion and cultured in defined media. Under these conditions, ES-like colonies emerged expressing pluripotency markers. These cells were characterized by immunocytochemistry, teratoma assays, and transcriptomic analyses using bulk and single-cell RNA sequencing datasets. Gene expression profiles were compared with ESCs and SSCs using datasets from GEO (GSE43850, GSE38776, GSE149512). Protein–protein interaction (PPI) networks and co-expression modules were explored through STRING, Cytoscape, and WGCNA. ES-like cells derived from SSCs exhibited strong expression of OCT4, DAZL, and VASA. Transcriptomic analysis revealed key differentially expressed genes and shared regulatory networks with ESCs. WGCNA identified key co-expression modules and hub regulatory RNA binding genes (Ctdsp1, Rest, and Stra8) potentially responsible for the reprogramming process. Teratoma assays confirmed pluripotency, and single-cell RNA-seq validated expression of critical markers in cultured SSCs. This study demonstrates that SSCs can acquire pluripotency features and be reprogrammed into ES-like cells. The integration of transcriptomic and network-based analyses reveals novel insights into the molecular drivers of SSC reprogramming, highlighting their potential utility in stem cell-based therapies and male fertility preservation. Full article

The emergence of multidrug-resistant Pseudomonas aeruginosa strains is increasingly becoming a critical threat to global health. Among the resistance mechanisms, the MexAB–OprM efflux pump confers P. aeruginosa with an efficient method to export a broad spectrum of antibiotics. The antimicrobial peptide Esc (1-21)-1c was shown to downregulate this efflux system, though its mechanism of action has not been unveiled thus far. Here, we employed a combination of molecular modeling and experimental methods to investigate the precise peptide inhibitory mechanism. Functional proteomic experiments revealed the P. aeruginosa protein Q9I5H3, homologous to E. coli QseB, as a putative key target of Esc(1-21)-1c. Molecular docking predicted stable peptide–protein interactions, which were experimentally validated through fluorescence spectroscopy. Furthermore, electrophoretic mobility shift assays demonstrated that Q9I5H3 specifically binds the MexAB–OprM promoter and that Esc(1-21)-1c competitively inhibits this interaction in a dose-dependent manner. These findings reveal a previously uncharacterized regulatory pathway for efflux pump control and highlight Q9I5H3 as a promising therapeutic target against multidrug-resistant P. aeruginosa. Full article

We investigate the impact of dataset augmentation and synthetic generation techniques on the accuracy of supervised audio classification based on state-of-the-art neural networks used as classifiers. Dataset augmentation techniques are applied upon the raw sound and its transformed image format. Specifically, sound augmentation techniques are applied prior to spectral-based transformation and include time stretching, pitch shifting, noise addition, volume controlling, and time shifting. Image augmentation techniques are applied after the transformation of the sound into a scalogram, involving scaling, shearing, rotation, and translation. Synthetic sound generation is based on the AudioGen generative model, triggered through a series of customized prompts. Augmentation and synthetic generation are applied to three sound categories: (a) human sounds, (b) animal sounds, and (c) sounds of things, with each category containing ten sound classes with 20 samples retrieved from the ESC-50 dataset. Sound- and image-orientated neural network classifiers have been used to classify the augmented datasets and their synthetic additions. VGGish and YAMNet (sound classifiers) employ spectrograms, while ResNet50 and DarkNet53 (image classifiers) employ scalograms. The streamlined AI-based process of augmentation and synthetic generation, enhanced classifier fine-tuning and inference allowed for a consistent, multicriteria-comparison of the impact. Classification accuracy has increased for all augmentation and synthetic generation scenarios; however, the increase has not been uniform among the techniques, the sound types, and the percentage of the training set population increase. The average increase in classification accuracy ranged from 2.05% for ResNet50 to 9.05% for VGGish. Our findings reinforce the benefit of audio augmentation and synthetic generation, providing guidelines to avoid accuracy degradation due to overuse and distortion of key audio features. Full article

Type 1 diabetes (T1D) is a chronic condition with an increasing prevalence worldwide and a significant improvement in life expectancy in the last decades. T1D confers an increased risk of cardiovascular events, driven by elevated LDL cholesterol (LDL-C) and qualitative lipoprotein abnormalities, such as dysfunctional HDL and smaller, denser LDL-C. Lipid-lowering outcome trials have overwhelmingly focused on type 2 diabetes or the general population, resulting in very limited T1D-specific evidence. Recommendations from major medical associations (ADA, ESC/EAS, ACC/AHA, ISPAD) create additional ambiguity regarding the treatment of dyslipidemia in T1D. This review synthesizes the available evidence on dyslipidemia management in T1D, including published observational cohorts, randomized controlled trials, and international guideline recommendations from January 2000 to June 2025. LDL-C remains the primary modifiable risk factor. Each 1 mmol/L increase is associated with 35–50% greater cardiovascular (CV) risk in T1D cohorts. Statin therapy reduces CV risk by up to 25% in patients with diabetes; however, evidence remains limited in patients with T1D. Ezetimibe provides an additional 18% LDL-C lowering and a 14% event reduction in mixed-diabetes trials, while PCSK9 inhibitors offer a potent 40–60% LDL-C reduction and an 18% MACE reduction. The uptake of statins in eligible adults with T1D remains below 50%. Statins remain the cornerstone of dyslipidemia management in T1D, with emerging evidence supporting ezetimibe and PCSK9 inhibitors. The heterogeneity across international guidelines and the scarcity of T1D-specific outcome data underscore the need for targeted research and evidence-based strategies. Full article

Background and Clinical Significance: Arterial and venous thromboses are typically distinct clinical entities, each governed by unique pathophysiological mechanisms. The concurrent manifestation of both, particularly in the setting of massive pulmonary embolism (PE), is exceptionally rare and poses significant diagnostic and therapeutic challenges. Case Presentation: This report describes a 61-year-old male with well-controlled hypertension and type 2 diabetes who developed extensive thromboses involving deep vein thrombosis (DVT) of the right popliteal vein, arterial thrombosis of the left iliac artery, and massive PE. The patient was initially managed conservatively, in accordance with the European Society of Cardiology (ESC) 2019 Guidelines for Acute PE, using unfractionated heparin (UFH), low-molecular-weight heparin, a direct oral anticoagulant (DOAC), and adjunctive therapy. This approach was chosen due to the absence of hemodynamic instability. However, given failed percutaneous revascularization and persistent arterial occlusion, surgical thromboendarterectomy (TEA) was ultimately required. Post hoc genetic testing was prompted by the complex presentation in the absence of classical provoking factors—such as trauma, surgery, malignancy, or antiphospholipid syndrome—consistent with recommendations for selective thrombophilia testing in atypical or severe cases. The analysis revealed four thrombophilia-associated polymorphisms: heterozygous Factor V Leiden (FVL; R506Q genotype), Plasminogen Activator Inhibitor-1 (PAI-1; 4G/5G genotype), Methylenetetrahydrofolate reductase (MTHFR; c.677C > T genotype), and homozygous Angiotensin-Converting Enzyme Insertion/Deletion (ACE I/D; DD genotype). Conclusions: While each variant has been individually associated with thrombotic risk, their co-occurrence in a single patient with simultaneous arterial and venous thromboses has not, to our knowledge, been previously documented. This case underscores the potential for gene–gene interactions to amplify thrombotic risk, even in the presence of variants traditionally considered to confer only modest to moderate risk. It highlights the need for a multidisciplinary approach and raises questions regarding pharmacogenetics, anticoagulation, and future research into cumulative genetic risk in complex thrombotic phenotypes. Full article

The exponential growth of autonomous systems demands robust security mechanisms that can operate within the extreme constraints of real-time embedded environments. This paper introduces SMART DShot, a groundbreaking machine learning-enhanced framework that transforms the security landscape of unmanned aerial vehicle motor control systems through seamless integration of adaptive timing correction and real-time anomaly detection within Digital Shot (DShot) communication protocols. Our approach addresses critical vulnerabilities in Electronic Speed Controller (ESC) interfaces by deploying four synergistic algorithms—Kalman Filter Timing Correction (KFTC), Recursive Least Squares Timing Correction (RLSTC), Fuzzy Logic Timing Correction (FLTC), and Hybrid Adaptive Timing Correction (HATC)—each optimized for specific error characteristics and attack scenarios. Through comprehensive evaluation encompassing 32,000 Monte Carlo test iterations (500 per scenario × 16 scenarios × 4 algorithms) across 16 distinct operational scenarios and PolarFire SoC Field-Programmable Gate Array (FPGA) implementation, we demonstrate exceptional performance with 88.3% attack detection rate, only 2.3% false positive incidence, and substantial vulnerability mitigation reducing Common Vulnerability Scoring System (CVSS) severity from High (7.3) to Low (3.1). Hardware validation on PolarFire SoC confirms practical viability with minimal resource overhead (2.16% Look-Up Table utilization, 16.57 mW per channel) and deterministic sub-10 microsecond execution latency. The Hybrid Adaptive Timing Correction algorithm achieves 31.01% success rate (95% CI: [30.2%, 31.8%]), representing a 26.5% improvement over baseline approaches through intelligent meta-learning-based algorithm selection. Statistical validation using Analysis of Variance confirms significant performance differences (F(3,1996) = 30.30, p < 0.001) with large effect sizes (Cohen’s d up to 4.57), where 64.6% of algorithm comparisons showed large practical significance. SMART DShot establishes a paradigmatic shift from reactive to proactive embedded security, demonstrating that sophisticated artificial intelligence can operate effectively within microsecond-scale real-time constraints while providing comprehensive protection against timing manipulation, de-synchronization, burst interference, replay attacks, coordinated multi-channel attacks, and firmware-level compromises. This work provides essential foundations for trustworthy autonomous systems across critical domains including aerospace, automotive, industrial automation, and cyber–physical infrastructure. These results conclusively demonstrate that ML-enhanced motor control systems can achieve both superior security (88.3% attack detection rate with 2.3% false positives) and operational performance (31.01% timing correction success rate, 26.5% improvement over baseline) simultaneously, establishing SMART DShot as a practical, deployable solution for next-generation autonomous systems. Full article

Background/objectives: Proteus mirabilis is a frequent causative agent of urinary and wound infections in both community and hospital settings. It develops resistance to expanded-spectrum cephalosporins (ESCs) due to the production of extended-spectrum β-lactamases (ESBLs) or plasmid-mediated AmpC β-lactamases (p-AmpCs). Recently, carbapenem-resistant isolates of P. mirabilis emerged due to the production of carbapenemases, mostly belonging to Ambler classes B and D. Here, we report an outbreak of infections due to carbapenem-resistant P. mirabilis that were observed in a psychiatric hospital in Zagreb, Croatia. The characteristics of ESBL and carbapenemase-producing P. mirabilis isolates, associated with an outbreak, were analyzed. Materials and methods: The antibiotic susceptibility testing was performed by the disk-diffusion and broth dilution methods. The double-disk synergy test (DDST) and inhibitor-based test with clavulanic and phenylboronic acid were applied to screen for ESBLs and p-AmpCs, respectively. Carbapenemases were screened by the modified Hodge test (MHT), while carbapenem hydrolysis was investigated by the carbapenem inactivation method (CIM) and EDTA-carbapenem-inactivation method (eCIM). The nature of the ESBLs, carbapenemases, and fluoroquinolone-resistance determinants was investigated by PCR. Plasmids were characterized by PCR-based replicon typing (PBRT). Selected isolates were subjected to molecular characterization of the resistome by an Inter-Array Genotyping Kit CarbaResisit and whole-genome sequencing (WGS). Results: In total, 20 isolates were collected and analyzed. All isolates exhibited resistance to amoxicillin alone and when combined with clavulanic acid, cefuroxime, cefotaxime, ceftriaxone, cefepime, imipenem, ceftazidime–avibactam, ceftolozane–tazobactam, gentamicin, amikacin, and ciprofloxacin. There was uniform susceptibility to ertapenem, meropenem, and cefiderocol. The DDST and combined disk test with clavulanic acid were positive, indicating the production of an ESBL. The MHT was negative in all except one isolate, while the CIM showed moderate sensitivity, but only with imipenem as the indicator disk. Furthermore, eCIM tested positive in all of the CIM-positive isolates, consistent with a metallo-β-lactamase (MBL). PCR and sequencing of the selected amplicons identified VIM-1 and VIM-4. The Inter-Array Genotyping Kit CarbaResist and WGS identified β-lactam resistance genes bla_VIM, bla_CTX-M-15, and bla_TEM genes; aminoglycoside resistance genes aac(3)-IId, aph(6)-Id, aph(3″)-Ib, aadA1, armA, and aac(6′)-IIc; as well as resistance genes for sulphonamides sul1 and sul2, trimethoprim dfr1, chloramphenicol cat, and tetracycline tet(J). Conclusions: This study revealed an epidemic spread of carbapenemase-producing P. mirabilis in two wards in a psychiatric hospital. Due to the extensively resistant phenotype (XDR), therapeutic options were limited. This is the first report of carbapenemase-producing P. mirabilis in Croatia. Full article

Epigenetic regulation, particularly DNA methylation, plays a crucial role in embryonic development by controlling gene expression patterns. The disruption of this regulation by environmental factors can have long-lasting consequences. Opioid drugs, such as morphine, are known to cross the placental barrier and affect the developing central nervous system, yet their precise epigenetic effects during early development remain unclear. This study aimed to elucidate the impact of chronic morphine exposure on the DNA methylation landscape and gene expression in mouse embryonic stem cells (mESCs). mESCs were chronically exposed to morphine (10 μM for 24 h). Genome-wide bisulfite sequencing was performed to identify DNA methylation changes, while RNA sequencing (RNA-Seq) assessed corresponding gene expression alterations. Global levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were quantified using mass spectrometry. Morphine exposure induced global DNA hypomethylation and identified 16,808 differentially methylated genes (DMGs) related to development, cell signalling, metabolism, and transcriptional regulation. Integrative transcriptomic analysis with RNA-Seq data revealed 651 overlapping genes, including alterations in key epigenetic regulators involved on DNA methylation machinery. Specifically, Tet1 was upregulated with promoter hypomethylation, while Dnmt1 was downregulated, without changes in promoter methylation after morphine exposiure. Mass spectrometry results confirmed a global decrease in 5mC levels alongside increased 5hmC, indicating the involvement of both passive and active demethylation pathways. These findings demonstrate for the first time that morphine disrupts the epigenetic homeostasis of mESCs by promoting global and gene-specific DNA demethylation, which might be key to the phenotypic changes that occur in adulthood. This work provides novel mechanistic insights into how opioid exposure during early development may lead to persistent epigenetic alterations, with potential long-term implications for neurodevelopment and disease susceptibility. Full article

Background: In the emergency setting, many diagnostic pathways incorporate change in high-sensitivity cardiac troponin (hs-cTn) concentrations (i.e., the delta) to classify patients as low-risk (rule-out) or high-risk (rule-in) for possible myocardial infarction (MI). However, the impact of analytical variation on the delta for correct classification is unknown, especially at concentrations below and around the 99th percentile. Our objective was to assess the impact of delta variation for correct risk classification across the European Society of Cardiology (ESC 0/1 h and 0/2 h), the High-STEACS, and the common change criteria (3C) pathways. Methods: A yearlong accuracy study for hs-cTnT was performed where laboratories across Canada tested three patient-based samples (level 1 target value = 6 ng/L, level 2 target value = 9 ng/L, level 3 target value = 12 ng/L) monthly across 41 different analyzers. The assigned low-delta between levels 1 and 2 was 3 ng/L (i.e., 9 − 6 = 3 ng/L) and the assigned high-delta between levels 1 and 3 was 6 ng/L (i.e., 12 − 6 = 6 ng/L). The low- and high-deltas for each analyzer were determined monthly from the measured values, with the difference calculated from the assigned deltas. The obtained deltas were then assessed via the different pathways on correct classification (i.e., percent correct with 95% confidence intervals, CI) and using non-parametric analyses. Results: The median (interquartile range) difference between the measured versus assigned low-delta (n = 436) and high-delta (n = 439) was −1 ng/L (−1 to 0). The correct classification differed among the pathways. The ESC 0/1 h pathway yielded the lowest percentage of correct classification at 35.3% (95% CI: 30.8 to 40.0) for the low-delta and 90.0% (95% CI: 86.8 to 92.6) for the high-delta. The 3C and ESC 0/2 h pathways yielded higher and equivalent estimates on correct classification: 95.2% (95% CI: 92.7 to 97.0) for the low-delta and 98.2% (95% CI: 96.4 to 99.2) for the high-delta. The High-STEACS pathway yielded 99.5% (95% CI: 98.4 to 99.9) of correct classifications for the high-delta but only 36.2% (95% CI: 31.7 to 40.9) for the low-delta. Conclusions: Analytical variation will impact risk classification for MI when using hs-cTn deltas alone per the pathways. The 3C and ESC 0/2 h pathways have <5% misclassification when using deltas for hs-cTnT in this dataset. Additional studies with different hs-cTnI assays at concentrations below and near the 99th percentile are warranted to confirm these findings. Full article

Background: Atherosclerotic cardiovascular disease (ASCVD) is often perceived as a male-dominant condition, yet recent European data show that more women live with and die from it. Gender disparities have been reported in the management of dyslipidemia, with women less likely to receive high-intensity lipid-lowering therapy and to reach low-density lipoprotein cholesterol (LDL-C) goals. This study aimed to assess sex-specific differences in response to and tolerance of PCSK9-targeted therapies—monoclonal antibodies (evolocumab, alirocumab) and small interfering RNA (inclisiran)—as well as LDL-C goal attainment according to current ESC guidelines. Methods: We conducted a prospective registry of patients initiating PCSK9-targeted therapy at a specialized lipid center between April 2018 and June 2024. Baseline lipid profiles were recorded and monitored over follow-up. Results: Of the 341 patients, 122 (35.8%) were women and 219 (64.2%) were men, with a mean age of 66.4 ± 12.6 years for the women and 63.9 ± 11.8 years for the men. The women more frequently had heterozygous familial hypercholesterolemia (HeFH) (61.5% vs. 38.4%, p < 0.001) and a lower prevalence of previous cardiovascular events compared to the men (62.3% vs. 84.5%, p < 0.001). A higher proportion of the women were classified as high cardiovascular risk compared to the men (37.7% vs. 15.5%, p < 0.001). Risk categories were assigned according to ESC guidelines, with LDL-C targets of <70 mg/dL for high-risk patients and <55 mg/dL for very high risk patients, along with a ≥50% LDL-C reduction for both categories. In the very high risk group, fewer women achieved LDL-C targets at the first two follow-up visits (first follow-up: 50.0% vs. 76.6%, p = 0.008; second follow-up: 55.3% vs. 68.1%, p = 0.049). Although treatment prescription and tolerance were similar between sexes, women showed smaller LDL-C reductions at the first follow-up (51.7 ± 23.9% vs. 57.3 ± 24.9%, p = 0.044). Conclusions: PCSK9-targeted therapies were effective in both sexes at third follow-up, although women showed a tendency toward a delayed response and lower target attainment, indicating the potential need for more personalized management strategies. Full article