Paolo Melillo

Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2.

OBJECTIVE The aim of this study was to show the clinical data of long-term (3-year) follow-up of 5 patients affected by Leber congenital amaurosis type 2 (LCA2) treated with a single unilateral injection of adeno-associated virus AAV2-hRPE65v2. DESIGN Clinical trial. PARTICIPANTS Five LCA2 patients with RPE65 gene mutations. METHODS After informed consent and confirmation of trial eligibility criteria, the eye with worse visual function was selected for subretinal delivery of adeno-associated virus (AAV2-hRPE65v2). Subjects were evaluated before and after surgery at designated follow-up visits (1, 2, 3, 14, 30, 60, 90, 180, 270, and 365 days, 1.5 years, and 3 years) by complete ophthalmic examination. Efficacy for each subject was monitored with best-corrected visual acuity, kinetic visual field, nystagmus testing, and pupillary light reflex. MAIN OUTCOME MEASURES Best-corrected visual acuity, kinetic visual field, nystagmus testing, and pupillary light reflex. RESULTS The data showed a statistically significant improvement of best-corrected visual acuity between baseline and 3 years after treatment in the treated eye (P<0.001). In all patients, an enlargement of the area of visual field was observed that remained stable until 3 years after injection (average values: baseline, 1058 deg(2) vs. 3 years after treatment, 4630 deg(2)) and a reduction of the nystagmus frequency compared with baseline at the 3-year time point. Furthermore, a statistically significant difference was observed in the pupillary constriction of the treated eye (P<0.05) compared with the untreated eye in 3 patients at 1- and 3-year time points. No patients experienced serious adverse events related to the vector in the 3-year postinjection period. CONCLUSIONS The long-term follow-up data (3 years) on the 5-patient Italian cohort involved in the LCA2 gene therapy clinical trial clearly showed a stability of improvement in visual and retinal function that had been achieved a few months after treatment. Longitudinal data analysis showed that the maximum improvement was achieved within 6 months after treatment, and the visual improvement was stable up to the last observed time point. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Nonlinear heart rate variability features for real-life stress detection. Case study : students under stress due to university examination

BackgroundThis study investigates the variations of Heart Rate Variability (HRV) due to a real-life stressor and proposes a classifier based on nonlinear features of HRV for automatic stress detection.Methods42 students volunteered to participate to the study about HRV and stress. For each student, two recordings were performed: one during an on-going university examination, assumed as a real-life stressor, and one after holidays. Nonlinear analysis of HRV was performed by using Poincaré Plot, Approximate Entropy, Correlation dimension, Detrended Fluctuation Analysis, Recurrence Plot. For statistical comparison, we adopted the Wilcoxon Signed Rank test and for development of a classifier we adopted the Linear Discriminant Analysis (LDA).ResultsAlmost all HRV features measuring heart rate complexity were significantly decreased in the stress session. LDA generated a simple classifier based on the two Poincaré Plot parameters and Approximate Entropy, which enables stress detection with a total classification accuracy, a sensitivity and a specificity rate of 90%, 86%, and 95% respectively.ConclusionsThe results of the current study suggest that nonlinear HRV analysis using short term ECG recording could be effective in automatically detecting real-life stress condition, such as a university examination.

Which is the best laparoscopic approach for inguinal hernia repair : TEP or TAPP? A systematic review of the literature with a network meta-analysis

BackgroundTotally extraperitoneal (TEP) repair and transabdominal preperitoneal (TAPP) repair are the most used laparoscopic techniques for inguinal hernia treatment. However, many studies have shown that laparoscopic hernia repair compared with open hernia repair (OHR) may offer less pain and shorter convalescence. Few studies compared the clinical efficacy between TEP and TAPP technique. The purpose of this study is to provide a comparison between TEP and TAPP for inguinal hernia repair to show the best approach.MethodsWe performed an indirect comparison between TEP and TAPP techniques by considering only randomized, controlled trials comparing TEP with OHR and TAPP with OHR in a network meta-analysis. We considered the following outcomes: operative time, postoperative complications, hospital stay, postoperative pain, time to return to work, and recurrences.ResultsThe two techniques improved some short outcomes (such as time to return to work) with respect to OHR. In the network meta-analysis, TEP and TAPP were equivalent for operative time, postoperative complications, postoperative pain, time to return to work, and recurrences, whereas TAPP was associated with a slightly longer hospital stay compared with TEP.ConclusionsTEP and TAPP improved clinical outcomes compared with OHR, but the network meta-analysis showed that TEP and TAPP efficacy is equivalent. TAPP was associated with a slightly longer hospital stay compared with TEP.

Remote Health Monitoring of Heart Failure With Data Mining via CART Method on HRV Features

Disease management programs, which use no advanced information and computer technology, are as effective as telemedicine but more efficient because less costly. We proposed a platform to enhance effectiveness and efficiency of home monitoring using data mining for early detection of any worsening in patients condition. These worsenings could require more complex and expensive care if not recognized. In this letter, we briefly describe the remote health monitoring platform we designed and realized, which supports heart failure (HF) severity assessment offering functions of data mining based on the classification and regression tree method. The system developed achieved accuracy and a precision of 96.39% and 100.00% in detecting HF and of 79.31% and 82.35% in distinguishing severe versus mild HF, respectively. These preliminary results were achieved on public databases of signals to improve their reproducibility. Clinical trials involving local patients are still running and will require longer experimentation.

Discrimination Power of Short-Term Heart Rate Variability Measures for CHF Assessment

In this study, we investigated the discrimination power of short-term heart rate variability (HRV) for discriminating normal subjects versus chronic heart failure (CHF) patients. We analyzed 1914.40 h of ECG of 83 patients of which 54 are normal and 29 are suffering from CHF with New York Heart Association (NYHA) classification I, II, and III, extracted by public databases. Following guidelines, we performed time and frequency analysis in order to measure HRV features. To assess the discrimination power of HRV features, we designed a classifier based on the classification and regression tree (CART) method, which is a nonparametric statistical technique, strongly effective on nonnormal medical data mining. The best subset of features for subject classification includes square root of the mean of the sum of the squares of differences between adjacent NN intervals (RMSSD), total power, high-frequencies power, and the ratio between low- and high-frequencies power (LF/HF). The classifier we developed achieved sensitivity and specificity values of 79.3% and 100 %, respectively. Moreover, we demonstrated that it is possible to achieve sensitivity and specificity of 89.7% and 100 %, respectively, by introducing two nonstandard features ΔAVNN and ΔLF/HF, which account, respectively, for variation over the 24 h of the average of consecutive normal intervals (AVNN) and LF/HF. Our results are comparable with other similar studies, but the method we used is particularly valuable because it allows a fully human-understandable description of classification procedures, in terms of intelligible “if ... then ...” rules.

Classification Tree for Risk Assessment in Patients Suffering From Congestive Heart Failure via Long-Term Heart Rate Variability

This study aims to develop an automatic classifier for risk assessment in patients suffering from congestive heart failure (CHF). The proposed classifier separates lower risk patients from higher risk ones, using standard long-term heart rate variability (HRV) measures. Patients are labeled as lower or higher risk according to the New York Heart Association classification (NYHA). A retrospective analysis on two public Holter databases was performed, analyzing the data of 12 patients suffering from mild CHF (NYHA I and II), labeled as lower risk, and 32 suffering from severe CHF (NYHA III and IV), labeled as higher risk. Only patients with a fraction of total heartbeats intervals (RR) classified as normal-to-normal (NN) intervals (NN/RR) higher than 80% were selected as eligible in order to have a satisfactory signal quality. Classification and regression tree (CART) was employed to develop the classifiers. A total of 30 higher risk and 11 lower risk patients were included in the analysis. The proposed classification trees achieved a sensitivity and a specificity rate of 93.3% and 63.6%, respectively, in identifying higher risk patients. Finally, the rules obtained by CART are comprehensible and consistent with the consensus showed by previous studies that depressed HRV is a useful tool for risk assessment in patients suffering from CHF.

Acute mental stress assessment via short term HRV analysis in healthy adults: A systematic review with meta-analysis

Mental stress reduces performances, on the work place and in daily life, and is one of the first causes of cognitive dysfunctions, cardiovascular disorders and depression. This study systematically reviewed existing literature investigating, in healthy subjects, the associations between acute mental stress and short term Heart Rate Variability (HRV) measures in time, frequency and non-linear domain. The goal of this study was to provide reliable information about the trends and the pivot values of HRV measures during mental stress. A systematic review and meta-analysis of the evidence was conducted, performing an exhaustive research of electronic repositories and linear researching references of papers responding to the inclusion criteria. After removing duplicates and not pertinent papers, journal papers describing well-designed studies that analyzed rigorously HRV were included if analyzed the same population of healthy subjects at rest and during mental stress. 12 papers were shortlisted, enrolling overall 758 volunteers and investigating 22 different HRV measures, 9 of which reported by at least 2 studies and therefore meta-analyzed in this review. Four measures in time and non-linear domains, associated with a normal degree of HRV variations resulted significantly depressed during stress. The power of HRV fluctuations at high frequencies was significantly depressed during stress, while the ratio between low and high frequency resulted significantly increased, suggesting a sympathetic activation and a parasympathetic withdrawal during acute mental stress. Finally, among the 15 non-linear measures extracted, only 2 were reported by at least 2 studies, therefore pooled, and only one resulted significantly depressed, suggesting a reduced chaotic behaviour during mental stress. HRV resulted significantly depressed during mental stress, showing a reduced variability and less chaotic behaviour. The pooled frequency domain measures demonstrated a significant autonomic balance shift during acute mental stress towards the sympathetic activation and the parasympathetic withdrawal. Pivot values for the pooled mean differences of HRV measures are provided. Further studies investigating HRV non-linear measures during mental stress are still required. However, the method proposed to transform and then meta-analyze the HRV measures can be applied to other fields where HRV proved to be clinically significant.

Automatic prediction of cardiovascular and cerebrovascular events using heart rate variability analysis.

Background There is consensus that Heart Rate Variability is associated with the risk of vascular events. However, Heart Rate Variability predictive value for vascular events is not completely clear. The aim of this study is to develop novel predictive models based on data-mining algorithms to provide an automatic risk stratification tool for hypertensive patients. Methods A database of 139 Holter recordings with clinical data of hypertensive patients followed up for at least 12 months were collected ad hoc. Subjects who experienced a vascular event (i.e., myocardial infarction, stroke, syncopal event) were considered as high-risk subjects. Several data-mining algorithms (such as support vector machine, tree-based classifier, artificial neural network) were used to develop automatic classifiers and their accuracy was tested by assessing the receiver-operator characteristics curve. Moreover, we tested the echographic parameters, which have been showed as powerful predictors of future vascular events. Results The best predictive model was based on random forest and enabled to identify high-risk hypertensive patients with sensitivity and specificity rates of 71.4% and 87.8%, respectively. The Heart Rate Variability based classifier showed higher predictive values than the conventional echographic parameters, which are considered as significant cardiovascular risk factors. Conclusions Combination of Heart Rate Variability measures, analyzed with data-mining algorithm, could be a reliable tool for identifying hypertensive patients at high risk to develop future vascular events.

Heart rate variability and target organ damage in hypertensive patients

BackgroundWe evaluated the association between linear standard Heart Rate Variability (HRV) measures and vascular, renal and cardiac target organ damage (TOD).MethodsA retrospective analysis was performed including 200 patients registered in the Regione Campania network (aged 62.4 ± 12, male 64%). HRV analysis was performed by 24-h holter ECG. Renal damage was assessed by estimated glomerular filtration rate (eGFR), vascular damage by carotid intima-media thickness (IMT), and cardiac damage by left ventricular mass index.ResultsSignificantly lower values of the ratio of low to high frequency power (LF/HF) were found in the patients with moderate or severe eGFR (p-value < 0.001). Similarly, depressed values of indexes of the overall autonomic modulation on heart were found in patients with plaque compared to those with a normal IMT (p-value <0.05). These associations remained significant after adjustment for other factors known to contribute to the development of target organ damage, such as age. Moreover, depressed LF/HF was found also in patients with left ventricular hypertrophy but this association was not significant after adjustment for other factors.ConclusionsDepressed HRV appeared to be associated with vascular and renal TOD, suggesting the involvement of autonomic imbalance in the TOD. However, as the mechanisms by which abnormal autonomic balance may lead to TOD, and, particularly, to renal organ damage are not clearly known, further prospective studies with longitudinal design are needed to determine the association between HRV and the development of TOD.

Macular Function and Morphologic Features in Juvenile Stargardt Disease: Longitudinal Study

PURPOSE To evaluate disease progression in a cohort of patients with a clinical and genetic diagnosis of Stargardt disease. DESIGN Longitudinal cohort study. PARTICIPANTS A total of 56 selected patients with a clinical and molecular diagnosis of Stargardt disease, an early age of onset, and a median follow-up length of 2 years. METHODS Patients underwent routine examination, including full-field electroretinography, microperimetry, and optical coherence tomography. MAIN OUTCOME MEASURES Best-corrected visual acuity (BCVA), mean retinal sensitivity, fixation stability, preferred retinal locus, inner segment/outer segment (IS/OS) junction loss, and atrophic lesion area. RESULTS A total of 56 patients with a mean age at disease onset of 15.3 years (range, 3-28 years), a mean disease duration of 12.1 years, and a mean age at baseline of 27.4 years were analyzed. The median BCVA was 20/200 in both eyes. Optical coherence tomography parameters (IS/OS alteration and retinal pigment epithelium lesion area) were obtained in only 49 patients because the signal quality was poor in the remaining 7 patients. Optical coherence tomography revealed a mean retinal pigment epithelium lesion area of 2.6 mm(2), preserved foveal IS/OS in 4.1% of patients, loss of foveal IS/OS in 59.2% of patients, and extensive loss of macular IS/OS in 36.7% of patients. Microperimetric findings showed a reduced macular sensitivity (mean, 10 decibels [dB]) and an unstable fixation in half of the patient cohort. The longitudinal analysis showed a significant progressive reduction of BCVA and macular sensitivity (at an estimated rate of 0.04 decimals and 1.19 dB/year, respectively) associated with a significant enlargement of retinal pigment epithelium lesion area (0.282 mm(2)/year). No significant changes in ophthalmoscopic findings and electroretinographic responses were detected. CONCLUSIONS This study highlights the importance of microperimetry and optical coherence tomography in monitoring patients with Stargardt disease. Quantifying the decline of visual functionality and detecting morphologic macular changes prove useful in evaluating disease progression over a short-term follow-up and should be taken into account for the design of future clinical trials of gene therapy to treat retinal dystrophy.