Antibacterial copper-filled TiO2 coating of cardiovascular implants to prevent infective endocarditis-A pilot study.

BACKGROUND: Infective endocarditis (IE) poses a significant health risk, especially in patients with prosthetic heart valves. Despite advances in treatment, mortality rates remain high. This study aims to investigate the antibacterial properties of a copper titanium dioxide (4× Cu-TiO2) coating on cardiovascular implants against Staphylococcus aureus, a common causative agent of IE. METHODS: Titanium oxide carriers functionalized with copper ions were employed as an antibacterial coating for heart and vascular prostheses. The coating's antibacterial efficacy was assessed using S. aureus ATCC 29213. Microscopic evaluations were conducted on both biological and artificial materials. Antibacterial activity was qualitatively assessed via a modified disc diffusion method and quantitatively measured through colony counts in NaCl suspensions. RESULTS: The coating process was successfully applied to all tested cardiovascular prosthetic materials. Qualitative assessments of antibacterial effectiveness revealed an absence of bacterial growth in the area directly beneath the coated valve. Quantitative evaluations showed a significant reduction in bacterial colonization on coated mechanical valves, with 2.95 × 104 CFU per valve, compared to 1.91 × 105 CFU in control valves. CONCLUSIONS: The 4× Cu-TiO2 coating demonstrated promising antibacterial properties against S. aureus, suggesting its potential as an effective strategy for reducing the risk of bacterial colonization of cardiovascular implants. Further studies are needed to assess the longevity of the coating and its efficacy against other pathogens.

Lung transplantation despite preformed donor-specific antihuman leukocyte antigen antibodies: a 9-year single-center experience.

Pretransplant allosensitization to human leukocyte antigens (HLA) increases the recipient's waiting list time and mortality in lung transplantation. Rather than waiting for crossmatch-negative donors, since 2013, recipients with preformed donor-specific antiHLA antibodies (pfDSA) have been managed with repeated IgA- and IgM-enriched intravenous immunoglobulin (IgGAM) infusions, usually in combination with plasmapheresis before IgGAM and a single dose of antiCD20 antibody. This retrospective study presents our 9-year experience with patients transplanted with pfDSA. Records of patients transplanted between February 2013 and May 2022 were reviewed. Outcomes were compared between patients with pfDSA and those without any de novo donor-specific antiHLA antibodies. The median follow-up time was 50 months. Of the 1,043 patients who had undergone lung transplantation, 758 (72.7%) did not develop any early donor-specific antiHLA antibodies, and 62 (5.9%) patients exhibited pfDSA. Among the 52 (84%) patients who completed treatment, pfDSA was cleared in 38 (73%). In pfDSA vs control patients and at 8-year follow-up, respectively, graft survival (%) was 75 vs 65 (P = .493) and freedom from chronic lung allograft dysfunction (%) was 63 vs 65 (P = .525). In lung transplantation, crossing the preformed HLA-antibody barrier is safe using a treatment protocol based on IgGAM. Patients with pfDSA have a good 8-year graft survival rate and freedom from chronic lung allograft dysfunction, similar to control patients.

Lungs From Donors ≥70 Years of Age for Transplantation-Do Long-Term Outcomes Justify Their Use?

Donor shortages have led transplant centers to extend their criteria for lung donors. Accepting lung donors ≥70 years of age has previously shown good short-term outcomes; however, no mid- and long-term outcome data on these extended criteria donors has been published to date. In this study, all patients who underwent lung transplantation between 06/2010 and 12/2019 were included in the analysis, and the outcomes were compared between patients receiving organs from donors <70 years of age and patients transplanted with lungs from donors ≥70 years of age. Among the 1,168 lung-transplanted patients, 62 patients received lungs from donors ≥70 years of age. The recipient age of those receiving older organs was significantly higher, and they were more likely to suffer from obstructive lung disease. Older donors were exposed to significantly shorter periods of mechanical ventilation prior to donation, had higher Horowitz indices, and were less likely to have smoked. The postoperative time on mechanical ventilation, time on ICU, and total hospital stay were comparable. The overall survival as well as CLAD-free survival showed no differences between both groups in the follow-up period. Utilization of lungs from donors ≥70 years of age leads to excellent mid- and long-term results that are similar to organs from younger donors when the organs from older donors are carefully preselected.

Self-adapting infectious dynamics on random networks.

Self-adaptive dynamics occurs in many fields of research, such as socio-economics, neuroscience, or biophysics. We consider a self-adaptive modeling approach, where adaptation takes place within a set of strategies based on the history of the state of the system. This leads to piecewise deterministic Markovian dynamics coupled to a non-Markovian adaptive mechanism. We apply this framework to basic epidemic models (SIS, SIR) on random networks. We consider a co-evolutionary dynamical network where node-states change through the epidemics and network topology changes through the creation and deletion of edges. For a simple threshold base application of lockdown measures, we observe large regions in parameter space with oscillatory behavior, thereby exhibiting one of the most reduced mechanisms leading to oscillations. For the SIS epidemic model, we derive analytic expressions for the oscillation period from a pairwise closed model, which is validated with numerical simulations for random uniform networks. Furthermore, the basic reproduction number fluctuates around one indicating a connection to self-organized criticality.

Intracranial Hemorrhages on Extracorporeal Membrane Oxygenation: Differences Between COVID-19 and Other Viral Acute Respiratory Distress Syndrome.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) is a potentially lifesaving procedure in acute respiratory distress syndrome (ARDS) due to COVID-19. Previous studies have shown a high prevalence of clinically silent cerebral microbleeds in patients with COVID-19. Based on this fact, together with the hemotrauma and the requirement of therapeutic anticoagulation on ECMO support, we hypothesized an increased risk of intracranial hemorrhages (ICHs). We analyzed ICH occurrence rate, circumstances and clinical outcome in patients that received ECMO support due to COVID-19-induced ARDS in comparison to viral non-COVID-19-induced ARDS intracerebral hemorrhage. DESIGN: Multicenter, retrospective analysis between January 2010 and May 2021. SETTING: Three tertiary care ECMO centers in Germany and Switzerland. PATIENTS: Two-hundred ten ARDS patients on ECMO support (COVID-19, n = 142 vs viral non-COVID, n = 68). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Evaluation of ICH occurrence rate, parameters of coagulation and anticoagulation strategies, inflammation, and ICU survival. COVID-19 and non-COVID-19 ARDS patients showed comparable disease severity regarding Sequential Organ Failure Assessment score, while the oxygenation index before ECMO cannulation was higher in the COVID group (82 vs 65 mm Hg). Overall, ICH of any severity occurred in 29 of 142 COVID-19 patients (20%) versus four of 68 patients in the control ECMO group (6%). Fifteen of those 29 ICH events in the COVID-19 group were classified as major (52%) including nine fatal cases (9/29, 31%). In the control group, there was only one major ICH event (1/4, 25%). The adjusted subhazard ratio for the occurrence of an ICH in the COVID-19 group was 5.82 (97.5% CI, 1.9-17.8; p = 0.002). The overall ICU mortality in the presence of ICH of any severity was 88%. CONCLUSIONS: This retrospective multicenter analysis showed a six-fold increased adjusted risk for ICH and a 3.5-fold increased incidence of ICH in COVID-19 patients on ECMO. Prospective studies are needed to confirm this observation and to determine whether the bleeding risk can be reduced by adjusting anticoagulation strategies.

Balancing Quarantine and Self-Distancing Measures in Adaptive Epidemic Networks.

We study the relative importance of two key control measures for epidemic spreading: endogenous social self-distancing and exogenous imposed quarantine. We use the framework of adaptive networks, moment-closure, and ordinary differential equations to introduce new model types of susceptible-infected-recovered (SIR) dynamics. First, we compare computationally expensive, adaptive network simulations with their corresponding computationally efficient ODE equivalents and find excellent agreement. Second, we discover that there exists a critical curve in parameter space for the epidemic threshold, which suggests a mutual compensation effect between the two mitigation strategies: as long as social distancing and quarantine measures are both sufficiently strong, large outbreaks are prevented. Third, we study the total number of infected and the maximum peak during large outbreaks using a combination of analytical estimates and numerical simulations. Also for large outbreaks we find a similar compensation mechanism as for the epidemic threshold. This means that if there is little incentive for social distancing in a population, drastic quarantining is required, and vice versa. Both pure scenarios are unrealistic in practice. The new models show that only a combination of measures is likely to succeed to control epidemic spreading. Fourth, we analytically compute an upper bound for the total number of infected on adaptive networks, using integral estimates in combination with a moment-closure approximation on the level of an observable. Our method allows us to elegantly and quickly check and cross-validate various conjectures about the relevance of different network control measures. In this sense it becomes possible to adapt also other models rapidly to new epidemic challenges.

The influence of a transport process on the epidemic threshold.

By generating transient encounters between individuals beyond their immediate social environment, transport can have a profound impact on the spreading of an epidemic. In this work, we consider epidemic dynamics in the presence of the transport process that gives rise to a multiplex network model. In addition to a static layer, the (multiplex) epidemic network consists of a second dynamic layer in which any two individuals are connected for the time they occupy the same site during a random walk they perform on a separate transport network. We develop a mean-field description of the stochastic network model and study the influence the transport process has on the epidemic threshold. We show that any transport process generally lowers the epidemic threshold because of the additional connections it generates. In contrast, considering also random walks of fractional order that in some sense are a more realistic model of human mobility, we find that these non-local transport dynamics raise the epidemic threshold in comparison to a classical local random walk. We also test our model on a realistic transport network (the Munich U-Bahn network), and carefully compare mean-field solutions with stochastic trajectories in a range of scenarios.

Stability analysis of multiplayer games on adaptive simplicial complexes.

We analyze the influence of multiplayer interactions and network adaptation on the stability of equilibrium points in evolutionary games. We consider the Snowdrift game on simplicial complexes. In particular, we consider as a starting point the extension from only two-player interactions to coexistence of two- and three-player interactions. The state of the system and the topology of the interactions are both adaptive through best-response strategies of nodes and rewiring strategies of edges, respectively. We derive a closed set of low-dimensional differential equations using pairwise moment closure, which yields an approximation of the lower moments of the system. We numerically confirm the validity of these moment equations. Moreover, we demonstrate that the stability of the fixed points remains unchanged for the considered adaption process. This stability result indicates that rational best-response strategies in games are very difficult to destabilize, even if higher-order multiplayer interactions are taken into account.

Graphop mean-field limits and synchronization for the stochastic Kuramoto model.

Models of coupled oscillator networks play an important role in describing collective synchronization dynamics in biological and technological systems. The Kuramoto model describes oscillator's phase evolution and explains the transition from incoherent to coherent oscillations under simplifying assumptions, including all-to-all coupling with uniform strength. Real world networks, however, often display heterogeneous connectivity and coupling weights that influence the critical threshold for this transition. We formulate a general mean-field theory (Vlasov-Focker Planck equation) for stochastic Kuramoto-type phase oscillator models, valid for coupling graphs/networks with heterogeneous connectivity and coupling strengths, using graphop theory in the mean-field limit. Considering symmetric odd-valued coupling functions, we mathematically prove an exact formula for the critical threshold for the incoherence-coherence transition. We numerically test the predicted threshold using large finite-size representations of the network model. For a large class of graph models, we find that the numerical tests agree very well with the predicted threshold obtained from mean-field theory. However, the prediction is more difficult in practice for graph structures that are sufficiently sparse. Our findings open future research avenues toward a deeper understanding of mean-field theories for heterogeneous systems.

Vibrational circular dichroism studies of exceptionally strong chirality inducers in liquid crystals.

7,7'-Disubstituted 2,2'-methylenedioxy-1,1'-binaphthyls are highly efficient chirality inducers in nematic liquid crystals. The absolute configuration of these compounds is, however, hard to determine as they only crystallize as racemic mixtures. In this work a Vibrational Circular Dichroism (VCD) study is reported that provides an unambiguous determination of the absolute configuration of these compounds. An in-depth General Coupled Oscillator (GCO) analysis of the source of the VCD signal reveals that the unusual structure of these binaphthyl compounds inherently leads to strong and robust VCD bands. Combined with linear transit calculations, our VCD studies allow for the determination of key structural parameters.

Reduced Models of Cardiomyocytes Excitability: Comparing Karma and FitzHugh-Nagumo.

Since Noble adapted in 1962 the model of Hodgkin and Huxley to fit Purkinje fibres, the refinement of models for cardiomyocytes has continued. Most of these models are high-dimensional systems of coupled equations so that the possible mathematical analysis is quite limited, even numerically. This has inspired the development of reduced, phenomenological models that preserve qualitatively the main feature of cardiomyocyte's dynamics. In this paper, we present a systematic comparison of the dynamics between two notable low-dimensional models, the FitzHugh-Nagumo model (FitzHugh in Bull Math Biophys 17:257-269, 1955, J Gen Physiol 43:867-896, 1960, Biophys J 1:445-466, 1961) as a prototype of excitable behaviour and a polynomial version of the Karma model (Karma in Phys Rev Lett 71(7):16, 1993, Chaos 4:461, 1994) which is specifically developed to fit cardiomyocyte's behaviour well. We start by introducing the models and considering their pure ODE versions. We analyse the ODEs employing the main ideas and steps used in the setting of geometric singular perturbation theory. Next, we turn to the spatially extended models, where we focus on travelling wave solutions in 1D. Finally, we perform numerical simulations of the 1D PDE Karma model varying model parameters in order to systematically investigate the impact on wave propagation velocity and shape. In summary, our study provides a reference regarding key similarities as well as key differences of the two models.

A geometric analysis of the SIRS epidemiological model on a homogeneous network.

We study a fast-slow version of an SIRS epidemiological model on homogeneous graphs, obtained through the application of the moment closure method. We use GSPT to study the model, taking into account that the infection period is much shorter than the average duration of immunity. We show that the dynamics occurs through a sequence of fast and slow flows, that can be described through 2-dimensional maps that, under some assumptions, can be approximated as 1-dimensional maps. Using this method, together with numerical bifurcation tools, we show that the model can give rise to periodic solutions, differently from the corresponding model based on homogeneous mixing.

Antileishmanial activity evaluation of a natural amide and its synthetic analogs against Leishmania (V.) braziliensis: an integrated approach in vitro and in silico.

Leishmaniasis is considered a neglected disease, which makes it an unattractive market for the pharmaceutical industry; hence, efforts in the search for biologically active substances are hampered by this lack of financial motivation. Thus, in the present study, we report the leishmanicidal activity and the possible mechanisms of action of compounds with promising activity against the species Leishmania (V.) braziliensis, the causative agent of the skin disease leishmaniasis. The natural compound 1a (piplartine) and the analog 2a were the most potent against promastigote forms with growth inhibition values for 50% of the parasite population (IC50) = 8.58 and 11.25 µM, respectively. For amastigote forms, the ICa50 values were 1.46 and 16.7 µM, respectively. In the molecular docking study, piplartine showed favorable binding energy (-7.13 kcal/mol) and with 50% inhibition of trypanothione reductase (IC50) = 91.1 µM. Preliminary investigations of the mechanism of action indicate that piplartine increased ROS levels, induced loss of cell membrane integrity, and caused accumulation of lipid bodies after 24 h of incubation at its lowest effective concentration (IC50), which was not observed for the synthetic analog 2a. The mode of action for the leishmanicidal activity of piplartine (1a) was assigned to involve affinity for the trypanothione reductase of Leishmania (V.) braziliensis TR.

A qualitative mathematical model of the immune response under the effect of stress.

In recent decades, many studies have been developed in psychoneuroimmunology that associate stress, arising from multiple different sources and situations, to changes in the immune system, from the medical or immunological point of view as well as from the biochemical one. In this paper, we identify important behaviors of this interplay between the immune system and stress from medical studies and seek to represent them qualitatively in a paradigmatic, yet simple, mathematical model. To that end, we develop an ordinary differential equation model with two equations, for infection level and immune system, respectively, which integrates the effects of stress as an independent parameter. In addition, we perform a geometric analysis of the model for different stress values as well as the corresponding bifurcation analysis. In this context, we are able to reproduce a stable healthy state for little stress, an oscillatory state between healthy and infected states for high stress, and a "burn-out" or stable sick state for extremely high stress. The mechanism between the different dynamical regimes is controlled by two saddle-node in cycle bifurcations. Furthermore, our model is able to capture an induced infection upon dropping from moderate to low stress, and it predicts increasing infection periods upon increasing stress before eventually reaching a burn-out state.

Increased frequency of CD4+ CD25high CD127low T cells early after lung transplant is associated with improved graft survival - a retrospective study.

In this retrospective study, we analyzed the presence of any association of three CD4+ CD25high regulatory T-cell subpopulations at 3 weeks after lung transplantation with the later incidence of chronic lung allograft dysfunction and graft survival. Among lung-transplanted patients between January 2009 and April 2018, only patients with sufficient T-cell measurements at 3 weeks after transplantation were included into the study. Putative regulatory T cells were defined as CD4+ CD25high T cells, detected in peripheral blood and further analyzed for CD127low , FoxP3+ , and CD152+ using fluorescence-activated cell sorting (FACS) analysis. Associations of regulatory T cells with chronic lung allograft dysfunction (CLAD) and graft survival were evaluated using Cox analysis. During the study period, 724 (71%) patients were included into the study. Freedom from chronic lung allograft dysfunction (CLAD) and graft survival amounted to 66% and 68% at 5 years. At the multivariable analysis, increasing frequencies of CD127low were associated with better freedom from CLAD (hazard ratio for each 1% increase of %CD127low , HR = 0.989, 95% CI = 0.981-0.996, P = 0.003) and better graft survival (HR = 0.991, 95% CI = 0.984-0.999, P = 0.026). A higher frequency of CD127low regulatory T cells in peripheral blood early after lung transplantation estimated a protective effect against chronic lung allograft dysfunction, mortality, and re-transplantation.

Correction to: In silico evaluation and in vitro growth inhibition of Plasmodium falciparum by natural amides and synthetic analogs.

The original version of the article above contained an error in the text.

In silico evaluation and in vitro growth inhibition of Plasmodium falciparum by natural amides and synthetic analogs.

Malaria, caused by protozoa of the genus Plasmodium, is a disease that infects hundreds of millions of people annually, causing an enormous social burden in many developing countries. Since current antimalarial drugs are starting to face resistance by the parasite, the development of new therapeutic options has been prompted. The enzyme Plasmodium falciparum enoyl-ACP reductase (PfENR) has a determinant role in the fatty acid biosynthesis of this parasite and is absent in humans, making it an ideal target for new antimalarial drugs. In this sense, the present study aimed at evaluating the in silico binding affinity of natural and synthetic amides through molecular docking, in addition to their in vitro activity against P. falciparum by means of the SYBR Green Fluorescence Assay. The in vitro results revealed that the natural amide piplartine (1a) presented partial antiplasmodial activity (20.54 µM), whereas its synthetic derivatives (1m-IC50 104.45 µM), (1b, 1g, 1k, and 14f) and the natural amide piperine (18a) were shown to be inactive (IC50 > 200 µM). The in silico physicochemical analyses demonstrated that compounds 1m and 14f violated the Lipinski's rule of five. The in silico analyses showed that 14f presented the best binding affinity (- 13.047 kcal/mol) to PfENR and was also superior to the reference inhibitor triclosan (- 7.806 kcal/mol). In conclusion, we found that the structural modifications in 1a caused a significant decrease in antiplasmodial activity. Therefore, new modifications are encouraged in order to improve the activity observed.

Transplantation of donor lungs with pulmonary embolism - a retrospective study.

Lung transplantation from donors with fulminant pulmonary arterial embolism as a cause of death remains controversial. An analysis was performed comparing preoperative characteristics and outcomes of 25 donors with a primary diagnosis of pulmonary arterial embolism to 1085 recipients of donor lungs without pulmonary arterial embolism. No early functional impairment of donor lungs with pulmonary embolism was detectable as depicted by the incidence of primary graft dysfunction immediately after surgery (P = 0.66), 24 (P = 0.79), 48 (P = 0.99) and 72 h (P = 0.99) after transplantation. Pulmonary function testing at 1 year (P = 0.003) and at last outpatient control (P < 0.05) showed superior results in the cohort receiving lungs from donors with pulmonary embolism. Incidence of chronic lung allograft dysfunction (CLAD) showed no difference within the first year after lung transplantation, however, 5 year-CLAD free survival was superior in recipients (70.4% vs. 55.1%, P = 0.006) of donor lungs with pulmonary embolism. Overall survival was similar in both groups. Lungs from donors with fulminant pulmonary embolism prior to brain death can safely be used for lung transplantation without impairing postoperative outcomes. Lung function testing shows favorable midterm results in recipients of donor lungs with pulmonary embolism.

A gradient flow formulation for the stochastic Amari neural field model.

We study stochastic Amari-type neural field equations, which are mean-field models for neural activity in the cortex. We prove that under certain assumptions on the coupling kernel, the neural field model can be viewed as a gradient flow in a nonlocal Hilbert space. This makes all gradient flow methods available for the analysis, which could previously not be used, as it was not known, whether a rigorous gradient flow formulation exists. We show that the equation is well-posed in the nonlocal Hilbert space in the sense that solutions starting in this space also remain in it for all times and space-time regularity results hold for the case of spatially correlated noise. Uniqueness of invariant measures, ergodic properties for the associated Feller semigroups, and several examples of kernels are also discussed.

Risk factors for critical limb ischemia in patients undergoing femoral cannulation for venoarterial extracorporeal membrane oxygenation: Is distal limb perfusion a mandatory approach?

BACKGROUND: Venoarterial extracorporeal membrane oxygenation support is a well-established tool in the care of severe refractory cardiac and respiratory failure. The application of this support may serve as a bridge to transplant, recovery or to implantation of a ventricular assist device. Venoarterial extracorporeal membrane oxygenation support can be administered through an open surgical access via the common femoral or axillary artery or a percutaneous approach using Seldinger technique. Both techniques may obstruct the blood flow to the lower limb and may cause a significant ischemia with possible limb loss. Malperfusion of the distal limb can be avoided using an ipsilateral distal limb perfusion, which may be established by adding a single-lumen catheter during venoarterial extracorporeal membrane oxygenation treatment to overcome the obstruction. The aim of this study is to distinguish the presence or absence of a distal limb perfusion regarding the incidence of distal limb ischemia. Furthermore, expected risk factors of open and percutaneous femoral venoarterial extracorporeal membrane oxygenation installation were evaluated for the development of distal limb ischemia. METHODS: Between January 2012 and September 2015, 489 patients received venoarterial extracorporeal membrane oxygenation support at our institution. In total, 307 patients (204 male, 103 female) with femoral cannulation were included in the analysis. The cohort was distinguished by the presence (group A; n = 237) or absence (group B; n = 70) of a distal limb perfusion during peripheral venoarterial extracorporeal membrane oxygenation treatment. Furthermore, a risk factor analysis for the development of distal limb ischemia was performed. RESULTS: The main indications for venoarterial extracorporeal membrane oxygenation therapy were a low cardiac output syndrome (LCOS) (53%) and failed weaning of extracorporeal circulation (23%). A total of 23 patients (7.49%) under venoarterial extracorporeal membrane oxygenation support developed severe distal limb malperfusion (3.38% in group A vs 21.42% in group B). Preemptive installation of distal limb perfusion extended the intervention-free intervals to 7.8 ± 19.3 days in group A and 6.3 ± 12.5 in group B. A missing distal limb perfusion (p = 0.001) was identified as a main risk factor for critical limb ischemia. Other comorbidities such as arterial occlusion disease (p = 0.738) were not statistically significantly associated. Surgical intervention due to vascular complications after extracorporeal membrane oxygenation explantation was needed in 14 cases (4.22% in group A and 5.71% in group B). CONCLUSION: We were able to identify the absence of distal limb perfusion as an independent risk factor for the development of critical distal limb ischemia during femoral venoarterial extracorporeal membrane oxygenation treatment. The application of a distal limb perfusion should be considered as a mandatory approach in the context of femoral venoarterial extracorporeal membrane oxygenation treatment regardless of the implantation technique.