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Introduction: Increasing evidence suggests that microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have emerged as attractive targets in viral infections, including Human immunodeficiency virus (HIV). Objective: To deepen the understanding of the molecular mechanisms that lead to HIV and provide potential targets for the future development of molecular therapies for its treatment. Methods and Materials: Four miRNAs were selected as candidates based on a previous systematic review. A combination of bioinformatic analyses was performed to identify their target genes, lncRNAs and biological processes that regulate them. Results: In the constructed miRNA–mRNA network, 193 gene targets are identified. These miRNAs potentially control genes from several important processes, including signal transduction and cancer. LncRNA-XIST, lncRNA-NEAT1 and lncRNA-HCG18 interact with all four miRNAs. Conclusions: This preliminary result forms the basis for improving reliability in future studies to fully understand the role these molecules and their interactions play in HIV.

Background: Dynamic Knee Valgus (DKV) is an undesirable multi-joint movement pattern associated with anterior cruciate ligament injury and patellofemoral pain syndrome, especially in sport activities. We assessed DKV in young athletes who followed a postural program to reduce a posterior rigidity mostly attributable to the tightness of hamstring muscles. Methods: We considered 12-18-year-old athletes that followed a six-week program simply based on hamstring stretching and abdominal muscle activation/strengthening. DKV was assessed during a single-limb squat and the frontal plane projection angle (FPPA) between the femur and tibia was considered. Results: Sixty-six athletes with a significant DKV (FPPA>=10°) were identified. Twenty-one subjects exhibited the considered rigidity profile and completed the intervention program. The mean reduction of the FPPA after the intervention was 8.1° (±7.9°), significantly asymmetric y about 3° (p

The term ‘lifestyle’ includes different factors that contribute to the maintenance of a good health status. Increasing evidences suggest that lifestyle factors may influence epigenetic mechanisms, such as miRNAs expression. The dysregulation of miRNAs can modify the expression of genes and molecular pathways that may lead to functional alterations. This review summarizes human studies highlighting that diet, physical activity, smoking and alcohol consumption may affect the miRNA machinery and several biological functions. Most miRNAs are involved in molecular pathways that influence inflammation, cell cycle regulation and carcinogenesis resulting in the onset or progression of pathological conditions. Investigating these interactions will be pivotal for understanding the etiology of pathologic processes, the potential new treatment strategies and for preventing diseases.

Environmental contaminants exposure may lead to detrimental changes to the microRNAs (miRNAs) expression resulting in several health effects. miRNAs, small non-coding RNAs that regulate gene expression, have multiple transcript targets and thereby regulate several signalling molecules. Even a minor alteration in the abundance of one miRNA can have deep effects on global gene expression. Altered patterns of miRNAs can be responsible for changes linked to various health outcomes, suggesting that specific miRNAs are activated in pathophysiological processes. In this review, we provide an overview of studies investigating the impact of air pollution, organic chemicals, and heavy metals on miRNA expression and the potential biologic effects on humans. Abbreviations: AHRR, aryl-hydrocarbon receptor repressor; AHR, aryl-hydrocarbon receptor; As, arsenic; BCL2, B-cell lymphoma 2; BCL2L11, B-cell lymphoma 2 like 11; BCL6, B-cell lymphoma 6; BPA, bisphenol A; CVD, cardiovascular diseases; CD40, cluster of differentiation 40; CCND1, Cyclin D1; CDKN1A, cyclin-dependent kinase inhibitor 1A; Cr, chromium; CTBP1, C-terminal binding protein 1; CXCL12, C-X-C motif chemokine ligand 12; DAZAP1, deleted in azoospermia associated protein 1; DEP, diesel exhaust particles; EGFR, epidermal growth factor receptor; eNOS, endothelial nitric oxide synthase; EVs, extracellular vesicles; FAK, focal adhesion kinase; FAS, fas cell surface death receptor; FOXO, forkhead box O; HbA1c, glycated hemoglobin; Hg, mercury; HLA-A, human leukocyte antigen A; HMGB, high-mobility group protein B; IFNAR2, interferon alpha receptor subunit 2; IL-6, interleukin-6; IRAK1, interleukin 1 receptor associated kinase 1; JAK/STAT, janus kinase/signal transducers and activators of transcription; MAPK, mitogen-activated protein kinase; miRNAs, microRNAs; MVs, microvesicles; NCDs, noncommunicable diseases; NFAT, nuclear factor of activated T cells; NFkB, nuclear factor kappa B; NRF2, nuclear factor, erythroid-derived 2; NRG3, neuregulin 3; O3, ozone; OP, organophosphorus pesticides; PAHs, polycyclic aromatic hydrocarbons; Pb, lead; PCBs, polychlorinated biphenyls; PDCD4, programmed cell death 4; PDGFB, platelet derived growth factor subunit beta; PDGFR, platelet-derived growth factor receptor; PI3K/Akt, phosphoinositide-3-kinase/protein kinase B; PKA, protein kinase A; PM, particulate matter; PRKCQ, protein kinase C theta; PTEN, phosphatase and tensin homolog; SORT1, sortilin 1; TGFβ, transforming growth factor-β; TLR, toll-like receptor; TNF, tumor necrosis factors; TRAF1, tumor necrosis factors-receptor associated factors 1; TRAP, traffic-related air pollution; TREM1, triggering receptor expressed on myeloid cells 1; TRIAP1, TP53 regulated inhibitor of apoptosis 1; VCAM-1, vascular cell adhesion molecule 1; VEGFA, vascular endothelial growth factor A; XRCC2, X-ray repair cross complementing 2; YBX2, Y-box-binding protein 2; ZEB1, zinc finger E-box-binding homeobox 1; ZEB2, zinc finger E-box-binding homeobox 2; 8-OH-dG, 8-hydroxy-guanine.

Objectives: This review systematically summarizes the evidence on the economic impact of magnetic resonance image-guided RT (MRIgRT). Methods: We systematically searched INAHTA, MEDLINE, and Scopus up to March 2022 to retrieve health economic studies. Relevant data were extracted on study type, model inputs, modeling methods and economic results. Results: Five studies were included. Two studies performed a full economic assessment to compare the cost-effectiveness of MRIgRT with other forms of image-guided radiation therapy. One study performed a cost minimization analysis and two studies performed an activity-based costing, all comparing MRIgRT with X-ray computed tomography image-guided radiation therapy (CTIgRT). Prostate cancer was the target condition in four studies and hepatocellular carcinoma in one. Considering the studies with a full economic assessment, MR-guided stereotactic body radiation therapy was found to be cost effective with respect to CTIgRT or conventional or moderate hypofractionated RT, even with a low reduction in toxicity. Conversely, a greater reduction in toxicity is required to compete with extreme hypofractionated RT without MR guidance. Conclusions: This review highlights the great potential of MRIgRT but also the need for further evidence, especially for late toxicity, whose reduction is expected to be the real added value of this technology.

Lay abstract miRNAs play important role in the regulation of gene expression and are involved in various physiological processes. Dysregulation of their function can lead to human diseases including cancer, cardiovascular and metabolic diseases, liver conditions and immune dysfunction. The aim of this work is to systematically analyze the current scientific literature to identify miRNAs linked to the mechanism, development and treatment of HIV. A total of 35 articles were included and the miRNAs that were found with significantly different levels in compared groups of subjects (e.g., subjects with HIV vs healthy persons, persons able to limit the disease progression without therapy vs those whose immune system is already compromised by HIV) were highlighted. The most frequently reported miRNAs were: the hsa-miR-29 family, hsa-miR-146b-5p and hsa-miR-150-5p. To our knowledge, this is the first attempt to systematically identify the miRNAs associated with HIV and could be a useful contribution to general knowledge in this field.

In this paper a smart sensing system is proposed with the aim of improving health, safety, and comfort of workers. Different innovative sensors are integrated into a unique board to collect data referred to the physiological state. A remote Bluetooth Low Energy (BLE) interface is used to transmit the extracted parameters to a monitoring mobile App. Main assessments of worker conditions include measurements of heart rate, blood oxygen saturation, skin temperature, vibration, and motion levels. Vital parameters of heart rate and blood oxygen saturation are obtained from processing red and infrared signals detected by means of an accurate photoplethysmography (PPG) sensor. For the sake of evaluating the body temperature, a non-invasive sensor is put in contact directly with the skin. The skin temperature varies at different locations and the used sensor allows the small differences to be appreciated. In addition to vital parameters, an indicator of human motion that relates to fatigue and working stress is extracted through an Inertial Measurement Unit (IMU) from which the root mean square (RMS) of acceleration signals is obtained. Since the IMU is suitably positioned on the final board, it also provides the correct worker posture to alert in case of incorrect situations.

Thermal stress is a factor that must be considered, particularly in working environments where severe microclimatic conditions can lead to a loss of well-being or, in the worst-case scenario, to worker health damage. When it comes to thermal comfort, the best conditions for ensuring worker activity, productivity, and well-being include not only the proper design of spaces and cooling/heating systems, but also constant, real-time monitoring of the worker's physical condition. This work aims to present a complete system comprising various components capable not only of ensuring the worker's thermal comfort through the use of innovative textiles for optimal heat exchange between the individual and the environment, but also of continuously monitoring certain physiological parameters useful in determining whether the worker is subject to thermal stress. The system developed also allows the worker to be warned in the event of thermal stress and provides control and analysis tools to safety operators. This work, in particular, provides ample space for the description and validation of the textile component, in addition to presenting the system architecture and describing the main components. Finally, the wireless sensors designed to monitor physiological parameters are described and validated, and a brief functional validation of some of the architecture's software components is presented.

Background: In silico medicine allows for pre-clinical and clinical simulated assessment of medical technologies and the building of patient-specific models to support medical decisions and forecast personal health status. While there is increasing trust in the potential central role of in silico medicine, there is a need to recognize its degree of reliability and evaluate its economic impact. An in silico platform has been developed within a Horizon 2020-funded project (In-Silc) for simulations functional to designing, developing, and assessing drug-eluting bioresorbable vascular scaffolds. The main purpose of this study was to compare the costs of 2 alternative strategies: the adoption of In-Silc platform versus the performance of only physical bench tests. Methods: A case study was provided by a medical device company. The values of the model parameters were principally set by the project partners, with use of interviews and semi-structured questionnaires, and, when not available, through literature searches or derived by statistical techniques. An economic model was built to represent the 2 scenarios. Results: The InSilc strategy is superior to the adoption of physical bench tests only. Ceteris paribus, the costs are 424,355€ for the former versus 857,811€ for the latter. Conclusions: In silico medicine tools can decrease the cost of the research and development of medical devices such as bioresorbable vascular scaffolds. Further studies are needed to explore the impact of such solutions on the innovation capacity of companies and the consequent potential advantages for target patients and the healthcare system.

In this paper a Battery-Assisted Passive (BAP) RFID based-on sensing system is proposed with the goal of backscattering sensor data to a reader in human monitoring activities. A suitable Printed Circuit Board (PCB) has been designed to integrate the sensors, the tag and the antenna. The sensors consist in two accurate units able to return the body temperature and the systolic pulse signals, from which the heart rate has been estimated. For the sake of transmitting the gathered sensor information, a data packet has been arranged and returned to the interrogating reader. The device size has been minimized by adopting an 866 MHz ceramic antenna. A very appreciable working distance between the tag and the reader has been obtained both in case of device worn or not. In addition to the electromagnetic properties, design aspects of sensors, microcontroller, and RFID chip and have been taken into consideration to realize a comfortable device.

In this work, an UHF RFID tag integrated with an Inertial Measurement Unit (IMU) sensor has been designed, realized, and tested. It leverages on a specific RFID chip provided with both wireless and wired memory access. High robustness, effectiveness, and working range, are assured through the use of an on-board battery to boost the chip sensitivity and to supply an ultra-low power microcontroller and the sensors. In such a context, specific electromagnetic aspects have been faced to insulate the battery from the radiofrequency (RF) circuitry and a Planar Inverted-F Antenna (PIFA) has been designed to match the RFID chip input impedance. Different devices have been realized, tested, and then applied on specific human body segments to feed a virtual human-body biomechanical model and validate the RFID-based approach.

Chronic respiratory diseases constitute a serious public health problem in all countries, and Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are two of the most prevalent. Positive airway pressure (PAP) is recommended for ongoing treatment of OSA in adults while Long-term oxygen therapy (LTOT) is indicated for stable COPD patients with Chronic Respiratory Insufficiency. In real contexts, the clinical efficacy of these therapies is limited by an often-low adherence with consequent rising back of symptoms and adverse consequences on the quality of life. Until now, several driving factors have been identified for a low adherence to CPAP and LTOT and several solutions are proposed in many papers. In this review we identify and discuss the driving factors reported for a low adherence (addressing personal conditions, social context and specificities of the device) and the strategies adopted to mitigate them (behavioral, educational and supportive interventions) and to monitor actual compliance (self-reporting, eHealth solutions and consumptions of device accessories). An overall picture of these aspects allows planning the healthcare service and adequate support for OSA and COPD patients with an attention to the individual, social and cultural level. Further investigation is still needed to explore the value of combinations of the reported approaches on different patient phenotypes and at what cost.

Background: In silico medicine allows for pre-clinical and clinical simulated assessment of medical technologies and the building of patient-specific models to support medical decisions and forecast personal health status. While there is increasing trust in the potential central role of in silico medicine, there is a need to recognize its degree of reliability and evaluate its economic impact. An in silico platform has been developed within a Horizon 2020-funded project (In-Silc) for simulations functional to designing, developing, and assessing drug-eluting bioresorbable vascular scaffolds.The main purpose of this study was to compare the costs of 2 alternative strategies: the adoption of In-Silc platform versus the performance of only physical bench tests. Methods: A case study was provided by a medical device company. The values of the model parameters were principally set by the project partners, with use of interviews and semi-structured questionnaires, and, when not available, through literature searches or derived by statistical techniques. An economic model was built to represent the 2 scenarios. Results: The InSilc strategy is superior to the adoption of physical bench tests only. Ceteris paribus, the costs are 424,355EUR for the former versus 857,811EUR for the latter. Conclusions: In silico medicine tools can decrease the cost of the research and development of medical devices such as bioresorbable vascular scaffolds. Further studies are needed to explore the impact of such solutions on the innovation capacity of companies and the consequent potential advantages for target patients and the healthcare system.

This paper presents the design and the development of a Battery Assisted Passive Radio-Frequency IDentification (RFID) tag in the Ultra High-Frequency band integrated with inertial measurement unit (IMU) sensors tested for the biomechanical analysis of human body movements. Enhanced by a compact and efficient meandered Planar Inverted-F Antenna (PIFA), the device exploits a specific RFID chip having a dual-access --wired and wireless-- to the memory. A properly decoupled cell battery is also foreseen to boost the chip sensitivity and to supply power to an ultra-low power microcontroller and to the sensors. The device has been realized using off-the-shelf low-cost discrete components on FR4 substrate, validated, and tested in capturing real human movements. Two sensor-tags have been applied on the pelvis and on the torso of an individual moving in front of the RFID Reader antenna. Afterward, sensor data have been collected, processed, and filtered with specific algorithms, and used to control a musculoskeletal virtual model in the OpenSense software tool. The results show that the whole system correctly reproduces the performed movements, demonstrating the appropriateness of the proposed RFID-sensor in wireless movement capture applications.

An overuse of invasive and non-invasive anatomical testing for the diagnosis of coronary artery disease (CAD) affects patients’ and healthcare professionals’ safety, and the sustainability of Healthcare Systems. Pre-test probability (PTP) models can be routinely used as gatekeeper for initial patient management. Although with different positions, international organizations clearly underline the need for more information on the various risk factors acting as modifier of the PTP.This systematic review addresses validation of PTP models adopting variables available at the first-line assessment of a suspected stable CAD. A comprehensive search has been done in MEDLINE®, HealthSTAR, and Global Health databases.Nearly all the models considered in the 27 analysed papers include age, sex, and chest pain symptoms. Other common risk factors are smoking, hypertension, diabetes mellitus and dyslipidaemia. Only one model considers genetic profile. Reported AUCs range from 0.51 to 0.81. Relevant heterogeneity sources have been highlighted, such as the sample size, the presence of a PTP cut-off and the adoption of different definitions of CAD which can prevent comparisons of results. Very few papers address a complete validation, making then impossible to understand the reasons why the model does not show a good discrimination capability on a different data set.We consequently recommend a more clear statement of endpoints, their consistent measurement both in the derivation and validation phases, more comprehensive validation analyses and the enhancement of threshold validations of PTP to assess the effects of PTP on clinical management.

Smart Breath Analyzers were developed as sensing terminals of a telemedicine architecture devoted to remote monitoring of patients suffering from Chronic Obstructive Pulmonary Disease (COPD) and home-assisted by non-invasive mechanical ventilation via respiratory face mask. The devices based on different sensors (CO2/O2 and Volatile Organic Compounds (VOCs), relative humidity and temperature (R.H. &amp, T) sensors) monitor the breath air exhaled into the expiratory line of the bi-tube patient breathing circuit during a noninvasive ventilo-therapy session, the sensor raw signals are transmitted pseudonymized to National Health Service units by TCP/IP communication through a cloud remote platform. The work is a proof-of-concept of a sensors-based IoT system with the perspective to check continuously the effectiveness of therapy and/or any state of exacerbation of the disease requiring healthcare. Lab tests in controlled experimental conditions by a gas-mixing bench towards CO2/O2 concentrations and exhaled breath collected in a sampling bag were carried out to test the realized prototypes. The Smart Breath Analyzers were also tested in real conditions both on a healthy volunteer subject and a COPD suffering patient.

Chronic obstructive pulmonary (COPD) disease is a progressive illness that will intensify over time. Exacerbation are frequent and likely caused by bacterial and viral respiratory infections. The management of COPD includes home assistance by noninvasive ventilation (NIV), but no remote monitoring system is generally applied. In this work a telemedicine device based on Smart Breath Analyzer (SBA) devoted to the remote-monitoring of parameters in the exhaled air of COPD patients during NIV was developed. System architecture and preliminary pre-clinical test results were here presented.

Purpose: The importance of working toward quality improvement in healthcare implies an increasing interest in analysing, understanding and optimizing process logic and sequences of activities embedded in healthcare processes. Their graphical representation promotes faster learning, higher retention and better compliance. The study identifies standardized graphical languages and notations applied to patient care processes and investigates their usefulness in the healthcare setting. Data sources: Peer-reviewed literature up to 19 May 2016. Information complemented by a questionnaire sent to the authors of selected studies. Study selection: Systematic review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Data extraction: Five authors extracted results of selected studies. Results of data synthesis: Ten articles met the inclusion criteria. One notation and language for healthcare process modelling were identified with an application to patient care processes: Business Process Model and Notation and Unified Modeling LanguageTM. One of the authors of every selected study completed the questionnaire. Users' comprehensibility and facilitation of inter-professional analysis of processes have been recognized, in the filled in questionnaires, as major strengths for process modelling in healthcare. Conclusion: Both the notation and the language could increase the clarity of presentation thanks to their visual properties, the capacity of easily managing macro and micro scenarios, the possibility of clearly and precisely representing the process logic. Both could increase guidelines/path- ways applicability by representing complex scenarios through charts and algorithms hence contributing to reduce unjustified practice variations which negatively impact on quality of care and patient safety.

ObjectiveExternally validated pretest probability models for risk stratification of subjects with chest pain and suspected stable coronary artery disease (CAD), determined through invasive coronary angiography or coronary CT angiography, are analysed to characterise the best validation procedures in terms of discriminatory ability, predictive variables and method completeness.DesignSystematic review and meta-analysis.Data sourcesGlobal Health (Ovid), Healthstar (Ovid) and MEDLINE (Ovid) searched on 22 April 2020.Eligibility criteriaWe included studies validating pretest models for the first-line assessment of patients with chest pain and suspected stable CAD. Reasons for exclusion: acute coronary syndrome, unstable chest pain, a history of myocardial infarction or previous revascularisation; models referring to diagnostic procedures different from the usual practices of the first-line assessment; univariable models; lack of quantitative discrimination capability.MethodsEligibility screening and review were performed independently by all the authors. Disagreements were resolved by consensus among all the authors. The quality assessment of studies conforms to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). A random effects meta-analysis of area under the receiver operating characteristic curve (AUC) values for each validated model was performed.Results27 studies were included for a total of 15 models. Besides age, sex and symptom typicality, other risk factors are smoking, hypertension, diabetes mellitus and dyslipidaemia. Only one model considers genetic profile. AUC values range from 0.51 to 0.81. Significant heterogeneity (p0.12). Values of I2 >90% for most analyses and not significant meta-regression results undermined relevant interpretations. A detailed discussion of individual results was then carried out.ConclusionsWe recommend a clearer statement of endpoints, their consistent measurement both in the derivation and validation phases, more comprehensive validation analyses and the enhancement of threshold validations to assess the effects of pretest models on clinical management.PROSPERO registration numberCRD42019139388.

Context Disease management broke through in the early 1990s to counterbalance hyper-specialization with a more comprehensive approach. Its role became immediately relevant in chronic conditions and, consequently, in Obstructive Sleep Apnoea (OSA). This is a common chronic condition for which is important to organise services at the local level, taking into account organisational factors and the characteristics of the assisted population. Objectives The aim of this work is to propose and apply, coherently with a disease management approach, a combination of healthcare process modelling and population analysis as a way to identify critical issues and explore shared solutions. Methods A multidisciplinary working group was created with scholars who are skilled in process analysis, statistics and medicine. Through semi-structured interviews and on-site meetings, healthcare processes were represented with a standard graphical language: Unified Modeling Language™. Population analysis was based on statistical analysis performed on a 5-year retrospective cohort assisted by a Community Pulmonary Service. Results A shared graphic presentation of the current healthcare process and the results of the statistical analyses constituted the knowledge base to identify critical issues and recommend corresponding solutions, which include: a) refine the local patient database with additional details on comorbidities and risk factors; b) support a greater involvement of “gate-keepers” in the screening phase; c) provide practical tools for the definition of strategies to increment the adherence to therapy; d) include recommendations for physical exercise and interdisciplinary cooperation; and e) define process indicators for measuring the quality of the screening and therapeutic phases. Conclusion The concomitant analyses of formalised processes and critical risk factors represent a useful approach for systematically identifying areas of improvement in healthcare processes and allow us to discuss solutions. Moreover, the specific adoption of UML® for graphical modelling and representation of patient care processes allows us to formalise them by adopting a standard language that can be taken as the basis for implementing web services to support the execution of the modelled processes.

In this work we proposed a novel tele-medicine system called Smart Breath Network (SBN) with the perspective to improve the life of patients affected by a well-known respiratory disease called Chronic Obstructive Pulmonary Disease (COPD). The main therapy for COPD is home-assisted ventilation that requires frequent home intervention by specialized hospital staff in order to adjust dispensing and to verify the effectiveness of the therapy. Moreover, healthcare services need to improve the care of patients with difficult access to services, particularly those in rural or remote areas without sustaining high costs of service maintenance. The SBN system tries to fill the gap between healthcare services, that need to take care of a growing number of home-assisted COPD patients due to the today’s alarming air pollution. The SBN network gathers all patient’s respiratory data from Smart Breath Analyzers (SBAs) devices that are low-cost, simple to use, compact-sized devices that fit to almost any ventilator with bi-tube capabilities.

In this work we developed a Smart Breath Analyzer device devoted to the tele-monitoring of exhaled air in patients suffering Chronic Obstructive Pulmonary disease (COPD) and home-assisted by mechanical ventilation. The device based on sensors allows remote monitoring of a patient during a ventilotherapy session, and transmit the monitored signals to health service unit by TCP/IP communication through a cloud remote platform. The aim is to check continuously the effectiveness of therapy and/or any state of exacerbation of the disease requiring healthcare. By preliminary experimental tests, the prototype was validated on a volunteer subject.

Resumen Introduccion y objetivos Los polimorfismos de nucleotido unico situados en un lugar de union de microacidos ribonucleicos (miARN) pueden tener diferentes efectos en la expresion genica, y ello puede influir en el riesgo de enfermedad. Este estudio tiene como objetivo evaluar la asociacion existente entre los polimorfismos de nucleotido unico y los haplotipos presentes en la region 3’UTR del gen GATA4 y el riesgo de cardiopatia congenita. Metodos Se utilizaron algoritmos de bioinformatica para analizar los polimorfismos de nucleotido unico en los presuntos lugares de union de miARN en la region 3’UTR del gen GATA4 y para calcular la diferencia de energia de hibridacion libre (ΔFE, kcal/mol) para cada alelo de tipo natural (wild-type) en comparacion con cada variante alelica. Resultados Formaron la poblacion de estudio 146 pacientes caucasicos (73 varones; edad, 6,68 ± 7,79 anos) y 265 recien nacidos sanos (147 varones). Se considero que la suma de todos los ΔFE predecia la importancia biologica de los polimorfismos de nucleotido unico al unirse a mas miARN. A continuacion se determino el genotipo de los 4 polimorfismos (+1158 C > T, + 1256 A > T, + 1355 G > A, +1521 C > G) que tenian el valor predicho de ΔFE total mas alto (9,91, 14,85, 11,03 y 21,66 kcal/mol respectivamente) en un estudio de casos y controles (146 pacientes y 250 controles). Al aplicar una correccion por multiplicidad de pruebas, tan solo el alelo +1158 T mostro una diferencia significativa entre los pacientes y los controles. El analisis de los haplotipos puso de manifiesto que el haplotipo T-T-G-C (mas infrecuente en los pacientes con cardiopatias congenitas que en los controles) se asociaba a una disminucion del riesgo significativa (p = 0,03), mientras que el haplotipo muy infrecuente C-A-A-C, que se daba de manera muy poco comun en los controles (0,3%) en comparacion con los pacientes con la enfermedad (2,4%), se asociaba a un aumento de 4 veces en el riesgo de enfermedad (p = 0,04). Conclusiones Las variantes frecuentes de la region 3’UTR del gen GATA4 interaccionan de manera conjunta y con ello afectan a la susceptibilidad a la cardiopatia congenita, probablemente mediante la alteracion de la regulacion postranscripcional de los miARN.

In this work we developed a Smart Breath Analyzer device devoted to the tele-monitoring of exhaled air in patients suffering chronic respiratory failure and home-assisted by mechanical ventilation. The device originates from the need for continuous and remote monitoring of the patient during a ventilo-therapy session; monitoring data acquired by sensors are transmitted to the healthcare center by TCP/IP communication through a cloud remote platform in order to check continuously the effectiveness of therapy and/or any state of disease exacerbation. The device was both characterized and calibrated with known concentrations of O 2 /CO 2 in laboratory field and in a real condition of exhaled air from an healthy volunteer.

MiRNAs are gene (post-transcriptional) regulators that bind the 3'UTR of target genes. Single-nucleotide polymorphisms (SNPs) located within a miRNA binding site can impact miRNAdependent gene regulation by weakening or reinforcing the microRNA:mRNA bond. We present a general in silico approach enabling researchers to "predict" which of the several SNPs of 3'UTR of H2AFX gene can mainly affect its regulation. H2AFX gene encodes a member of the H2A histone family which is central in the detection of and response to DNA double-strand breaks. All the 17 common SNPs located within the 3'UTR of H2AFX gene were analyzed for putative miRNA-binding sites by using different databases (such as dbSNP and miRBase) and pre-existing algorithms (such as MicroSNiPer and RNAcofold) in order to calculate the minimum free energies of hybridization of the microRNA:mRNA duplex, for both the wild-type and mutant alleles. The difference in these energies was also calculated. Since in each tissue one target sequence can bind only one miRNA at a time, the sum of all the difference of energies can be considered a relevant parameter for predicting the importance of a SNP with respect to miRNA regulation. We used tertiles to classify the SNPs and provide a priority list based on their theoretically strongest impact on miRNA binding. By using the described approach, we provided the basis for a reasoned, user-friendly algorithm-driven selection of SNPs impacting miRNA biology. The proposed method is helpful for selecting SNPs having a more powerful (putative) biological function, minimizing workflow and costs for experimental and clinical investigations.

The pricing and reimbursement policies for pharmaceuticals are relevant to balance timely and equitable access for all patients, financial sustainability, and reward for valuable innovation. The proliferation of high-cost specialty medicines is particularly true in rare diseases (RDs) where the pricing mechanism is characterised by a lack of transparency. This work provides an overall picture of current strategies for the definition of the reimbursed prices of orphan drugs (ODs) and highlights some potential improvements. Current strategies and suggestions are presented along 4 dimensions: (1) comprehensive value assessment, (2) early dialogs among relevant stakeholders, (3) innovative reimbursement approaches, and (4) societal participation in producing ODs. Comprehensive value assessment could be achieved by clarifying the approach of distributive justice to adopt, ensuring a representative participation of stakeholders, and with a broad consideration of value-bearing factors. With respect to early dialogs, cross-border cooperation can be determinant to companies and agencies. The cost-benefit ratio of early dialogs needs to be demonstrated and the “regulatory capture” effect should be monitored. Innovative reimbursement approaches were developed to balance the need for evidence-based decisions with the timely access to innovative drugs. The societal participation in producing ODs needs to be recognised in a collaborating framework where adaptive agreements can be developed with mutual satisfaction. Such agreements could also impact on coverage and reimbursement decisions as additional elements for the determination of a comprehensive societal value of ODs. Further research is needed to investigate the highlighted open challenges so that RDs will not remain, in practical terms, orphan diseases.

We report the clinical presentation and genetic screening of 2 patients with thoracic aortic aneurysms. A novel TGFBR2 mutation in the 5'untranslated region (c.-59C>T) was identified in a 31-year-old man with a Stanford type A aortic dissection. Bioinformatics tools showed that c.-59C>T variant was predicted to affect exonic splicing enhancer, as validated by quantitative real-time RT-PCR, revealing a sixfold increase of TGFBR2 mRNA in aneurysmal aortic tissue collected during surgery. A previously described missense mutation, p.E239K, in the SMAD3 gene was identified in a 60-year-old man who presented with diffuse vasculopathy. These findings suggest that the features of aneurysmal disease extending beyond the ascending aorta may help to target SMAD3 genetic screening and that alterations in the core splicing machinery can contribute to aneurysmal disease.

Somatic mutations and dysregulation by microRNAs (miRNAs) may have a pivotal role in the Congenital Heart Defects (CHDs). The purpose of the study was to assess both somatic and germline mutations in the GATA4 and NKX2.5 genes as well as to identify 3'UTR single nucleotide polymorphisms (SNPs) in the miRNA target sites. We enrolled 30 patients (13 males; 13.4±8.3 years) with non-syndromic CHD. GATA4 and NKX2.5 genes were screened in cardiac tissue of sporadic and in blood samples of familial cases. Computational methods were used to detect putative miRNAs in the 3'UTR region and to assess the Minimum Free Energy of hybridization (MFE, kcal/mol). Difference of MFEs (ΔMFE) ≥4 kcal/mol between alleles was considered biologically relevant on miRNA binding. The sum of all ΔMFEs (|ΔMFEtot|=∑|ΔMFE|) was calculated in order to predict the biological importance of SNPs binding more miRNAs. No evidence of novel GATA4 and NKX2.5 mutations was found both in sporadic and familial patients. Bioinformatic analysis revealed 27 putative miRNAs binding to identified SNPs in the 3'UTR of GATA4. ΔMFE ≥4 kcal/mol between alleles was obtained for the +354A>C (miR-4299), +587A>G (miR-604), +1355G>A (miR-548v, miR-139-5p) and +1521C>G (miR-583, miR-3125, miR-3928) SNPs. The +1521C>G SNP showed the highest ΔMFEtot (21.66 kcal/mol). Luciferase reporter assays indicated that miR-583 was dose-dependently effective in regulating +1521 C allele compared with +1521 G allele. Based on the analysis of 100 CHD cases and 204 healthy newborns, the +1521 G allele was also associated with a lower risk of CHD (OR=0.5, 95% CI 0.3-0.9, p=0.03), likely due to the relatively low binding of the miRNA and high levels of protein. These results suggest that common SNPs in the 3'UTR of GATA4 alter miRNA gene regulation contributing to the pathogenesis of CHDs.

Congenital hearing loss is the most frequent birth defect. The American Academy of Pediatrics and the Joint Committee on Infant Hearing established quality of care process indicators for Universal Newborn Hearing Screening starting from 1999. In a previous systematic review of Universal Newborn Hearing Screening studies we highlighted substantial variability in program design and in reported performance data. In order to overcome these heterogeneous findings we think it is necessary to optimize the implementation of Universal Newborn Hearing Screening programs with an appropriate application of the planning, executing, and monitoring, verifications and reporting phases. For this reason we propose a conceptual framework that logically integrates these three phases and, consequently, a tool (a check-list) for their rationalization and standardization. Our paper intends to stimulate debate on how to ameliorate the routine application of high quality Universal Newborn Hearing Screening programs. The conceptual framework is proposed to optimize, rationalise and standardise their implementation. The checklist is intended to allow an inter-program comparison by removing heterogeneity in processes description and assessment. Electronic supplementary material The online version of this article (doi:10.1186/s13052-016-0223-1) contains supplementary material, which is available to authorized users.

Introduction and objectives Single-nucleotide polymorphisms within a microRNA binding site can have different effects on gene expression, influencing the risk of disease. This study aimed to evaluate the association between single-nucleotide polymorphisms and haplotypes in the 3’UTR of the GATA4 gene and congenital heart disease risk. Methods Bioinformatics algorithms were used to analyze single-nucleotide polymorphisms in putative microRNA-binding sites of GATA4 3’UTR and to calculate the difference in free energy of hybridization (ΔFE, kcal/mol) for each wild-type vs the variant allele. Results The study population comprised 146 Caucasian patients (73 males; 6.68 ± 7.79 years) and a 265 healthy newborn participants (147 males). The sum of all |ΔFE| was considered to predict the biological importance of single-nucleotide polymorphisms binding more microRNAs. Next, the 4 polymorphisms (+1158 C > T, +1256 A > T, +1355 G > A, +1521 C > G) with the highest predicted |ΔFE tot | (9.91, 14.85, 11.03, 21.66 kcal/mol, respectively) were genotyped in a case-control study (146 patients and 250 controls). Applying a correction for multiple testing only the +1158 T allele was found to be associated with a reduced risk showing significant difference between patients and controls. Haplotype analysis showed that the T-T-G-C haplotype (more uncommon in congenital heart diseases than in controls) was associated with a significantly decreased risk ( P = .03), while the rare C-A-A-C haplotype, which was very uncommon in controls (0.3%) compared with the disease (2.4%), was associated with a 4-fold increased risk of disease ( P = .04). Conclusions Common variants in 3’UTR of the GATA4 gene jointly interact, affecting the congenital heart disease susceptibility, probably by altering microRNA posttranscriptional regulation.

MiRNAs are gene (post-transcriptional) regulators that bind the 3'UTR of target genes. Single-nucleotide polymorphisms (SNPs) located within a miRNA binding site can impact miRNAdependent gene regulation by weakening or reinforcing the microRNA:mRNA bond. We present a general in silico approach enabling researchers to "predict" which of the several SNPs of 3'UTR of H2AFX gene can mainly affect its regulation. H2AFX gene encodes a member of the H2A histone family which is central in the detection of and response to DNA double-strand breaks. All the 17 common SNPs located within the 3'UTR of H2AFX gene were analyzed for putative miRNA-binding sites by using different databases (such as dbSNP and miRBase) and pre-existing algorithms (such as MicroSNiPer and RNAcofold) in order to calculate the minimum free energies of hybridization of the microRNA:mRNA duplex, for both the wild-type and mutant alleles. The difference in these energies was also calculated. Since in each tissue one target sequence can bind only one miRNA at a time, the sum of all the difference of energies can be considered a relevant parameter for predicting the importance of a SNP with respect to miRNA regulation. We used tertiles to classify the SNPs and provide a priority list based on their theoretically strongest impact on miRNA binding. By using the described approach, we provided the basis for a reasoned, user-friendly algorithm-driven selection of SNPs impacting miRNA biology. The proposed method is helpful for selecting SNPs having a more powerful (putative) biological function, minimizing workflow and costs for experimental and clinical investigations.

OBJECTIVE At present, the level of care for adult congenital heart disease is not completely satisfactory in many European countries including Italy. The aim of this multicentre study was to evaluate the possibility of creating an active connection among different centres involved in the care of this patient population. METHODS This study lasted two years, from December 2002 to December 2004. It involved six clinical centres located in the north, centre and south of Italy; a research centre (ISBEM) affiliated to the National Research Centre was also involved. Each centre was supposed to contribute with written information (about their specific subject) on the web site; our target readers were physicians, nurses and patients. The intranet part of the web connection was used for a registry to be filled with very simple information (demographic data, main diagnosis, reason for hospitalisation, type of treatment) about patients hospitalised after January 2000. The aim of the registry was to get a snapshot of the composition of the treated population, and the spectrum of the lesions. RESULTS The main results are the following: (i) the creation of the web site www.guch-italia.it which can be accessed without a specific password; (ii) the creation of a registry in which we entered the clinical information of 1,231 patients; (iii) the presentation of guidelines on the web site, extrapolated from the recommendations for the management of adults with congenital heart disease from the Canadian Cardiovascular Society Consensus Conference. CONCLUSIONS With this study we tried to create a national network of centres that have as an objective to optimise the assistance to patients with adult congenital heart disease, trying to make the approach as much homogeneous as possible.

Background Congenital anomalies and their primary prevention are a crucial public health issue. This work aimed to estimate the prevalence of congenital anomalies in Brindisi, a city in southeastern Italy at high risk of environmental crisis. Methods This research concerned newborns up to 28 days of age, born between 2001 and 2010 to mothers resident in Brindisi and discharged with a diagnosis of congenital anomaly. We classified cases according to the coding system adopted by the European Network for the Surveillance of Congenital Anomalies (EUROCAT). Prevalence rates of congenital anomalies in Brindisi were compared with those reported by EUROCAT. Logistic regression models were adapted to evaluate the association between congenital anomalies and municipality of residence of the mother during pregnancy. Results Out of 8,503 newborns we recorded 194 subjects with congenital anomalies (228.2/10,000 total births), 1.2 times higher than the one reported by the EUROCAT pool of registries. We observed 83 subjects with congenital heart diseases with an excess of 49.1%. Odds Ratios for congenital heart diseases significantly increased for newborns to mothers resident in Brindisi (OR 1.75 CI 95% 1.30-2.35). Conclusions Our findings indicated an increased prevalence of Congenital Anomalies (especially congenital heart diseases) in the city of Brindisi. More research is needed in order to analyze the role of factors potentially involved in the causation of congenital anomalies.