Search

This report of the BOOST2012 workshop presents the results of four working groups that studied key aspects of jet substructure. We discuss the potential of first-principle QCD calculations to yield a precise description of the substructure of jets and study the accuracy of state-of-the-art Monte Carlo tools. Limitations of the experiments’ ability to resolve substructure are evaluated, with a focus on the impact of additional (pile-up) proton proton collisions on jet substructure performance in future LHC operating scenarios. A final section summarizes the lessons learnt from jet substructure analyses in searches for new physics in the production of boosted top quarks.

An abstract of the study "Poznan multidisciplinary heart failure care: 6 months experience," by M. Wierzchowiecki and colleagues, is presented.

CRISPR tiling screens have advanced the identification and characterization of regulatory sequences but are limited by low resolution arising from the indirect readout of editing via guide RNA sequencing. This study introduces CRISPR-CLEAR , an end-to-end experimental assay and computational pipeline, which leverages targeted sequencing of CRISPR-introduced alleles at the endogenous target locus following dense base-editing mutagenesis. This approach enables the dissection of regulatory elements at nucleotide resolution, facilitating a direct assessment of genotype-phenotype effects., Competing Interests: Competing interests Competing interests L.P. has financial interests in Edilytics, Inc., Excelsior Genomics, and SeQure Dx, Inc. L.P.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. The remaining authors declare no competing interests.

Hairy cell leukemia (HCL) represents 2% of all leukemia cases, with men aged above 55 years being the most affected. The most common symptoms of this type of leukemia include splenomegaly, monocytopenia, and neutropenia. In the basic blood count examination, leukopenia with monocytopenia and granulocytopenia, as well as aplastic anemia and/or thrombocytopenia occur. The mutation of β-rapidly accelerated fibrosarcoma ( BRAF ) proto-oncogene, which can be found in nearly 100% of patients, is an important feature of HCL. Immunophenotypic analysis of the HCL cells reveals high expression of B-lineage antigens, including CD19, CD20, and CD22. Additionally, CD11c, CD25, CD103, and CD123 belong to specific markers of HCL. Lactate dehydrogenase activity and β-2-microglobulin concentration are also important in the patient's assessment. The differential diagnosis between HCL, hairy cell leukemia variant (HCL-V) and splenic marginal zone lymphoma (SMZL) is of first importance. Currently, the main treatment for HCL involves the use of purine analogues, excluding pregnant women, individuals with severe infections, and those with relapsing HCL., Competing Interests: Potential conflict of interest None declared., (Copyright Croatian Society of Medical Biochemistry and Laboratory Medicine.)

CRISPR base editing screens enable analysis of disease-associated variants at scale; however, variable efficiency and precision confounds the assessment of variant-induced phenotypes. Here, we provide an integrated experimental and computational pipeline that improves estimation of variant effects in base editing screens. We use a reporter construct to measure guide RNA (gRNA) editing outcomes alongside their phenotypic consequences and introduce base editor screen analysis with activity normalization (BEAN), a Bayesian network that uses per-guide editing outcomes provided by the reporter and target site chromatin accessibility to estimate variant impacts. BEAN outperforms existing tools in variant effect quantification. We use BEAN to pinpoint common regulatory variants that alter low-density lipoprotein (LDL) uptake, implicating previously unreported genes. Additionally, through saturation base editing of LDLR, we accurately quantify missense variant pathogenicity that is consistent with measurements in UK Biobank patients and identify underlying structural mechanisms. This work provides a widely applicable approach to improve the power of base editing screens for disease-associated variant characterization., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

CRISPR base editing screens are powerful tools for studying disease-associated variants at scale. However, the efficiency and precision of base editing perturbations vary, confounding the assessment of variant-induced phenotypic effects. Here, we provide an integrated pipeline that improves the estimation of variant impact in base editing screens. We perform high-throughput ABE8e-SpRY base editing screens with an integrated reporter construct to measure the editing efficiency and outcomes of each gRNA alongside their phenotypic consequences. We introduce BEAN, a Bayesian network that accounts for per-guide editing outcomes and target site chromatin accessibility to estimate variant impacts. We show this pipeline attains superior performance compared to existing tools in variant classification and effect size quantification. We use BEAN to pinpoint common variants that alter LDL uptake, implicating novel genes. Additionally, through saturation base editing of LDLR , we enable accurate quantitative prediction of the effects of missense variants on LDL-C levels, which aligns with measurements in UK Biobank individuals, and identify structural mechanisms underlying variant pathogenicity. This work provides a widely applicable approach to improve the power of base editor screens for disease-associated variant characterization., Competing Interests: Competing interests L.P. has financial interests in Edilytics, Inc., Excelsior Genomics, and SeQure Dx, Inc. L.P.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. The remaining authors declare no competing interests.

According to the DESI 2022 digital economy and society ranking, Poland still ranks in one of the last position. Although, in digitising healthcare Poland has made significant progress over the last five years, some inequities in the usage of eHealth have been recognised. This has become an especially important topic after the COVID-19 pandemic. Suddenly, eHealth innovations were much needed to maintain the accessibility of healthcare. Thus, the aim of this study was to explore determinants of eHealth usage by Poles and identify existing potential barriers. Data was collected from the databases of Statistic Poland and statistical methods were employed in this research. The results showed that five variables such as Internet access, Internet use, Internet skills and average monthly disposable income per capita in PLN, along with the number of practicing physicians per capita were important determinants explaining eHealth usage by the analysed Poles between the age of 16-74. The findings showed to increase the usage of eHealth, health policy makers should ensure that Poles acquire and improve Internet skills. Based on results of the research an extended model of eHealth development in Poland, consisting of a central governmental institution and local facilities coordinating remote electronic services, collecting statistical data and providing educational campaigns, was proposed as well., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jankowiak, Rój. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The global effort to sequence millions of SARS-CoV-2 genomes has provided an unprecedented view of viral evolution. Characterizing how selection acts on SARS-CoV-2 is critical to developing effective, long-lasting vaccines and other treatments, but the scale and complexity of genomic surveillance data make rigorous analysis challenging. To meet this challenge, we develop Bayesian Viral Allele Selection (BVAS), a principled and scalable probabilistic method for inferring the genetic determinants of differential viral fitness and the relative growth rates of viral lineages, including newly emergent lineages. After demonstrating the accuracy and efficacy of our method through simulation, we apply BVAS to 6.9 million SARS-CoV-2 genomes. We identify numerous mutations that increase fitness, including previously identified mutations in the SARS-CoV-2 Spike and Nucleocapsid proteins, as well as mutations in non-structural proteins whose contribution to fitness is less well characterized. In addition, we extend our baseline model to identify mutations whose fitness exhibits strong dependence on vaccination status as well as pairwise interaction effects, i.e. epistasis. Strikingly, both these analyses point to the pivotal role played by the N501 residue in the Spike protein. Our method, which couples Bayesian variable selection with a diffusion approximation in allele frequency space, lays a foundation for identifying fitness-associated mutations under the assumption that most alleles are neutral., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Jankowiak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: Elevated concentration of CRP has been associated with the risk of diabetes as well as cardiovascular events and microvascular complications in T1D patients. We hypothesize that the +1846 C > T CRP gene polymorphism may have impact on the risk of T1D and/or its complications., Methods: We have examined 400 young patients with T1D and 250 healthy age-matched controls. The +1846 C > T CRP gene polymorphism was genotyped by ARMS-PCR method. The analysis covers microvascular complications, concentrations of serum pro- and anti-inflammatory markers, adhesion molecules, proangiogenic factor as well as blood pressure., Results: CT genotype (OR = 1.799) and T allele (OR = 1.733) are associated with increased risk of T1D, while CC genotype decreases the risk of this condition (OR = 0.458). Moreover, increased risk of hypertension corresponds with TT and T variant (OR = 3.116 and OR = 1.830, resp.) while CC genotype is decreasing the risk (OR = 0.547). Furthermore, CT variant is connected with lower risk of retinopathy (OR = 0.512) whereas TT variant decreases the risk of this complication (OR = 2.228). Our data also implies various effects of CRP +1846 C > T polymorphism on the inflammatory status of T1D patients., Conclusions: Although further studies are required, the +1846 C > T CRP gene polymorphism could be considered a genetic marker to predict susceptibility to retinopathy and hypertension in T1D adolescents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Repeated emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased fitness underscores the value of rapid detection and characterization of new lineages. We have developed PyR 0 , a hierarchical Bayesian multinomial logistic regression model that infers relative prevalence of all viral lineages across geographic regions, detects lineages increasing in prevalence, and identifies mutations relevant to fitness. Applying PyR 0 to all publicly available SARS-CoV-2 genomes, we identify numerous substitutions that increase fitness, including previously identified spike mutations and many nonspike mutations within the nucleocapsid and nonstructural proteins. PyR 0 forecasts growth of new lineages from their mutational profile, ranks the fitness of lineages as new sequences become available, and prioritizes mutations of biological and public health concern for functional characterization.

Autoimmune disease results from the immune response against self-antigens, while cancer develops when the immune system does not respond to malignant cells. Thus, for years, autoimmunity and cancer have been considered as two separate fields of research that do not have a lot in common. However, the discovery of immune checkpoints and the development of anti-cancer drugs targeting PD-1 (programmed cell death receptor 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) pathways proved that studying autoimmune diseases can be extremely helpful in the development of novel anti-cancer drugs. Therefore, autoimmunity and cancer seem to be just two sides of the same coin. In the current review, we broadly discuss how various regulatory cell populations, effector molecules, genetic predisposition, and environmental factors contribute to the loss of self-tolerance in autoimmunity or tolerance induction to cancer. With the current paper, we also aim to convince the readers that the pathways involved in cancer and autoimmune disease development consist of similar molecular players working in opposite directions. Therefore, a deep understanding of the two sides of immune tolerance is crucial for the proper designing of novel and selective immunotherapies., Competing Interests: NM-T and PT are the co-authors of 2 patents related to the presented content and are shareholders of PolTREG S.A. company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sakowska, Arcimowicz, Jankowiak, Papak, Markiewicz, Dziubek, Kurkowiak, Kote, Kaźmierczak-Siedlecka, Połom, Marek-Trzonkowska and Trzonkowski.)

The purpose of this study is to identify inequities in the distribution of socioeconomic determinants of health within Poland and their impact on the health status of Poles, as measured by mortality rate. We hypothesised that (1) there are inequities in the socioeconomic characteristics within geographically defined population groups and (2) some socioeconomic determinants of health have a particularly strong impact on the health status of Poles. Poland is administratively divided into three levels: voivodeships, powiats and gminas. We used a dataset covering all 380 powiats in Poland for the year 2018. We employed a two-stage nested Theil index and Herfindahl-Hirschman Index. In order to identify which of these determinants has the strongest impact on health, we conducted a regression analysis. The study revealed some inequities in the distribution of socioeconomic determinants of health. The mortality rate can be partly understood from variations within voivodeships in the distribution of health determinants. Important national inequalities were found in the case of two determinants, which simultaneously proved their significant impact on Poles' health in the regression analysis. Thus, type of employment and access to modern infrastructure should be of particular concern for public authorities.

The hallmark of preeclampsia (PE) is a shift toward persistent inflammatory response, accompanied by endothelial dysfunction. The driving forces in PE are proinflammatory cytokine and growth factors, in parallel with reduced functionality of anti-inflammatory effectors, like regulatory T cells are observed. Unfortunately, no conclusive mechanism underlying preeclampsia has been identified. For this reason, research on preeclampsia is needed to provide a state of the art understanding of the pathophysiology, identification of new diagnostics tools and the development of targeted therapies. The 68 patients were divided into three groups: gestational hypertension (GH) group (n = 19) and PE group (n = 28) and a control group (n = 21). We have tested a set of 53 cytokines, chemokines and growth factors in preeclampsia and gestational hypertension, and then compared them with normal pregnancies. Using a diagnostic test assessment characteristic parameters (IL-22, MDC/CCL22, IL-2/IL-4 ratio) have been identified and cut-off values have been proposed to diagnose preeclampsia. All parameters had high negative or positive predictive values, above 80%. In conclusion, we have proposed a potential set of immune parameters to diagnose preeclampsia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Stefańska, Zieliński, Jankowiak, Zamkowska, Sakowska, Adamski, Jassem-Bobowicz, Piekarska, Leszczyńska, Świątkowska-Stodulska, Kwiatkowski, Preis, Trzonkowski and Marek-Trzonkowska.)

Objectives: Preeclampsia (PE) affects 2-5% of pregnant women. Hypertensive disorders of pregnancy are associated with adverse maternal and perinatal outcomes., Material and Methods: This study included 88 women showing gestational hypertension (GH) or PE symptoms, and their newborns., Results: The rate of FGR was 43% for mothers with PE, compared to 8% with GH. The association was significant, p = < 0.001 but with moderate strength, Cramer's V = 0.40. The risk of FGR increased nine times when PE occurred, as the odds ratio was 9.25 (CI: 2.46-34.83), p = 0.001. PE was associated with FGR risk if delivery time was less than 34 weeks compared to a delivery time of more than 34 weeks. This was 82% of FGR cases for < 34 weeks, compared with 35% of cases in > 34 group, (p = 0.001; Cramer's V = 0.50). PE was also associated (p = 0.01, Cramer's V = 0.27) with the type of delivery, as the caesarean section rate was 74%, compared to 50% in the GH group. This made it three times higher the likelihood of delivery by caesarean section, as the odds ratio was 3.10 (CI: 1.24-7.75), p=0,02. Delivery time was significantly (p < 0.001) shortened to 38 weeks (27-41), compared to 40 weeks (38-42) GH mothers. There was no distinction in median age for PE and GH mothers (p = 0.124). The overall clinical status of neonates was proportional despite the mother's PE. The sum of Apgar points in the first, and then the second to third minute, did not differ significantly, p = 0.370 and 0.560, respectively. The number of peripheral blood platelets and leucocytes was not reduced (p = 0.821 and 0.534) in infants when the mother suffered from PE., Conclusions: The prediction of adverse maternal outcomes from hypertensive diseases of pregnancy is key to optimal management, including the timing of delivery and planning for the most appropriate place of care.

Equitable access to cardiological rehabilitation services is one of the important elements in the effectiveness of the treatment of cardiovascular diseases as cardiological rehabilitation is an important part of circulatory system disease prevention and treatment. However, in many countries among others, Poland suffers from the underutilization of cardiac rehabilitation services. Cardiovascular diseases are the worldwide number one cause of mortality, morbidity, and disability and are responsible for the substantial increase in health care costs. Thus, the aim of the research was the analysis of geographical accessibility to cardiac rehabilitation services in Poland. Perkal's method was employed in this research. The conducted research allowed to recognize the regional variation, but also made it possible to classify Polish voivodeships in terms of the level of availability achieved. This enables the identification of voivodeships that provide a good, or even very good, access to cardiology rehabilitation services and those characterized by low, or very low access. It was found that there was a slight regional variability in the access to cardiological rehabilitation services. However, the sufficient development of a rehabilitation infrastructure has been also recognized.

Preeclampsia (PE) is a disorder that affects 3-5% of normal pregnancies. It was believed for a long time that the kidney, similarly to all vessels in the whole system, only sustained endothelial damage. The current knowledge gives rise to a presumption that the main role in the development of proteinuria is played by damage to the podocytes and their slit diaphragm. The podocyte damage mechanism in preeclampsia is connected to free VEGF and nitric oxide (NO) deficiency, and an increased concentration of endothelin-1 and oxidative stress. From national cohort studies, we know that women who had preeclampsia in at least one pregnancy carried five times the risk of developing end-stage renal disease (ESRD) when compared to women with physiological pregnancies. The focal segmental glomerulosclerosis (FSGS) is the dominant histopathological lesion in women with a history of PE. The kidney's podocytes are not subject to replacement or proliferation. Podocyte depletion exceeding 20% resulted in FSGS, which is a reason for the later development of ESRD. In this review, we present the mechanism of kidney (especially podocytes) injury in preeclampsia. We try to explain how this damage affects further changes in the morphology and function of the kidneys after pregnancy.

Preeclampsia affects 2-5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality. We aimed to extensively evaluate proteinuria in women with preeclampsia and to determine the analytical sensitivity and specificity of and the cutoff values for urine protein-to-creatinine ratio (UPCR) and total protein in 24 h urine samples. This study included 88 women. We used the urine dipstick test, UPCR, and total protein measurement in a 24 h urine sample. The patients were divided in gestational hypertension (GH, n = 44) and preeclampsia (PE, n = 44) groups. In the GH group, 25% (11/44) of the patients presented incidentally positive results. UPCR and total protein in 24 h urine specimens were increased in the GH group compared to the PE group. Receiver operating characteristic analysis showed a UPCR cutoff of 30 mg/mmol as significant for preeclampsia, while the sensitivity and specificity were 89% (95% CI, 75-97) and 100% (95% CI, 87-100), respectively. In the 24 h urine protein test, sensitivity and specificity were 80% (95% CI, 61-92) and 100% (95% CI, 88-100), respectively, for the cutoff value of 0.26 g/24 h. In comparison to the other commonly used tests here considered, UPCR determination is a reliable, relatively faster, and equally accurate method for the quantitation of proteinuria, correlates well with 24 h urine protein estimations, and could be used as an alternative to the 24 h proteinuria test for the diagnosis of preeclampsia.

The purpose of this study is to analyse the disparities in the distribution of percutaneous coronary intervention (PCI) centres in Poland and the impact of eventual inequities on access to the invasive treatment of acute myocardial infarctions (AMI). To examine the distribution of PCI centres against population size and geographic size in Poland, the Gini coefficient calculated based on the Lorenz Curve was engaged. In addition, the regression function was employed to estimate the impact of distribution of PCI centres on access to invasive procedures (coronarographies and primary percutaneous coronary intervention). Data were collected from the public statistical system and Polish National Health Fund database for the year 2018. The relation and the level of equity was measured based on the aggregated data at a district (voivodeship) level. The results of the Gini coefficient analysis show that the distribution of invasive cardiology units measured against population size is more equitable than when measured against geographic size. In addition, the regression analysis shows the moderate size of the positive correlation between number of PCI centres per 100,000 population and the number of all categories of the invasive treatment of AMI per 100,000 population, and the lack of similar correlation in case of the number of PCI centres expressed per 1000 km 2 , which could be evidence of an insufficiency of PCI centres in areas where the concentration of PCI centres per 100,000 population is lower. The main implication for policy makers that results from this research is the need for a correction of PCI centres distribution per 100,000 inhabitants to ensure better access to invasive procedures.

Unlabelled: In the last years multidisciplinary care (MDC) of patients with chronic heart failure has proved to be effective. Because of specificity of the medical care organization in different countries the outcome of the programs may be various. The aim of this study was to evaluate the effect of MDC on patients' survival, hospitalization rate and stay., Material and Methods: 129 chronic heart failure patients admitted to Department of Cardiology were randomized to MDC or routine care (RC) groups. All patients were referred to their primary care physicians. In 64 patients from MDC group, aged 68 +/- 10.5 years, a follow-up was performed on 14 day, 3 and 6 months, on the basis of heart failure clinic, by cardiologist, heart failure nurse, psychologist and physiotherapist. Patients received heart failure nurse and cardiologist broad educational program systematically. Every day heart failure nurse telephone counseling and home-based interventions were also available to the patients. 65 patients from RC group, aged 72 +/- 11.5 years, were referred only to their primary care physicians., Results: There was the lower duration of hospitalization in MDC than in RC group (8.3 +/- 5.31 vs 13.5 +/- 6.99 days; p < 0.05). A tendency to the lower duration of heart failure hospitalization and frequency of total and heart failure hospitalization in MDC group was observed (9.8 +/- 5.46 vs 12.1 +/- 6.23 days, 18.8 vs 25.0, and 12.5 vs 16.9% respectively). No significant differences were found between MDC and RC total and heart failure mortality (15.6 vs 16.9%, and 10.9 vs 12.3%, respectively)., Conclusion: Six months multidisciplinary care of chronic heart failure patients has appeared more efficient than routine primary care.

Introduction: Recent trials have demonstrated the effectiveness of multidisciplinary care (MDC) for patients with chronic heart failure (CHF). However, results of the assessment of different programmes in individual countries could be different because of local specificities of health care systems., Aim: We sought to determine whether MDC for patients with CHF has an influence on mortality, rate of rehospitalisation, quality of life (QoL) and self-care (SC) during a one-year study period., Methods: 160 patients with CHF treated in our unit were randomly assigned to receive either MDC or routine care (RC). Patients from the MDC group (n=80; mean age 67+/-10.2 years) attended follow-up visits at the heart failure clinic after 14 days and 3, 6, 9 and 12 months after discharge. They were cared for by a team which consisted of a cardiologist, a heart failure nurse (HF nurse), a psychologist and a physiotherapist. This group of patients received comprehensive education from the HF nurse and the cardiologist. Telephone counselling and home-based interventions by the HF nurse were also available daily. Patients from the RC group (n=80, mean age 69.5+/-10.7 years) were cared for by their primary care physician only. In both groups QoL and SC scores were calculated based on a 21 and 12-item questionnaire completed by the patients at discharge and after one year., Results: After one-year follow-up the two groups did not differ in terms of either total and HF mortality or number of sudden deaths. In the MDC group when compared to the RC group we observed a significant decrease in the total number of hospital readmissions (by 37%, p <0.05), a decrease in hospital admissions due to HF (by 48%; p <0.05) and decreased length of stay during both all-cause readmissions and those due to HF (p <0.05). After one year of follow-up both QoL and SC scores were significantly lower in the MDC group than in the RC group (p <0.001), indicating improved QoL in the MDC group., Conclusions: The one-year multidisciplinary care programme for patients with chronic heart failure in Poznań demonstrated significant improvement of treatment results in terms of frequency of readmissions and length of hospital stay as well as improved Qol. A tendency to decreased total and heart failure related mortality and decreased number of sudden deaths was also observed.