Bottom-up data integration in polymer models of chromatin organization.

Cellular functions crucially depend on the precise execution of complex biochemical reactions taking place on the chromatin fiber in the tightly packed environment of the cell nucleus. Despite the availability of large datasets probing this process from multiple angles, bottom-up frameworks that allow the incorporation of the sequence-specific nature of biochemistry in a unified model of 3D chromatin structure remain scarce. Here, we propose Sequence-Enhanced Magnetic Polymer (SEMPER), a novel stochastic polymer model that naturally incorporates observational data about sequence-driven biochemical processes, such as binding of transcription factor proteins, in a 3D model of chromatin structure. We introduce a novel approximate Bayesian algorithm to quantify a posteriori the relative importance of various factors, including the polymeric nature of DNA, in determining chromatin epigenetic state, thus providing a transparent way to generate biological hypotheses. Although accurate prediction of contact frequencies (a problem already extensively studied in the literature) is not our main aim, as a by-product of the inference procedure and without additional input from the genome 3D structure, our model can predict with reasonable accuracy some notable and nontrivial conformational features of chromatin folding within the nucleus. Our work highlights the importance of introducing physically realistic statistical models for predicting chromatin states from epigenetic data and opens the way to a new class of more systematic approaches to interpreting epigenomic data.

A cross-organizational Lean deployment in an Italian regional healthcare system.

PURPOSE: This study explores how Lean was deployed in several hospitals in the Apulia region in Italy over 3.5 years. DESIGN/METHODOLOGY/APPROACH: An exploratory qualitative design was drawn up based on semi-structured interviews. FINDINGS: The drivers of Lean in hospitals were to increase patient satisfaction and improve workplace well-being by eliminating non-value-add waste. The participants highlighted three key elements of the pivotal implementation stages of Lean: introduction, spontaneous and informal dissemination and strategic level implementation and highlighted critical success and failure factors that emerged for each of these stages. During the introduction, training and coaching from an external consultant were among the most impactful factors in the success of pilot projects, while time constraints and the adoption of process analysis tools were the main barriers to implementation. The experiences of the Lean teams strongly influence the process of spontaneous dissemination aided by the celebration of project results and the commitment of the departmental hospital heads. PRACTICAL IMPLICATIONS: Lean culture can spread to allow many projects be conducted spontaneously, but the Lean paradigm can struggle to be adopted strategically. Lean in healthcare can fail because of the lack of alignment of Lean with leadership in healthcare and with their strategic vision, a lack of employees' project management skills and crucially the absence of a Lean steering committee. ORIGINALITY/VALUE: The absence of managerial expertise and a will to support Lean implementation do not allow for systemic adoption of Lean. This is one of the first and largest long-term case studies on a Lean cross-regional multi-hospital application in healthcare.

Phase behaviour of semiflexible lattice polymers in poor-solvent solution: Mean-field theory and Monte Carlo simulations.

We study a solution of interacting semiflexible polymers with curvature energy in poor-solvent conditions on the d-dimensional cubic lattice using mean-field theory and Monte Carlo computer simulations. Building upon past studies on a single chain, we construct a field-theory representation of the system and solve it within a mean-field approximation supported by Monte Carlo simulations in d = 3. A gas-liquid transition is found in the temperature-density plane that is then interpreted in terms of real systems. Interestingly, we find this transition to be independent of the bending rigidity. Past classical Flory-Huggins and Flory mean-field results are shown to be particular cases of this more general framework. Perspectives in terms of guiding experimental results towards optimal conditions are also proposed.

Spatial Organization of Slit-Confined Melts of Ring Polymers with Nonconserved Topology: A Lattice Monte Carlo Study.

We present Monte Carlo computer simulations for melts of semiflexible randomly knotted and randomly concatenated ring polymers on the fcc lattice and in slit confinement. Through systematic variation of the slit width at fixed melt density, we explore the influence of confinement on single-chain conformations and interchain interactions. We demonstrate that confinement makes chains globally larger and more elongated while enhancing both contacts and knottedness propensities. As for multichain properties, we show that ring-ring contacts decrease with the confinement, yet neighboring rings overlap more as confinement grows. These aspects are accompanied by a marked decrease in the links formed between pairs of neighboring rings. In connection with the quantitative relation between links and entanglements in polymer melts recently established by us [Ubertini M. A.; Rosa A.Macromolecules2023, 56, 3354-3362], we propose that confinement can be used to set polymer networks that act softer under mechanical stress and suggest a viable experimental setup to validate our results.

Low-Intensity vs. High-Intensity Antithrombotic Therapy After Transcatheter Aortic Valve Replacement: Meta-Analysis of Randomized Controlled Trials.

Background: The optimal antithrombotic therapy after transcatheter aortic valve replacement (TAVR) is controversial. We performed a systematic review and meta-analysis of randomized controlled trials comparing high-intensity vs. low-intensity antithrombotic therapy after TAVR in the absence of an established indication for anticoagulation. Methods: The primary efficacy and safety endpoints were a composite of death or thromboembolic events and Valve Academic Research Consortium 2-defined significant bleeding, respectively. All analyses were by intention to treat. Risk ratios (RRs) were calculated using the inverse variance random-effects model. Results: Four studies comprising 3358 patients (mean age 81 years, mean Society of Thoracic Surgery score 3.3%) were identified. Two studies compared anticoagulation vs. antiplatelet therapy after TAVR; the other 2 trials compared dual-antiplatelet therapy vs. mono-antiplatelet therapy after TAVR. The incidence of death or thromboembolic events (RR 0.66 [95% confidence interval (CI) 0.55-0.80], p < 0.0001, I2 = 0%), death (RR 0.68 [95% CI 0.51-0.92], I2 = 11%, p = 0.01), and Valve Academic Research Consortium 2-defined major bleeding (RR 0.69 [95% CI 0.48 - 1.00], p = 0.003, I2 = 44%) was significantly lower in patients on low-intensity antithrombotic therapy than in those on high-intensity antithrombotic therapy. Conclusions: In an elderly patient population undergoing TAVR, routine initiation of a high-intensity antithrombotic therapy in the absence of a clinical indication for anticoagulation was associated with increased risk of death or thromboembolic complications, increased risk of death, and increased risk of significant bleeding. Routine initiation of an anticoagulation therapy or dual-antiplatelet therapy after TAVR in the absence of an established indication for anticoagulation may not be advisable.

Scaling properties of RNA as a randomly branching polymer.

Formation of base pairs between the nucleotides of a ribonucleic acid (RNA) sequence gives rise to a complex and often highly branched RNA structure. While numerous studies have demonstrated the functional importance of the high degree of RNA branching-for instance, for its spatial compactness or interaction with other biological macromolecules-RNA branching topology remains largely unexplored. Here, we use the theory of randomly branching polymers to explore the scaling properties of RNAs by mapping their secondary structures onto planar tree graphs. Focusing on random RNA sequences of varying lengths, we determine the two scaling exponents related to their topology of branching. Our results indicate that ensembles of RNA secondary structures are characterized by annealed random branching and scale similarly to self-avoiding trees in three dimensions. We further show that the obtained scaling exponents are robust upon changes in nucleotide composition, tree topology, and folding energy parameters. Finally, in order to apply the theory of branching polymers to biological RNAs, whose length cannot be arbitrarily varied, we demonstrate how both scaling exponents can be obtained from distributions of the related topological quantities of individual RNA molecules with fixed length. In this way, we establish a framework to study the branching properties of RNA and compare them to other known classes of branched polymers. By understanding the scaling properties of RNA related to its branching structure, we aim to improve our understanding of the underlying principles and open up the possibility to design RNA sequences with desired topological properties.

Topological Analysis and Recovery of Entanglements in Polymer Melts.

The viscous flow of polymer chains in dense melts is dominated by topological constraints whenever the single-chain contour length, N, becomes larger than the characteristic scale Ne, defining comprehensively the macroscopic rheological properties of the highly entangled polymer systems. Even though they are naturally connected to the presence of hard constraints like knots and links within the polymer chains, the difficulty of integrating the rigorous language of mathematical topology with the physics of polymer melts has limited somehow a genuine topological approach to the problem of classifying these constraints and to how they are related to the rheological entanglements. In this work, we tackle this problem by studying the occurrence of knots and links in lattice melts of randomly knotted and randomly concatenated ring polymers with various bending stiffness values. Specifically, by introducing an algorithm that shrinks the chains to their minimal shapes that do not violate topological constraints and by analyzing those in terms of suitable topological invariants, we provide a detailed characterization of the topological properties at the intrachain level (knots) and of links between pairs and triplets of distinct chains. Then, by employing the Z1 algorithm on the minimal conformations to extract the entanglement length Ne, we show that the ratio N/Ne, the number of entanglements per chain, can be remarkably well reconstructed in terms of only two-chain links.

The joint effect of framing and defaults on choice behavior.

The framing effect leads people to prefer a sure alternative over a risky one (risk aversion) when alternatives are described as potential gains compared to a context-dependent reference point. The reverse (risk propensity) happens when the same alternatives are described as potential losses. The default effect is the tendency to prefer a preselected alternative over other non-preselected given options, without facilitating nor incentivizing the choice. These two effects have mainly been studied separately. Here we provided novel empirical evidence of additive effects due to the application of both framing and default within the same decision problem in a large sample size (N = 960). In the baseline condition, where no default was provided, we measured the proportion of risky choices in life-or-death and financial decisions both presented in terms of potential gains or losses following the structure of the Asian disease problem. In the sure default condition, the same layout was proposed with a flag on the sure option, whereas in the risky default condition, the flag was on the risky option. In both default conditions, we asked participants whether they wanted to change the preselected option. Overall, the comparison between these conditions revealed three distinct main effects: (i) a classic framing effect, (ii) a larger risk propensity in the life-or-death scenario than in the financial one, and (iii) a larger default effect when the flag was on the risky, rather than on the sure, option. Therefore, we conclude that default options can enhance risk propensity. Finally, individual beliefs about the source of the default significantly moderated the strength of the effect. Underlying mechanisms and practical implications are discussed considering prominent theories in this field.

Entanglement Length Scale Separates Threading from Branching of Unknotted and Non-concatenated Ring Polymers in Melts.

Current theories on the conformation and dynamics of unknotted and non-concatenated ring polymers in melt conditions describe each ring as a tree-like double-folded object. While evidence from simulations supports this picture on a single ring level, other works show pairs of rings also thread each other, a feature overlooked in the tree theories. Here we reconcile this dichotomy using Monte Carlo simulations of the ring melts with different bending rigidities. We find that rings are double-folded (more strongly for stiffer rings) on and above the entanglement length scale, while the threadings are localized on smaller scales. The different theories disagree on the details of the tree structure, i.e., the fractal dimension of the backbone of the tree. In the stiffer melts we find an indication of a self-avoiding scaling of the backbone, while more flexible chains do not exhibit such a regime. Moreover, the theories commonly neglect threadings and assign different importance to the impact of the progressive constraint release (tube dilation) on single ring relaxation due to the motion of other rings. Despite that each threading creates only a small opening in the double-folded structure, the threading loops can be numerous and their length can exceed substantially the entanglement scale. We link the threading constraints to the divergence of the relaxation time of a ring, if the tube dilation is hindered by pinning a fraction of other rings in space. Current theories do not predict such divergence and predict faster than measured diffusion of rings, pointing at the relevance of the threading constraints in unpinned systems as well. Revision of the theories with explicit threading constraints might elucidate the validity of the conjectured existence of topological glass.

Lean Management Approach for Reengineering the Hospital Cardiology Consultation Process: A Report from AORN "A. Cardarelli" of Naples.

BACKGROUND: Consultations with specialists are essential for safe and high-quality care for all patients. Cardiology consultations, due to a progressive increase in cardiology comorbidities, are becoming more common in hospitals prior to any type of treatment. The appropriateness and correctness of the request, the waiting time for delivery and the duration of the visit are just a few of the elements that can affect the quality of the process. METHODS: In this work, a Lean approach and Telemedicine are used to optimize the cardiology consultancy process provided by the Cardiology Unit of "Antonio Cardarelli" Hospital of Naples (Italy), the largest hospital in the southern Italy. RESULTS: The application of corrective actions, with the introduction of portable devices and telemedicine, led to a reduction in the percentage of waiting for counseling from 29.6% to 18.3% and an increase in the number of patients treated. CONCLUSIONS: The peculiarity of the study is to apply an innovative methodology such as Lean Thinking in optimizing the cardiology consultancy process, currently little studied in literature, with benefits for both patients and medical staff.

The Physical Behavior of Interphase Chromosomes: Polymer Theory and Coarse-Grain Computer Simulations.

Fluorescence in situ hybridization and chromosome conformation capture methods point to the same conclusion: that chromosomes appear to the external observer as compact structures with a highly nonrandom three-dimensional organization. In this work, we recapitulate the efforts made by us and other groups to rationalize this behavior in terms of the mathematical language and tools of polymer physics. After a brief introduction dedicated to some crucial experiments dissecting the structure of interphase chromosomes, we discuss at a nonspecialistic level some fundamental aspects of theoretical and numerical polymer physics. Then, we inglobe biological and polymer aspects into a polymer model for interphase chromosomes which moves from the observation that mutual topological constraints, such as those typically present between polymer chains in ordinary melts, induce slow chain dynamics and "constraint" chromosomes to resemble double-folded randomly branched polymer conformations. By explicitly turning these ideas into a multi-scale numerical algorithm which is described here in full details, we can design accurate model polymer conformations for interphase chromosomes and offer them for systematic comparison to experiments. The review is concluded by discussing the limitations of our approach and pointing to promising perspectives for future work.

Comparing echocardiographic characteristics in genotype positive-phenotype positive hypertrophic cardiomyopathy and hypertensive left ventricular hypertrophy.

AIMS: There is little information about hypertrophic cardiomyopathy (HCM) with pathologic genetic mutations and concurrent hypertension (HTN). Hypertensive left ventricular hypertrophy (LVH) does not exclude an underlying genetic aetiology. METHODS AND RESULTS: This was a single-centre case-control study of 39 adults with pathologic HCM mutations, confirmed by genetic testing, compared to 39 age- and gender-matched patients with hypertensive LVH. The gene-positive HCM cohort was further stratified by the coexisting presence or absence of HTN. Clinical and echocardiographic characteristics were compared. Of 39 gene-positive HCM, 43.6% (17/39) had concurrent HTN. The gene-positive HCM cohort had larger left atrial (LA) area (22.1 cm2 vs. 18.9 cm2, P = 0.002), more diastolic predominant pulmonary vein flow (38.5% vs. 7.7%, P = 0.001), and more moderate diastolic dysfunction (33.3% vs. 12.8%, P = 0.032) when compared with the hypertensive LVH cohort. Greater left ventricular (LV) mass (277.7 g vs. 207.7 g, P = 0.025), increased frequency of severe LVH (58.8% vs. 27.3%, P = 0.047), and more abnormal global longitudinal strain (GLS) (-14.1% vs. -16.9%, P = 0.049) was observed in the gene-positive HCM cohort with concurrent HTN. CONCLUSION: Gene-positive HCM, compared to hypertensive LVH, is characterized by more advanced diastolic dysfunction and larger LA size. Gene-positive HCM patients with concomitant HTN had greater LV mass, more severe LVH, and more abnormal GLS, suggesting HTN may negatively affect the progression of myocardial dysfunction in genetic HCM. LVH out-of-proportion to pressure burden in HTN patients should raise suspicion of underlying genetic HCM.

Lean Perspectives in an Organizational Change in a Scientific Direction of an Italian Research Institute: Experience of the Cancer Institute of Bari.

Lean management is a relatively new organizational vision transferred from the automotive industry to the healthcare and administrative sector based on analyzing a production process to emphasize value and reduce waste. This approach is particularly interesting in a historical moment of cuts and scarcity of economic resources and could represent a low-cost organizational solution in many production companies. In this work, we analyzed the presentation and the initial management of current ministerial research projects up to the approval by the Scientific Directorate of an Italian research institute. Furthermore, the initial mode in 2021 ("as is") and the potential mode ("to be") according to a Lean model are studied, according to the current barriers highlighted by the final users of the process and carrying out some perspective analyses with some reference indicators.

Computer simulations of melts of ring polymers with nonconserved topology: A dynamic Monte Carlo lattice model.

We present computer simulations of a dynamic Monte Carlo algorithm for polymer chains on a fcc lattice which explicitly takes into account the possibility to overcome topological constraints by controlling the rate at which nearby polymer strands may cross through each other. By applying the method to systems of interacting ring polymers at melt conditions, we characterize their structure and dynamics by measuring, in particular, the amounts of knots and links which are formed during the relaxation process. In comparison with standard melts of unknotted and unconcatenated rings, our simulations demonstrate that the mechanism of strand crossing makes polymer dynamics faster provided the characteristic timescale of the process is smaller than the typical timescale for chain relaxation in the unperturbed state, in agreement with recent experiments employing solutions of DNA rings in the presence of the type II topoisomerase enzyme. In the opposite case of slow rates the melt is shown to become slower, and this prediction may be easily validated experimentally.

Advanced heart failure and heart transplantation in adult congenital heart disease in the current era.

BACKGROUND: Adults with congenital heart disease (ACHD) may undergo heart transplantation (HTx) despite increased risk of poor short-term outcomes due to factors including surgical complexity and antibody sensitization. We assessed the clinical characteristics and outcomes of patients with ACHD in the current era referred for HTx at a single high-volume transplant center. METHODS: From 2010 to 2020, 37 ACHD patients were evaluated for HTx. ACHD HTx recipients were compared to non-ACHD HTx recipients matched for age, sex, listing status, and prior cardiac surgery. RESULTS: Of the 37 patients with ACHD, eight (21.6%) were declined for HTx. Of 29 ACHD patients listed, 19 (65.5%) underwent HTx. Compared with non-ACHD HTx controls, the ACHD HTx recipients had more treated cellular (21.1% vs. 15.8%, P = .010) and antibody-mediated (15.8% vs. 10.5%, P = .033) rejection. There was no difference in hospital readmission or allograft vasculopathy at 1 year. There was a nonsignificant higher 1-year mortality in ACHD HTx recipients (21.1% vs. 7.9%, P = .21). CONCLUSION: At a high-volume transplant center, ACHD patients undergoing HTx appear to have a marginally higher risk of rejection, but no significant increase in 1-year mortality. With careful selection and management, HTx for patients with ACHD may be feasible in the current era.

Lean adoption in hospitals: the role of contextual factors and introduction strategy.

BACKGROUND: In the scientific literature, many studies describe the application of lean methodology in the hospital setting. Most of the articles focus on the results rather than on the approach adopted to introduce the lean methodology. In the absence of a clear view of the context and the introduction strategy, the first steps of the implementation process can take on an empirical, trial and error profile. Such implementation is time-consuming and resource-intensive and affects the adoption of the model at the organizational level. This research aims to outline the role contextual factors and introduction strategy play in supporting the operators introducing lean methodology in a hospital setting. METHODOLOGY: The methodology is revealed in a case study of an important hospital in Southern Italy, where lean has been successfully introduced through a pilot project in the pathway of cancer patients. The originality of the research is seen in the detailed description of the contextual elements and the introduction strategy. RESULTS: The results show significant process improvements and highlight the spontaneous dissemination of the culture of change in the organization and the streamlined adoption at the micro level. CONCLUSION: The case study shows the importance of the lean introduction strategy and contextual factors for successful lean implementation. Furthermore, it shows how both factors influence each other, underlining the dynamism of the organizational system.

Nanorheology of active-passive polymer mixtures differentiates between linear and ring polymer topology.

We study the motion of dispersed nanoprobes in entangled active-passive polymer mixtures. By comparing the two architectures of linear vs. unconcatenated and unknotted circular polymers, we demonstrate that novel, rich physics emerge. For both polymer architectures, nanoprobes of size smaller than the entanglement threshold of the solution move faster as activity is increased and more energy is pumped in the system. For larger nanoprobes, a surprising phenomenon occurs: while in linear solutions they move qualitatively as before, in active-passive ring solutions nanoprobes decelerate with respect to the purely passive conditions. We rationalize this effect in terms of the non-equilibrium, topology-dependent association (clustering) of nanoprobes to the cold component of the ring mixture reminiscent of the recently discovered [Weber et al., Phys. Rev. Lett., 2016, 116, 058301] phase separation in scalar active-passive mixtures. We conclude with a potential connection to the microrheology of the chromatin in the nuclei of the cells.

Single-molecule stretching experiments of flexible (wormlike) chain molecules in different ensembles: Theory and a potential application of finite chain length effects to nick-counting in DNA.

We propose a formalism for deriving force-elongation and elongation-force relations for flexible chain molecules from analytical expressions for their radial distribution function, which provides insight into the factors controlling the asymptotic behavior and finite chain length corrections. In particular, we apply this formalism to our previously developed interpolation formula for the wormlike chain end-to-end distance distribution. The resulting expression for the asymptotic limit of infinite chain length is of similar quality to the numerical evaluation of Marko and Siggia's variational theory and considerably more precise than their interpolation formula. A comparison to numerical data suggests that our analytical finite chain length corrections achieve a comparable accuracy. As an application of our results, we discuss the possibility of inferring the time-dependent number of nicks in single-molecule stretching experiments on double-stranded DNA from the accompanying changes in the effective chain length.

The impact of depression on heart transplant outcomes: A retrospective single-center cohort study.

BACKGROUND: Depression is prevalent in patients with heart failure and after heart transplant. We identified the prevalence of pre- and post-transplant depression and its association with clinical characteristics and post-transplant outcomes. METHODS: We reviewed 114 adults transplanted 1/1/2015 to 12/31/2015 and identified patients with pre- and post-transplant depression. Clinical characteristics and outcomes were compared. RESULTS: Of 114 patients, 35.1% had pre-transplant depression and 26.3% had post-transplant depression. Patients with post-transplant depression within the first year were significantly more likely to have acute rejection (10% vs 0%), longer intensive care unit (11.7 days vs 7.8 days) and hospital stay (31.7 days vs 16.3 days), and discharge to inpatient rehabilitation (26.7% vs 8.3%). Patients with post-transplant depression within the first year had significantly higher 5-year mortality (30% vs 9.5%, p = .009). However, after adjustment for total artificial heart/biventricular assist device, acute rejection, intensive care unit, and hospital length of stay, this relationship was no longer significant (HR 2.11; 95% CI 0.18-25.27; p = .556). CONCLUSIONS: Depression is common among heart transplant candidates and recipients. While pre-transplant depression did not impact outcomes, patients with post-transplant depression were more likely to have had a complicated course, suggesting the need for increased vigilance regarding depression in such patients.

Absence of electrocardiographic left ventricular hypertrophy in patients undergoing Transcatheter aortic valve replacement is associated with increased mortality.

BACKGROUND: We examined the association between the absence ECG LVH and all-cause mortality in patients with severe AS undergoing TAVR. METHODS: We conducted a retrospective single center study on 399 TAVR patients from 2012 to 2016. ECGs were reviewed for LVH diagnosed by Sokolow-Lyon's voltage criteria. All patients met echocardiographic criteria for LVH. Logistic regression was used to examine the association between ECG LVH and covariates. Survival analysis was performed using Cox regression analysis and Kaplan Meier curves. RESULTS: Patients without ECG LVH were younger (81.0 ± 8.4 vs. 84.0 ± 7.7 years, p = 0.001) with a higher BMI (29.3 ± 7.0 vs. 27.1 ± 5.6 kg/m2, p = 0.006) and lower FEV1 (65.6 ± 22.8 vs. 74.1 ± 21.6%, p = 0.002). In multivariable analysis, increased BMI and decreased FEV1 remained predictive of the absence of ECG LVH. Over a mean follow-up time of 32 (± 17.0) months, the 5-year cumulative survival was 79% in the ECG LVH group and 58% in the group without ECG LVH (p = 0.039). Absence of ECG LVH remained predictive of all-cause mortality (HR 1.56, 95% CI 1.01-2.59, p = 0.045) in multivariable Cox regression analysis. When patients were grouped by comorbidities, patients with the highest mortality were those with increased BMI or decreased FEV1. CONCLUSIONS: Absence of LVH by ECG criteria in patients with severe AS undergoing TAVR was associated with increased all-cause mortality. Routinely performed, noninvasive and inexpensive ECG may aid in identification of high-risk patients that may not benefit from TAVR and warrant further evaluation of underlying comorbidities.