Bioinformatic analysis of endometrial miRNA expression profile at day 26-28 of pregnancy in the mare.

The establishment of the fetomaternal interface depends on precisely regulated communication between the conceptus and the uterine environment. Recent evidence suggests that microRNAs (miRNAs) may play an important role in embryo-maternal dialogue. This study aimed to determine the expression profile of endometrial miRNAs during days 26-28 of equine pregnancy. Additionally, the study aimed to predict target genes for differentially expressed miRNAs (DEmiRs) and their potential role in embryo attachment, adhesion, and implantation. Using next-generation sequencing, we identified 81 DEmiRs between equine endometrium during the pre-attachment period of pregnancy (day 26-28) and endometrium during the mid-luteal phase of the estrous cycle (day 10-12). The identified DEmiRs appear to have a significant role in regulating the expression of genes that influence cell fate and properties, as well as endometrial receptivity formation. These miRNAs include eca-miR-21, eca-miR-126-3p, eca-miR-145, eca-miR-451, eca-miR-491-5p, members of the miR-200 family, and the miRNA-17-92 cluster. The target genes predicted for the identified DEmiRs are associated with ion channel activity and sphingolipid metabolism. Furthermore, it was noted that the expression of mucin 1 and leukemia inhibitory factor, genes potentially regulated by the identified DEmiRs, was up-regulated at day 26-28 of pregnancy. This suggests that miRNAs may play a role in regulating specific genes to create a favorable uterine environment that is necessary for proper attachment, adhesion, and implantation of the embryo in mares.

Tamoxifen decreases ovarian toxicity without compromising cancer treatment in a rat model of mammary cancer.

BACKGROUND: Premenopausal women diagnosed with breast cancer often face aggressive chemotherapy resulting in infertility. Tamoxifen (TAM) is a selective estrogen receptor modulator that was previously suggested as a protective agent against chemotherapy-induced ovarian failure. In the current study, we examined mechanisms of the protective action of TAM in the ovaries of tumor-bearing rats treated with the chemotherapy drug cyclophosphamide (CPA). RESULTS: TAM prevented CPA-induced loss of ovarian follicular reserves. The protective TAM effect in the rat ovary partially resulted from decreased apoptosis. In addition, transcriptomic and proteomic screening also implicated the importance of DNA repair pathways as well as cell adhesion and extracellular matrix remodeling in the protective ovarian actions of TAM. CONCLUSIONS: Tamoxifen shielded the ovary from the side effects of chemotherapy without lessening the tumoricidal actions of mammary cancer treatment.

Clinical outcomes in patients with acute myocardial infarction treated with primary percutaneous coronary intervention stratified according to duration of pain-to-balloon time and type of myocardial infarction.

BACKGROUND: Based on the clinical outcomes of patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), treated with primary percutaneous coronary intervention (pPCI), this study intended to assess mortality and major adverse cardiac and cerebrovascular event (MACCE) rates according to duration of pain-to-balloon (PTB) time and type of MI. METHODS: This is a retrospective cohort study based on the prospectively collected ORPKI registry which covers PCIs performed in Poland chosen between January 2014 and December 2017. Under assessment were 1,994 STEMI and 923 NSTEMI patients. Study endpoints included mortality and MACCE rates (in-hospital, 30-day, 12- and 36-month). Predictors of all-cause mortality in the overall group, STEMI and NSTEMI were assessed by multivariable analysis. RESULTS: Kaplan-Meier survival curve analysis did not reveal significant differences between the STEMI and NSTEMI group for all-cause mortality or MACCE at the 36-month follow-up. While in the long PTB time group, MACCE rate was significantly greater in STEMI patients when compared to NSTEMI (p = 0.004). Among STEMI patients, the short, medium and long PTB time groups differed significantly in the rate of all-cause mortality (p = 0.006) and MACCE (p = 0.04) at 1,095 days of follow-up, which were the greatest in the long PTB time group. CONCLUSIONS: Before considering the length of PTB time, there were no statistically significant differences in mortality or MACCE frequency between the STEMI and NSTEMI group at 36-month follow-up. Longer PTB times are related to significantly greater mortality at the 36-month follow-up in the STEMI, but not in the NSTEMI group.

COVID-19 pandemic influence on epilepsy course in pediatric patients.

INTRODUCTION: In 2020, Coronavirus Disease 2019 (COVID-19) was declared as a global pandemic. Self-reported stress, anxiety, and insomnia, which are believed to be common triggers for epilepsy, are more likely to occur. We aimed to establish the influence of COVID-19 pandemic itself on changes in the daily life routine related to pandemic on epilepsy course in pediatric patients. The unique form of clinical care which is telemedicine was also taken into consideration. We wanted to evaluate patients' satisfaction with telemedicine and if changing stationary visits into telemedicine influenced epilepsy course in our patients. METHODS: Patients, who attended developmental neurology outpatient clinic in the period March-December 2020 were collected. As patients were minors, legal guardians were asked to fill out the questionnaire. Patients were divided according to the outcome into three groups: those with a worsened, stable, or improved course of epilepsy during the pandemic. Appropriate statistical tests for two-group and multi-group comparisons have been implemented. Post hoc p values were also calculated. RESULTS: Four hundred and two questionnaires were collected. Most of the patients had a stable course of epilepsy during the pandemic; in 13% of participants an improvement has been observed, worsening of the disease was seen in 16% of patients. Age, sex, type of epilepsy, number of seizure incidents before pandemic, and duration of the disease had no statistically significant connection with changes in the course of the disease. Behavioral changes and altered sleep patterns were found to be more common in the worsened group. Fifty-eight percent of patients were satisfied with telemedicine. Poorer satisfaction was connected with less frequent visits, cancellation of scheduled appointments, and lack of help in case of need in an emergency situation. CONCLUSION: Epilepsy course in pediatric patients seems to be stable during COVID-19 pandemic. Sleep disturbances and changes in a child's behavior may be related to increase in seizure frequency. Telemedicine is an effective tool for supervising children with epilepsy. Patients should be informed about possible ways of getting help in urgent cases.

Left atrial appendage thrombus in patients referred for electrical cardioversion for atrial fibrillation: a prospective single­center study.

INTRODUCTION: Left atrial appendage thrombus (LAAT) is a risk factor for stroke; however, the actual health risk associated with LAAT in patients with atrial fibrillation (AF) on chronic anticoagulation is unknown. OBJECTIVES: We aimed to assess the prevalence and predictors of LAAT, and its predictive role in relation to mortality, stroke, and systemic thromboembolic events among consecutive AF patients on oral anticoagulation (OAC) admitted for electrical cardioversion. PATIENTS AND METHODS: This was a prospective, single­ center cohort study. The participants underwent transesophageal echocardiography before electrical cardioversion. A total of 296 patients were enrolled. The primary outcome was the presence of LAAT. All participants were followed for 12 months to evaluate the incidence of systemic thromboembolic events, stroke, and death. RESULTS: Despite uninterrupted OAC in patients with AF of above 48-hour duration scheduled for cardio-version, we found a high prevalence of LAAT, reaching 14.5%. There was no difference in the prevalence of thrombi between different types of OAC (P = 0.26). The independent predictors of LAAT were chronic obstructive pulmonary disease, heart failure, prior myocardial infarction, greater left atrial diameter, lower left ventricular ejection fraction, higher CHA2DS2­VASc score, and reduced dabigatran dose. The optimal cutoff values for the prediction of LAAT were the age of at least 74 years, left atrial diameter equal or greater than 52 mm, left ventricular ejection fraction equal or lower than 40%, and CHA2DS2­VASc score equal or greater than 3. No strokes or systemic thromboembolic events occurred over the follow­up period. CONCLUSIONS: The presence of LAAT had no practical value for predicting stroke, thromboembolic events, or death in patients with AF and on chronic anticoagulation.

Comparison of safety and effectiveness between the right and left radial artery approach in percutaneous coronary intervention.

INTRODUCTION AND OBJECTIVES: There is a paucity of data comparing the left radial approach (LRA) and right radial approach (RRA) for percutaneous coronary intervention (PCI) in all-comers populations and performed by operators with different experience levels. Thus, we sought to compare the safety and clinical outcomes of the RRA and LRA during PCI in "real-world" patients with either stable angina or acute coronary syndrome (ACS). METHODS: To overcome the possible impact of the nonrandomized design, a propensity score was calculated to compare the 2 radial approaches. The study group comprised 18 716 matched pairs with stable angina and 46 241 with ACS treated with PCI and stent implantation between 2014 and 2017 in 151 tertiary invasive cardiology centers in Poland (the ORPKI Polish National Registry). RESULTS: The rates of death and periprocedural complications were similar for the RRA and LRA in stable angina patients. A higher radiation dose was observed with PCI via the LRA in both clinical presentations (stable angina: 1067.0±947.1 mGy vs 1007.4±983.5 mGy, P=.001; ACS: 1212.7±1005.5 mGy vs 1053.5±1029.7 mGy, P=.001). More contrast was used in LRA procedures but only in ACS patients (174.2±75.4mL vs 167.2±72.1mL, P=.001). Furthermore, periprocedural complications such as coronary artery dissection (0.16% vs 0.09%, P=.008), no-reflow phenomenon (0.65% vs 0.49%, P=.005), and puncture site bleeding (0.09% vs 0.05%, P=.04) were more frequently observed with the LRA in ACS patients. There was no difference in mortality between the 2 groups (P=.90). CONCLUSIONS: Our finding of poorer outcomes with the LRA may be related to lower operator experience with this approach. While both the LRA and RRA are safe in the setting of stable angina, the LRA was associated with a higher rate of periprocedural complications during PCI in ACS patients.

Isoprostane-8 and GDF-15 as novel markers of post-PE syndrome: Relation with prothrombotic factors.

BACKGROUND: Post-pulmonary embolism (PE) syndrome occurs in up to 50% of PE patients. The pathophysiology of this syndrome is obscure. OBJECTIVE: We investigated whether enhanced oxidative stress and prothrombotic state may be involved in post-PE syndrome. METHODS: We studied 101 normotensive noncancer PE patients (aged 56.5 ± 13.9 years) on admission, after 5-7 days and after a 3-month anticoagulation, mostly with rivaroxaban. A marker of oxidative stress, 8-isoprostane, endogenous thrombin potential, fibrinolysis proteins, clot lysis time (CLT) and fibrin clot permeability (Ks ), along with PE biomarkers, were determined. RESULTS: Patients who developed the post-PE syndrome (n = 31, 30.7%) had at baseline 77.6% higher N-terminal brain natriuretic propeptide and 46.8% higher growth differentiation factor 15, along with 14.1% longer CLT associated with 34.4% higher plasminogen activator inhibitor-1 as compared to subjects without post-PE syndrome (all P < .05). After 5-7 days, only hypofibrinolysis was noted in post-PE syndrome patients. When measured at 3 months, prolonged CLT and reduced Ks were observed in post-PE syndrome patients, accompanied by 23.8% higher growth differentiation factor 15 and 35.8% higher plasminogen activator inhibitor-1 (all P < .05). 8-isoprostane levels ≥108 pg/ml (odds ratio=4.36; 95% confidence interval 1.63-12.27) and growth differentiation factor 15 ≥ 1529 pg/ml (odds ratio=3.89; 95% confidence interval 1.29-12.16) measured at 3 months were associated with higher risk of developing post-PE syndrome. CONCLUSIONS: Enhanced oxidative stress and prothrombotic fibrin clot properties could be involved in the pathogenesis of the post-PE syndrome. Elevated growth differentiation factor 15 assessed at 3 months might be a new biomarker of this syndrome.

Perspective on Stem Cell Therapy in Organ Fibrosis: Animal Models and Human Studies.

Tissue fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components that result from the disruption of regulatory processes responsible for ECM synthesis, deposition, and remodeling. Fibrosis develops in response to a trigger or injury and can occur in nearly all organs of the body. Thus, fibrosis leads to severe pathological conditions that disrupt organ architecture and cause loss of function. It has been estimated that severe fibrotic disorders are responsible for up to one-third of deaths worldwide. Although intensive research on the development of new strategies for fibrosis treatment has been carried out, therapeutic approaches remain limited. Since stem cells, especially mesenchymal stem cells (MSCs), show remarkable self-renewal, differentiation, and immunomodulatory capacity, they have been intensively tested in preclinical studies and clinical trials as a potential tool to slow down the progression of fibrosis and improve the quality of life of patients with fibrotic disorders. In this review, we summarize in vitro studies, preclinical studies performed on animal models of human fibrotic diseases, and recent clinical trials on the efficacy of allogeneic and autologous stem cell applications in severe types of fibrosis that develop in lungs, liver, heart, kidney, uterus, and skin. Although the results of the studies seem to be encouraging, there are many aspects of cell-based therapy, including the cell source, dose, administration route and frequency, timing of delivery, and long-term safety, that remain open areas for future investigation. We also discuss the contemporary status, challenges, and future perspectives of stem cell transplantation for therapeutic options in fibrotic diseases as well as we present recent patents for stem cell-based therapies in organ fibrosis.

Giant Left Atrial Thrombus Despite Anticoagulation with Apixaban in a Patient with Mitral Stenosis and Atrial Fibrillation.

BACKGROUND In patients with atrial fibrillation (AF), the presence of a left atrial thrombus correlates with the highest risk of stroke. Mitral stenosis (MS) is an acquired disease that leads to atrial pressure overload and subsequent significant anatomical and electrical remodeling of the left atrium. This promotes the occurrence of AF and atrial thrombus formation. Proper anticoagulation decreases the stroke risk in AF patients. Unfortunately, there is insufficient data on the effectiveness of non-vitamin K antagonist oral anticoagulants (NOAC) in patients with AF and MS. CASE REPORT We present a case of 64-year-old woman referred for electrical cardioversion (CV) due to symptomatic AF. She was administered an apixaban for stroke prevention, but she missed the scheduled echocardiography prior to referral. Imaging performed on-site revealed a giant left atrial thrombus and moderate MS. High mobility of the intracardiac mass together with moderate AS and MS were assessed as significant predictors of distal embolization. The patient underwent mitral valve replacement with the thrombus removal. Her further recovery was uneventful. CONCLUSIONS Mitral stenosis significantly affects the anticoagulant selection in patients with atrial fibrillation. Thus, echocardiography is mandatory if the first diagnosis is atrial fibrillation to exclude contraindications for NOAC therapy.

Choosing a treatment method for post-catheterization pseudoaneurysms guided by the late to early velocity index.

Ultrasound-guided thrombin injection (UGTI) is often the first-line treatment for iatrogenic post-catheterization pseudoaneurysms (psA). There are also first reports of the use of biologically derived tissue glues (TG) instead of sole thrombin especially when UGTI was unsuccessful or in case of psA recurrence. Previously, we have established that a late to early velocity index (LEVI) < 0.2 could be a predictor of an increased risk of psA recurrence after standard UGTI. In this paper, we report our first experiences when the choice of the first-line treatment method was based on LEVI assessment. From May 2017 till January 2020 we included 36 patients with psA. Of them, 10 had LEVI < 0.2 and they underwent ultrasound-guided tissue glue injection (UGTGI) with biological TG and 26 had LEVI > 0.2 and they underwent UGTI. The injection set containing human thrombin and fibrinogen was used for UGTGI. Bovine thrombin was used for UGTI. The success rate was 100% and no psA recurrence was detected during a 2-week follow-up. It was significantly better when compared to the expected recurrence rates based on our previous 14 years of experience (0% vs. 13%, p = 0.01). All complications (10% in the UGTGI group and 15% in the UGTI group) were mild and transient and included clinical symptoms of paresthesia, numbness, tingling, or pain. Their rates were comparable to the rates we previously reported. No significant differences in other characteristics were observed. The approach to choose the first-line treatment method for iatrogenic psA based on LEVI is encouraging. It may increase the success rate and avoid unnecessary repetition of the procedure, without increasing complication rate while keeping costs of the procedure reasonable.

Transcriptional profiling of Chinese hamster ovary (CHO) cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a man-made chemical compound contaminating the environment. An exposure of organisms to TCDD results in numerous disorders. The main mechanism of TCDD action involves the induction of the aryl hydrocarbon receptor (AhR) pathway followed by the increase in the expression and activity of cytochrome P450 family 1 (CYP1) enzymes. The main aim of the present study was to identify, by means of RNA sequencing, transcripts involved in the mechanism of TCDD action in Chinese hamster ovary (CHO) cells, known to not express CYP1A1 enzyme. The CHO cells were treated with TCDD for 3, 12 or 24 h, and total RNA was isolated and sequenced. Thirty six (padjusted < 0.05) or six (padjusted < 0.05, log2FC ≥ 1.0/log2FC≤-1.0) differentially expressed genes (DEGs) were identified in TCDD-treated cells depending on the assumed statistical criteria. The dioxin up- and downregulated the expression of genes associated with ovarian follicle functions, development, cardiovascular system, signal transduction, inflammation and carcinogenesis. TCDD did not affect the expression of any of 522 miRNAs which were identified in the cells. The expression of CYP1A1, CYP1A2 and CYP1B1 was demonstrated neither in control nor in TCDD-treated CHO cells, although the respective genes were found in the cell genome. Twenty two other CYP enzymes were identified in CHO cells, however their expression was also not affected by TCDD.

Effects of cortisol on prostaglandin F2α secretion and expression of genes involved in the arachidonic acid metabolic pathway in equine endometrium - In vitro study.

Glucocorticoids (GCs) are known to play an important role in maintaining basal and stress-related homeostasis by interacting with endocrine mediators and prostaglandins (PGs). Although a growing body of evidence shows that GCs exert their regulatory action at a multitude of sites in the reproductive axis through corticosteroid receptors, little is known about the direct role of cortisol, an active form of GCs, in the equine endometrium. Thus, the study aimed to determine the effect of cortisol on PGF2α synthesis in the endometrial tissue and cells in vitro. In Exp.1, the immunolocalization and the expression of the glucocorticoid receptor (GCR) in the endometrium throughout the estrous cycle were established. In Exp. 2 and 3, the effects of cortisol on PGF2α secretion and transcripts associated with the arachidonic acid (AA) cascade in endometrial tissues, and cells were defined. Endometrial tissues obtained from the early, mid, and late luteal phases and the follicular phase of the estrous cycle were exposed to cortisol (100, 200, and 400 nM) for 24 h. Endometrial epithelial and stromal cells (early phase of estrous cycle) were exposed to cortisol (100 nM) for 24 h. Then, PGF2α secretion and transcripts associated with the AA cascade (PLA2G2A, PLA2G4A, PTGS2, and PGFS) were assessed. GCR was expressed in the cytoplasm and the nucleus in the luminal and glandular epithelium as well as in the stroma. Endometrial GCR protein abundance was up-regulated at the late luteal phase compared to the mid-luteal phase of the estrous cycle. Cortisol dose-dependently decreased PGF2α secretion, PLA2G2A and PLA2G4A transcripts in endometrial tissues. Additionally, cortisol treatment decreased PGF2α secretion from endometrial epithelial and stromal cells. Moreover, it affected PLA2G2A, PLA2G4A, and PTGS2 transcripts in endometrial stromal cells. These findings suggest that cortisol suppresses the synthesis of PGF2α by affecting the AA cascade in the equine endometrium during the estrous cycle.

Late to early velocity index as a predictor of iatrogenic femoral artery pseudoaneurysm recurrence in patients treated with ultrasound-guided thrombin injection.

INTRODUCTION: Ultrasound-guided thrombin injection (UGTI) is the preferred treatment of pseudoaneurysms (psA). The potential risk of complications increases with the number of UGTI treatments needed for complete psA obliteration. Identification of risk factors for recurrent psA is needed. MATERIAL AND METHODS: In total, 508 patients with femoral artery psA underwent UGTI, followed by ultrasound examination repeated twice, at 1-week intervals, to assess UGTI effectiveness. In cases of psA recurrence, the procedure was repeated. Clinical and ultrasound data were prospectively collected. RESULTS: The psA recurrence occurred in 76 (15%) patients. UGTI was repeated twice in 49 (64%), three times in 15 (20%) and more than three times in 12 (16%) patients. The median thrombin dose was 150 IU (80-250 IU), and was lower in initial procedures than repeated UGTI (p = 0.025). The median psA volume was 2.26 ml (0.86-5.47 ml). The median length of the communicating channel was 4 mm (0-12 mm). A time interval between vessel catheterization and UGTI greater than 7 days (p < 0.001), a late to early velocity index (LEVI) of < 0.2 identified during the outflow phase (p < 0.001), a psA volume > 5 ml (p = 0.032), and a short communicating channel between the psA and the artery (p = 0.037) predicted psA recurrence. Antiplatelet and anticoagulant agents did not increase the risk. CONCLUSIONS: The LEVI and time interval between artery cannulation and UGTI treatment are strong parameters identifying patients at risk of psA recurrence. The psA volume and communicating channel length are less substantial risks, but still significant. Concomitant antiplatelet and anticoagulant therapy do not affect the success rate of UGTI.

Right ventricular echocardiographic parameters associated with prothrombotic abnormalities in normotensive patients with acute pulmonary embolism.

BACKGROUND: In acute pulmonary embolism (PE) right ventricular (RV) pressure overload negatively affects prognosis. Recently we have shown that RV dilatation is associated with a prothrombotic state in PE. We investigated which RV echocardiographic parameters best indicate prothrombotic alterations in acute PE. METHODS: In 121 normotensive, noncancer PE patients, markers of RV dilatation and dysfunction were evaluated on admission using transthoracic echocardiography, along with prothrombotic state markers, i.e. increased endogenous thrombin generation (ETP), low fibrin clot permeability (Ks, a measure of clot density), and prolonged clot lysis time (CLT). RESULTS: RV parasternal long axis (RVOT PLAX) >30 mm was associated with ETP (OR 3.86; 95% CI 1.55-9.62; p = 0.004) and CLT (OR 4.08; 95% CI 1.58-10.54; p = 0.004) in the top quartiles, but not with Ks. RV short parasternal axis (RVOT PSAX) >27 mm showed similar associations with higher ETP (OR 3.54; 95% CI 1.50-8.37; p = 0.004) and prolonged CLT (OR 2.78; 95% CI 1.17-6.62; p = 0.021). RV basal diameter >41 mm solely predicted prolonged CLT (OR 2.93; 95% CI 1.23-6.99; p = 0.016). The right atrium area, pulmonary trunk diameter, and tricuspid regurgitation maximum velocity were not related to prothrombotic markers, except for tricuspid annular plane systolic excursion weakly associated with ETP. Multivariable analysis showed that RVOT PSAX is independently associated with prolonged CLT (OR 1.16; 95% CI 1.04-1.30; p = 0.007), low Ks (OR 1.21; 95% CI 1.02-1.44; p = 0.029), and higher ETP (OR 1.14; 95% CI 1.03-1.26; p = 0.009). CONCLUSIONS: Among RV echocardiographic parameters, the RVOT dilatation measured in PSAX best predicts prothrombotic alterations in PE patients.

Loose Fibrin Clot Structure and Increased Susceptibility to Lysis Characterize Patients with Central Acute Pulmonary Embolism: The Impact of Isolated Embolism.

BACKGROUND: Prothrombotic fibrin clot properties are associated with higher early mortality risk in acute pulmonary embolism (PE) patients. It is unknown whether different types of PE are associated with particular clot characteristics. METHODS: We assessed 126 normotensive, noncancer acute PE patients (median age: 59 [48-70] years; 52.4% males), who were categorized into central versus peripheral PE with or without concomitant deep vein thrombosis (DVT). Plasma fibrin clot permeability (K s), clot lysis time (CLT), thrombin generation, platelet-derived markers, and fibrinolytic parameters were measured on admission. Plasma fibrin clot morphology was assessed by scanning electron microscopy (SEM). RESULTS: Patients with central PE (n = 76; 60.3%) compared with peripheral PE (n = 50; 39.7%) had 17.8% higher K s and 14.3% shortened CLT (both p < 0.01 after adjustment for potential confounders including fibrinogen), with no differences between segmental and subsegmental PE. SEM analysis demonstrated larger fibrin fiber diameter and pore size in central PE compared with peripheral PE (both p < 0.01). For isolated PE, there was 23.3% higher K s in central PE than in peripheral PE (n = 24; 19%) with no differences in other variables. Central PE combined with DVT (n = 45; 35.7%), as compared with central isolated PE (n = 31; 24.6%), was associated with shortened CLT (all p < 0.05). CONCLUSION: Our findings suggest that looser fibrin networks composed of thicker fibers with increased susceptibility to lysis characterize patients with central PE, suggesting that fibrin clot phenotype affects the size of thrombi occluding the pulmonary arteries, highlighting the role of fibrin structures in thrombus formation and stability.

Effect of day- and night-time admissions on long-term clinical outcomes of patients with acute myocardial infarction treated with percutaneous coronary intervention.

INTRODUCTION: It has been suggested that the time of admission during the day and night may influence the clinical outcomes of patients with acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI). OBJECTIVES: The aim of this study was to assess the impact of day- and night­time admissions on the clinical outcomes of patients with AMI undergoing PCI. PATIENTS AND METHODS: This retrospective cohort study was based on the data on PCIs performed in Poland from January 2014 to December 2017, prospectively collected in the National Registry of Invasive Cardiology Procedures (ORPKI). Day hours were defined as the time interval between 7:00 am and 10:59 pm. The study endpoints included the all­cause in­hospital mortality rate and major adverse cardiovascular and cerebrovascular events (MACCEs) at 30­day,12­month, and 36­month follow­up. RESULTS: A total of 2919 patients were included in the study (2462 [84.3%] treated during the day hours). ST­segment elevation myocardial infarction (1993 [68.3%]) was the main indication for PCI. We demonstrated that the 30­day mortality rate was significantly higher in patients treated during the night hours than during the day hours (P = 0.01). Night hours were also among the independent predictors of increased 30­day mortality (hazard ratio, 1.54; 95% CI, 1.11-2.16; P = 0.01). No significant differences were observed in in­hospital, 12­month, and 36­month mortality rates between patients treated during the night and day hours. There were no significant differences in the MACCE rates at the follow­up timepoints. CONCLUSIONS: Primary PCI for AMI is associated with increased 30­day mortality among patients treated during the night hours compared with those managed during the day hours.

Prothrombotic fibrin clot properties associated with NETs formation characterize acute pulmonary embolism patients with higher mortality risk.

Venous thromboembolism is associated with formation of denser fibrin clots resistant to lysis. We investigated whether prothrombotic plasma clot properties are associated with the severity of acute pulmonary embolism (PE). We enrolled 126 normotensive acute PE patients (aged 58 ± 14 years) and 25 age- and sex-matched healthy controls. Plasma fibrin clot permeability (Ks), clot lysis time (CLT), endogenous thrombin potential (ETP), plasminogen activator inhibitor-1 (PAI-1), and citrullinated histone H3 (citH3) were evaluated on admission. PE patients compared to controls had 370% higher citH3 levels, 41% higher ETP, 16.5% reduced Ks, and 25.6% prolonged CLT. Patients with intermediate-high (n = 29) and intermediate-low (n = 77) PE mortality risk had reduced Ks and prolonged CLT, increased PAI-1 and ETP as compared to low-risk PE (n = 20) patients. Prolonged CLT was predicted by PAI-1 and citH3, while low Ks by C-reactive protein. During a 12-month follow-up 9 (7.1%) patients who had 24% higher ETP, 45% higher citH3 levels, and 18% prolonged CLT at baseline died. High ETP combined with elevated citH3 levels and prolonged CLT was associated with eightfold increased risk of PE-related death. Prothrombotic fibrin clot properties and enhanced neutrophil extracellular traps formation are associated with higher early mortality risk in acute PE patients, which suggests a prognostic role of these biomarkers.

Clinical presentation and 3-year outcomes of patients with acute coronary syndromes and non-obstructive coronary arteries on angiography.

BACKGROUND: With the emerging interest in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA), there is a need to define an even broader group of patients with the syndrome of myocardial ischemia with non-obstructive coronary arteries (INOCA). There are limited data on the clinical characteristics and prognoses of such patients who present with symptoms of acute coronary syndrome (ACS) and undergo urgent coronary angiography that reveals no significant lesions. The aim of this observational study was to compare patients with ACS INOCA and those with ACS with obstructive coronary artery disease (OCAD) both within unadjusted cohorts and with propensity score matched controls. METHODS AND RESULTS: This observational study was based on the data from the Polish National Registry of Invasive Cardiology Procedures. Of 9744 patients included, 7624 had OCAD and 2120 had ACS INOCA. In unadjusted cohorts, the overall survival and incidence of major adverse cardiovascular events (MACE: death, cardiac arrest, myocardial infarction, stroke, and heart failure hospitalization) until 36 months were higher in patients with ACS OCAD. Following propensity matching, higher win ratios of death (p = 0.02), additional revascularizations by percutaneous coronary intervention or coronary artery bypass graft surgery (p<0.001), and cardiac hospitalization (p<0.001) were observed in these patients. In contrast, the win ratios of myocardial infarction (p = 0.74), heart failure hospitalization (p = 0.86), and MACE (p = 0.07) were not significantly different between the groups. CONCLUSIONS: The prognosis of patients with ACS INOCA was more favorable than that of patients with ACS OCAD; however, the differences diminished after adjustments for the initial clinical profiles. An ACS incident should not be judged as trivial even when cardiac markers remain stable and no significant lesions are found on angiography.

The progress in outcomes of the management of patients with non-ST-segment elevation myocardial infarction between 2005 and 2014 in Poland - a propensity score matching analysis from the PL-ACS registry.

INTRODUCTION: Dynamic changes both in clinical profile and treatment strategy of non ST-segment elevation myocardial infarction (NSTEMI) patients have been observed recently. The exact impact of them on prognosis in a wide national population remains unclear. AIM: To evaluate the impact of treatment advances between 2005 and 2014 on the outcomes of NSTEMI cases. MATERIAL AND METHODS: NSTEMI patients from the Polish Registry of Acute Coronary Syndromes (PL-ACS) were included to the analysis. The mortality rate in a hospital observation as well as in 12-month follow-up was evaluated. RESULTS: The frequency of diabetes, hypertension, prior coronary artery interventions (especially percutaneous coronary intervention) raised. A frequency of invasive procedures increased remarkably (coronary angiography from 35.8% to 90.7%; p < 0.05 and percutaneous coronary intervention from 25.7% to 63.6%; p < 0.05). The usage of P2Y12 - inhibitors raised substantially from 56% to 93%; p < 0.05. In-hospital mortality decreased by fifty percent (in women from 6.6% to 3.3%; p < 0.001 and in men from 4.9% to 2.5%; p < 0.001, respectively). Similarly, 12-month mortality decreased up to one third (in women from 21.6% to 15.1%; p < 0.001 and in men from 17.8% to 12.8%; p < 0.001, respectively). Invasive strategy appeared to be the strongest factor decreasing mortality. Into in-hospital observation it reduces triple mortality risk whereas in 12-month follow up twice. Using propensity score matching analysis the impact of the treatment improvements on relative risk reduction was estimated on over 60%. CONCLUSIONS: In last decade the outcomes of NSTEMI in Poland improved substantially. The predominant impact on it had a routine invasive strategy.

Preclinical Characterization of an Antibody-Drug Conjugate Targeting CS-1 and the Identification of Uncharacterized Populations of CS-1-Positive Cells.

Multiple myeloma is a hematologic cancer that disrupts normal bone marrow function and has multiple lines of therapeutic options, but is incurable as patients ultimately relapse. We developed a novel antibody-drug conjugate (ADC) targeting CS-1, a protein that is highly expressed on multiple myeloma tumor cells. The anti-CS-1 mAb specifically bound to cells expressing CS-1 and, when conjugated to a cytotoxic pyrrolobenzodiazepine payload, reduced the viability of multiple myeloma cell lines in vitro In mouse models of multiple myeloma, a single administration of the CS-1 ADC caused durable regressions in disseminated models and complete regression in a subcutaneous model. In an exploratory study in cynomolgus monkeys, the CS-1 ADC demonstrated a half-life of 3 to 6 days; however, no highest nonseverely toxic dose was achieved, as bone marrow toxicity was dose limiting. Bone marrow from dosed monkeys showed reductions in progenitor cells as compared with normal marrow. In vitro cell killing assays demonstrated that the CS-1 ADC substantially reduced the number of progenitor cells in healthy bone marrow, leading us to identify previously unreported CS-1 expression on a small population of progenitor cells in the myeloid-erythroid lineage. This finding suggests that bone marrow toxicity is the result of both on-target and off-target killing by the ADC.