A new targeted CFTR mutation panel based on next-generation sequencing technology

Searching for mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) is a key step in the diagnosis of and neonatal and carrier screening for cystic fibrosis (CF), and it has implications for prognosis and personalized therapy. The large number of mutations and genetic and phenotypic variability make this search a complex task. Herein, we developed, validated, and tested a laboratory assay for an extended search for mutations in CFTR using a next-generation sequencing based method, with a panel of 188 CFTR mutations customized for the Italian population. Overall, 1426 dried blood spots from neonatal screening, 402 genomic DNA samples from various origins, and 1138 genomic DNA samples from patients with CF were analyzed. The assay showed excellent analytical and diagnostic operative characteristics. We identified and experimentally validated 159 (of 188) CFTR mutations. The assay achieved detection rates of 95.0% and 95.6% in two large-scale case series of CF patients from central and northern Italy, respectively. These detection rates are among the highest reported so far with a genetic test for CF based on a mutation panel. This assay appears to be well suited for diagnostics, neonatal and carrier screening, and assisted reproduction, and it represents a considerable advantage in CF genetic counseling

Diagnosis of prostate cancer with magnetic resonance imaging in men treated with 5-alpha-reductase inhibitors

Purpose The primary aim of this study was to evaluate if exposure to 5-alpha-reductase inhibitors (5-ARIs) modifies the effect of MRI for the diagnosis of clinically significant Prostate Cancer (csPCa) (ISUP Gleason grade >= 2).Methods This study is a multicenter cohort study including patients undergoing prostate biopsy and MRI at 24 institutions between 2013 and 2022. Multivariable analysis predicting csPCa with an interaction term between 5-ARIs and PIRADS score was performed. Sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values of MRI were compared in treated and untreated patients.Results 705 patients (9%) were treated with 5-ARIs [median age 69 years, Interquartile range (IQR): 65, 73; median PSA 6.3 ng/ml, IQR 4.0, 9.0; median prostate volume 53 ml, IQR 40, 72] and 6913 were 5-ARIs naive (age 66 years, IQR 60, 71; PSA 6.5 ng/ml, IQR 4.8, 9.0; prostate volume 50 ml, IQR 37, 65). MRI showed PIRADS 1-2, 3, 4, and 5 lesions in 141 (20%), 158 (22%), 258 (37%), and 148 (21%) patients treated with 5-ARIs, and 878 (13%), 1764 (25%), 2948 (43%), and 1323 (19%) of untreated patients (p < 0.0001). No difference was found in csPCa detection rates, but diagnosis of high-grade PCa (ISUP GG >= 3) was higher in treated patients (23% vs 19%, p = 0.013). We did not find any evidence of interaction between PIRADS score and 5-ARIs exposure in predicting csPCa. Sensitivity, specificity, PPV, and NPV of PIRADS >= 3 were 94%, 29%, 46%, and 88% in treated patients and 96%, 18%, 43%, and 88% in untreated patients, respectively.Conclusions Exposure to 5-ARIs does not affect the association of PIRADS score with csPCa. Higher rates of high-grade PCa were detected in treated patients, but most were clearly visible on MRI as PIRADS 4 and 5 lesions.Trial registration The present study was registered at ClinicalTrials.gov number: NCT05078359

Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: The Pros-IT CNR study

Background: The National Research Council (CNR) prostate cancer monitoring project in Italy (Pros-IT CNR) is an observational, prospective, ongoing, multicentre study aiming to monitor a sample of Italian males diagnosed as new cases of prostate cancer. The present study aims to present data on the quality of life at time prostate cancer is diagnosed. Methods: One thousand seven hundred five patients were enrolled. Quality of life is evaluated at the time cancer was diagnosed and at subsequent assessments via the Italian version of the University of California Los Angeles-Prostate Cancer Index (UCLA-PCI) and the Short Form Health Survey (SF-12). Results: At diagnosis, lower scores on the physical component of the SF-12 were associated to older ages, obesity and the presence of 3+ moderate/severe comorbidities. Lower scores on the mental component were associated to younger ages, the presence of 3+ moderate/severe comorbidities and a T-score higher than one. Urinary and bowel functions according to UCLA-PCI were generally good. Almost 5% of the sample reported using at least one safety pad daily to control urinary loss; less than 3% reported moderate/severe problems attributable to bowel functions, and sexual function was a moderate/severe problem for 26.7%. Diabetes, 3+ moderate/severe comorbidities, T2 or T3-T4 categories and a Gleason score of eight or more were significantly associated with lower sexual function scores at diagnosis. Conclusions: Data collected by the Pros-IT CNR study have clarified the baseline status of newly diagnosed prostate cancer patients. A comprehensive assessment of quality of life will allow to objectively evaluate outcomes of different profile of care

Edge Machine Learning for AI-Enabled IoT Devices: A Review

In a few years, the world will be populated by billions of connected devices that will be placed in our homes, cities, vehicles, and industries. Devices with limited resources will interact with the surrounding environment and users. Many of these devices will be based on machine learning models to decode meaning and behavior behind sensors’ data, to implement accurate predictions and make decisions. The bottleneck will be the high level of connected things that could congest the network. Hence, the need to incorporate intelligence on end devices using machine learning algorithms. Deploying machine learning on such edge devices improves the network congestion by allowing computations to be performed close to the data sources. The aim of this work is to provide a review of the main techniques that guarantee the execution of machine learning models on hardware with low performances in the Internet of Things paradigm, paving the way to the Internet of Conscious Things. In this work, a detailed review on models, architecture, and requirements on solutions that implement edge machine learning on Internet of Things devices is presented, with the main goal to define the state of the art and envisioning development requirements. Furthermore, an example of edge machine learning implementation on a microcontroller will be provided, commonly regarded as the machine learning “Hello World”

Brain Functional Connectivity Changes After Transcranial Direct Current Stimulation in Epileptic Patients

Focal epilepsy is a network pathology, where the brain connectivity of the epileptic focus (EF) influences seizure frequency and cortical dysfunction. Growing evidence supports a clinical efficacy of cathodal transcranial direct current stimulation (ctDCS) in drug-resistant epilepsy (DRE). ctDCS effects can be merely attributed to the inhibition of cortical excitability, which is abnormally increased in epilepsy, but its effect on brain network of DRE patients has never been reported. We aimed at exploring the hypothesis that functional connectivity (FC) changes may explain part of ctDCS clinical effects in DRE patients. We assessed the ctDCS-induced changes of electroencephalography-derived brain FC of a group of six temporal lobe DRE patients receiving a seizure reduction after ctDCS. By a single-subject eLORETA analysis, we compared the FC among the EF region and other nine bilateral macro-regions, before and after Real and Sham ctDCS in a double-blind Sham-controlled crossover design. FC changed after Real ctDCS in all patients despite no appreciable changes occurred after Sham. Most of FC changes (73%) involved the EF region. The epileptic seizure reduction correlated with the increase of the EF FC, in the whole frequency band and in the theta band. This small-sample analysis clearly revealed that ctDCS induced FC changes in the brain network of temporal lobe DRE patients. Our data support the hypothesis that FC changes may contribute to explain the effects of ctDCS in epilepsy, offering a new scenario in the personalization of neuromodulation interventions in epileptic people

Understanding the biomimetic properties of Gallium in Pseudomonas aeruginosa: a XAS and XPS study

Pyochelin (PCH) is a siderophore (extracellural chelator) produced by the pathogenic bacterium Pseudomonas aeruginosa (PAO). PCH is implicated in Iron (Fe3+) transport to PAO, and is crucial for its metabolism and pathogenicity. Due to chemical similarity with Fe3+, Gallium (Ga3+) interferes with vital Iron-dependent processes in bacterial cells, thereby opening new perspectives for the design of specific metal-based antibacterial drugs. However, a structural basis of the Fe3+-mimetic properties of Ga3+ complexed with the PCH siderophore is still lacking. A precise knowledge of the coordination chemistry at the metal site is one of the topmost issues in the production of novel biomimetic metal-based drugs. The elucidation of this issue by means of a deep structural spectroscopic investigation could lead to an improved interference with, or a specific inhibition of, relevant biological pathways. For this reason, we applied synchrotron radiation induced X-ray Photoelectron Spectroscopy (SR-XPS) and X-ray Absorption Spectroscopy (XAS) to probe the electronic nature and coordination chemistry of Fe3+ and Ga3+ coordinative sites in PCH metal complexes. Combined XAFS and SR-XPS studies allow to demonstrate that both Fe and Ga have the same valence state in Fe-PCH and Ga-PCH, and have the same octahedral coordination geometry. Moreover, the similar next neighbour distribution for Fe and Ga, resulting from the EXAFS data analysis, strongly supports the similar coordination chemistry at the origin of the biomimetic behaviour of Ga

Brain Functional Connectivity Changes After Transcranial Direct Current Stimulation in Epileptic Patients

Focal epilepsy is a network pathology, where the brain connectivity of the epileptic focus (EF) influences seizure frequency and cortical dysfunction. Growing evidence supports a clinical efficacy of cathodal transcranial direct current stimulation (ctDCS) in drug-resistant epilepsy (DRE). ctDCS effects can be merely attributed to the inhibition of cortical excitability, which is abnormally increased in epilepsy, but its effect on brain network of DRE patients has never been reported. We aimed at exploring the hypothesis that functional connectivity (FC) changes may explain part of ctDCS clinical effects in DRE patients. We assessed the ctDCS-induced changes of electroencephalography-derived brain FC of a group of six temporal lobe DRE patients receiving a seizure reduction after ctDCS. By a single-subject eLORETA analysis, we compared the FC among the EF region and other nine bilateral macro-regions, before and after Real and Sham ctDCS in a double-blind Sham-controlled crossover design. FC changed after Real ctDCS in all patients despite no appreciable changes occurred after Sham. Most of FC changes (73%) involved the EF region. The epileptic seizure reduction correlated with the increase of the EF FC, in the whole frequency band and in the theta band. This small-sample analysis clearly revealed that ctDCS induced FC changes in the brain network of temporal lobe DRE patients. Our data support the hypothesis that FC changes may contribute to explain the effects of ctDCS in epilepsy, offering a new scenario in the personalization of neuromodulation interventions in epileptic people

Quality of Life in Female Patients Following Ileal Neobladder and Ileal Conduit: Where Are We?

Women undergoing a radical cystectomy (RC) followed by a urinary diversion (UD) for bladder cancer (BC), experience a substantial reduction in health-related quality of life (HRQOL). At present, studies comparing long-term QOL outcomes for different UD methods in female patients are lacking. We summarize the current state of the QoL assessment in female patients after an RC

Quality of Life in Female Patients Following Ileal Neobladder and Ileal Conduit: Where AreWe?

Women undergoing a radical cystectomy (RC) followed by a urinary diversion (UD) for bladder cancer (BC), experience a substantial reduction in health-related quality of life (HRQOL). At present, studies comparing long-term QOL outcomes for different UD methods in female patients are lacking. We summarize the current state of the QoL assessment in female patients after an RC

Neuronal dynamics enable the functional differentiation of resting state networks in the human brain

Intrinsic brain activity is organized in spatial–temporal patterns, called resting‐state networks (RSNs), exhibiting specific structural–functional architecture. These networks presumably reflect complex neurophysiological processes and have a central role in distinct perceptual and cognitive functions. In this work, we propose an innovative approach for characterizing RSNs according to their underlying neural oscillations. We investigated specific electrophysiological properties, including spectral features, fractal dimension, and entropy, associated with eight core RSNs derived from high‐density electroencephalography (EEG) source‐reconstructed signals. Specifically, we found higher synchronization of the gamma‐band activity and higher fractal dimension values in perceptual (PNs) compared with higher cognitive (HCNs) networks. The inspection of this underlying rapid activity becomes of utmost importance for assessing possible alterations related to specific brain disorders. The disruption of the coordinated activity of RSNs may result in altered behavioral and perceptual states. Thus, this approach could potentially be used for the early detection and treatment of neurological disorders