Systematic in-silico evaluation of fibrosis effects on re-entrant wave dynamics in atrial tissue.

Despite the key role of fibrosis in atrial fibrillation (AF), the effects of different spatial distributions and textures of fibrosis on wave propagation mechanisms in AF are not fully understood. To clarify these aspects, we performed a systematic computational study to assess fibrosis effects on the characteristics and stability of re-entrant waves in electrically-remodelled atrial tissues. A stochastic algorithm, which generated fibrotic distributions with controlled overall amount, average size, and orientation of fibrosis elements, was implemented on a monolayer spheric atrial model. 245 simulations were run at changing fibrosis parameters. The emerging propagation patterns were quantified in terms of rate, regularity, and coupling by frequency-domain analysis of correspondent synthetic bipolar electrograms. At the increase of fibrosis amount, the rate of reentrant waves significantly decreased and higher levels of regularity and coupling were observed (p < 0.0001). Higher spatial variability and pattern stochasticity over repetitions was observed for larger amount of fibrosis, especially in the presence of patchy and compact fibrosis. Overall, propagation slowing and organization led to higher stability of re-entrant waves. These results strengthen the evidence that the amount and spatial distribution of fibrosis concur in dictating re-entry dynamics in remodeled tissue and represent key factors in AF maintenance.

Long-term maintenance treatment of rosacea: experts' opinion.

BACKGROUND: Rosacea is a chronic inflammatory dermatosis characterized by remissions and flares. Although the rosacea active treatment phase is well established, the long-term maintenance phase is still challenging. OBJECTIVE: To discuss and make recommendations on how to treat patients during the long-term maintenance phase for the main rosacea phenotypes. METHODS: A panel of six board-certified Brazilian dermatologists and one American dermatologist gathered to compose a consensus based upon an initial statement on how to treat rosacea during the long-term maintenance phase based on the methodology Nominal Group Technique. The experts discussed each factor based upon an initial statement on how to treat rosacea patients in the long-term maintenance phase. A sequence of comprehensive narrative reviews was performed; a questionnaire preparation about the definition of the maintenance phase and its management was presented; an interpersonal discussion and ranking of the ideas were conducted. Recommendations were made if the specialists had 75% agreement. RESULTS: The maintenance treatment phase, which starts by achieving IGA 0 or 1 grades at the active phase, should be considered at least during the 9-month period after remission. The recommendations of all treatments target this period. Daily skincare regimen and sunscreen are crucial. Active treatment phase should be recommended if signs or symptoms reappear or worsen. CONCLUSION: Maintenance phase success depends on patient's adherence to daily skin care, appropriate treatments, continued follow-up with dermatologist, and self-assessment to identify new signs and symptoms indicating disease relapse.

Quantitative assessment of transmural fibrosis profile in the human atrium: evidence for a three-dimensional arrhythmic substrate by slice-to-slice histology.

AIMS: Intramural fibrosis represents a crucial factor in the formation of a three-dimensional (3D) substrate for atrial fibrillation (AF). However, the transmural distribution of fibrosis and its relationship with atrial overload remain largely unknown. The aim of this study is to quantify the transmural profile of atrial fibrosis in patients with different degrees of atrial dilatation and arrhythmic profiles by a high-resolution 3D histology method. METHODS AND RESULTS: Serial microtome-cut tissue slices, sampling the entire atrial wall thickness at 5 µm spatial resolution, were obtained from right atrial appendage specimens in 23 cardiac surgery patients. Atrial slices were picrosirius red stained, imaged by polarized light microscopy, and analysed by a custom-made segmentation algorithm. In all patients, the intramural fibrosis content displayed a progressive decrease alongside tissue depth, passing from 68.6 ± 11.6% in the subepicardium to 10-13% in the subendocardium. Distinct transmural fibrotic profiles were observed in patients with atrial dilatation with respect to control patients, where the first showed a slower decrease of fibrosis along tissue depth (exponential decay constant: 171.2 ± 54.5 vs. 80.9 ± 24.4 µm, P < 0.005). Similar slow fibrotic profiles were observed in patients with AF (142.8 ± 41.7 µm). Subepicardial and midwall levels of fibrosis correlated with the degree of atrial dilatation (ρ = 0.72, P < 0.001), while no correlation was found in subendocardial layers. CONCLUSIONS: Quantification of fibrosis transmural profile at high resolution is feasible by slice-to-slice histology. Deeper penetration of fibrosis in subepicardial and midwall layers in dilated atria may concur to the formation of a 3D arrhythmic substrate.

Unsupervised Classification of Atrial Electrograms for Electroanatomic Mapping of Human Persistent Atrial Fibrillation.

OBJECTIVE: Ablation treatment for persistent atrial fibrillation (persAF) remains challenging due to the absence of a 'ground truth' for atrial substrate characterization and the presence of multiple mechanisms driving the arrhythmia. We implemented an unsupervised classification to identify clusters of atrial electrograms (AEGs) with similar patterns, which were then validated by AEG-derived markers. METHODS: 956 bipolar AEGs were collected from 11 persAF patients. CARTO variables (Biosense Webster; ICL, ACI and SCI) were used to create a 3D space, and subsequently used to perform an unsupervised classification with k-means. The characteristics of the identified groups were investigated using nine AEG-derived markers: sample entropy (SampEn), dominant frequency, organization index (OI), determinism, laminarity, recurrence rate (RR), peak-to-peak (PP) amplitude, cycle length (CL), and wave similarity (WS). RESULTS: Five AEG classes with distinct characteristics were identified (F = 582, P<0.0001). The presence of fractionation increased from class 1 to 5, as reflected by the nine markers. Class 1 (25%) included organized AEGs with high WS, determinism, laminarity, and RR, and low SampEn. Class 5 (20%) comprised fractionated AEGs with in low WS, OI, determinism, laminarity, and RR, and in high SampEn. Classes 2 (12%), 3 (13%) and 4 (30%) suggested different degrees of AEG organization. CONCLUSIONS: Our results expand and reinterpret the criteria used for automated AEG classification. The nine markers highlighted electrophysiological differences among the five classes found by the k-means, which could provide a more complete characterization of persAF substrate during ablation target identification in future clinical studies.

A Divergence-Based Approach for the Identification of Atrial Fibrillation Focal Drivers From Multipolar Mapping: A Computational Study.

The expanding role of catheter ablation of atrial fibrillation (AF) has stimulated the development of novel mapping strategies to guide the procedure. We introduce a novel approach to characterize wave propagation and identify AF focal drivers from multipolar mapping data. The method reconstructs continuous activation patterns in the mapping area by a radial basis function (RBF) interpolation of multisite activation time series. Velocity vector fields are analytically determined, and the vector field divergence is used as a marker of focal drivers. The method was validated in a tissue patch cellular automaton model and in an anatomically realistic left atrial (LA) model with Courtemanche-Ramirez-Nattel ionic dynamics. Divergence analysis was effective in identifying focal drivers in a complex simulated AF pattern. Localization was reliable even with consistent reduction (47%) in the number of mapping points and in the presence of activation time misdetections (noise <10% of the cycle length). Proof-of-concept application of the method to human AF mapping data showed that divergence analysis consistently detected focal activation in the pulmonary veins and LA appendage area. These results suggest the potential of divergence analysis in combination with multipolar mapping to identify AF critical sites. Further studies on large clinical datasets may help to assess the clinical feasibility and benefit of divergence analysis for the optimization of ablation treatment.

MicroRNAs: New contributors to mechano-electric coupling and atrial fibrillation.

Atrial fibrillation (AF) is a multifactorial disease, which often occurs in the presence of underlying cardiac abnormalities and is supported by electrophysiological and structural alterations, generally referred to as atrial remodeling. Abnormal substrates are commonly encountered in various conditions that predispose to AF, such as hypertension, heart failure, obesity, and sleep apnea, in which atrial stretch plays a key mechanistic role. Emerging evidence suggests a role for microRNAs (small non-coding RNAs) in the pathogenesis of AF, where they can act as post-transcriptional regulators of the genes involved in atrial remodeling. This review summarizes the experimental and clinical evidence that supports the role of microRNAs in the modulation of atrial electrical and structural remodeling with a focus on overload-induced atrial alterations, and discusses the potential contribution of microRNAs to mechano-electrical coupling and AF.

Águas termais: da balneoterapia à genômica / Thermal spring waters: From balneotherapy to genomics

O presente artigo de revisão relata os dados científicos disponíveis sobre a água termal La Roche-Posay e esclarece seus mecanismos de ação, suas indicações e seus benefícios clínicos. Além disso, estudos clínicos e avaliação genômica do microbioma da pele demonstraram que esta água termal melhora a diversidade do microbioma da pele e reduz a gravidade das lesões cutâneas em dermatoses inflamatórias, tais como dermatite atópica e psoríase. Justifica-se, portanto, o uso de água rica em selênio em formulações tópicas na prevenção ou tratamento de doenças de pele e como coadjuvante para aumentar a qualidade de vida dos pacientes dermatológicos.

This review article reports the scientific data available on La Roche-Posay thermal water and clarifies its mechanisms of action, indications, and clinical benefits. Clinical studies and genomic evaluation of the skin microbiome have shown that La Roche-Posay thermal water improves the skin microbiome's diversity and reduces the severity of skin lesions in inflammatory dermatoses, such as atopic dermatitis and psoriasis. Therefore, it justifies the use of selenium-rich water in topical formulations to prevent or treat skin diseases and as an adjunct to increase dermatological patients' quality of life

Assessment of prurigo of pregnancy in patients without atopic background.

BACKGROUND: Prurigo of pregnancy (PP), a specific pregnancy dermatosis, has been associated with atopic background in the patient and/or the patient's family. However, this association was not validated in some studies, and cases without atopic background have been reported. OBJECTIVE: This study aimed to evaluate the clinical features of PP not related to atopic background and search for comorbid conditions in medical and obstetric records. METHODS: In this case series, patients with typical PP presentation (i.e., pruritic, discrete papulonodules on the extensor surfaces of the extremities) diagnosed at the dermatology clinics of tertiary referral hospitals were evaluated. The exclusion criteria included missing historical data, inadequate follow-up, laboratory test results suggestive of other pruritic conditions, history of atopic disease, and family history of atopy. Clinical and laboratory data including course, response to treatment, serum total immunoglobulin E level, and comorbidities in the medical and obstetric history were collected. RESULTS: Twenty patients developed PP predominantly during the late second or early third trimester. Nine patients reported that itching developed first, versus 10 patients who reported that lesions started first (one patient was uncertain about onset). There was no recurrence postpartum (mean postpartum follow-up, 17 months). Serum total immunoglobulin E level was elevated in 3 of 14 patients tested (21.4%). Obstetric history (n = 12) included polymorphic eruption of pregnancy (16.6%), PP (16.6%), and gestational pruritus (8.3%). Two of 20 patients (10%) had a history of pruritic skin condition (prurigo nodularis and pruritus of unclear etiology) while not pregnant. Medical history (n = 20) included psychiatric disease (20%) (obsessive compulsive disorder and anxiety), hypothyroidism (10%), and obesity (10%). CONCLUSION: PP can develop in patients without an atopic background. This finding should be considered when classifying specific pregnancy dermatoses. A thorough medical and family history with a focus on atopy should be obtained from every patient with a gestational eruption, and patients should be counseled accordingly.

Declining clinical benefit of ICD in heart failure patients: Temporal trend of mortality outcomes from randomized controlled trials.

BACKGROUND: The risk of sudden cardiac death in patients with heart failure has declined over time thanks to the sequential introduction of new treatments. However, current guidelines recommendations for implantable cardioverter-defibrillator (ICD) are based on randomized controlled trials (RCTs) carried out in the past three decades and their meta-analyses. To highlight potential changes over time in ICD clinical benefit in primary prevention of sudden cardiac death, we analyzed the temporal trends of RCT risk of mortality outcomes in this time frame. METHODS: By searching MEDLINE and the Cochrane Library electronic databases we identified seven RCTs (6095 patients enrolled between 1990 and 2014) on ICD versus contemporary standard medical therapy for sudden cardiac death prevention, in patients with chronic heart failure of ischemic and non-ischemic origin and reduced ejection fraction. Linear regression analysis was applied to identify the association between RCT mortality outcomes and time. RESULTS: Ordered according to the start of randomization, the trials showed a statistically significant (p=0.03) progressive decline in the baseline annualized event rate of sudden cardiac death in RCT control arms, and a significant (p=0.04) increase in the number of patients unresponsive to ICD treatment (i.e. patients experiencing sudden cardiac death in ICD arms). These two factors synergistically contributed to a significant (p<0.01) and progressive reduction in the clinical benefit of ICD, assessed by the number needed to treat for total mortality at 3 years. CONCLUSIONS: The clinical benefit of ICD, implanted according to the current guidelines, has significantly and progressively declined over time due to the reduction in sudden cardiac death risk and to the increase of ICD unresponsive patients.

Implementation and validation of real-time algorithms for atrial fibrillation detection on a wearable ECG device.

BACKGROUND: Due to the growing epidemic of atrial fibrillation (AF), new strategies for AF screening, diagnosis, and monitoring are required. Wearable devices with on-board AF detection algorithms may improve early diagnosis and therapy outcomes. In this work, we implemented optimized algorithms for AF detection on a wearable ECG monitoring device and assessed their performance. METHODS: The signal processing framework was composed of two main modules: 1) a QRS detector based on a finite state machine, and 2) an AF detector based on the Shannon entropy of the symbolic word series obtained from the instantaneous heart rate. The AF detector was optimized off-line by tuning its parameters to reduce the computational burden while preserving detection accuracy. On-board performance was assessed in terms of detection accuracy, memory usage, and computation time. RESULTS: The on-board implementation of the QRS detector produced an overall accuracy of 99% on the MIT-BIH Arrhythmia Database, with memory usage = 672 bytes, and computation time ≤90 µs. The on-board implementation of the optimized AF algorithm gave an overall accuracy of 98.1% (versus 98.3% of the original version) on the MIT-BIH AF Database, with increased sensitivity (99.2% versus 98.5%) and decreased specificity (97.3% versus 98.2%), memory usage = 4648 bytes, and computation time ≤ 75 µs (consistent with real-time detection). CONCLUSIONS: This study demonstrated the feasibility of real-time AF detection on a wearable ECG device. It constitutes a promising step towards the development of novel ECG monitoring systems to tackle the growing AF epidemic.

Assessing the accuracy of computer-planned osteotomy guided by stereolithographic template: A methodological framework applied to the mandibular bone harvesting.

Intraoral autologous bone grafting represents a preferential choice for alveolar reconstruction prior to dental implant placement. Bone block harvesting guided by a computer-planned lithographic template is a novel and promising technique for optimizing the volume of harvested material, while controlling the osteotomy 3D position with respect to delicate anatomical structures. We provide a quantitative framework to non-invasively estimate the accuracy of this technique. In the proposed framework, the planned osteotomy geometry was compared to the real outcome of the procedure, obtained by segmentation of post-procedural cone beam computed tomography data. The comparison required the rigid registration between pre and post-procedural mandibular models, which was automatically accomplished by minimizing the sum of squared distances via a stochastic multi-trial iterative closest point algorithm. Bone harvesting accuracy was quantified by calculating a set of angular and displacement errors between the planned and real planes which characterized the excision block. The application of the framework to four cases showed its capability to quantify the tolerance associated with computer-guided bone harvesting techniques with submillimetric accuracy (<0.4 mm), within the limits of native image resolution. The validation methodology proved suitable for defining the safety margins of osteotomy surgical planning.

Upregulation of miR-133b and miR-328 in Patients With Atrial Dilatation: Implications for Stretch-Induced Atrial Fibrillation.

Atrial stretch and dilatation are common features of many clinical conditions predisposing to atrial fibrillation (AF). MicroRNAs (miRs) are emerging as potential molecular determinants of AF, but their relationship with atrial dilatation (AD) is poorly understood. The present study was designed to assess the specific miR expression profiles associated with AD in human atrial tissue. The expressions of a preselected panel of miRs, previously described as playing a role in cardiac disease, were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in atrial tissue samples from 30 cardiac surgery patients, who were characterized by different grades of AD and arrhythmic profiles. Our results showed that AD per se was associated with significant up-regulation of miR-328-3p and miR-133b (p < 0.05) with respect to controls, with a fold-change of 1.53 and 1.74, respectively. In a multivariate model including AD and AF as independent variables, miR-328-3p expression was mainly associated with AD grade (p < 0.05), while miR-133b was related to both AD (p < 0.005) and AF (p < 0.05), the two factors exerting opposite modulation effects. The presence of AF was associated with significant (p < 0.05) up-regulation of the expression level of miR-1-3p, miR-21-5p, miR-29a-3p, miR-208b-3p, and miR-590-5p. These results showed the existence of specific alterations of miR expression associated with AD, which may pave the way to future experimental studies to test the involvement of post-transcriptional mechanisms in the stretch-induced formation of a pro-arrhythmic substrate.