Out-Patient versus In-Patient Arteriovenous Fistula Creation for Dialysis: Assessing Cost-Effectiveness Alongside Clinical Implications.

(1) Background: The surgical procedure to create an arteriovenous fistula (AVF) can be performed in either an ambulatory or in-patient hospital setting, depending on the case's complexity, the anesthesia type used, and the patient's comorbidities. The main scope of this study is to assess the cost-effectiveness and clinical implications of surgically creating an AVF in both ambulatory and in-hospital settings. (2) Methods: We conducted a retrospective observational study, in which we initially enrolled all patients with end-stage kidney disease (ESKD) admitted to the Vascular Surgery Department, Emergency County Hospital of Targu Mures, Romania, to surgically create an AVF for dialysis, between January 2020 and December 2022. The primary endpoint of this study is to assess the cost-effectiveness of surgically creating an AVF in an ambulatory vs. in-hospital setting by comparing the costs required for the two types of admissions. Further, the 116 patients enrolled in this study were divided into two groups based on their preference for hospitalization: out-patients and in-patients. (3) Results: Regarding in-patient comorbidities, there was a higher prevalence of peripheral artery disease (PAD) (p = 0.006), malignancy (p = 0.020), and previous myocardial infarction (p = 0.012). In addition, active smoking (p = 0.006) and obesity (p = 0.018) were more frequent among these patients. Regarding the laboratory data, the in-patients had lower levels of white blood cells (WBC) (p = 0.004), neutrophils count (p = 0.025), lymphocytes (p = 0.034), and monocytes (p = 0.032), but there were no differences between the two groups regarding the systemic inflammatory biomarkers or the AVF type. Additionally, we did not register any difference regarding the outcomes: local complications (p = 0.588), maturation failure (p = 0.267), and primary patency (p = 0.834). In our subsequent analysis, we discovered no significant difference between the hospitalization type chosen by patients regarding AVF primary patency failure (p = 0.195). We found no significant association between the hospitalization type and the recorded outcomes (all ps > 0.05) in both multivariate linear regression and Cox proportional hazard analysis. (4) Conclusions: In conclusion, there are no significant differences in the clinical implications, short-term and long-term complications of AVF for out-patient and in-patient admissions. Additionally, we found no variation in the costs associated with laboratory tests and surgical supplies for an AVF creation. Therefore, it is safe to perform ambulatory AVFs, which can reduce the risk of hospital-acquired infections and provide greater comfort to the patient.

Obscure Bleeding from a Metastatic Small Bowel Tumor Diagnosed Using Motorized Spiral Enteroscopy: A Case Study and a Literature Review.

Small bowel tumors are relatively rare, representing only around 5% of all gastrointestinal neoplasms, with a progressively increasing incidence. Currently, there are no established guidelines for diagnostic approaches, screening procedures, or management strategies for small bowel tumors. We present here the case of a patient with a rare type of metastatic tumor of the small bowel originating from primary lung adenocarcinoma who presented with abdominal pain, severe iron-deficiency anemia, and melena. The initial investigations, gastroscopy and colonoscopy, failed to identify the bleeding source. The obscure bleeding source and diagnosis were achieved through power motorized spiral enteroscopy (MSE), which allowed the visualization and biopsy of the tumor. Histopathological examination established the presence of a poorly differentiated non-mucinous adenocarcinoma originating from the lung. This case is reported to provide evidence of the efficiency of MSE in the diagnosis of small bowel tumors, with the method providing higher insertion depth in a reduced amount of time.

Flexible Ureteroscopy Without Radiation Exposure.

Introduction:Renal stones are a common pathology in daily practice with a continuously increasing incidence. Using flexible ureteroscopy (fURS), urologists can treat difficult renal stones through the natural orifice and maintain a satisfactory stone-free rate. Even though advancing technologies offer the opportunity for minimally invasive surgery, the surgeon is still exposed to a considerable amount of ionizing radiation during several procedures. In this study, the aim is to determine the efficacy of flexible ureteroscopy without fluoroscopy in terms of stone-free rates and complications. Materials and methods:In the Urology Department of Saint John Clinical Emergency Hospital in Bucharest, Romania, a retrospective study was conducted on 98 patients diagnosed with renal calculi between September 2020 and December 2021. Using two different groups, the demographic characteristics of patients, characteristics of stones (size, number, location), the use of fluoroscopy, the operative time (in minutes) and postoperative complications, and the stone-free rate were compared. In one of the groups, fluoroscopy was used during fURS (Group I), while in the second group (Group II), no ionizing radiation was used during fURS. Results:Twenty-four males and 23 females were enrolled in Group I, whereas 31 males and 20 females were enrolled in Group II. The mean age of subjects was 63.2 years old in the fluoroscopy group and 61.6 years old in the group without fluoroscopy. While the stone characteristics revealed some variations in stone location between the compared groups, there were no statistical differences in mean stone diameter (1.489 mm - Group I vs. 1.588 mm - Group II). Stone-free rates and complications classified using Clavien-Dindo modified system for urological surgeries were used to analyze the main results. Group II had a slightly higher stone-free rate, but statistical studies found no significant differences; therefore, both methods are deemed equal in this field. Identified complications were classified as Clavien I and II and were successfully treated for both groups. Conclusion:This study reveals that by adhering to additional intraoperative measurements for guiding the access sheath, fURS without fluoroscopy can be performed safely and with a high success rate.

Hyponatremia and Renal Venous Congestion in Heart Failure Patients.

OBJECTIVE: The interrelationship between the heart and kidneys has a great importance in the homeostasis of the cardiovascular system. Heart failure patients present intrarenal arterial hypoperfusion and intrarenal venous congestion due to reduced left ventricle ejection fraction, which triggers numerous neurohormonal factors. The aim of this study was to investigate intrarenal vascularization (arterial and venous), as well as the links between it and systemic congestion and, on the other side, with the mortality in patients with heart failure. Material and Methods. This cross-sectional study was performed on a group of 44 patients with heart failure in different stages of evolution and 44 healthy subjects, matched for age and gender, as controls. Serum natremia, NT-proBNP, and creatinine analyses were performed in all patients and controls. Renal and cardiac ultrasonography was done in all patients and controls, recording intrarenal arterial resistive index (RRI), intrarenal venous flow (IRVF) pattern, renal venous stasis index (RVSI), and left ventricular ejection fraction (LVEF). Data are recorded and presented as mean ± standard deviation. Statistical analyses were performed using the Student t-test, ANOVA test, and the Pearson correlation. Differences were considered statistically significant at the value of p < 0.05. RESULTS: Hyponatremia was identified in 47.72% of the HF patients. This study revealed correlations between serum natremia and LVEF, NT-proBNP, serum creatinine, interlobar venous RVSI (p < 0.00001), and interlobar artery RRI (p ≤ 0.002). Hyponatremia and renal venous congestion represent negative prognostic factors in HF patients. CONCLUSION: In HF patients, hyponatremia was correlated with cardiac dysfunction and intrarenal venous congestion. Hyponatremia and renal venous congestion represented negative prognostic factors in HF patients.

Muography applications developed by IFIN-HH.

Cosmic-ray muons have been studied at IFIN-HH for more than 20 years. Starting as fundamental physics research, the muon flux measurements bring new directions of study regarding muography. Two new directions have been recently developed: underground muon scanning of old mining sites in order to detect the possible presence of unknown cavities and underwater scanning of ships in commercial harbours in order to prevent the illegal traffic of radioactive materials. The main goal of the first direction of study is to improve the security of underground civilian and industrial infrastructures, by starting the development of a new, innovative detection system that can be used to identify potentially dangerous conditions using a non-invasive, totally safe method. The method proposed uses information provided by a device placed underground that measures directional cosmic muon flux and identifies anomalies produced by irregularities in the geological layers above. For the second direction of study, the method proposed is based on the detection and analysis of the cosmic muon flux. The high-density materials (uranium, lead-used for radiation shielding, etc.) cause a decrease in the directional muon flux. The detection system will be submerged underneath the ship that will be scanned, being able to locate illegal radioactive materials without exposing any personnel to radiation or contamination. Correlated with simulations based on the known configuration of the ship scanned, the data provided by the detection system will provide the location and dimensions of the undeclared material transported.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

A spectrum of modularity in multi-functional gene circuits.

A major challenge in systems biology is to understand the relationship between a circuit's structure and its function, but how is this relationship affected if the circuit must perform multiple distinct functions within the same organism? In particular, to what extent do multi-functional circuits contain modules which reflect the different functions? Here, we computationally survey a range of bi-functional circuits which show no simple structural modularity: They can switch between two qualitatively distinct functions, while both functions depend on all genes of the circuit. Our analysis reveals two distinct classes: hybrid circuits which overlay two simpler mono-functional sub-circuits within their circuitry, and emergent circuits, which do not. In this second class, the bi-functionality emerges from more complex designs which are not fully decomposable into distinct modules and are consequently less intuitive to predict or understand. These non-intuitive emergent circuits are just as robust as their hybrid counterparts, and we therefore suggest that the common bias toward studying modular systems may hinder our understanding of real biological circuits.

Dynamics of gene circuits shapes evolvability.

To what extent does the dynamical mechanism producing a specific biological phenotype bias the ability to evolve into novel phenotypes? We use the interpretation of a morphogen gradient into a single stripe of gene expression as a model phenotype. Although there are thousands of three-gene circuit topologies that can robustly develop a stripe of gene expression, the vast majority of these circuits use one of just six fundamentally different dynamical mechanisms. Here we explore the potential for gene circuits that use each of these six mechanisms to evolve novel phenotypes such as multiple stripes, inverted stripes, and gradients of gene expression. Through a comprehensive and systematic analysis, we find that circuits that use alternative mechanisms differ in the likelihood of reaching novel phenotypes through mutation. We characterize the phenotypic transitions and identify key ingredients of the evolutionary potential, such as sensitive interactions and phenotypic hubs. Finally, we provide an intuitive understanding on how the modular design of a particular mechanism favors the access to novel phenotypes. Our work illustrates how the dynamical mechanism by which an organism develops constrains how it can evolve. It is striking that these dynamical mechanisms and their impact on evolvability can be observed even for such an apparently simple patterning task, performed by just three-node circuits.

A unified design space of synthetic stripe-forming networks.

Synthetic biology is a promising tool to study the function and properties of gene regulatory networks. Gene circuits with predefined behaviours have been successfully built and modelled, but largely on a case-by-case basis. Here we go beyond individual networks and explore both computationally and synthetically the design space of possible dynamical mechanisms for 3-node stripe-forming networks. First, we computationally test every possible 3-node network for stripe formation in a morphogen gradient. We discover four different dynamical mechanisms to form a stripe and identify the minimal network of each group. Next, with the help of newly established engineering criteria we build these four networks synthetically and show that they indeed operate with four fundamentally distinct mechanisms. Finally, this close match between theory and experiment allows us to infer and subsequently build a 2-node network that represents the archetype of the explored design space.

Design principles of stripe-forming motifs: the role of positive feedback.

Interpreting a morphogen gradient into a single stripe of gene-expression is a fundamental unit of patterning in early embryogenesis. From both experimental data and computational studies the feed-forward motifs stand out as minimal networks capable of this patterning function. Positive feedback within gene networks has been hypothesised to enhance the sharpness and precision of gene-expression borders, however a systematic analysis has not yet been reported. Here we set out to assess this hypothesis, and find an unexpected result. The addition of positive-feedback can have different effects on two different designs of feed-forward motif- it increases the parametric robustness of one design, while being neutral or detrimental to the other. These results shed light on the abundance of the former motif and especially of mutual-inhibition positive feedback in developmental networks.

Synthetic lethal hubs associated with vincristine resistant neuroblastoma.

Chemotherapy of cancer experiences a number of shortcomings including development of drug resistance. This fact also holds true for neuroblastoma utilizing chemotherapeutics as vincristine. We performed a comparative analysis of molecular and cellular mechanisms associated with vincristine resistance utilizing cell line as well as human tissue data. Differential gene expression analysis revealed molecular features, processes and pathways afflicted with drug resistance mechanisms in general, and specifically with vincristine significantly involving actin associated features. However, specific mode of resistance as well as underlying genotype of parental, vincristine sensitive cells apparently exhibited significant heterogeneity. No consensus profile for vincristine resistance could be derived, but resistance-associated changes on the level of individual neuroblastoma cell lines as well as individual patient profiles became clearly evident. Based on these prerequisites we utilized the concept of synthetic lethality aimed at identifying hub proteins which when inhibited promise to induce cell death due to a synthetic lethal interaction with down-regulated, chemoresistance associated features. Our screening procedure identified synthetic lethal hub proteins afflicted with actin associated processes holding synthetic lethal interactions to down-regulated features individually found in all chemoresistant cell lines tested, therefore promising an improved therapeutic window. Verification of such synthetic lethal hub candidates in human neuroblastoma tissue expression profiles indicated the feasibility of this screening approach for addressing vincristine resistance in neuroblastoma.

Avoiding transcription factor competition at promoter level increases the chances of obtaining oscillation.

BACKGROUND: The ultimate goal of synthetic biology is the conception and construction of genetic circuits that are reliable with respect to their designed function (e.g. oscillators, switches). This task remains still to be attained due to the inherent synergy of the biological building blocks and to an insufficient feedback between experiments and mathematical models. Nevertheless, the progress in these directions has been substantial. RESULTS: It has been emphasized in the literature that the architecture of a genetic oscillator must include positive (activating) and negative (inhibiting) genetic interactions in order to yield robust oscillations. Our results point out that the oscillatory capacity is not only affected by the interaction polarity but by how it is implemented at promoter level. For a chosen oscillator architecture, we show by means of numerical simulations that the existence or lack of competition between activator and inhibitor at promoter level affects the probability of producing oscillations and also leaves characteristic fingerprints on the associated period/amplitude features. CONCLUSIONS: In comparison with non-competitive binding at promoters, competition drastically reduces the region of the parameters space characterized by oscillatory solutions. Moreover, while competition leads to pulse-like oscillations with long-tail distribution in period and amplitude for various parameters or noisy conditions, the non-competitive scenario shows a characteristic frequency and confined amplitude values. Our study also situates the competition mechanism in the context of existing genetic oscillators, with emphasis on the Atkinson oscillator.

Human synthetic lethal inference as potential anti-cancer target gene detection.

BACKGROUND: Two genes are called synthetic lethal (SL) if mutation of either alone is not lethal, but mutation of both leads to death or a significant decrease in organism's fitness. The detection of SL gene pairs constitutes a promising alternative for anti-cancer therapy. As cancer cells exhibit a large number of mutations, the identification of these mutated genes' SL partners may provide specific anti-cancer drug candidates, with minor perturbations to the healthy cells. Since existent SL data is mainly restricted to yeast screenings, the road towards human SL candidates is limited to inference methods. RESULTS: In the present work, we use phylogenetic analysis and database manipulation (BioGRID for interactions, Ensembl and NCBI for homology, Gene Ontology for GO attributes) in order to reconstruct the phylogenetically-inferred SL gene network for human. In addition, available data on cancer mutated genes (COSMIC and Cancer Gene Census databases) as well as on existent approved drugs (DrugBank database) supports our selection of cancer-therapy candidates. CONCLUSIONS: Our work provides a complementary alternative to the current methods for drug discovering and gene target identification in anti-cancer research. Novel SL screening analysis and the use of highly curated databases would contribute to improve the results of this methodology.

Mutate now, die later. Evolutionary dynamics with delayed selection.

We analyze here the evolutionary consequences of selection with delay in a population genetics context. In the classical works on evolutionary dynamics, an individual produces off-springs in direct proportion to its fitness, a process in which mutations may occur. In the present scenario of delayed selection, individuals that acquire deleterious mutations can still reproduce unharmed for several generations. During this time delay, the damage passed on to off-springs can potentially be repaired by subsequent compensatory mutations. In the absence of such a repair, the individual becomes sterile. Here we study the population-genetic effects of such a time delay by means of both numerical simulations and theoretical modeling. The results show that delayed selection lowers the extinction threshold, endangering the survival of the population. Surprisingly, however, no traces of this delay effect are encountered in the sequence diversity of the population. These conclusions suggest that delayed selection is hard to detect in genetic data and thus could be a wide-spread but rarely detected phenomenon.

Neutrality and robustness in evo-devo: emergence of lateral inhibition.

Embryonic development is defined by the hierarchical dynamical process that translates genetic information (genotype) into a spatial gene expression pattern (phenotype) providing the positional information for the correct unfolding of the organism. The nature and evolutionary implications of genotype-phenotype mapping still remain key topics in evolutionary developmental biology (evo-devo). We have explored here issues of neutrality, robustness, and diversity in evo-devo by means of a simple model of gene regulatory networks. The small size of the system allowed an exhaustive analysis of the entire fitness landscape and the extent of its neutrality. This analysis shows that evolution leads to a class of robust genetic networks with an expression pattern characteristic of lateral inhibition. This class is a repertoire of distinct implementations of this key developmental process, the diversity of which provides valuable clues about its underlying causal principles.

Synthetic protocell biology: from reproduction to computation.

Cells are the building blocks of biological complexity. They are complex systems sustained by the coordinated cooperative dynamics of several biochemical networks. Their replication, adaptation and computational features emerge as a consequence of appropriate molecular feedbacks that somehow define what life is. As the last decades have brought the transition from the description-driven biology to the synthesis-driven biology, one great challenge shared by both the fields of bioengineering and the origin of life is to find the appropriate conditions under which living cellular structures can effectively emerge and persist. Here, we review current knowledge (both theoretical and experimental) on possible scenarios of artificial cell design and their future challenges.

Generic Darwinian selection in catalytic protocell assemblies.

To satisfy the minimal requirements for life, an information carrying molecular structure must be able to convert resources into building blocks and also be able to adapt to or modify its environment to enhance its own proliferation. Furthermore, new copies of itself must have variable fitness such that evolution is possible. In practical terms, a minimal protocell should be characterized by a strong coupling between its metabolism and genetic subsystem, which is made possible by the container. There is still no general agreement on how such a complex system might have been naturally selected for in a prebiotic environment. However, the historical details are not important for our investigations as they are related to assembling and evolution of protocells in the laboratory. Here, we study three different minimal protocell models of increasing complexity, all of them incorporating the coupling between a 'genetic template', a container and, eventually, a toy metabolism. We show that for any local growth law associated with template self-replication, the overall temporal evolution of all protocell's components follows an exponential growth (efficient or uninhibited autocatalysis). Thus, such a system attains exponential growth through coordinated catalytic growth of its component subsystems, independent of the replication efficiency of the involved subsystems. As exponential growth implies the survival of the fittest in a competitive environment, these results suggest that protocell assemblies could be efficient vehicles in terms of evolving through Darwinian selection.

Phenotypic diversity and chaos in a minimal cell model.

Gánti's chemoton model (Gánti, T., 2002. On the early evolution of biological periodicity. Cell. Biol. Int. 26, 729) is considered as an iconic example of a minimal protocell including three key subsystems: membrane, metabolism and information. The three subsystems are connected through stoichiometrical coupling which ensures the existence of a replication cycle for the chemoton. Our detailed exploration of a version of this model indicates that it displays a wide range of complex dynamics, from regularity to chaos. Here, we report the presence of a very rich set of dynamical patterns potentially displayed by a protocell as described by this implementation of a chemoton-like model. The implications for early cellular evolution and synthesis of artificial cells are discussed.

Complex dynamics in a simple model of pulsations for super-asymptotic giant branch stars.

When intermediate mass stars reach their last stages of evolution they show pronounced oscillations. This phenomenon happens when these stars reach the so-called asymptotic giant branch (AGB), which is a region of the Hertzsprung-Russell diagram located at about the same region of effective temperatures but at larger luminosities than those of regular giant stars. The period of these oscillations depends on the mass of the star. There is growing evidence that these oscillations are highly correlated with mass loss and that, as the mass loss increases, the pulsations become more chaotic. In this paper we study a simple oscillator which accounts for the observed properties of this kind of stars. This oscillator was first proposed and studied in Icke et al. [Astron. Astrophys. 258, 341 (1992)] and we extend their study to the region of more massive and luminous stars -the region of super-AGB stars. The oscillator consists of a periodic nonlinear perturbation of a linear Hamiltonian system. The formalism of dynamical systems theory has been used to explore the associated Poincare map for the range of parameters typical of those stars. We have studied and characterized the dynamical behavior of the oscillator as the parameters of the model are varied, leading us to explore a sequence of local and global bifurcations. Among these, a tripling bifurcation is remarkable, which allows us to show that the Poincare map is a nontwist area preserving map. Meandering curves, hierarchical-islands traps and sticky orbits also show up. We discuss the implications of the stickiness phenomenon in the evolution and stability of the super-AGB stars. (c) 2002 American Institute of Physics.