Automated detection of QRS fragmentation in ECG and its application in Selvester Scoring System

This thesis was developed as part of a research visit to the University of Southampton in collaboration with expert cardiologists from Southampton Hospitals NHS Trust. This project describes an algorithmic procedure to detect and categorize fragmented QRS complexes (f-QRS) in 12 lead-electrocardiogram. In fact, the f-QRS is considered a biomarker of various heart diseases, such as myocardial ischemia and scar. The proposed algorithm of detecting f-QRS can then be applied in the development of an automated Selvester scoring system, which is used to localize and quantify the size of myocardial scar in the heart’s tissue. The latest refined version of the Selvester score is heavily based on the presence and categorization of f-QRS, which allows the discrimination among the various confounding condition considered, such as Left Bundle Brunch Block (LBBB), Right Bundle Branch Block (RBBB), Left Ventricular Hypertrophy (LVH) and Left Anterior Fascicular block (LAFB). An algorithm in Matlab was developed to detect and categorize the f-QRS into the three fragmentation categories, notching, slurring, slowing, using the Stationary Wavelet Transform (SWT). Following, the rules of the Selvester Scoring System were implemented as an extension to this algorithm resulting in a fully automated Selvester scoring technique. 12-lead standard electrocardiogram from 62 patients with confirmed myocardial scar was used, in order to test the f-QRS detection and the Selvester scores and compare the algortihm’s results with manual Selvester scoring results made by cardiologists

Alterations of lipid metabolism in chronic nephropathies: mechanisms, diagnosis and treatment.

Nephropathic subjects show an increased tendency to develop cardiovascular diseases, mainly as the consequence of several risk factors including increased oxidative stress, inflammation, physical inactivity, anemia, vascular calcification, and endothelial dysfunction. The alterations in lipid metabolism represent a relatively lesser important cause of genesis and progression of atherosclerosis. Unfortunately, in these patients the atherogenic potential of dyslipidemia may depend more on apolipoproteins than on lipid abnormalities, and may not always be recognized by measurement of plasma lipids alone. The aim of this review was therefore to analyze the main lipid alterations that can occur in nephropathic patients, as well as their causes and their effects on the cardiovascular system. The clinical evidence and recommendations for the use of lipid-regulating drugs in patients with chronic kidney disease, nephrotic syndrome, in patients undergoing hemo- and peritoneal dialysis and in transplanted patients was also reviewed. Moreover, we analyzed the link between dyslipidemia and kidney disease onset and progression and the role of statins in preventing it

Aerobic Microbial Inactivation Kinetics of Shrimp Using a Fixed Minimal Ozone Discharge: A Fact or Fib During Iced Storage?

AbstractAmong researchers worldwide, the combination of preservation methods aimed to achieve improved effects on microbial inactivation of seafood products is an area of research receiving increasing interest. Globally also, the demand for high quality minimally processed food products are on the increase. Ozone treatment, three decade – long declared 'Generally Recognized As Safe' and approved as food contact sanitizing agent has evolved up to recent times where it assumes the likes of domestic food-processing facilities manufactured with environment-friendly status ensuring consumer safety. On the other hand, the subject of inactivation kinetics of seafood microorganisms following ozone treatment is still under debate. Furthermore, kinetic models remain the economical and quick approach to predict the preservation parameters. Nevertheless, there is paucity of information regards aerobic microbial inactivation of crustacean product arising from fixed minimal ozone discharge. Is the phenomenon of aerobic microbial inactivation kinetics of shrimp product subject to a fixed minimal ozone discharge during iced storage a fact or fib? To answer this, the aerobic microbial inactivation kinetics of shrimp during iced storage of up to 11 days was inspected. The process conditions comprised of a fixed ozone concentration of 100mg/h minimally discharged at wash time of 1min as well as iced storage of up to 11 days. Minimal ozone treatment was applied either prior to or during iced storage situations. Aerobic microbial inactivation presented significant effects during iced storage (P<0.05). Line of fit that could best describe the aerobic microbial inactivation kinetics showed adequacy only at the fourth order of storage time 'x' variable, which could only but account for between 75 - 96% of explained variance. Overall, aerobic microbial inactivation kinetics of shrimp using a fixed minimal ozone discharge appears quantitatively possible even though it decreases as iced storage progresses

RR Lyrae mid-infrared Period-Luminosity-Metallicity and Period-Wesenheit-Metallicity relations based on Gaia DR3 parallaxes

We present new empirical infrared Period-Luminosity-Metallicity (PLZ) and Period-Wesenheit-Metallicity (PWZ) relations for RR Lyrae based on the latest Gaia EDR3 parallaxes. The relations are provided in the WISE $W1$ and $W2$ bands, as well as in the $W(W1, V - W1)$ and $W(W2, V - W2)$ Wesenheit magnitudes. The relations are calibrated using a very large sample of Galactic halo field RR Lyrae stars with homogeneous spectroscopic [Fe/H] abundances (over 1,000 stars in the $W1$ band), covering a broad range of metallicities ($-2.5 \lesssim \textrm{[Fe/H]} \lesssim 0.0$). We test the performance of our PLZ and PWZ relations by determining the distance moduli of both galactic and extragalactic stellar associations: the Sculptor dwarf spheroidal galaxy in the Local Group (finding $\bar{\mu}_{0}=19.47 \pm 0.06$), the Galactic globular clusters M4 ($\bar{\mu}_{0}=11.16 \pm 0.05$) and the Reticulum globular cluster in the Large Magellanic Cloud ($\bar{\mu}_{0}=18.23 \pm 0.06$). The distance moduli determined through all our relations are internally self-consistent (within $\lesssim$ 0.05 mag) but are systematically smaller (by $\sim$ 2-3$\sigma$) than previous literature measurements taken from a variety of methods/anchors. However, a comparison with similar recent RR Lyrae empirical relations anchored with EDR3 likewise shows to varying extents a systematically smaller distance modulus for PLZ/PWZ RR Lyrae relations.Comment: Accepted by ApJ, 14 pages, 5 Figures, 2 Table

Melanocortin-1 Receptor Positively Regulates Human Artery Endothelial Cell Migration.

Background/aims Melanocortin receptors (MCRs) belong to a hormonal signalling pathway with multiple homeostatic and protective actions. Microvascular and umbilical vein endothelial cells (ECs) express components of the melanocortin system, including the type 1 receptor (MC1R), playing a role in modulating inflammation and vascular tone. Since ECs exhibit a remarkable heterogeneity, we investigated whether human artery ECs express any functional MCR and whether its activation affects cell migration. Methods We used reverse transcription real-time PCR to examine the expression of melanocortin system components in primary human artery ECs. We assessed MC1R protein expression and activity by western blot, immunohistochemistry, cAMP production, and intracellular Ca²⁺ mobilization assays. We performed gap closure and scratch tests to examine cell migration after stimulation with alpha-melanocyte-stimulating hormone (α-MSH), the receptor highest-affinity natural ligand. We assessed differential time-dependent transcriptional changes in migrating cells by microarray analysis. Results We showed that human aortic ECs (HAoECs) express a functionally active MC1R. Unlike microvascular ECs, arterial cells did not express the α-MSH precursor proopiomelanocortin, nor produced the hormone. MC1R engagement with a single pulse of α-MSH accelerated HAoEC migration both in the directional migration assay and in the scratch wound healing test. This was associated with an enhancement in Ca²⁺ signalling and inhibition of cAMP elevation. Time-course genome-wide expression analysis in HAoECs undergoing directional migration allowed identifying dynamic co-regulation of genes involved in extracellular matrix-receptor interaction, vesicle-mediated trafficking, and metal sensing - which have all well-established influences on EC motility -, without affecting the balance between pro- and anticoagulant genes. Conclusion Our work broadens the knowledge on peripherally expressed MC1R. These results indicate that the receptor is constitutively expressed by arterial ECs and provide evidence of a novel homeostatic function for MC1R, whose activation may participate in preventing/healing endothelial dysfunction or denudation in macrovascular arteries

Alpha-synuclein/synapsin III pathological interplay boosts the motor response to methylphenidate

: Loss of dopaminergic nigrostriatal neurons and fibrillary α-synuclein (α-syn) aggregation in Lewy bodies (LB) characterize Parkinson's disease (PD). We recently found that Synapsin III (Syn III), a phosphoprotein regulating dopamine (DA) release with α-syn, is another key component of LB fibrils in the brain of PD patients and acts as a crucial mediator of α-syn aggregation and toxicity. Methylphenidate (MPH), a monoamine reuptake inhibitor (MRI) efficiently counteracting freezing of gait in advanced PD patients, can bind α-syn and controls α-syn-mediated DA overflow and presynaptic compartmentalization. Interestingly, MPH results also efficient for the treatment of attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental psychiatric syndrome associated with Syn III and α-syn polymorphisms and constituting a risk factor for the development of LB disorders. Here, we studied α-syn/Syn III co-deposition and longitudinal changes of α-syn, Syn III and DA transporter (DAT) striatal levels in nigrostriatal neurons of a PD model, the human C-terminally truncated (1-120) α-syn transgenic (SYN120 tg) mouse, in comparison with C57BL/6J wild type (wt) and C57BL/6JOlaHsd α-syn null littermates. Then, we analyzed the locomotor response of these animals to an acute administration of MPH (d-threo) and other MRIs: cocaine, that we previously found to stimulate Syn III-reliant DA release in the absence of α-syn, or the selective DAT blocker GBR-12935, along aging. Finally, we assessed whether these drugs modulate α-syn/Syn III interaction by fluorescence resonance energy transfer (FRET) and performed in silico studies engendering a heuristic model of the α-syn conformations stabilized upon MPH binding. We found that only MPH was able to over-stimulate a Syn III-dependent/DAT-independent locomotor activity in the aged SYN120 tg mice showing α-syn/Syn III co-aggregates. MPH enhanced full length (fl) α-syn/Syn III and even more (1-120) α-syn/Syn III interaction in cells exhibiting α-syn/Syn III inclusions. Moreover, in silico studies confirmed that MPH may reduce α-syn fibrillation by stabilizing a protein conformation with increased lipid binding predisposition. Our observations indicate that the motor-stimulating effect of MPH can be positively fostered in the presence of α-syn/Syn III co-aggregation. This evidence holds significant implications for PD and ADHD therapeutic management

Non-Small Cell Lung Cancer Harboring Concurrent EGFR Genomic Alterations: A Systematic Review and Critical Appraisal of the Double Dilemma

The molecular pathways which promote lung cancer cell features have been broadly explored, leading to significant improvement in prognostic and diagnostic strategies. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have dramatically altered the treatment approach for patients with metastatic non-small cell lung cancer (NSCLC). Latest investigations by using next-generation sequencing (NGS) have shown that other oncogenic driver mutations, believed mutually exclusive for decades, could coexist in EGFR-mutated NSCLC patients. However, the exact clinical and pathological role of concomitant genomic aberrations needs to be investigated. In this systematic review, we aimed to summarize the recent data on the oncogenic role of concurrent genomic alterations, by specifically evaluating the characteristics, the pathological significance, and their potential impact on the treatment approach

GOLIAH (Gaming Open Library for Intervention in Autism at Home): a 6-month single blind matched controlled exploratory study

BackgroundTo meet the required hours of intensive intervention for treating children with autism spectrum disorder (ASD), we developed an automated serious gaming platform (11 games) to deliver intervention at home (GOLIAH) by mapping the imitation and joint attention (JA) subset of age-adapted stimuli from the Early Start Denver Model (ESDM) intervention. Here, we report the results of a 6-month matched controlled exploratory study.MethodsFrom two specialized clinics, we included 14 children (age range 5–8 years) with ASD and 10 controls matched for gender, age, sites, and treatment as usual (TAU). Participants from the experimental group received in addition to TAU four 30-min sessions with GOLIAH per week at home and one at hospital for 6 months. Statistics were performed using Linear Mixed Models.ResultsChildren and parents participated in 40% of the planned sessions. They were able to use the 11 games, and participants trained with GOLIAH improved time to perform the task in most JA games and imitation scores in most imitation games. GOLIAH intervention did not affect Parental Stress Index scores. At end-point, we found in both groups a significant improvement for Autism Diagnostic Observation Schedule scores, Vineland socialization score, Parental Stress Index total score, and Child Behavior Checklist internalizing, externalizing and total problems. However, we found no significant change for by time × group interaction.ConclusionsDespite the lack of superiority of TAU + GOLIAH versus TAU, the results are interesting both in terms of changes by using the gaming platform and lack of parental stress increase. A large randomized controlled trial with younger participants (who are the core target of ESDM model) is now discussed. This should be facilitated by computing GOLIAH for a web platform.Trial registration Clinicaltrials.gov NCT0256041

Prevalence and Spectrum of Germline BRCA1 and BRCA2 Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome

About 10–20% of breast/ovarian (BC/OC) cancer patients undergoing germline BRCA1/2 genetic testing have been shown to harbor Variants of Uncertain Significance (VUSs). Since little is known about the prevalence of germline BRCA1/2 VUS in Southern Italy, our study aimed at describing the spectrum of these variants detected in BC/OC patients in order to improve the identification of potentially high-risk BRCA variants helpful in patient clinical management. Eight hundred and seventy-four BC or OC patients, enrolled from October 2016 to December 2020 at the “Sicilian Regional Center for the Prevention, Diagnosis and Treatment of Rare and Heredo-Familial Tumors” of University Hospital Policlinico “P. Giaccone” of Palermo, were genetically tested for germline BRCA1/2 variants through Next-Generation Sequencing analysis. The mutational screening showed that 639 (73.1%) out of 874 patients were BRCA-w.t., whereas 67 (7.7%) were carriers of germline BRCA1/2 VUSs, and 168 (19.2%) harbored germline BRCA1/2 pathogenic/likely pathogenic variants. Our analysis revealed the presence of 59 different VUSs detected in 67 patients, 46 of which were affected by BC and 21 by OC. Twenty-one (35.6%) out of 59 variants were located on BRCA1 gene, whereas 38 (64.4%) on BRCA2. We detected six alterations in BRCA1 and two in BRCA2 with unclear interpretation of clinical significance. Familial anamnesis of a patient harboring the BRCA1-c.3367G&gt;T suggests for this variant a potential of pathogenicity, therefore it should be carefully investigated. Understanding clinical significance of germline BRCA1/2 VUS could improve, in future, the identification of potentially high-risk variants useful for clinical management of BC or OC patients and family members

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns