Cangrelor - Expanding therapeutic options in patients with acute coronary syndrome.

Cangrelor is the only intravenous P2Y12 receptor antagonist. It is an adenosine triphosphate analog that selectively, directly, and reversibly binds to the platelet P2Y12 receptors exerting its antiaggregatory effect. Cangrelor is characterized by linear, dose-dependent pharmacokinetics and rapid onset of action providing potent platelet inhibition exceeding 90%. Cangrelor is rapidly metabolized by endothelial endonucleotidase; thus, its half-life is 2.9 to 5.5 min, and its antiplatelet effect subsides within 60 to 90 min. Data originating from three pivotal cangrelor trials (CHAMPION PLATFORM, CHAMPION PCI, and CHAMPION PHOENIX) indicate that cangrelor reduces the risk of periprocedural thrombotic complications during percutaneous coronary intervention at the expense of mild bleedings. Its unique pharmacological properties allow it to overcome the limitations of oral P2Y12 receptor inhibitors, mainly related to the delayed and decreased bioavailability and antiplatelet effect of these agents, which are often observed in the setting of acute coronary syndrome. Subgroups of patients who could theoretically benefit the most from cangrelor include those in whom pharmacokinetics and pharmacodynamics of oral P2Y12 receptor antagonists are most disturbed, namely patients with ST-segment elevation myocardial infarction, those treated with opioids, with mild therapeutic hypothermia, or in cardiogenic shock. Cangrelor could also be useful if bridging is required in patients undergoing surgery. According to the current guidelines cangrelor may be considered in P2Y12 receptor inhibitor-naïve patients undergoing percutaneous coronary intervention in both acute and stable settings.

Preliminary analysis of oral and gut microbiome of an elderly patient with late-diagnosed phenylketonuria.

Phenylketonuria (PKU) is a metabolic and genetic disorder caused by a phenylalanine hydroxylase (PAH) gene deficiency that raises Phe levels in organs. Dietary therapy involves an elimination diet and Phe-free items, which may alter microbiota. The study examined the oral and intestinal microbiomes of a 63-year-old PKU patient and a control man, living in rural areas. iSeq100 (Illumina) sequenced the stool and oral 16S rRNA gene V3-V4 region. PKU guts had more Firmicutes and fewer Bacteroidetes than control. Clostridia predominated in PKU, while Bacteroidia dominated in control. Oral Bacteroidetes. Firmicutes, Proteobacteria, and Fusobacteria phyla were similar in both men. The microbiome may differ from those fed a Phe-free diet from birth due to late diagnosis and treatment of PKU. Due to the age of the 63-year-old patient's and late therapy, the results differ from earlier studies. No study has compared an older PKU patient's gut and oral microbiomes.

Fe(II), Mn(II), and Zn(II) Binding to the C-Terminal Region of FeoB Protein: An Insight into the Coordination Chemistry and Specificity of the Escherichia coli Fe(II) Transporter.

The interactions between two peptide ligands [Ac763CCAASTTGDCH773 (P1) and Ac743RRARSRVDIELLATRKSVSSCCAASTTGDCH773 (P2)] derived from the cytoplasmic C-terminal region of Eschericha coli FeoB protein and Fe(II), Mn(II), and Zn(II) ions were investigated. The Feo system is regarded as the most important bacterial Fe(II) acquisition system, being one of the key virulence factors, especially in anaerobic conditions. Located in the inner membrane of Gram-negative bacteria, FeoB protein transports Fe(II) from the periplasm to the cytoplasm. Despite its crucial role in bacterial pathogenicity, the mechanism in which the metal ion is trafficked through the membrane is not yet elucidated. In the gammaproteobacteria class, the cytoplasmic C-terminal part of FeoB contains conserved cysteine, histidine, and glutamic and aspartic acid residues, which could play a vital role in Fe(II) binding in the cytoplasm, receiving the metal ion from the transmembrane helices. In this work, we characterized the complexes formed between the whole cytosolic C-terminal sequence of E. coli FeoB (P2) and its key polycysteine region (P1) with Fe(II), Mn(II), and Zn(II) ions, exploring the specificity of the C-terminal region of FeoB. With the help of a variety of potentiometric, spectroscopic (electron paramagnetic resonance and NMR), and spectrometric (electrospray ionization mass spectrometry) techniques and molecular dynamics, we propose the metal-binding modes of the ligands, compare their affinities toward the metal ions, and discuss the possible physiological role of the C-terminal region of E. coli FeoB.

Pretreatment with P2Y12 Receptor Inhibitors in Acute Coronary Syndromes-Is the Current Standpoint of ESC Experts Sufficiently Supported?

Excessive platelet reactivity plays a pivotal role in the pathogenesis of acute myocardial infarction. Today, the vast majority of patients presenting with acute coronary syndromes qualify for invasive treatment strategy and thus require fast and efficient platelet inhibition. Since 2008, in cases of ST-elevation myocardial infarction, the European Society of Cardiology guidelines have recommended pretreatment with a P2Y12 inhibitor. This approach has become the standard of care in the majority of centers worldwide. Nevertheless, the latest guidelines for the management of patients presenting with acute coronary syndrome without persisting ST-elevation preclude routine pretreatment with the P2Y12 receptor inhibitor. Those who oppose pretreatment support their stance with trials failing to prove the benefits of this strategy at the cost of an increased risk of major bleeding, especially in individuals inappropriately diagnosed with an acute coronary syndrome, thus having no indication for platelet inhibition. However, adequate platelet inhibition requires even up to several hours after application of a loading dose of P2Y12 receptor inhibitors. Omission of data from pharmacokinetic and pharmacodynamic studies in the absence of data from clinical studies makes generalization of the pretreatment recommendations difficult to accept. We aimed to review the scientific evidence supporting the current recommendations regarding pretreatment with P2Y12 inhibitors.

Effects of Multidisciplinary Rehabilitation Program in Patients with Long COVID-19: Post-COVID-19 Rehabilitation (PCR SIRIO 8) Study.

Up to 80% of COVID-19 survivors experience prolonged symptoms known as long COVID-19. The aim of this study was to evaluate the effects of a multidisciplinary rehabilitation program in patients with long COVID-19. The rehabilitation program was composed of physical training (aerobic, resistance, and breathing exercises), education, and group psychotherapy. After 6 weeks of rehabilitation in 97 patients with long COVID-19, body composition analysis revealed a significant decrease of abdominal fatty tissue (from 2.75 kg to 2.5 kg; p = 0.0086) with concomitant increase in skeletal muscle mass (from 23.2 kg to 24.2 kg; p = 0.0104). Almost 80% of participants reported dyspnea improvement assessed with the modified Medical Research Council scale. Patients' physical capacity assessed with the 6 Minute Walking Test increased from 320 to 382.5 m (p < 0.0001), the number of repetitions in the 30 s Chair Stand Test improved from 13 to 16 (p < 0.0001), as well as physical fitness in the Short Physical Performance Battery Test from 14 to 16 (p < 0.0001). The impact of fatigue on everyday functioning was reduced in the Modified Fatigue Impact Scale from 37 to 27 (p < 0.0001). Cardiopulmonary exercise test did not show any change. The multidisciplinary rehabilitation program has improved body composition, dyspnea, fatigue and physical capacity in long COVID-19 patients.

Comparison of reorganized versus unaltered cardiology departments during the COVID-19 era: A subanalysis of the COV-HF-SIRIO 6 study.

BACKGROUND: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, numerous cardiology departments were reorganized to provide care for COVID-19 patients. We aimed to compare the impact of the COVID-19 pandemic on hospital admissions and in-hospital mortality in reorganized vs. unaltered cardiology departments. METHODS: The present research is a subanalysis of a multicenter retrospective COV-HF-SIRIO 6 study that includes all patients (n = 101,433) hospitalized in 24 cardiology departments in Poland between January 1, 2019 and December 31, 2020, with a focus on patients with acute heart failure (AHF). RESULTS: Reduction of all-cause hospitalizations was 50.6% vs. 21.3% for reorganized vs. unaltered cardiology departments in 2020 vs. 2019, respectively (p < 0.0001). Considering AHF alone respective reductions by 46.5% and 15.2% were registered (p < 0.0001). A higher percentage of patients was brought in by ambulance to reorganized vs. unaltered cardiology departments (51.7% vs. 34.6%; p < 0.0001) alongside with a lower rate of self-referrals (45.7% vs. 58.4%; p < 0.0001). The rate of all-cause in-hospital mortality in AHF patients was higher in reorganized than unaltered cardiology departments (10.9% vs. 6.4%; p < 0.0001). After the exclusion of patients with concomitant COVID-19, the mortality rates did not differ significantly (6.9% vs. 6.4%; p = 0.55). CONCLUSIONS: A greater reduction in hospital admissions in 2020 vs. 2019, higher rates of patients brought by ambulance together with lower rates of self-referrals and higher all-cause in-hospital mortality for AHF due to COVID-19 related deaths were observed in cardiology departments reorganized to provide care for COVID-19 patients vs. unaltered ones.

Single nucleotide polymorphisms in the bovine SLC2A12 and SLC5A1 glucose transporter genes - the effect on gene expression and milk traits of Holstein Friesian cows.

In this study, novel single nucleotide polymorphisms (SNPs) were found in the 5'-regulatory regions (promoters) of the bovine glucose transporter (GT) genes SLC2A12 and SLC5A1. These polymorphisms were shown to associate with certain milk production traits in HF cows, including milk yield, milk composition, and somatic cell count. It was shown that the SNP g.-671C > G (NC_037336.1: g.72224078C > G) in the SLC2A12 gene could be an effective marker of cattle production traits and that genotypes CC and CG are associated with the best productivity. The polymorphisms found in the SLC5A1 gene promoter also influenced milk production traits in HF cows, albeit to a lesser extent, and we propose that these polymorphisms could be useful as genetic markers for milk production traits in marker-assisted selection (MAS); however, this must be confirmed on larger populations of cattle. In addition, the presence of polymorphisms within promoter regions appears to affect the expression of GT genes in the cow mammary gland and modify transcription factor (TF) binding capacity.

Identification of the c.829_832delAATA Deletion Variants in the BRCA1 Gene Associated with Hereditary Breast/Ovarian Cancer - Case Report.

Determination of the BRCA1/BRCA2 mutation status in patients with breast and/or ovarian cancer is commonly performed using various molecular techniques. The use of targeted PCR-based tests only may not be sufficient, as not all possible variants are investigated. In the present study, we used next-generation sequencing (NGS) techniques to identify novel pathogenic variants in BRCA1 and BRCA2. In this study, material (blood and FFPE) collected from a 67-year-old patient with ovarian cancer was used. The presence of hereditary mutations characteristic for the Polish population was examined using Sanger sequencing. BRCA1 and BRCA2 gene exons were amplified using the Devyser BRCA kit and sequenced on the Miniseq. No germline mutations characteristic for the Polish population were detected. However, 12 single nucleotide variants and 2 indels were identified. We found a new deleterious mutation of gene BRCA1 (c.829_832delAATA). To our knowledge, this mutation has not been reported yet in the Polish population and elsewhere. The use of the NGS technique increases the possibility of detecting mutational changes in patients with ovarian and/or breast cancer. Quick determination of pathogenic variants is important to facilitate specific therapy, in addition to the identification of familial predisposition to cancer.

Diurnal Variability of Platelet Aggregation in Patients with Myocardial Infarction Treated with Prasugrel and Ticagrelor.

BACKGROUND: Contemporary antiplatelet treatment in acute myocardial infarction (AMI) is based on one of two P2Y12 receptor inhibitors, prasugrel or ticagrelor. The aim of this study was to compare diurnal variability of platelet reactivity between patients receiving prasugrel and ticagrelor during the initial phase of maintenance treatment after AMI. METHODS: It was a prospective, two-center, pharmacodynamic, observational study. Blood for platelet testing was sampled at four time points on day four after AMI (8:00, 12:00, 16:00, 20:00). Diurnal variability of platelet reactivity was expressed as a coefficient of variation (CV) of the above-mentioned measurements. RESULTS: 73 invasively-treated patients were enrolled (ticagrelor: n = 47, prasugrel: n = 26). CV was greater in patients treated with ticagrelor compared with prasugrel according to a VASP assay (47.8 [31.6-64.6]% vs. 21.3 [12.9-25.5]%, p < 0.001), while no statistical differences were detected when the CVs of platelet aggregation according to Multiplate were compared between ticagrelor- and prasugrel-treated patients. Ticagrelor-treated patients showed more pronounced platelet inhibition than prasugrel at 16:00 and 20:00 (VASP16:00: 20.6 ± 15.0 vs. 24.9 ± 12.8 PRI, p = 0.049; VASP20:00: 18.6 ± 17.7 vs. 26.0 ± 11.7 PRI, p = 0.002). CONCLUSIONS: Ticagrelor shows greater diurnal variability in platelet aggregation than prasugrel during the initial maintenance phase of AMI treatment, and this is due to the continuous increase of platelet inhibition after the morning maintenance dose. Both drugs provide an adequate antiplatelet effect early after AMI. Evaluation of the clinical significance of these findings warrants further investigation.

Impact of COVID-19 pandemic on acute heart failure admissions and mortality: a multicentre study (COV-HF-SIRIO 6 study).

AIMS: The coronavirus disease-2019 (COVID-19) pandemic has changed the landscape of medical care delivery worldwide. We aimed to assess the influence of COVID-19 pandemic on hospital admissions and in-hospital mortality rate in patients with acute heart failure (AHF) in a retrospective, multicentre study. METHODS AND RESULTS: From 1 January 2019 to 31 December 2020, a total of 101 433 patients were hospitalized in 24 Cardiology Departments in Poland. The number of patients admitted due to AHF decreased by 23.4% from 9853 in 2019 to 7546 in 2020 (P < 0.001). We noted a significant reduction of self-referrals in the times of COVID-19 pandemic accounting 27.8% (P < 0.001), with increased number of AHF patients brought by an ambulance by 15.9% (P < 0.001). The length of hospital stay was overall similar (7.7 ± 2.8 vs. 8.2 ± 3.7 days; P = not significant). The in-hospital all-cause mortality in AHF patients was 444 (5.2%) in 2019 vs. 406 (6.5%) in 2020 (P < 0.001). A total number of AHF patients with concomitant COVID-19 was 239 (3.2% of AHF patients hospitalized in 2020). The rate of in-hospital deaths in AHF patients with COVID-19 was extremely high accounting 31.4%, reaching up to 44.1% in the peak of the pandemic in November 2020. CONCLUSIONS: Our study indicates that the COVID-19 pandemic led to (i) reduced hospital admissions for AHF; (ii) decreased number of self-referred AHF patients and increased number of AHF patients brought by an ambulance; and (iii) increased in-hospital mortality for AHF with very high mortality rate for concomitant AHF and COVID-19.

Thermodynamic Stability and Speciation of Ga(III) and Zr(IV) Complexes with High-Denticity Hydroxamate Chelators.

Increasing attention has been recently devoted to 89Zr(IV) and 68Ga(III) radionuclides, due to their favorable decay characteristics for positron emission tomography (PET). In the present paper, a deep investigation is presented on Ga(III) and Zr(IV) complexes with a series of tri-(H3L1, H3L3, H3L4 and desferrioxamine E, DFOE) and tetrahydroxamate (H4L2) ligands. Herein, we describe the rational design and synthesis of two cyclic complexing agents (H3L1 and H4L2) bearing three and four hydroxamate chelating groups, respectively. The ligand structures allow us to take advantage of the macrocyclic effect; the H4L2 chelator contains an additional side amino group available for a possible further conjugation with a biomolecule. The thermodynamic stability of Ga(III) and Zr(IV) complexes in solution has been measured using a combination of potentiometric and pH-dependent UV-vis titrations, on the basis of metal-metal competition. The Zr(IV)-H4L2 complex is characterized by one of the highest formation constants reported to date for a tetrahydroxamate zirconium chelate (log ß = 45.9, pZr = 37.0), although the complex-stability increase derived from the introduction of the fourth hydroxamate binding unit is lower than that predicted by theoretical calculations. Solution studies on Ga(III) complexes revealed that H3L1 and H4L2 are stronger chelators in comparison to DFOB. The complex stability obtained with the new ligands is also compared with that previously reported for other hydroxamate ligands. In addition to increasing the library of the thermodynamic stability data of Ga(III) and Zr(IV) complexes, the present work allows new insights into Ga(III) and Zr(IV) coordination chemistry and thermodynamics and broadens the selection of available chelators for 68Ga(III) and 89Zr(IV).

A new approach to ticagrelor-based de-escalation of antiplatelet therapy after acute coronary syndrome. A rationale for a randomized, double-blind, placebo-controlled, investigator-initiated, multicenter clinical study.

The risk of ischemic events gradually decreases after acute coronary syndrome (ACS), reaching a stable level after 1 month, while the risk of bleeding remains steady during the whole period of dual antiplatelet treatment (DAPT). Several de-escalation strategies of antiplatelet treatment aiming to enhance safety of DAPT without depriving it of its efficacy have been evaluated so far. We hypothesized that reduction of the ticagrelor maintenance dose 1 month after ACS and its continuation until 12 months after ACS may improve adherence to antiplatelet treatment due to better tolerability compared with the standard dose of ticagrelor. Moreover, improved safety of treatment and preserved anti-ischemic benefit may also be expected with additional acetylsalicylic acid (ASA) withdrawal. To evaluate these hypotheses, we designed the Evaluating Safety and Efficacy of Two Ticagrelor-based De-escalation Antiplatelet Strategies in Acute Coronary Syndrome - a randomized clinical trial (ELECTRA-SIRIO 2), to assess the influence of ticagrelor dose reduction with or without continuation of ASA versus DAPT with standard dose ticagrelor in reducing clinically relevant bleeding and maintaining anti-ischemic efficacy in ACS patients. The study was designed as a phase III, randomized, multicenter, double-blind, investigator-initiated clinical study with a 12-month follow-up (ClinicalTrials.gov Identifier: NCT04718025; EudraCT number: 2020-005130-15).

Efficacy and safety of mirabegron in children and adolescents with neurogenic detrusor overactivity: An open-label, phase 3, dose-titration study.

AIMS: To evaluate the efficacy and safety of mirabegron in children and adolescents (aged 3 to <18 years) with neurogenic detrusor overactivity (NDO) using clean intermittent catheterization. METHODS: In this open-label, multicenter, baseline-controlled, Phase III study (NCT02751931), participants received once-daily mirabegron at an adult dose equivalent of 25 mg. Dose was increased to 50 mg equivalent unless there were safety/tolerability concerns. The primary efficacy endpoint was change from baseline to Week 24 in maximum cystometric capacity (MCC). Secondary urodynamic assessments, Pediatric Incontinence Questionnaire (PIN-Q), Patient Global Impression of Severity (PGI-S), Clinician Global Impression of Change (CGI-C), and Acceptability questionnaires were included. RESULTS: Overall, 86 participants (55 aged 3 to <12 years, 31 aged 12 to <18 years) received treatment; 68 were included in efficacy assessments. A statistically significant increase in MCC from baseline to Week 24 was observed (87.20 ml, 95% confidence interval: 66.07, 108.33; p < .001); this increase was apparent from Week 4. Significant increases in bladder compliance, bladder volume until first detrusor contraction, average volume per catheterization, maximum daytime catheterized volume and number of dry days per week. Significant decreases in detrusor pressure and number of leakage episodes per day were also observed. Significant improvement in PGI-S but not PIN-Q was observed. Most participants reported their condition had either much or very much improved using the CGI-C. Mirabegron was well tolerated in this population with a profile aligned with that in adults. CONCLUSIONS: Mirabegron was effective and well-tolerated in the treatment of pediatric patients with NDO.

The effect of single-nucleotide polymorphism in the promoter region of bovine alpha-lactalbumin (LALBA) gene on LALBA expression in milk cells and milk traits of cows.

Polymorphisms of milk protein genes have been proposed as candidate markers for dairy production traits in cattle. In the present study, a polymorphism was detected in the 5'-flanking (promoter) region of the bovine alpha-lactalbumin (LALBA) gene, a T/C transition located at nucleotide -1,001 relative to the transcription start site g.-1001T > C (NC_037332.1:g.31183170T > C), which is recognizable with PstI restriction endonuclease. In silico analyses showed that this mutation created novel retinoid X receptor alpha and vitamin D receptor transcription factor binding sites. Real-time PCR found that cows with different genetic variants of the promoter demonstrated different levels of expression of LALBA mRNA in milk somatic cells (MSCs). The TT genotype cows demonstrated low expression, whereas those with CT demonstrated much higher expression (P < 0.05). ELISA analysis found milk LALBA protein levels also differed between the TT and CT cows (P < 0.05) and that these levels were not correlated with the mRNA abundance in MSC. Association analysis found that the g.-1001T > C polymorphism in the promoter region of the LALBA gene influenced milk production traits in Polish Holstein-Friesian cows. High daily milk yield and dry matter yield, and high lactose yield and concentration were associated with the TT genotype. The TT genotype cows also had a lower number of somatic cells in the milk, considered as an indicator of udder health status. Therefore, the TT genotype could be more desirable from the breeder's perspective.

Insulin Autoimmune Syndrome as Part of Pre-Clinical LADA.

Hypoglycemia presents relatively typical symptoms. However, when it occurs spontaneously - like in insulin autoimmune syndrome - it is difficult to perform scheduled biochemical tests at the laboratory. The study presents the case of a 31-year-old Caucasian female whose recurrent hypoglycemia symptoms were the reason for further diagnostics. The final results revealed a positive test for insulin autoantibody and glutamic acid decarboxylase autoantibody. Therefore, not only the potential causes of hypoglycemia but also an active autoimmune process typical for latent autoimmune diabetes in adults were confirmed. It was concluded that autoimmune hypoglycemia can be a part of the autoimmune process associated with diabetes and pre-diabetes in adults.

Pharmacodynamic and clinical efficacy of reduced ticagrelor maintenance doses in patients with coronary artery disease.

OBJECTIVE: An increasing body of data indicates that a reduction of ticagrelor maintenance dose (MD) in stabilized patients might improve ticagrelor's safety profile and adherence to the treatment. The aim of this review was to discuss the rationale and summarize the current pharmacodynamic and clinical outcomes-based evidence from reduced MD of ticagrelor in patients with coronary artery disease (CAD). METHODS: A narrative systematic review based on a literature search using the PubMed database from its inception through to June 2020. A search strategy included a combination of relevant search terms regarding ticagrelor reduced MD. The pre-determined inclusion criteria were: (1) randomized or observational trials; (2) presentation of clinical or pharmacodynamic results; (3) evaluation of any ticagrelor MD below 90 mg BID in patients with CAD. RESULTS: Studies evaluating the following ticagrelor reduced MD have been identified: 90 mg QD, 60 mg BID, 60 mg QD, 45 mg BID, 22.5 mg BID. Majority of trials assessing doses <60 mg BID were performed in Asian patients only. Antiplatelet effect of ticagrelor in CAD decreases with the dose, however even reduced MDs provide sufficient platelet inhibition, which is greater than in clopidogrel-treated patients. De-escalation of ticagrelor dose shows a propensity towards a reduced rate of bleeding and non-bleeding adverse events. CONCLUSIONS: Ticagrelor doses below 90 mg BID generally show an acceptable profile of platelet inhibition. The number of studies reporting clinical outcomes in CAD patients receiving reduced MD of ticagrelor are limited, however available results indicate that in a stable setting this strategy offers improved safety with preserved efficacy in the prevention of thrombotic events.

Zinc(II)-The Overlooked Éminence Grise of Chloroquine's Fight against COVID-19?

Zn(II) is an inhibitor of SARS-CoV-2's RNA-dependent RNA polymerase, and chloroquine and hydroxychloroquine are Zn(II) ionophores-this statement gives a curious mind a lot to think about. We show results of the first clinical trials on chloroquine (CQ) and hydroxychloroquine (HCQ) in the treatment of COVID-19, as well as earlier reports on the anticoronaviral properties of these two compounds and of Zn(II) itself. Other FDA-approved Zn(II) ionophores are given a decent amount of attention and are thought of as possible COVID-19 therapeutics.