Quantification of Aortic Valve Fibrotic and Calcific Tissue from CTA: Prospective Comparison with Histology.

Background Quantifying the fibrotic and calcific composition of the aortic valve at CT angiography (CTA) can be useful for assessing disease severity and outcomes of patients with aortic stenosis (AS); however, it has not yet been validated against quantitative histologic findings. Purpose To compare quantification of aortic valve fibrotic and calcific tissue composition at CTA versus histologic examination. Materials and Methods This prospective study included patients who underwent CTA before either surgical aortic valve replacement for AS or orthotopic heart transplant (controls) at two centers between January 2022 and April 2023. At CTA, fibrotic and calcific tissue composition were quantified using automated Gaussian mixture modeling applied to the density of aortic valve tissue components, calculated as [(volume/total tissue volume) × 100]. For histologic evaluation, explanted valve cusps were stained with Movat pentachrome as well as hematoxylin and eosin. For each cusp, three 5-µm slices were obtained. Fibrotic and calcific tissue composition were quantified using a validated artificial intelligence tool and averaged across the aortic valve. Correlations were assessed using the Spearman rank correlation coefficient. Intermodality and interobserver variability were measured using the intraclass correlation coefficient (ICC) and Bland-Altman plots. Results Twenty-nine participants (mean age, 63 years ± 10 [SD]; 23 male) were evaluated: 19 with severe AS, five with moderate AS, and five controls. Fibrocalcific tissue composition strongly correlated with histologic findings (r = 0.92; P < .001). The agreement between CTA and histologic findings for fibrocalcific tissue quantification was excellent (ICC, 0.94; P = .001), with underestimation of fibrotic composition at CTA (bias, -4.9%; 95% limits of agreement [LoA]: -18.5%, 8.7%). Finally, there was excellent interobserver repeatability for fibrotic (ICC, 0.99) and calcific (ICC, 0.99) aortic valve tissue volume measurements, with no evidence of a difference in measurements between readers (bias, -0.04 cm3 [95% LoA: -0.27 cm3, 0.19 cm3] and 0.02 cm3 [95% LoA: -0.14 cm3, 0.19 cm3], respectively). Conclusion In a direct comparison, standardized quantitative aortic valve tissue characterization at CTA showed excellent concordance with histologic findings and demonstrated interobserver reproducibility. Clinical trial registration no. NCT06136689 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Almeida in this issue.

Demographical and Clinical Factors Predictive for Aortic Dilatation. When should we be Concerned about the Size?

Background: Thoracic aortic aneurysms are often an accidental finding and result from a degenerative process. Medical therapy includes pharmacological control of arterial hypertension and smoking cessation, that slows the growth of aneurysms. An association between the dilatation of the ascending and abdominal aorta has been already reported. The aim of the study was to identify possible demographic and clinical factors that may implicate further imaging diagnostics in patients with ascending aorta dilatation. Methods: There were 181 (93 (53%) males and 88 (47%) females) patients with a median age of 54 (41-62) years who underwent cardiac magnetic resonance due to non-vascular diseases, were enrolled into retrospective analysis. Results: Multivariable analysis revealed ascending aorta dilatation (odds ratios (OR) = 7.45, 95% confidence interval (CI): 1.98-28.0, p = 0.003) and co-existence of coronary artery disease (OR = 8.68, 95% CI: 2.15-35.1, p = 0.002) as significant predictors for thoracic descending aorta dilatation. In patients with abdominal aorta dilatation, the multivariable analysis showed a predictive value of ascending aortic dilatation (OR = 14.8, 95% CI: 2.36-92.8, p = 0.004) and age (OR = 1.04, 95% CI: 1.00-1.08, p = 0.027). In addition, cut-off values were established for age groups determining the risk of thoracic aorta dilatation over 49 years and abdominal aorta dilatation over 54 years. Conclusions: The results of our analysis showed predictive factors, including ascending aorta dilatation and co-existence of coronary artery disease, particularly over 49 years of age for thoracic, while ascending aorta dilatation and age, particularly over 54 years, for abdominal aorta dilatation. These features may be considered to increase clinical vigilance in patients with aortic diameter abnormalities.

Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-κB signaling pathways.

Metabolic diseases that include obesity and metabolic-associated fatty liver disease (MAFLD) are a rapidly growing worldwide public health problem. The pathogenesis of MAFLD includes abnormally increased lipogenesis, chronic inflammation, and mitochondrial dysfunction. Mounting evidence suggests that hydrogen sulfide (H2S) is an important player in the liver, regulating lipid metabolism and mitochondrial function. However, direct delivery of H2S to mitochondria has not been investigated as a therapeutic strategy in obesity-related metabolic disorders. Therefore, our aim was to comprehensively evaluate the influence of prolonged treatment with a mitochondria sulfide delivery molecule (AP39) on the development of fatty liver and obesity in a high fat diet (HFD) fed mice. Our results demonstrated that AP39 reduced hepatic steatosis in HFD-fed mice, which was corresponded with decreased triglyceride content. Furthermore, treatment with AP39 downregulated pathways related to biosynthesis of unsaturated fatty acids, lipoprotein assembly and PPAR signaling. It also led to a decrease in hepatic de novo lipogenesis by downregulating mTOR/SREBP-1/SCD1 pathway. Moreover, AP39 administration alleviated obesity in HFD-fed mice, which was reflected by reduced weight of mice and adipose tissue, decreased leptin levels in the plasma and upregulated expression of adipose triglyceride lipase in epididymal white adipose tissue (eWAT). Finally, AP39 reduced inflammation in the liver and eWAT measured as the expression of proinflammatory markers (Il1b, Il6, Tnf, Mcp1), which was due to downregulated mTOR/NF-κB pathway. Taken together, mitochondria-targeted sulfide delivery molecules could potentially provide a novel therapeutic approach to the treatment/prevention of obesity-related metabolic disorders.

Assessment of COVID-19 risk factors of early and long-term mortality with prediction models of clinical and laboratory variables.

BACKGROUND: Coronavirus disease (COVID-19) may lead to serious complications and increased mortality. The outcomes of patients who survive the early disease period are burdened with persistent long-term symptoms and increased long-term morbidity and mortality. The aim of our study was to determine which baseline parameters may provide the best prediction of early and long-term outcomes. METHODS: The study group comprised 141 patients hospitalized for COVID-19. Demographic data, clinical data and laboratory parameters were collected. The main study endpoints were defined as in-hospital mortality and 1-year mortality. The associations between the baseline data and the study endpoints were evaluated. Prediction models were created. RESULTS: The in-hospital mortality rate was 20.5% (n = 29). Compared with survivors, nonsurvivors were significantly older (p = 0.001) and presented comorbidities, including diabetes (0.027) and atrial fibrillation (p = 0.006). Assessment of baseline laboratory markers and time to early death revealed negative correlations between time to early death and higher IL-6 levels (p = 0.032; Spearman rho - 0.398) and lower lymphocyte counts (p = 0.018; Pearson r -0.438). The one-year mortality rate was 35.5% (n = 50). The 1-year nonsurvivor subgroup was older (p < 0.001) and had more patients with arterial hypertension (p = 0.009), diabetes (p = 0.023), atrial fibrillation (p = 0.046) and active malignancy (p = 0.024) than did the survivor subgroup. The model composed of diabetes and atrial fibrillation and IL-6 with lymphocyte count revealed the highest value for 1-year mortality risk prediction. CONCLUSIONS: Diabetes and atrial fibrillation, as clinical factors, and LDH, IL-6 and lymphocyte count, as laboratory determinants, are the best predictors of COVID-19 mortality risk.

SKA3 Expression as a Prognostic Factor for Patients with Pancreatic Adenocarcinoma.

The spindle and kinetochore-associated complex subunit 3 (SKA3) is a protein essential for proper chromosome segregation during mitosis and thus responsible for maintaining genome stability. Although its involvement in the pathogenesis of various cancer types has been reported, the potential clinicopathological significance of SKA3 in pancreatic ductal adenocarcinoma (PDAC) has not been fully elucidated. Therefore, this study aimed to assess clinicopathological associations and prognostic value of SKA3 in PDAC. For this purpose, in-house immunohistochemical analysis on tissue macroarrays (TMAs), as well as a bioinformatic examination using publicly available RNA-Seq dataset, were performed. It was demonstrated that SKA3 expression at both mRNA and protein levels was significantly elevated in PDAC compared to control tissues. Upregulated mRNA expression constituted an independent unfavorable prognostic factor for the overall survival of PDAC patients, whereas altered SKA3 protein levels were associated with significantly better clinical outcomes. The last observation was particularly clear in the early-stage tumors. These findings render SKA3 a promising prognostic biomarker for patients with pancreatic ductal adenocarcinoma. However, further studies are needed to confirm this conclusion.

Neutrophil Extracellular Trap Formation in Advanced Heart Failure Patients-Preliminary Report.

In end-stage heart failure, which is characterized by persistent or progressive ventricular dysfunction despite optimal medical therapy, a left ventricular assist device (LVAD) can be beneficial. Congestive heart failure provokes inflammatory and prothrombotic activation. The aim of this study was to evaluate the serum concentration of citrullinated histone 3 (CH3) representing neutrophil extracellular trap (NET) formation in patients referred for LVAD implantation. There were 10 patients with a median age of 61 (57-65) years enrolled in a prospective single-center analysis who underwent LVAD implantation. The CH3 plasma concentration was measured preoperatively and on the 1st and 7th postoperative days, followed by control measurements on the median (Q1-3) 88th (49-143) day. The preoperative CH3 concentration strongly correlated with brain natriuretic peptide (r = 0.879, p < 0.001). Significant differences in CH3 serum concentration were observed between pre- and postoperative measurements, including an increase on the first postoperative day (p < 0.001), as well as a decrease on the seventh day (p = 0.016) and in follow-up (p < 0.001). CH3 concentration, as a marker of NET formation, decreases after LVAD implantation.

Recovery of Metals from the "Black Mass" of Waste Portable Li-Ion Batteries with Choline Chloride-Based Deep Eutectic Solvents and Bi-Functional Ionic Liquids by Solvent Extraction.

Lithium-ion portable batteries (LiPBs) contain valuable elements such as cobalt (Co), nickel (Ni), copper (Cu), lithium (Li) and manganese (Mn), which can be recovered through solid-liquid extraction using choline chloride-based Deep Eutectic Solvents (DESs) and bi-functional ionic liquids (ILs). This study was carried out to investigate the extraction of metals from solid powder, black mass (BM), obtained from LiPBs, with various solvents used: six choline chloride-based DESs in combination with organic acids: lactic acid (1:2, DES 1), malonic acid (1:1, DES 2), succinic acid (1:1, DES 3), glutaric acid (1:1, DES 4) and citric acid (1:1, DES 5 and 2:1, DES 6). Various additives, such as didecyldimethylammonium chloride (DDACl) surfactant, hydrogen peroxide (H2O2), trichloroisocyanuric acid (TCCA), sodium dichloroisocyanurate (NaDCC), pentapotassium bis(peroxymonosulphate) bis(sulphate) (PHM), (glycine + H2O2) or (glutaric acid + H2O2) were used. The best efficiency of metal extraction was obtained with the mixture of {DES 2 + 15 g of glycine + H2O2} in two-stage extraction at pH = 3, T = 333 K, 2 h. In order to obtain better extraction efficiency towards Co, Ni, Li and Mn (100%) and for Cu (75%), the addition of glycine was used. The obtained extraction results using choline chloride-based DESs were compared with those obtained with three bi-functional ILs: didecyldimethylammonium bis(2,4,4-trimethylpentyl) phosphinate, [N10,10,1,1][Cyanex272], didecyldimethylammonium bis(2-ethylhexyl) phosphate, [N10,10,1,1][D2EHPA], and trihexyltetradecylphosphonium bis(2,4,4-trimethylpentyl) phosphinate, [P6,6,6,14][Cyanex272]/toluene. The results of the extraction of all metal ions with these bi-functional ILs were only at the level of 35-50 wt%. The content of metal ions in aqueous and stripped organic solutions was determined by ICP-OES. In this work, we propose an alternative and highly efficient concept for the extraction of valuable metals from BM of LiPBs using DESs and ILs at low temperatures instead of acid leaching at high temperatures.

Long-Term Nitrogen Dioxide Exposure as a Possible 5-Year Mortality Risk Factor in Diabetic Patients Treated Using Off-Pump Surgical Revascularization-A Retrospective Analysis.

Background: There is mounting evidence that diabetic-related cardiac metabolism abnormalities with oxidative stress and inflammatory mechanism activation align with the functional impairments that result in atherosclerotic lesion formation. Among the possible non-traditional coronary lesion risk factors, environmental exposure may be significant, especially in diabetic patients. Methods: A total of 140 diabetic patients (115 (82%) males and 25 (18%) females) with a mean age of 65 (60-71) underwent surgical revascularization due to multivessel coronary disease. The possible all-cause mortality risk factors, including demographical and clinical factors followed by chronic air pollution exposure, were identified. Results: All patients were operated on using the off-pump technique and followed for 5.6 (5-6.1) years. The multivariable model for 5-year mortality prediction presented the nitrogen dioxide chronic exposure (HR: 3.99, 95% CI: 1.16-13.71, p = 0.028) and completeness of revascularization (HR: 0.19, 95% CI: 0.04-0.86, p = 0.031) as significant all-cause mortality risk factors. Conclusions: Ambient air pollutants such as an excessive chronic nitrogen dioxide concentration (>15 µg/m3) may increase 5-year all-cause mortality in diabetic patients following surgical revascularization.

Long-Term Survival after Coronary Artery Surgical Revascularization-Does Ambient Temperature Matter?

Background and Objectives: The progression of global warming results in an increased exposure to extreme heat, leading to exaggeration of preexisting diseases and premature deaths. The aim of the study was to present possible risk factors for all-cause long-term mortality in patients who underwent surgical revascularization, including an assessment of the influence of ambient temperature exposure. Materials and Methods: Retrospective analysis included 153 (123 (80%) males and 30 (20%) females) patients who underwent off-pump revascularization and were followed for a median time of 2533 (1035-3250) days. The demographical, clinical data and ambient temperature exposure were taken into analysis for prediction of all-cause mortality. Individual exposure was calculated based on the place of habitation. Results: In the multivariate logistic regression model with backward stepwise elimination method, risk factors such as dyslipidaemia (p = 0.001), kidney disease (p = 0.005), age (p = 0.006), and body mass index (p = 0.007) were found to be significant for late mortality prediction. In addition to traditional factors, environmental characteristics, including tropical nights (p = 0.043), were revealed to be significant. Conclusions: High night-time ambient temperatures known as tropical nights may be regarded as additional long-term mortality risk factor after surgical revascularization.

Translation and cross-cultural adaptation of Polish version of Neuropathic Pain Questionnaire (NPQ-PL) and its comparisons with different questionnaires.

AIM OF THE STUDY: The aim of this study was to assess the validity and reliability of the Polish version of the Neuropathic Pain Questionnaire (NPQ-PL), and to compare it to other diagnostic tools. CLINICAL RATIONALE FOR THE STUDY: Neuropathic pain is a burdensome condition, of which the exact prevalence is difficult to estimate. During initial screening, pain questionnaires are helpful in alerting clinicians about the need for further evaluation. MATERIAL AND METHODS: The NPQ-PL has been developed following the guidelines for translation and cultural adaptation. A total of 140 patients with chronic pain (ChP), 90 with neuropathic pain (NP), and 50 with nociceptive pain (NoP), were enrolled into this study. RESULTS: The study group consisted of 60.71% women and 39.29% men; the mean age of patients (standard deviation, SD) was 53.22 years (15.81), and the average NPQ-PL score (SD) was 0.49 (1.27). Statistically significant relationships were found between higher age distribution and greater pain intensity in the NP group compared to the NoP group. There were also significant differences in pain levels between people of different ages, with the predominance in the elderly. Cronbach's alpha coefficient of the whole questionnaire was 0.85 and the intraclass correlation coefficient (ICC) for test-retest reliability was 0.635. Using receiver-operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.97 and the best cut-off value was 0.002, which resulted in the highest sensitivity (93.3%) and specificity (96.0%). CONCLUSIONS AND CLINICAL IMPLICATIONS: The NPQ-PL is a valid tool for discriminating between neuropathic and nociceptive pain. It can be used by physicians of various disciplines when assessing patients with ChP of various origins.

Analysis of seroconversion following COVID-19 vaccination among multiple sclerosis patients treated with disease-modifying therapies in Poland.

CLINICAL RATIONALE FOR THE STUDY: The rapid spread of SARS-CoV-2 throughout the world has highlighted the importance of vaccinations to control the pandemic and to protect people at risk for severe disease courses. Disease-modifying therapies (DMT) in multiple sclerosis (MS), whether immunomodulatory or immunosuppressive, may affect the immune response. Therefore, the question arose as to whether these vaccinations would be effective. AIM OF THE STUDY: We planned a study to assess the immune response to SARS-CoV-2 vaccines by type of therapy. MATERIAL AND METHODS: Participants were recruited from 14 Polish MS centres. The data was obtained by neurologists using a questionnaire. We collected data on 353 MS patients (269 females, 84 males) who received complete primary SARS-CoV-2 vaccination. All persons with MS (PwMS) were treated with disease-modifying therapies. RESULTS: 305 out of 353 PwMS (86.4%) were positive for IgG Abs against SARS-CoV-2 S domain S1 Ag after vaccination. A strong immune response was noted in 129 PwMS (36.5%). The rate of seroconversion after SARS-CoV-2 vaccination in PwMS who received immunomodulatory DMTs (interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab) was 91.5%, in PwMS receiving immune reconstruction therapy (alemtuzumab, cladribine) was 92%, and in immunosuppressive DMTs (fingolimod, ocrelizumab), the seroconversion rate was 59%. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study shows that, in PwMS receiving immunomodulatory therapy, the immune response to vaccination is generally excellent. Even in immunosuppressive patients, seroconversion is satisfactory.

Relation between Systemic Inflammatory Index (SII) and Hair Trace Elements, Metals and Metalloids Concentration in Epicardial Coronary Artery Disease-Preliminary Report.

Background: Coronary artery atherosclerosis development and progression are related to generic, clinical, and lifestyle factors combined with inflammatory activation. The relationship between trace element concentration and morbidity is under investigation to gain a clearer understanding of underlying pathological processes. Methods: Thirty-five consecutive patients (22 males and 13 females) with a median [interquartile range (IQR)] age of 67 (61-73) years presenting with anginal symptoms were included in the single center prospective analysis in 2022 and divided into a epicardial coronary artery disease (CAD) and non-CAD group. Scalp hair chemical analysis and inflammatory markers from a peripheral blood count were analyzed. Results: The correlation analysis of elements and inflammatory indexes showed statistical significance between median hair lithium (Li) concentration and the systemic inflammatory index (SII) (r = -0.476, p = 0.046), antimony (Sb) (r = -0.521, p = 0.028) followed by chromium (Cr) (r = -0.478, p = 0.045) and iron (Fe) (r = -0.604, p = 0.008) in the CAD group. Similar correlations were not found in non-CAD group. Conclusions: The correlation between scalp hair lithium (Li), antimony (Sb), chromium (Cr) and iron (Fe) concentration and the systemic inflammatory index (SII) were revealed only in patients with coronary artery disease. Our analysis identified a strong correlation between inflammatory activation and iron concentration.

Coronary Artery Bypass Surgery: Comparing the Long-Term Impact of Total Arterial Grafting With Multiarterial Plus Saphenous Vein Grafting.

INTRODUCTION: This study aimed to compare the long-term outcomes in a propensity matched population receiving total arterial grafting (TAG) and multiple arterial grafts (MAG) in addition to saphenous vein graft (SVG) following multivessel coronary artery bypass grafting requiring at least three distal anastomoses. METHODS: In this retrospective study, 655 patients from two centers met the inclusion criteria and were divided into two groups: TAG group (n = 231) and MAG + SVG group (n = 424). Propensity score matching was performed resulting in 231 pairs. RESULTS: No significant differences were observed between both groups in terms of early outcomes. Survival probabilities at 5, 10, and 15 y were 89.1% versus 94.2%, 76.2% versus 76.1%, and 66.7% versus 69.8% in the TAG and MAG + SVG groups, respectively (hazard ratio stratified on matched pairs: 0.90; 95% confidence interval [0.45-1.77]; P = 0.754). Freedom from major adverse cardiac and cerebral events (MACCE) in the matched cohort did not show any significant difference between both groups. Probabilities at 5, 10, and 15 y were 82.7% versus 85.6%, 62.2% versus 75.3%, and 48.8% versus 59.5% in the TAG and MAG + SVG groups, respectively (hazard ratio stratified on matched pairs: 1.12; 95% confidence interval [0.65-1.92]; P = 0.679). Subgroup analyses of the matched cohort showed no significant difference between TAR with three arterial conduits compared to TAR with two arterial conduits with sequential grafting and MAG + SVG in terms of long-term survival and freedom from MACCE. CONCLUSIONS: Multiple arterial revascularizations in addition to SVG may yield comparable long-term outcomes in terms of survival and freedom from MACCE compared to total arterial revascularization.

The Influence of the FFAR4 Agonist TUG-891 on Liver Steatosis in ApoE-Knockout Mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) constitutes an independent risk factor for the development of coronary heart disease. Low-grade inflammation has been shown to play an important role in the development of atherosclerosis and NAFLD. Free fatty acid receptor 4 (FFAR4/GPR120), which is involved in damping inflammatory reactions, may represent a promising target for the treatment of inflammatory diseases. Our objective was to evaluate the effect of TUG-891, the synthetic agonist of FFAR4/GPR120, on fatty liver in vivo. METHODS: The effect of TUG-891 on fatty liver was investigated in apoE-/- mice fed a high-fat diet (HFD), using microscopic, biochemical, molecular, and proteomic methods. RESULTS: Treatment with TUG-891 inhibited the progression of liver steatosis in apoE-/- mice, as evidenced by histological analysis, and reduced the accumulation of TG in the liver. This action was associated with a decrease in plasma AST levels. TUG-891 decreased the expression of liver genes and proteins involved in de novo lipogenesis (Srebp-1c, Fasn and Scd1) and decreased the expression of genes related to oxidation and uptake (Acox1, Ehhadh, Cd36, Fabp1). Furthermore, TUG-891 modified the levels of selected factors related to glucose metabolism (decreased Glut2, Pdk4 and Pklr, and increased G6pdx). CONCLUSION: Pharmacological stimulation of FFAR4 may represent a promising lead in the search for drugs that inhibit NAFLD.

The Potential of Congo Red Supplied Aggregates of Multitargeted Tyrosine Kinase Inhibitor (Sorafenib, BAY-43-9006) in Enhancing Therapeutic Impact on Bladder Cancer.

Bladder cancer is a common malignancy associated with high recurrence rates and potential progression to invasive forms. Sorafenib, a multi-targeted tyrosine kinase inhibitor, has shown promise in anti-cancer therapy, but its cytotoxicity to normal cells and aggregation in solution limits its clinical application. To address these challenges, we investigated the formation of supramolecular aggregates of sorafenib with Congo red (CR), a bis-azo dye known for its supramolecular interaction. We analyzed different mole ratios of CR-sorafenib aggregates and evaluated their effects on bladder cancer cells of varying levels of malignancy. In addition, we also evaluated the effect of the test compounds on normal uroepithelial cells. Our results demonstrated that sorafenib inhibits the proliferation of bladder cancer cells and induces apoptosis in a dose-dependent manner. However, high concentrations of sorafenib also showed cytotoxicity to normal uroepithelial cells. In contrast, the CR-BAY aggregates exhibited reduced cytotoxicity to normal cells while maintaining anti-cancer activity. The aggregates inhibited cancer cell migration and invasion, suggesting their potential for metastasis prevention. Dynamic light scattering and UV-VIS measurements confirmed the formation of stable co-aggregates with distinctive spectral properties. These CR-sorafenib aggregates may provide a promising approach to targeted therapy with reduced cytotoxicity and improved stability for drug delivery in bladder cancer treatment. This work shows that the drug-excipient aggregates proposed and described so far, as Congo red-sorafenib, can be a real step forward in anti-cancer therapies.

Cladribine tablets for highly active relapsing-remitting multiple sclerosis in Poland: a real-world, multi-centre, retrospective, cohort study during the COVID-19 pandemic.

INTRODUCTION: Treatment with cladribine tablets is indicated in highly active relapsing-remitting multiple sclerosis (RRMS). Cladribine tablets proved safe and effective in the pivotal CLARITY trial, but that trial included primarily treatment-naïve patients. In clinical practice however, cladribine tablets are often given to patients who have failed other treatments. Therefore, this study investigated the real-world safety and efficacy of cladribine tablets. MATERIAL AND METHODS: We gathered data from nine MS clinical centres across Poland for patients with RRMS who started treatment with cladribine tablets from December 2019 to June 2022. RESULTS: We enrolled 140 patients, with follow-up data available for 136 in year 1 and for 66 in year 2. At baseline, the mean age was 35.6 years, mean disease duration was 7.3 years, median EDSS score was 2.5, and 94% of patients were treatment- -experienced. Thirty-nine patients (27.9%) had undergone COVID-19, and 94 (67.1%) were vaccinated against COVID-19. The annualised relapse rate (ARR) decreased from 1.49 at baseline to 0.33 in year 1 (p < 0.001) and to 0.25 in year 2 (p < 0.001). The percentage of relapse-free patients increased from 11.5% at baseline to 70.2% in year 1 and 82.1% in year 2. The percentage of patients with active lesions decreased from 91.4% at baseline to 36.2% in year 1 and 18.2% in year 2. EDSS score remained stable or improved in 83.7% of patients in year 1 and 89.6% in year 2. No evidence of disease activity (NEDA-3) was achieved in 42.7% of patients in year 1 and 66.7% in year 2. Only one patient (0.72%) had grade 4 lymphopenia and 21 (15.1%) had grade 3 lymphopenia. Varicella zoster virus infections occurred in three patients. Eight patients discontinued treatment with cladribine: five due to inefficacy, one due to lymphopenia, and two due to a personal decision. CONCLUSIONS: Cladribine tablets proved safe and effective in a real-world cohort of treatment-experienced patients. However, the efficacy measures improved to a lesser extent in our cohort than in the pivotal clinical trial, which is probably due to a higher proportion of treatment-experienced patients in our cohort.

The Significance of Simple Inflammatory Markers in Off Pump Surgery-Review.

The inflammatory background of coronary artery disease is gaining more attention in recent times. Off pump surgery is minimally invasive type of surgical revascularization with relatively low number of applications in cardiac surgery centers worldwide that allows for perioperative inflammatory reactions minimalization. The simple inflammatory markers (neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelets to lymphocyte ratio (PLR), systemic inflammatory index (SII), systemic inflammatory response index (SIRI), aggregate index of systemic inflammation (AISI)) possess a clinically significant impact on patients' prognosis and may help to improve patients' long-term results. The review presents the current knowledge regarding their utility in clinical practice. Assessment of inflammatory indices obtained from whole blood count analysis allows to indicate those patients who need scrupulous follow-up due to predicted worse long-term survival. Perioperative measurement and analysis of simple whole blood counts is inexpensive and easily available and may improve the results of surgical revascularization by better identification of patients at higher risk of worse outcomes.

Behavioural responses of Konik Polski horses to natural, familiar sound of thunderstorm, and unfamiliar similar-sounding sounds of volcanic eruption and sea storms.

BACKGROUND: It is not clear, if modern Konik Polski horses have retained the ability to identify sounds in terms of danger. The aim of the study was to identify differences in their behaviour in response to the reproduction of volcanic eruption and sea storm sounds, assumed to be unfamiliar to these horses, as compared to their response to a thunderclap sound, considered by the horses as potentially dangerous. The study included 13 adult mares of the Konik Polski breed, kept under a free-range system. Their behavioural responses to the reproduction of the three natural sounds with an intensity of over 50 dB, were registered. They were analysed distance of each horse to the central point of the pasture and to the exit from the enclosure, and time and/or frequencies of elements of behaviour categorised as: increased anxiety (walking, trotting and cantering), vigilance (snoring, vocalisation, high head position, high tail position, sticking together), foraging (time of grazing), comfort (playing, examining the surroundings, sniffing), maintenance of hygiene (rubbing against objects, auto- or allogrooming, rolling) and resting. The obtained data were analysed by the Dwass, Steel and Critchlow-Fligner method using the SAS program. RESULTS: Most of analysed elements increased in response to reproduced sounds and decreased after sounds were stop playing (p < 0.05), however, they were no significant differences in general response to each studied sound. CONCLUSIONS: The responses of horses to similar sounds of both known and unknown origins, i.e. the sound of a thunderstorm, sea storm and volcanic eruption, are similar. The sound stimuli applied were not too stressful for the horses.

Inhaled silica nanoparticles exacerbate atherosclerosis through skewing macrophage polarization towards M1 phenotype.

BACKGROUND AND AIMS: Exposure to environmental nanoparticles is related to the adverse impact on health, including cardiovascular system. Various forms of nanoparticles have been reported to interact with endothelium and induce inflammation. However, the potential role of nanoparticles in the pathogenesis of atherosclerosis and their mechanisms of action are still unclear. The aim of this study was to investigate the effect of two broadly used nanomaterials, which also occur in natural environment - silicon oxide (SiO2) and ferric oxide (Fe2O3) in the form of nanoparticles (NPs) - on the development of atherosclerosis. METHODS: We used apolipoprotein E-knockout mice exposed to silica and ferric oxide nanoparticles in a whole body inhalation chamber. RESULTS: Inhaled silica nanoparticles augmented the atherosclerotic lesions and increased the percentage of pro-inflammatory M1 macrophages in both the plaque and the peritoneum in apoE-/- mice. Exposure to ferric oxide nanoparticles did not enhance atherogenesis process, however, it caused significant changes in the atherosclerotic plaque composition (elevated content of CD68-positive macrophages and enlarged necrotic core accompanied by the decreased level of M1 macrophages). Both silica and ferric oxide NPs altered the phenotype of T lymphocytes in the spleen by promoting polarization towards Th17 cells. CONCLUSIONS: Exposure to silica and ferric oxide nanoparticles exerts impact on atherosclerosis development and plaque composition. Pro-atherogenic abilities of silica nanoparticles are associated with activation of pro-inflammatory macrophages.

SPDL1 Is an Independent Predictor of Patient Outcome in Colorectal Cancer.

Spindle Apparatus Coiled-Coil Protein 1 (SPDL1) is a relatively recently identified coiled-coil domain containing protein and an important determinant of DNA fidelity by ensuring faithful mitosis. Hence, SPDL1 is suspected to underlie genomic (in-)stability in human cancers, yet its exact roles in these diseases remain largely underexplored. Given that genomic instability (GIN) is a crucial feature in colorectal cancer (CRC), we primarily asked whether the expression of this protein may account for differences in clinicopathological features and survival rates of CRC patients. Protein expression was evaluated by immunohistochemistry in the institutional tissue microarray (TMA), and gene expression by the analysis of publicly available datasets. To place the prognostic relevance in a predicted biological context, gene co-expression set around SPDL1 identified by public data mining was annotated and assessed for enrichment in gene ontology (GO) categories, BRITE hierarchies, and Reactome pathways. The comparison with adjacent normal tissue revealed a high expression of SPDL1 protein in a subset of tumor cases (48.84%), and these had better prognosis than the SPDL1-low expression counterpart even after adjustment for multiple confounders. SPDL1-high expression within tumors was associated with a median 56-month survival advantage, but not with any clinicopathological characteristics of our cohort. In the TCGA cohort, SPDL1 was overexpressed in tumor tissue and positively associated with improved survival, chromosome instability phenotype, and various GIN markers. In addition to the genes critically involved in the cell cycle and mitosis, a gene set co-expressed with SPDL1 contained checkpoint members of both chromosome segregation and DNA replication, as well as those associated with defective DNA repair, and retrograde vesicle-mediated transport. In conclusion, SPDL1 is an independent predictor of CRC patient survival in a possible connection with chromosomal instability.