Stratification of THROMBOTIC RISK in patients that are undergoing to PICC implantation. The “CoRa-MaPiCC STUDY”

Background: The PICC is a central venous system inserted in the peripherally vein. The central peripheral catheter catheter system (PICC=peripherally inserted central catheters) is a widely used procedure in clinical practice by medical and nurse team. PICC has potential complications that are rare but not entirely irrelevant. It is used for continuous and discontinuous treatment and, after a correct insertion procedure, it can be used for a period of time between 1 week to 3 months. The last-generation dispositive has an high-biocompatibility due to the high quality of the materials (silicone or polyurethane), a total length of 40-60 cm and a diameter between 16 to 25 Gauge or 2 to 5 French. Aims: The aim of our study is to evaluate the trombotic risk related to the positioning of the device in relation to the individual risk factors. Therefore we have elaborated the CoRaMaPicc protocol that allows, based on the preliminary data evaluation, to reduce the trombotic risk in patients with high cardiovascular risk profile. Methods: The study has started in July 2016. We have enrolled 30 patients (18 males and 12 females with range age of 30-99 yrs and mean age of 82+13,5 yrs). Enrolled patients have Body mass Index or (BMI) with range from 16,3-26,5 Kg/mq and mean BMI value of 23,5+2,5 Kg/mq. Enrolled patients were subjected to laboratory assessment of cardiovascular risk factors like laboratory assessment of Methyl-Tetra-Hydro-Folate-Reductase or (MTHFR) and Homocysteine, Fibrinogen, D-Dimer, International Normalized Ratio (INR), Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT), Platelets (PLT), trombotic risk evaluation (CHA2DS2-VASc Score), and bledding risk evaluation (HAS-BLED Score). Before the insertion procedure of the PICC, single or duble lumen (Groshong or Power PICC type), the patient were subjected to a preliminary ultrasound and echo-doppler vein evaluation to underline the presence of atipical anatomical state of the patients veins. After the procedure the patients were subjected to second ultrasound and echo-doppler vein evaluation and then to a radiographic examination to verify the correct position of the PICC. All patients were enrolled for follow- Up to evaluate trombotic complications. Statistical analysis was performed using the Survival Analysis test to evaluate the patients during the follow-up period in relation to thrombotic events. The data obtained from our study have been described taking also into account the data present in the international literature. Setting: The study was performed using a specific setting in a room of the Internal Medicine Department of the Alfredo Fiorini Hospital (Terracina, Italy), guarantee an aseptic procedure , the right comfort for the patients and the appropriate privacy. Discussion: More data in the literature underline the presence of non-eliminable risk factors like anatomic state of the patients vein that can play a variable role of procedural risk factor and can predispose to procedural or post-procedural complication after the implantation procedure. In specific cases it is difficult to asses an echo-doppler examination of heart for meteorism or ascites and radiographic exams for the presence of pleural effusion. The CoRaMaPiCC protocol use different technique to explore the post-insertion period and the follow-up time at 12 week. In case of meteorism or ascites the ultrasound examination of the heart cameras was replaced by the radiographyc evaluation while in case of pleural effusion, the evaluation of the device position was deduced using the only ultrasound approach (when the vein system is explorable). Procedural algorithm utilized in our implant protocol allows to improve the diagnostic capabilities of the conditions that can predispose to thrombotic complications. During the study period (1 year), the PICCs were removed for death (7 patients; 4 patients for irreversible heart disease, 1 patient for cardiogenic shock 1 patient for septic shock and 1 patient for Creutzfeld-Jacob disease), for spontaneously remotion (1 patient for low compliance of the patient) and for end of therapy (22 patients). The presence of cardiovascular risk factors alone is not sufficient for determining statistically significant changes in the thrombotic risk. As reported historically by the description of the wirkow triad, the presence of three clinical signs, and in particular the presence of endothelial damage (functio lesa) is a sine qua non condition for the occurrence of thrombotic episodes. Conclusion: The CoRaMaPicc protocol allows, based on the evaluation of the data, to minimize endothelial damage and therefore to reduce the incidence of the wirchof's triade related with an high trombotic risk. The data were elaborated considering the different thrombotic risk linked to the presence of the homozygous MTHR mutation responsible for the increase of homocysteine values and therefore of the further thrombotic risk. Further studies are needed to expand the number of enrolled patients and increase the follow-up period. Our data give comfortable results but further evaluation are needed to have conclusive results

NeuronAlg: An Innovative Neuronal Computational Model for Immunofluorescence Image Segmentation

Background: Image analysis applications in digital pathology include various methods for segmenting regions of interest. Their identification is one of the most complex steps and therefore of great interest for the study of robust methods that do not necessarily rely on a machine learning (ML) approach. Method: A fully automatic and optimized segmentation process for different datasets is a prerequisite for classifying and diagnosing indirect immunofluorescence (IIF) raw data. This study describes a deterministic computational neuroscience approach for identifying cells and nuclei. It is very different from the conventional neural network approaches but has an equivalent quantitative and qualitative performance, and it is also robust against adversative noise. The method is robust, based on formally correct functions, and does not suffer from having to be tuned on specific data sets. Results: This work demonstrates the robustness of the method against variability of parameters, such as image size, mode, and signal-to-noise ratio. We validated the method on three datasets (Neuroblastoma, NucleusSegData, and ISBI 2009 Dataset) using images annotated by independent medical doctors. Conclusions: The definition of deterministic and formally correct methods, from a functional and structural point of view, guarantees the achievement of optimized and functionally correct results. The excellent performance of our deterministic method (NeuronalAlg) in segmenting cells and nuclei from fluorescence images was measured with quantitative indicators and compared with those achieved by three published ML approaches

The role of network connectivity on epileptiform activity

A number of potentially important mechanisms have been identified as key players to generate epileptiform activity, such as genetic mutations, activity-dependent alteration of synaptic functions, and functional network reorganization at the macroscopic level. Here we study how network connectivity at cellular level can affect the onset of epileptiform activity, using computational model networks with different wiring properties. The model suggests that networks connected as in real brain circuits are more resistant to generate seizure-like activity. The results suggest new experimentally testable predictions on the cellular network connectivity in epileptic individuals, and highlight the importance of using the appropriate network connectivity to investigate epileptiform activity with computational models

Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia

© 2019 by The American Society of Hematology Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment

Non-invasive localization of atrial ectopic beats by using simulated body surface P-wave integral maps

Non-invasive localization of continuous atrial ectopic beats remains a cornerstone for the treatment of atrial arrhythmias. The lack of accurate tools to guide electrophysiologists leads to an increase in the recurrence rate of ablation procedures. Existing approaches are based on the analysis of the P-waves main characteristics and the forward body surface potential maps (BSPMs) or on the inverse estimation of the electric activity of the heart from those BSPMs. These methods have not provided an efficient and systematic tool to localize ectopic triggers. In this work, we propose the use of machine learning techniques to spatially cluster and classify ectopic atrial foci into clearly differentiated atrial regions by using the body surface P-wave integral map (BSPiM) as a biomarker. Our simulated results show that ectopic foci with similar BSPiM naturally cluster into differentiated non-intersected atrial regions and that new patterns could be correctly classified with an accuracy of 97% when considering 2 clusters and 96% for 4 clusters. Our results also suggest that an increase in the number of clusters is feasible at the cost of decreasing accuracy.This work was partially supported by The "Programa Prometeu" from Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana (www.edu.gva.es/fio/index_es.asp) Award Number: PROMETEU/2016/088 to JS; The "Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016" from the Ministerio de Economia, Industria y Competitividad of Spain, Agencia Estatal de Investigacion (www.mineco.gob.es) and the European Commission (European Regional Development Funds - ERDF -FEDER) (ec.europa.eu/regional_policy/es/funding/erdf/) Award Number: DPI2016-75799-R to JS and The "Programa Estatal de Investigacion, Desarrollo e Innovacion Orientado a los Retos de la Sociedad" from the Ministerio de Economia y Competitividad of Spain, Agencia Estatal de Investigacion (www.mineco.gob.es) and the European Commission (European Regional Development Funds - ERDF -FEDER) (ec.europa.eu/regional_policy/es/funding/erdf/) Award Number: TIN2014-59932-JIN to AFA and RS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ferrer Albero, A.; Godoy, EJ.; Lozano, M.; Martínez Mateu, L.; Alonso Atienza, F.; Saiz Rodríguez, FJ.; Sebastián Aguilar, R. (2017). Non-invasive localization of atrial ectopic beats by using simulated body surface P-wave integral maps. PLoS ONE. 12(7):1-23. https://doi.org/10.1371/journal.pone.0181263S12312

Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage

Graph-theoretical derivation of brain structural connectivity

Brain connectivity at the single neuron level can provide fundamental insights into how information is integrated and propagated within and between brain regions. However, it is almost impossible to adequately study this problem experimentally and, despite intense efforts in the field, no mathematical description has been obtained so far. Here, we present a mathematical framework based on a graph-theoretical approach that, starting from experimental data obtained from a few small subsets of neurons, can quantitatively explain and predict the corresponding full network properties. This model also changes the paradigm with which large-scale model networks can be built, from using probabilistic/empiric connections or limited data, to a process that can algorithmically generate neuronal networks connected as in the real system

On the structural connectivity of large-scale models of brain networks at cellular level

The brain’s structural connectivity plays a fundamental role in determining how neuron networks generate, process, and transfer information within and between brain regions. The underlying mechanisms are extremely difficult to study experimentally and, in many cases, large-scale model networks are of great help. However, the implementation of these models relies on experimental findings that are often sparse and limited. Their predicting power ultimately depends on how closely a model’s connectivity represents the real system. Here we argue that the data-driven probabilistic rules, widely used to build neuronal network models, may not be appropriate to represent the dynamics of the corresponding biological system. To solve this problem, we propose to use a new mathematical framework able to use sparse and limited experimental data to quantitatively reproduce the structural connectivity of biological brain networks at cellular level

The role of implantable cardiac monitors in atrial fibrillation management

Continuous heart rhythm monitoring using implantable cardiac monitors (ICMs) for atrial fibrillation (AF) management is steadily increasing in current clinical practice, even in the absence of an established indication provided by international guidelines. The increasing use of such devices is mainly associated with recent technological improvements including miniaturization, easier implant procedures, and remote monitoring, all of which make this strategy continuously more appealing and promising. For these and other reasons, ICMs have been proven to be a safe and highly effective tool for detecting AF episodes. However, ICMs are not the best option for every patient, as limitations exist. Therefore, it is imperative to weigh the possible benefits against the potential limitations of using these devices when deciding individualized patient care

Le récit de crime. Retour sur un séminaire universitaire en milieu carcéral. Giacopelli M., Charbonnier G. et Raoult S. (dir.)

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