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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Uniqueness of laryngeal nerve injury following heart transplantation.

BACKGROUND: The incidence of recurrent laryngeal nerve injury (RLNI) after heart transplantation has not been well studied. This can manifest as vocal cord dysfunction causing dysphonia. Previous research is limited to aortic, coronary bypass, and valvular surgery. Identifying RLNI after heart transplantation is important in order to more accurately detail complications associated with this major surgery. METHODS: This is a retrospective study assessing 972 adult patients who underwent orthotopic heart transplantation between 2010-2019. Primary outcome was incidence of RLNI. Secondary outcomes were 1-year mortality and length of stay. Cardiology and otolaryngology notes were examined. Key word searches were used to identify possible RLNI in patients' health care record. RESULTS: 2.9% (29/972) of patients developed new RLNI confirmed by laryngoscopy during hospitalization. Patients with RLNI had a significantly increased risk of 1-year mortality (P = .015) and length of stay (P = .006) compared to those without RLNI. 68.9% (20/29) of RLNI was left-sided (68.9%). CONCLUSIONS: Recurrent laryngeal nerve injury is a recognizable adverse outcome following heart transplantation. This study supports that RLNI is associated with increased 1-year mortality and length of stay. Early otolaryngology evaluation may be warranted to evaluate vocal cord mobility and address potential management.

Randomly branching θ-polymers in two and three dimensions: Average properties and distribution functions.

Motivated by renewed interest in the physics of branched polymers, we present here a detailed characterization of the connectivity and spatial properties of 2- and 3-dimensional single-chain conformations of randomly branching polymers under θ-solvent conditions obtained by Monte Carlo computer simulations. The first part of the work focuses on polymer average properties, such as the average polymer spatial size as a function of the total tree mass and the typical length of the average path length on the polymer backbone. In the second part, we move beyond average chain behavior and we discuss the complete distribution functions for tree paths and tree spatial distances, which are shown to obey the classical Redner-des Cloizeaux functional form. Our results were rationalized first by the systematic comparison to a Flory theory for branching polymers and next by generalized Fisher-Pincus relationships between scaling exponents of distribution functions. For completeness, the properties of θ-polymers were compared to their ideal (i.e., no volume interactions) as well as good-solvent (i.e., above the θ-point) counterparts. The results presented here complement the recent work performed in our group [A. Rosa and R. Everaers, J. Phys. A: Math. Theor. 49, 345001 (2016); J. Chem. Phys. 145, 164906 (2016); and Phys. Rev. E 95, 012117 (2017)] in the context of the scaling properties of branching polymers.

Anticoagulation Therapy After Transcatheter Aortic Valve Replacement.

PURPOSE OF REVIEW: We review the prevalence; natural history; impact of subclinical clinical thrombosis on valve hemodynamics, clinical outcomes, and valve durability; and the role of anticoagulation after transcatheter aortic valve replacement (TAVR). RECENT FINDINGS: Subclinical leaflet thrombosis is a dynamic finding present in both transcatheter and surgical bioprosthetic aortic valves. This finding is less prevalent in patients on anticoagulation and resolves following initiation of anticoagulation. Routine anticoagulation after TAVR in high-surgical-risk patients was associated with increased mortality and thromboembolic complications. In the absence of a clinical indication for anticoagulation, there is no reason to initiate anticoagulation after TAVR for the prevention of subclinical leaflet thrombosis. In patients with an established indication for anticoagulation, for instance, atrial fibrillation, clinical or symptomatic valve thrombosis, or a clinical event related to valve thrombosis, anticoagulation should be initiated or continued after TAVR to treat the clinical indication.

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.

Microrheology of interphase chromosomes with spatial constraints: a computational study.

Chromatin fibers within the interior of the nucleus of the cell make stable interactions with the nucleoskeleton, an ensemble of 'extra-chromatin' structures which help ensuring genome stability. Although the role of these interactions appears crucial to the correct behavior of the cell, their impact on chromatin structure and dynamics remains to be elucidated. In order to tackle this important issue, in this work we introduce a simple polymer model for chromatin fibers in interphase which takes into account the two generic properties of chain-versus-chain mutual uncrossability and the presence of stable binding interactions to an extra-chromatin nuclear matrix. To study how these constraints affect chromatin structure from small to large scales, we employ extensive molecular dynamics computer simulations and we monitor the motion of nanoprobes of different sizes embedded within the polymer medium. Our results demonstrate that nanoprobes show hampered motion whenever their linear size becomes larger than chromatin stiffness. This transition is also displaying features which usually belong to the realm of glassy systems, namely long-tail correlations in the distribution functions of nanoprobe spatial displacements and heterogeneous behavior accompanied by ergodicity breaking.

Local loop opening in untangled ring polymer melts: a detailed "Feynman test" of models for the large scale structure.

The conformational statistics of ring polymers in melts or dense solutions is strongly affected by their quenched microscopic topological state. The effect is particularly strong for untangled (i.e. non-concatenated and unknotted) rings, which are known to crumple and segregate. Here we study these systems using a computationally efficient multi-scale approach, where we combine massive simulations on the fiber level with the explicit construction of untangled ring melt configurations based on theoretical ideas for their large scale structure. We find (i) that topological constraints may be neglected on scales below the standard entanglement length, Le, (ii) that rings with a size 1 ≤ Lr/Le ≤ 30 exhibit nearly ideal lattice tree behavior characterized by primitive paths which are randomly branched on the entanglement scale, and (iii) that larger rings are compact with gyration radii Rg2(Lr) ∝ Lr2/3. The detailed comparison between equilibrated and constructed ensembles allows us to perform a "Feynman test" of our understanding of untangled rings: can we convert ideas for the large scale ring structure into algorithms for constructing (nearly) equilibrated ring melt samples? We show that most structural observables are quantitatively reproduced by two different construction schemes: hierarchical crumpling and ring melts derived from the analogy to interacting branched polymers. However, the latter fail the "Feynman test" with respect to the magnetic radius, Rm, which we have defined based on an analogy to magnetostatics. While Rm is expected to vanish for double-folded structures, the observed values of Rm2(Lr) ∝ Rg2(Lr) provide a simple and computationally convenient measure of the presence of a non-negligible amount of local loop opening in crumpled rings.

Conformational statistics of randomly branching double-folded ring polymers.

The conformations of topologically constrained double-folded ring polymers can be described as wrappings of randomly branched primitive trees. We extend previous work on the tree statistics under different (solvent) conditions to explore the conformational statistics of double-folded rings in the limit of tight wrapping. In particular, we relate the exponents characterizing the ring statistics to those describing the primitive trees and discuss the distribution functions [Formula: see text] and [Formula: see text] for the spatial distance, [Formula: see text], and tree contour distance, L, between monomers as a function of their ring contour distance, [Formula: see text].

White matter tauopathy: Transient functional loss and novel myelin remodeling.

Early white matter (WM) changes are common in dementia and may contribute to functional decline. We here examine this phenomenon in an induced dementia model for the first time. We report a novel and selective form of myelin injury as the first manifestation of tauopathy in the adult central nervous system. Myelin pathology rapidly followed the induction of a P301 tau mutation associated with fronto-temporal dementia in humans (rTG4510 line). Damage involved focal disruption of the ad-axonal myelin lamella and internal oligodendrocyte tongue process, followed by myelin remodeling with features of re-myelination that included myelin thinning and internodal shortening. The evolution of the re-myelinated phenotype was complete in the molecular layer of the dentate gyrus after 1 month and in the optic nerve (ON) after 9 months of transgene induction and proceeded in the absence of actual demyelination, reactive glial changes or inflammatory response. The initial rapid myelin pathology was associated with loss of WM function and performance decline in a novel recognition test and both these effects largely reversed during the myelin re-modeling phase. The initial phase of myelin injury was accompanied by disruption of the vesicle population present in the axoplasm of hippocampal and ON axons. Axoplasmic vesicle release is significant for the regulation of myelin plasticity and disruption of this pathway may underlie the myelin damage and remodeling evoked by tauopathy. WM dysfunction early in tauopathy will disorder neural circuits, the current findings suggest this event may make a significant contribution to early clinical deficit in dementia.

The Ising model in swollen vs. compact polymers: Mean-field approach and computer simulations.

We study the properties of the classical Ising model with nearest-neighbor interaction for spins located at the monomers of long polymer chains in 2 and 3 dimensions. We compare results for two ensembles of polymers with very different single chain properties: 1) swollen, self-avoiding linear polymer chains in good solvent conditions and 2) compact, space-filling randomly branching polymers in melt. By employing a mean-field approach and Monte Carlo computer simulations, we show that swollen polymers cannot sustain an ordered phase. On the contrary, compact polymers may indeed produce an observable phase transition. Finally, we briefly consider the statistical properties of the ordered phase by comparing polymer chains within the same universality class but characterized by very different shapes.

Nanoprobe diffusion in entangled polymer solutions: Linear vs. unconcatenated ring chains.

We employ large-scale molecular dynamics computer simulations to study the problem of nanoprobe diffusion in entangled solutions of linear polymers and unknotted and unconcatenated circular (ring) polymers. By tuning both the diameter of the nanoprobe and the density of the solution, we show that nanoprobes of diameter smaller than the entanglement distance (tube diameter) of the solution display the same (Rouse-like) behavior in solutions of both polymer architectures. Instead, nanoprobes with larger diameters appear to diffuse markedly faster in solutions of rings than in solutions of linear chains. Finally, by analysing the distribution functions of spatial displacements, we find that nanoprobe motion in rings' solutions shows both Gaussian and ergodic behaviors, in all regimes considered, while, in solutions of linear chains, nanoprobes exceeding the size of the tube diameter show a transition to non-Gaussian and non-ergodic motion. Our results emphasize the role of chain architecture in the motion of nanoprobes dispersed in polymer solutions.