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The objective of the paper is to prove the validity of the claim that a minor can be an entrepreneur. Minors involved in a business activity may perform legal acts or make transactions through a statutory representative and, in some situations, with the consent of a guardianship court. The requirement of full legal capacity is not included in the definitions of an entrepreneur provided in normative acts. Only special laws, in explicitly specified cases, make the economic activity contingent on having full legal capacity.

Background Lipids play a central role in the pathogenesis of cardiovascular disease (CVD), a leading cause of morbidity and mortality worldwide. Plasma lipids and lipoproteins are routinely measured to help identify individuals at high risk of developing CVD and to monitor patients’ response to therapy. The landscape of lipid testing is rapidly changing, including new ways to estimate traditional lipid parameters (e.g., low-density lipoprotein-cholesterol [LDL-C] calculations) and new lipid parameters that show superiority for risk prediction (e.g., non-high-density lipoprotein-cholesterol [non-HDL-C], apolipoprotein B [apoB], and lipoprotein a [Lp(a)]). Content Various national guidelines for managing dyslipidemia to prevent CVD are available, which primarily focus on LDL-C for identifying those at high risk and setting thresholds for optimal response to therapy. However, LDL-C can be calculated and measured in various ways, each with advantages and disadvantages. Importantly, the recently established Sampson–NIH LDL-C equation appears to be superior to preceding calculations, as is clear from the literature and in guidelines. There is now a shift towards using lipid parameters other than LDL-C, such as non-HDL-C, apoB, and Lp(a), to identify high-risk patients and/or establish treatment targets. Summary The goal of this review is to discuss the present and future of lipid testing for CVD risk assessment through describing various national clinical guidelines, critically reviewing methods to calculate and measure LDL-C and discussing the clinical utility of additional lipid parameters.

We studied dielectric properties of a polar nematic phase (NF) sandwiched between two gold or ITO electrodes, serving as a cell surfaces. In bulk, NF is expected to exhibit a Goldstone mode (phason), because polarization can uniformly rotate with no energy cost. However, because the coupling between the direction of nematic director and polarization is finite, and the confinement, even in the absence of the aligning surface layer, induces some energy cost for a reorientation of polarization, the phason dielectric relaxation frequency is measured in a kHz regime. The phason mode is easily quenched by a bias electric field, which enables fluctuations in the magnitude of polarization to be followed in both, the ferronematic and nematic phases. This amplitude (soft) mode is also influenced by boundary conditions. A theory describing the phase and amplitude fluctuations in the NF phase shows that the free energy of the system and, consequently, the dielectric response are dominated by polarization-related terms with the flexoelectricity being relevant only at a very weak surface anchoring. Contributions due to the nematic elastic terms are always negligible. The model relates the observed low frequency mode to the director fluctuations weakly coupled to polarization fluctuations.

Introduction. Aging is a natural and prevalent process. It concerns all organs and systems, even if there are no signs of pathology. At present there is no age limit which indicates specifically the beginning of senility. The border between physiology and pathology is blurred; consequently, the treatment of some geriatric diseases is difficult, especially when preventive measures have not been taken. Rehabilitation should focus on personal well-being of the patients and improving their quality of life. Aim. The aim of this article is to discuss issues concerning the planning of complex rehabilitation of geriatric patients and its management. Materials and methods. This article analyses selected clinical aspects of: osteoarthritis, osteoporosis, pulmonary and circulatory disturbances, prevention of bedsore and contractures in bedridden patients. The process of planning the therapy, including cardiologic and orthopaedic rehabilitation, is presented. The application of the Get Up and Go Test to evaluate patients’ fitness and the SMART principle when planning a rehabilitation course is proposed. Essential factors in a correctly planned therapy of geriatric patients are emphasised. Discussion. Due to scientific evidence confirming the efficiency of regular physical activity in the case of senior patients, they should be motivated to undertake physical exercises and to cooperate. Rehabilitation aims at: improving general well–being, allowing to maintain an independent way of life, reducing the risk of some diseases and easing their course, reducing pain and disability effects. Complex geriatric rehabilitation concerns every patient in terms of motion ability, pain release, as well as psychological and social spheres of life. Properly conducted and systematically undertaken physical activities can improve physical and mental health of senior patients, even though they do not stop the aging process itself. Orthopaedic devices for geriatric patients decrease their disability. Improvement in motor functioning, personal care skills and independence restores patients’ self-confidence, reinforces their social and cultural integration and allows them to become professionally active again. Conclusions. Geriatric patients suffer from various diseases and require personalised rehabilitation. A well planned rehabilitation and physical therapy program should include all factors influencing the quality of life of such patients and should provide rehabilitation aims. Rehabilitation should be long-termed, complex and involve elements of prophylactics.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation. ispartof: BLOOD vol:141 issue:7 pages:713-724 ispartof: location:United States status: published

The article discusses criminal activities aimed at defrauding the EU budget, and effective measures for detection of such offences. The patterns of activities of the offenders are usually repetitive and entail misleading persons who manage EU funds. The performed analysis proved that patterns of attempts to defraud the EU budget can be identified solely on the basis of evidence which was properly collected and secured. Moreover, in order to identify the roles of individual entities involved with this process, law enforcement needs to take a series of appropriate investigative measures.

Based on decades of both basic science and epidemiologic research, there is overwhelming evidence for the causal relationship between high levels of cholesterol, especially low-density lipoprotein cholesterol and cardiovascular disease. Risk evaluation and monitoring the response to lipid-lowering therapies are heavily dependent on the accurate assessment of plasma lipoproteins in the clinical laboratory. This article provides an update of lipoprotein metabolism as it relates to atherosclerosis and how diagnostic measures of lipids and lipoproteins can serve as markers of cardiovascular risk, with a focus on recent advances in cardiovascular risk marker testing.

This special issue titled Mnemonic Wars: New Constellations has two objectives. First, it maps some of the current memory conflicts in different parts of the world, focusing on their topics and novel political, cultural and social constellations. Second, the issue problematizes how the different currents of revitalized national politics and globalization processes influence and sometimes even trigger memory wars. Who are the contemporary memory agents fostering confrontational memory politics? What tools, media and practices do they use to promote their interpretations of the past? How are these memory wars being played out internationally? In what ways do global developments, such as the spread of social media, the emergence of transnational memory politics or the establishment of transnational networks of memory activists, influence today’s memory conflicts? Finally, how do these discursive struggles translate into real-life conflicts? In their introductory article, the guest editors discern between the older and more recent approaches to research on memory conflicts and set the conceptual agenda for the entire issue.

Bone heat-induced changes complicate osteometric stature estimation of human remains from forensic settings. The validity of current methods has not been tested to a great extent. Our aim was to determine how precise are stature estimations obtained from three different approaches, namely by using (i) Rösing's method (Rösing 1977), (ii) a 10% shrinkage correction factor (Strzałko et al. 1972) and (iii) chemosteometry (Gonçalves et al. 2020). For this purpose, pre- and post-burned head measurements from the humerus, radius and femur were used. The sample comprised 46 human skeletons of known sex and age-at-death. These were experimentally burnt to maximum temperatures ranging from 700 to 1100°C (attained after 90-188 min) for other research purposes. Stature estimations were performed through measurements in both pre-burned and burned bones using the three approaches and based on the method of Olivier and Tissier (1975). Mean absolute differences and the relative technical errors of measurements (TEM%) between the pre-burned and the estimations were calculated. Absolute mean differences indicated that the chemosteometric approach allowed for potentially more precise stature estimations than the other two procedures. However, the TEM% was very low for all approaches (smaller or close to 1%), and stature estimations were thus well within the error margin reported by Olivier and Tissier (1975). Results suggest that the chemosteometric approach enables more accurate predictions of the actual heat-induced shrinkage of each bone thus rendering more precise stature estimations. Nonetheless, the other procedures also provided quite reliable estimations although they require confirmation that the bone is calcined.

The COVID-19 pandemic has caused anxiety and uncertainty as to how to function “normally” to take over the place of routine. The greater reliance on social media, the encouraging of beliefs in conspiracy theories have all been linked with lower levels of preventative behaviours during the COVID-19 pandemic. The perpetual deluge of (true) information, misinformation and disinformation, whether man-made or bot-made, can be toxic, especially in combination with an unawareness of what news really is and how it affects us, both individually and collectively. Therefore, the current pandemic is partly a challenge to filter (in real time) the sheer quantity of information published on a daily basis but also the inability of researchers, policy makers, journalists, and ordinary citizens to keep up with quickly changing facts. I assume that in a situation of uncertainty people seek information in order to make the best decision. Accepted information is an expression of trust in their own sources of information, including trust in scientists and doctors or a lack of trust in government decisions, and a lack of trust in pharmaceutical companies. Political trust received attention during the COVID-19 pandemic. Higher political trust led to higher compliance between behaviour and those government policies implemented to contain pandemics. The research’s intent is to illustrate which and how media sources of information constituted resistance to actions taken by state institutions and scientists in a situation of epidemiological emergency.

The Zofia and Jan Włodek Foundation in Cracow takes care e.g., of the photographic legacy of its patron Prof. Jan Zdzisław Włodek. Its most valuable element is a collections of 240 coloured positives on Autochrome plates manufactured by Lumière and Agfa- -Farbenplatten; it is one of the largest sets of photographs of this type taken by a single author which has been preserved in Poland. In 2020–2021, thanks to the financing from the Ministry of Culture and National Heritage, the collection underwent conservation and was digitized, following which it was made available to broad groups of viewers on the www.szukajwarchiwach.pl and www. zbioryspoleczne.pl portals. The unique photo technology used for their production constituted a real challenge in the set’s conservation and digitizing; moreover, attempts were made at an experimental digitizing of the selected autochromes with the use of directed bright-field. In order to promote the knowledge of the set, its author, and the works he conducted, videos and exhibitions were prepared, The whole project was quite challenging to a relatively small NGO. The key to its success was the cooperation of experts who proved to be flexible and creative in their approach to this particular task and peculiar conditions in which the project was implemented.

Background Estimation of atherosclerotic cardiovascular disease (ASCVD) risk is a key step in cardiovascular disease (CVD) prevention, but it requires entering additional risk factor information into a computer. We developed a simplified ASCVD risk score that can be automatically calculated by the clinical laboratory when a fasting standard lipid panel is reported. Methods Equations for an estimated ASCVD (eASCVD) risk score were developed for 4 race/sex groups (non-Hispanic White/Black, men/women), using the following variables: total cholesterol, high-density lipoprotein cholesterol, triglycerides, and age. The eASCVD score was derived using regression analysis to yield similar risk estimates as the standard ASCVD risk equations for non-diabetic individuals not on lipid-lowering therapy in the National Health and Nutrition Examination Survey (NHANES) (n = 6027). Results At a cutpoint of 7.5%/10-year, the eASCVD risk score had an overall sensitivity of 69.1% and a specificity of 97.5% for identifying statin-eligible patients with at least intermediate risk based on the standard risk score. By using the sum of other risk factors present (systolic blood pressure >130 mmHg, blood pressure medication use, and cigarette use), the overall sensitivity of the eASCVD score improved to 93.7%, with a specificity of 92.3%. Furthermore, it showed 90% concordance with the standard risk score in predicting cardiovascular events in the Atherosclerosis Risk in Communities (ARIC) study (n = 14 742). Conclusions Because the automated eASCVD risk score can be computed for all patients with a fasting standard lipid panel, it could be used as an adjunctive tool for the primary prevention of ASCVD and as a decision aid for statin therapy.

The article presents the concept of self-regulated learning as a key competence of a fourth grade student entering subject education. The increased number of school subjects and growing requirements for the student make it necessary to organise one’s own learning process well. The presented concept, based on the model of self-regulated learning according to Monique Boekaerts, indicates its complexity and the presence of both cognitive and motivational components. Based on the Monique Boekaerts model of self-regulation, a tool was constructed to test the level of self-regulated learning for students at the stage of subject education. The tool enables testing the level of self-regulation of learning and may be of significant importance in building awareness of self-regulation of learning and its development. The Self-Regulated Learning Questionnaire (SRLQ) consists of 34 items and has a Likert-type response format. The examined person marks their degree of consent or disagreement with each of the statements on a 4-point scale. The tool has been subjected to validation tests. The analysis of the reliability of the test items included in the Self-Regulated Learning Questionnaire showed that the reliability of the tool is satisfactory and amounts for the entire scale: α = 0.91, for the motivational subscale α = 0.87, and for the cognitive subscale α = 0.82.

W artykule omówiono kwestie dotyczące raportowania niefinansowego, które stało się obowiązkowe dla dużych przedsiębiorców od 2017 roku w Polsce. Praca omawia podstawy prawne, zmiany, jakie zaszły w raportowaniu ESG oraz nowe standardy, jakie zostały wprowadzone. Autorki poruszają także temat statystyk, z których jasno wynika rosnący trend raportowania niefinansowego również wśród tych podmiotów, które nie zostały do tego zobowiązane. Koniec niniejszego artykułu zwieńczony został informacjami na temat organizowanego od 2007 roku konkursu zrównoważonego rozwoju, w ramach którego sprawdzane są raporty niefinansowe za poszczególne lata.

Cel pracyW artykule zaprezentowano rezultaty projektu badawczego poświęconego ocenie zmian w procesie systemowej terapii rodzinnej prowadzonej w grupie klinicznej młodzieżowych pacjentów psychiatrycznych.MetodaDo oceny wykorzystano polską wersję kwestionariusza SCORE–15. Badanie przeprowadzono na grupie 109 rodzin, które wypełniły kwestionariusz przed pierwszą sesją. Przed czwartą sesją ankietę wypełniły 73 rodziny; a po ostatniej sesji ukończyło ją 28 rodzin.WynikiWyniki konsensualnych analiz jakościowych ujawniły zmiany w opisie rodziny, a także w opisie problemu. Analizy statystyczne wyników kwestionariusza SCORE–15 wykazały znaczące zmiany między pierwszą, czwartą i ostatnią sesją. Zmiany zostały zidentyfikowane w skali SCORE Total, a także w skalach VAS. Wskaźnik RCI wykazał 5 popraw i 2 pogorszenia po trzech sesjach oraz brak pogorszeń i 13 popraw pod koniec procesu terapii.WnioskiUzyskane wyniki wskazują na wiele istotnych zmian w badanych obszarach po przejściu rodzin przez systemową terapię. Badanie wykazało także, że spójna analiza jakościowa materiału opisowego może być bardzo użyteczna i może wzbogacić zarówno rozumienie procesu terapeutycznego, jak i sposób przekazywania rodzinom informacji o zmianach w ramach terapii.

Introduction: The aim of this study was to establish the most accurate and up-to-date anatomical knowledge of PVs ostia variations, diameters and ostial area, in order to provide physicians, especially heart and thoracic surgeons with exact knowledge concerning this area. Materials and methods: Major online medical databases such as PubMed, Embase, Scopus, Web of Science and Google Scholar were searched to gather all studies in which the variations, maximal diameter and ostial area of the PVs were investigated. During the study, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Additionally, The Critical Appraisal Tool for Anatomical Meta-analysis (CATAM) was used to provide the highest quality findings. Reults: The most common ostia variation is classical one, containing left superior pulmonary vein (LSPV), left inferior pulmonary vein (LIPV), right superior pulmonary vein (RSPV) and right inferior pulmonary vein (RIPV). Mean diameters and ostial areas of each pulmonary vein were established in general population and in multiple variations considering method of gathering the data and geographical location. Conclusion: Significant variability in PV ostia is observed. Left-sided PVs have smaller ostia than corresponding right-sided PVs, and the inferior PVs ostia are smaller than superior. The size of the LCPV ostium is the largest among all analyzed veins, while the ostium of RMPV is the smallest. It is hoped that the results from this meta-analysis will help clinicians in planning and performing procedures that involve pulmonary and cardiac area.

The first-in-class Bruton tyrosine kinase (BTK), ibrutinib, demonstrated remarkable activity in chronic lymphocytic leukemia (CLL). However, its toxicity profile renders it potentially inappropriate for use in patients with bleeding or cardiovascular disorders. In response to the high demand for a safer and efficient BTK inhibitor, with improved toxicity profile, acalabrutinib as a second-generation irreversible BTK inhibitor has been approved for the treatment of CLL.This review examines the activity of acalabrutinib in treating treatment-naïve and relapsed refractory CLL and its toxicity profile when compared to ibrutinib and other drugs. It will examine the outcomes of the ELEVATE-TN, ASCEND, and ELEVATE-RR studies in detail, with a particular focus on the safety and efficacy of acalabrutinib. The strengths and weaknesses of this drug will be highlighted and future directions for research will be identified.In patients with CLL, acalabrutinib demonstrates a superior safety profile than ibrutinib and similar activity. In the first direct comparison of acalabrutinib with ibrutinib in relapsed/refractory CLL, acalabrutinib was found to demonstrate non-inferior progression-free survival, with fewer cardiovascular adverse events.

We tested the hypothesis that isoform shifts in sarcomeres of the immature heart modify the effect of cardiac myosin-directed sarcomere inhibitors and activators. Omecamtiv mecarbil (OM) activates tension and is in clinical trials for the treatment of adult acute and chronic heart failure. Mavacamten (Mava) inhibits tension and is in clinical trials to relieve hypercontractility and outflow obstruction in advanced genetic hypertrophic cardiomyopathy (HCM), which is often linked to mutations in sarcomeric proteins. To address the effect of these agents in developing sarcomeres, we isolated heart fiber bundles, extracted membranes with Triton X-100, and measured tension developed over a range of Ca(2+) concentrations with and without OM or Mava treatment. We made measurements in fiber bundles from hearts of adult nontransgenic (NTG) controls expressing cardiac troponin I (cTnI), and from hearts of transgenic (TG-ssTnI) mice expressing the fetal/neonatal form, slow skeletal troponin I (ssTnI). We also compared fibers from 7- and 14-day-old NTG mice expressing ssTnI and cTnI. These studies were repeated with 7- and 14-day-old transgenic mice (TG-cTnT-R92Q) expressing a mutant form of cardiac troponin T (cTnT) linked to HCM. OM increased Ca(2+)-sensitivity and decreased cooperative activation in both ssTnI- and cTnI-regulated myofilaments with a similar effect: reducing submaximal tension in immature and mature myofilaments. Although Mava decreased tension similarly in cTnI- and ssTnI-regulated myofilaments controlled either by cTnT or cTnT-R92Q, its effect involved a depressed Ca(2+)-sensitivity in the mature cTnT-R92 myofilaments. Our data demonstrate an influence of myosin and thin-filament associated proteins on the actions of myosin-directed agents such as OM and Mava. SIGNIFICANCE STATEMENT: The effects of myosin-targeted activators and inhibitors on Ca(2+)-activated tension in developing cardiac sarcomeres presented here provide novel, ex vivo evidence as to their actions in early-stage cardiac disorders. These studies advance understanding of the molecular mechanisms of these agents, which are important in preclinical studies employing sarcomere Ca(2+)-response as a screening approach. The data also inform the use of commonly immature cardiac myocytes generated from human-inducible pluripotent stem cells in screening for sarcomere activators and inhibitors.

AimsP-selectin is a key surface adhesion molecule for the interaction of platelets with leukocytes. We have shown previously that the N-terminal domain of S. aureus extracellular fibrinogen-binding protein (Efb) binds to P-selectin and interferes with platelet-leukocyte aggregate formation. Here, we aimed to identify the minimal Efb motif required for binding platelets and to characterise its ability to interfering with the formation of platelet-leukocyte aggregates.Methods and ResultsUsing a library of synthetic peptides, we mapped the platelet-binding site to a continuous 20 amino acid stretch. The peptide Efb68-87 was able to bind to resting and, to a greater extent, thrombin-stimulated platelets in the absence of fibrinogen. Dot blots, pull-down assays and P-selectin glycoprotein ligand-1 (PSGL-1) competitive binding experiments identified P-selectin as the cellular docking site mediating Efb68-87 platelet binding. Accordingly, Efb68-87 did not bind to other blood cells and captured platelets from human whole blood under low shear stress conditions. Efb68-87 did not affect platelet activation as tested by aggregometry, flow cytometry and immunoblotting, but inhibited the formation of platelet-leukocyte aggregates (PLAs). Efb68-87 also interfered with the platelet-dependent stimulation of neutrophil extracellular traps (NETs) formation in vitro.ConclusionsWe have identified Efb68-87 as a novel selective platelet-binding peptide. Efb68-87 binds directly to P-selectin and inhibits interactions of platelets with leukocytes that lead to PLA and NET formation. As PLAs and NETs play a key role in thromboinflammation, Efb68-87 is an exciting candidate for the development of novel selective inhibitors of the proinflammatory activity of platelets.

BackgroundNeutrophil Extracellular Traps (NETs) are key mediators of immunothrombotic mechanisms and defective clearance of NETs from the circulation underlies an array of thrombotic, inflammatory, infectious, and autoimmune diseases. Efficient NET degradation depends on the combined activity of two distinct DNases, DNase1 and DNase1-like 3 (DNase1L3) that preferentially digest double-stranded DNA (dsDNA) and chromatin, respectively.MethodsHere, we engineered a dual-active DNase with combined DNase1 and DNase1L3 activities and characterized the enzyme for its NET degrading potential in vitro. Furthermore, we produced a mouse model with transgenic expression of the dual-active DNase and analyzed body fluids of these animals for DNase1 and DNase 1L3 activities. We systematically substituted 20 amino acid stretches in DNase1 that were not conserved among DNase1 and DNase1L3 with homologous DNase1L3 sequences.ResultsWe found that the ability of DNase1L3 to degrade chromatin is embedded into three discrete areas of the enzyme's core body, not the C-terminal domain as suggested by the state-of-the-art. Further, combined transfer of the aforementioned areas of DNase1L3 to DNase1 generated a dual-active DNase1 enzyme with additional chromatin degrading activity. The dual-active DNase1 mutant was superior to native DNase1 and DNase1L3 in degrading dsDNA and chromatin, respectively. Transgenic expression of the dual-active DNase1 mutant in hepatocytes of mice lacking endogenous DNases revealed that the engineered enzyme was stable in the circulation, released into serum and filtered to the bile but not into the urine.ConclusionTherefore, the dual-active DNase1 mutant is a promising tool for neutralization of DNA and NETs with potential therapeutic applications for interference with thromboinflammatory disease states.

In recent years, the scientific community has called for improvements in the credibility, robustness, and reproducibility of research, characterized by increased interest and promotion of open and transparent research practices. While progress has been positive, there is a lack of consideration about how this approach can be embedded into undergraduate and postgraduate research training. Specifically, a critical overview of the literature which investigates how integrating open and reproducible science may influence student outcomes is needed. In this paper, we provide the first critical review of literature surrounding the integration of open and reproducible scholarship into teaching and learning and its associated outcomes in students. Our review highlighted how embedding open and reproducible scholarship appears to be associated with (1) students’ scientific literacies (i.e., students’ understanding of open research, consumption of science, and the development of transferable skills); (2) student engagement (i.e., motivation and engagement with learning, collaboration, and engagement in open research), and (3) students’ attitudes towards science (i.e., trust in science and confidence in research findings). However, our review also identified a need for more robust and rigorous methods within pedagogical research, including more interventional and experimental evaluations of teaching practice. We discuss implications for teaching and learning scholarship.

In this perspective, we discussed emerging data indicating a role for Notch signalling in inherited disorders of the heart failure with focus on hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) linked to variants of genes encoding mutant proteins of the sarcomere. We recently reported an upregulation of elements in the Notch signalling cascade in cardiomyocytes derived from human inducible pluripotent stem cells expressing a TNNT2 variant encoding cardiac troponin T (cTnT-I79N +/− ), which induces hypertrophy, remodelling, abnormalities in excitation–contraction coupling and electrical instabilities (Shafaattalab S et al. 2021 Front . Cell Dev. Biol . 9 , 787581. ( doi:10.3389/fcell.2021.787581 )). Our search of the literature revealed the novelty of this finding and stimulated us to discuss potential connections between the Notch signalling pathway and familial cardiomyopathies. Our considerations focused on the potential role of these interactions in arrhythmias, microvascular ischaemia, and fibrosis. This finding underscored a need to consider the role of Notch signalling in familial cardiomyopathies which are trigged by sarcomere mutations engaging mechano-signalling pathways for which there is evidence of a role for Notch signalling with crosstalk with Hippo signalling. Our discussion included a role for both cardiac myocytes and non-cardiac myocytes in progression of HCM and DCM. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

Overall survival of patients with Nijmegen breakage syndrome depending on the time when they were treated due to malignancies: before and after 2000 year.

The dynamics of primary cancer incidence among patients with NBS described using the three-stage joint-point model.

Introduction: Hypertrophic cardiomyopathy (HCM) is a cardiovascular genetic disease caused largely by sarcomere protein mutations. Gaps in our understanding exist as to how maladaptive sarcomeric biophysical signals are transduced to intra- and extracellular compartments leading to HCM progression. To investigate early HCM progression, we focused on the onset of myofilament dysfunction during neonatal development and examined cardiac dynamics, coronary vascular structure and function, and mechano-transduction signaling in mice harboring a thin-filament HCM mutation.Methods: We studied postnatal days 7–28 (P7–P28) in transgenic (TG) TG-cTnT-R92Q and non-transgenic (NTG) mice using skinned fiber mechanics, echocardiography, biochemistry, histology, and immunohistochemistry.Results: At P7, skinned myofiber bundles exhibited an increased Ca2+-sensitivity (pCa50 TG: 5.97 ± 0.04, NTG: 5.84 ± 0.01) resulting from cTnT-R92Q expression on a background of slow skeletal (fetal) troponin I and α/β myosin heavy chain isoform expression. Despite the transition to adult isoform expressions between P7–P14, the increased Ca2+- sensitivity persisted through P28 with no apparent differences in gross morphology among TG and NTG hearts. At P7 significant diastolic dysfunction was accompanied by coronary flow perturbation (mean diastolic velocity, TG: 222.5 ± 18.81 mm/s, NTG: 338.7 ± 28.07 mm/s) along with localized fibrosis (TG: 4.36% ± 0.44%, NTG: 2.53% ± 0.47%). Increased phosphorylation of phospholamban (PLN) was also evident indicating abnormalities in Ca2+ homeostasis. By P14 there was a decline in arteriolar cross-sectional area along with an expansion of fibrosis (TG: 9.72% ± 0.73%, NTG: 2.72% ± 0.2%). In comparing mechano-transduction signaling in the coronary arteries, we uncovered an increase in endothelial YAP expression with a decrease in its nuclear to cytosolic ratio at P14 in TG hearts, which was reversed by P28.Conclusion: We conclude that those early mechanisms that presage hypertrophic remodeling in HCM include defective biophysical signals within the sarcomere that drive diastolic dysfunction, impacting coronary flow dynamics, defective arteriogenesis and fibrosis. Changes in mechano-transduction signaling between the different cellular compartments contribute to the pathogenesis of HCM.

Overall survival of patients with Nijmegen breakage syndrome after cancer diagnosis. Patients who underwent HSCT were marked with an asterix.

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Supplementary Table 1

Zanubrutinib (BGB-3111, Brukinsa®, BeiGene) is a next-generation irreversible inhibitor of Bruton’s tyrosine kinase (BTK), developed by BeiGene in 2012 for the treatment of B-cell malignancies. It was designed to minimize off-target inhibition of TEC- and EGFR-family kinases. Zanubrutinib is more selective than ibrutinib for BTK versus EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC. In addition, compared to ibrutinib, zanubrutinib has improved oral absorption and better target occupancy. Zanubrutinib demonstrated a lower incidence of off-target toxicities and reduced severity than ibrutinib. Moreover, zanubrutinib is similar to acalabrutinib, with less activity against TEC and ITK. The preliminary phase 1 results suggest that zanubrutinib has clinical activity and the drug is well tolerated in patients with B-cell lymphoid malignancies. Recent clinical trials have found it to demonstrate excellent efficacy and good tolerability in patients with chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia (WM) and mantle cell lymphoma (MCL). In recent phase 3 studies, zanubrutinib was compared with ibrutinib in patients with relapsed/refractory (R/R) MW and RR CLL. In both trials, zanubrutinib was found to demonstrate clinically meaningful advantages in safety and tolerability over ibrutinib; in particular, it was associated with a lower risk of atrial fibrillation/flutter and major bleeding events. In the recent SEQUOIA study, comparing zanubrutinib with bendamustine and rituximab (BR) in patients with previously untreated CLL, zanubrutinib significantly improved progression-free survival versus BR, with an acceptable safety profile consistent with previous studies. Zanubrutinib also demonstrated good activity and tolerability in patients with R/R MCL, marginal zone lymphoma and follicular lymphoma. Trials examining the efficacy and safety of the combination of zanubrutinib with obinutuzumab venetoclax and other drugs are ongoing. This review summarizes the clinical efficacy and safety of zanubrutinib in lymphoid malignancies.

Context Statins are the lipid-lowering therapy of choice for the prevention of atherosclerotic cardiovascular disease (ASCVD) but their effectiveness in lowering low-density lipoprotein cholesterol (LDL-C) can substantially differ between individuals. In this mini-review, we describe the different causes for a suboptimal statin response and an algorithm for the diagnosis and clinical management of these patients. Evidence Acquisition A PubMed search using the terms “statin resistance,” “statin sensitivity,” “statin pharmacokinetics,” “cardiovascular disease,” and “lipid-lowering therapies” was performed. Published papers in the past 10 years that were relevant to the topic were examined to provide content for this mini-review. Evidence Synthesis Suboptimal lowering of LDL-C by statins is a major problem in the clinical management of patients and limits the value of this therapeutic approach. There are multiple causes of statin hyporesponsiveness with compliance being the most common explanation. Other causes, such as analytical issues with LDL-C measurement and the presence of common lipid disorders (familial hypercholesterolemia, elevated lipoprotein[a] and secondary dyslipidemias) should be excluded before considering primary statin resistance from rare genetic variants in lipoprotein-related or drug-metabolism genes. A wide variety of nonstatin lipid-lowering drugs are now available and can be added to statins to achieve more effective LDL-C lowering. Conclusions The evaluation of statin hyporesponsiveness is a multistep process that can lead to the optimization of lipid-lowering therapy for the prevention of ASCVD. It may also lead to the identification of distinct types of dyslipidemias that require specific therapies and/or the genetic screening of family members.

Artykuł ma charakter przeglądowy i jego celem jest poprzez zrekonstruowanie portretu seryjnego zabójcy wskazanie głównych czynników, które powodują, że dziecko w życiu dorosłym przekształca się w psychopatycznego mordercę. Nie wszystko zostało zbadane i udowodnione odnośnie czynnika, który powoduje, że niektórzy się nimi stają. Artykuł ten wskazuje na czynniki środowiskowe i wychowawcze, które zwiększają szansę na uruchomienie tego mechanizmu, które często doprowadzają do wybierania przez ludzi drogi zła i stawania poza społecznymi normami. Analiza wybranej w artykule literatury ukazała, że ani narodowość ani rasa nie są tutaj determinujące.

Systematic studies on the insertion of SO2 into the Zn-C bond were performed. The direct trapping of a series of R2Zn compounds with SO2 provided a homologous series of diverse [(RSO2)ZnR] species that can be hardly obtained with alternative methods.

The fibroblast growth factor 21 (FGF21) is a new biomarker of mitochondrial diseases (MD). FGF21 concentration may be used to define the severity of mitochondrial disease.The study objective was to verify if the FGF21 concentration in paediatric patients with MD was correlated with the disease severity and stage and to assess the correlation between FGF21 levels and the genetic background of MD.The disease stage in MD subjects was determined on the basis of the International Paediatric Mitochondrial Disease Scale (IPMDS) and the concentrations of FGF21, lactic and pyruvic acids, alanine and creatine kinase in serum were assessed in those patients.The median age of children with MD (n = 32) was 33 months (range: 2-213), in the control group (n = 21) the median age was 42 months (range: 8-202). The concentrations of FGF21, lactic acid and pyruvic acid were higher in MD patients than in the control group. No correlation between the disease severity (IPMDS) and serum FGF21 concentration was found. The FGF21 concentration was higher in patients whose MD resulted from nuclear gene damage (nDNA), median FGF21 = 1022 (84-8873) pg/ml, than in patients with MD resulting from mitochondrial damage (mtDNA), median FGF21 = 736 (188-2906) pg/ml, or with an abnormal variant in the PDHA1 gene, median FGF21 = 58 (25-637) pg/ml.There is no correlation between the stage of MD and FGF21 level. Higher FGF21 values are seen in patients whose MD results from an abnormal nDNA variant rather than mtDNA damage.Czynnik wzrostu fibroblastów 21 (FGF21) jest nowym biomarkerem chorób mitochondrialnych. Wieksze stężenia FGF21 obserwowano w końcowej fazie choroby, dlatego FGF21 może być wykorzystane do określenia stopnia zaawansowania choroby mitochondrialnej (MD).Sprawdzenie, czy stężenie FGF21 u pacjentów pediatrycznych z MD jest skorelowane z ciężkością i choroby oraz ocena korelacji pomiędzy stężeniem FGF21 a podłożem genetycznym MD.Stopień zaawansowania MD określono na podstawie Międzynarodowej Pediatrycznej Skali Zaawansowania Choroby Mitochondrialnej (IPMDS). Jednocześnie u pacjentów oceniano stężenie FGF21, kwasu mlekowego i pirogronowego, alaniny i kinazy kreatynowej w surowicy.Mediana wieku dzieci z MD (n = 32) wynosiła 33 miesiące (2213), natomiast w grupie kontrolnej (n = 21) było 42 miesiące (zakres: 8202). Stężenia FGF21, kwasu mlekowego i kwasu pirogronowego były większe u pacjentów z MD niż w grupie kontrolnej. Nie stwierdzono korelacji pomiędzy stopniem zaawansowania choroby (IPMDS) a stężeniem FGF21. Stężenie FGF21 było większe u pacjentów, u których MD wynikało z uszkodzenia genu jądrowego (nDNA), mediana FGF21 = 1022 (84–8873) pg/ml, niż u pacjentów z MD wynikającym z uszkodzenia mitochondrialnego DNA (mtDNA), mediana FGF21 = 736 (188–2906) pg/ml, lub z nieprawidłowym wariantem w genie PDHA1, mediana FGF21 = 58 (25–637) pg/ml.Nie ma korelacji między stopniem zaawansowania MD a FGF21. Wyższe wartości FGF21 obserwowano u pacjentów, u których MD wynika z nieprawidłowego wariantu w nDNA niż z uszkodzenia mtDNA.

Au-Beta zeolites prepared by different methods and on supports of different compositions were studied in base-free glucose oxidation to gluconic acid. The catalysts were characterized by XRD, N2 adsorption/desorption, TEM, UV–vis and FTIR spectroscopy, ICP-OES and pyridine adsorption combined with FTIR measurements in order to estimate the structural/textural and surface properties of prepared materials and their impact on the activity and selectivity in glucose oxidation. A relationship between the gold particle size, depending on the method of gold deposition, and the effectiveness of glucose oxidation to gluconic acid, expressed by glucose conversion and the selectivity to gluconic acid, was observed. The optimal average gold nanoparticles (NPs) size corresponding to the maximum glucose conversion was ∼6 nm, whereas the normalization of structure/size sensitivity to exposed surface gold atoms (TOF) moved this optimum to Au NPs of ca. 24 nm. The presence of niobium in the support reduced the gold particle size, decreased the activity in glucose oxidation and affected the selectivity of the reaction, enhancing glucuronic acid formation. Addition of cerium dopant to the zeolite support for gold resulted in an increase in glucose conversion and stabilization of the catalyst activity for six investigated reaction cycles. Deactivation of the catalysts in successive reaction runs depended on the method of gold deposition and the type of zeolite support.

Background: Heart failure (HF) is associated with metabolic alterations, including ketogenesis. However, determinants of ketogenesis and risk of mortality in HF is not defined. Total ketone bodies (KB) include β-hydroxybutyrate, acetoacetate, and acetone and can be measured in plasma by nuclear magnetic resonance (NMR). The aim of this study is to determine the relationship between KB and clinical characteristics in a community HF cohort and to assess the association between KB and all-cause mortality. Methods: A population-based cohort of 1,389 HF patients was prospectively enrolled between 2003 and 2012. Plasma KB was measured by LP4 NMR LipoProfile ® assay/test on the Vantera® NMR analyzer platform. A conditional inference tree method (ctree R Package) was used to determine optimal KB group cut points. Associations between clinical characteristics and KB were measured with Wilcoxon rank sum test and Pearson’s Chi-squared test. Kaplan-Meier method estimated survival. Cox regression analyses were used to estimate associations between KB concentrations and mortality. Results: Among the 1,382 HF patients with KB measurements, the median age was 78 years (IQR 68-84) and 52% were men. Median KB was 180 μM (IQR 134-308). Patients were divided into two groups with lower KB (≤471.5 μM) and higher KB (>471.5 μM). Patients with higher KB (N=210) had lower BMI, higher BNP, and were more likely to be in the New York Heart Association class III-IV; however, these patients were less likely to have hyperlipidemia, coronary disease, or diabetes mellitus (P < 0.05). Age, sex, creatinine, ejection fraction, or Meta-Analysis Global Group in Chronic HF (MAGGIC) score did not differ by KB group. Higher KB was associated with worse survival (figure). After adjustment for the MAGGIC score, higher KB was associated with increased risk of mortality (HR 1.3; 95% CI, 1.08-1.48). Conclusions: In this community HF cohort, higher KB was associated with increased mortality, independent of the MAGGIC score.

Introduction: Over 6 million people in the U.S. have heart failure (HF), less than half are expected to survive beyond 5 years. The need to better stratify mortality risk in HF is recognized. Frailty is associated with mortality in HF but not routinely measured clinically. As frailty is linked to inflammation and malnutrition, we hypothesized that the Metabolic Vulnerability Index (MVX) a multimarker score of systemic inflammation (small HDL particles, GlycA) and malnutrition (leucine, valine, isoleucine, citrate), could serve as a biomarker of frailty to predict mortality risk. Methods: Clinical data and plasma were collected from 1,389 patients from a HF community cohort between 2003-2012. We measured frailty using the Rockwood Index as the proportion of deficits present out of 32 physical limitations and comorbidities. MVX was calculated from the nuclear magnetic resonance LipoProfile® test. Patients were categorized by frailty (0-0.15; 0.16-0.27; 0.28-0.78) and MVX (33.4-50, 50-60, 60-70, 70-85.8) cutpoints. Cox models estimated the association of frailty and MVX assignment with mortality, adjusted for Meta-Analysis Global Group in Chronic HF (MAGGIC) score, a validated clinical risk score for HF mortality. Results: Frailty and MVX scores were available in 985 patients (median age 77, IQR: 67-84; 48% women). Higher frailty was associated with higher MVX (p-trend < 0.001). The highest frailty and MVX groups experienced large increases in risk of death, after adjustment for MAGGIC score (HR=3.3, 95% CI=2.6-4.2) and (HR=2.7, 95% CI=2.1-3.5), respectively. When adjusted for one another and MAGGIC score, MVX and frailty associations with death were only minimally attenuated: frailty (HR=3.2, 95% CI=2.5-4.0) and MVX (HR=2.4, 95% CI=1.9-3.2) (Figure 1). Conclusion: In this community cohort of patients with HF, frailty and MVX are positively associated with one another. However, both indicators are independently associated with an increased risk of death and can contribute to risk stratification.

Objective3D microscopy and image data analysis are necessary for studying the morphology of cardiac lymphatic vessels (LyVs) and association with other cell types. We aimed to develop a methodology for 3D multiplexed lightsheet microscopy and highly sensitive and quantitative image analysis to identify pathological remodeling in the 3D morphology of LyVs in young adult mouse hearts with familial hypertrophic cardiomyopathy (HCM).MethodsWe developed a 3D lightsheet microscopy workflow providing a quick turn-around (as few as 5-6 days), multiplex fluorescence detection, and preservation of LyV structure and epitope markers. Hearts from non-transgenic (NTG) and transgenic (TG) HCM mice were arrested in diastole, retrograde perfused, immunolabeled, optically cleared, and imaged. We built an image processing pipeline to quantify LyV morphological parameters at the chamber and branch levels.ResultsChamber-specific pathological alterations of LyVs were identified, but most significantly in the right atrium (RA). TG hearts had a higher volume fraction of ER-TR7+fibroblasts and reticular fibers. In the RA, we found associations between ER-TR7+volume fraction and both LyV segment density and median diameter.ConclusionsThis workflow and study enabled multi-scale analysis of pathological changes in cardiac LyVs of young adult mice, inviting ideas for research on LyVs in cardiac disease.