Maelstrom Represses Canonical Polymerase II Transcription within Bi-directional piRNA Clusters in Drosophila melanogaster.

In Drosophila, 23-30 nt long PIWI-interacting RNAs (piRNAs) direct the protein Piwi to silence germline transposon transcription. Most germline piRNAs derive from dual-strand piRNA clusters, heterochromatic transposon graveyards that are transcribed from both genomic strands. These piRNA sources are marked by the heterochromatin protein 1 homolog Rhino (Rhi), which facilitates their promoter-independent transcription, suppresses splicing, and inhibits transcriptional termination. Here, we report that the protein Maelstrom (Mael) represses canonical, promoter-dependent transcription in dual-strand clusters, allowing Rhi to initiate piRNA precursor transcription. Mael also represses promoter-dependent transcription at sites outside clusters. At some loci, Mael repression requires the piRNA pathway, while at others, piRNAs play no role. We propose that by repressing canonical transcription of individual transposon mRNAs, Mael helps Rhi drive non-canonical transcription of piRNA precursors without generating mRNAs encoding transposon proteins.

iPhone 12 MagSafe technology and cardiac implantable devices: Assessment of the actual risk.

BACKGROUND: Pacemaker (PM) and implantable cardioverter defibrillators (ICD) are equipped with a magnetic sensor activated by external application of magnets to easily manage some functions of these devices. If activated inadvertently or outside a controlled environment and without the supervision of clinical personnel, this magnetic mode introduces a potential risk. In reality, the possibility of a static magnetic field affecting a PM or ICD is remote. However, the presence of the magnet in the iPhone 12 made the possibility of inadvertently activating the magnetic switch of PM and ICD less remote. OBJECTIVE: This study investigates the effects of magnetic interference of the iPhone 12 on a large set of cardiac implantable devices representative of the current market and proposes adequate rules of conduct. METHODS: We investigated the risk of the magnetic interference of the iPhone 12 and its MagSafe accessories on a comprehensive set of PMs and ICDs, including the subcutaneous ICD. For the first time, the magnetic interference phenomena were correlated with the magnetic field levels measured all around iPhone 12. RESULTS: We discovered that the magnets inside iPhone 12 trigger the magnetic mode in the 12 tested devices up to a distance of 1 cm. CONCLUSIONS: Considering the implications related to the activation of the magnetic switch, to date, it is advisable to follow Apple's indications relating to the safety distance of 15 cm, which is widely compatible with the results obtained from this paper and in line with the indications provided by the implantable cardiac device manufacturers.

A combined computational and experimental approach to assess the transfer function of real pacemaker leads for MR radiofrequency-induced heating.

OBJECTIVE: To propose and validate a variation of the classic techniques for the estimation of the transfer function (TF) of a real pacemaker (PM) lead. METHODS: The TF of three commercially available PM leads was measured by combining data from experimental measurements and numerical simulations generated by three sources: a) the experimental local SAR at the tip of the PM lead (single measurement point) exposed to a 64 MHz birdcage body coil; b) the experimental current distribution along the PM lead, obtained by directly injecting a 64 MHz signal inside the lead; c) the electric field (E-field) simulated with a computational model of the 64 MHz birdcage body coil adopted in the experimental measurement performed in a). The effect of the lead trajectory on the estimation of the TF was also estimated. RESULTS: The proposed methodology was validated by comparing the SAR obtained from the PM lead TF with experimental measurements: a maximum difference of 2.2 dB was observed. It was also shown that the estimation of the TF cannot be considered independent with the lead trajectory: a variation of the SAR estimation up to 3.4 dB was observed. CONCLUSION: For the three PM lead tested, the error in the SAR estimation is within the uncertainty level of SAR measurements (± 2 dB). Additionally, the estimation of the TF using the reciprocity principle is influenced by the particular lead trajectory adopted, even if the consequent variability in the SAR estimation is still close to the uncertainty level of SAR measurements.

[Assessment of the risk due to exposure to EMF with particular reference to the protection of sensitive subjects]. / La valutazione del rischio da esposizione a CEM con particolare riguardo alla tutela dei soggetti sensibili.

SUMMARY: Purpose. The work illustrates useful elements for the risk assessment for workers exposed to electromagnetic fields, also in reference to sensitive subjects such as those with active implantable medical devices (AIMD). Methods. The approach introduced by Legislative Decree 81/08 for risk assessment does not explicitly include operational criteria and specific measures for the protection of sensitive subjects. In the case of workers with DMIA, the employer may refer to relevant harmonized technical standards. Results. They are shown the results of in vitro tests performed on pacemakers following the indications of the technical reference standard and employing sources of electromagnetic fields that, due to the type of signal emitted, do not allow to exclude an a priori influence on the operation of the device. Conclusions. Workers at particular risk are generally protected if the requirements established for the population are respected. This measure may, under certain conditions, not be sufficient,making it necessary to carry out more in-depth and individual assessments. However, the cases illustrated here for AIMD showed interference phenomena only in limited experimental configurations despite the levels of the electric and magnetic fields generated by the sources exceeding the limits for the general population.

Brain-Heart Pathways to Blood Pressure-Related Hypoalgesia.

OBJECTIVE: High blood pressure (BP) is associated with reduced pain sensitivity, known as BP-related hypoalgesia. The underlying neural mechanisms remain uncertain, yet arterial baroreceptor signaling, occurring at cardiac systole, is implicated. We examined normotensives using functional neuroimaging and pain stimulation during distinct phases of the cardiac cycle to test the hypothesized neural mediation of baroreceptor-induced attenuation of pain. METHODS: Eighteen participants (10 women; 32.7 (6.5) years) underwent BP monitoring for 1 week at home, and individual pain thresholds were determined in the laboratory. Subsequently, participants were administered unpredictable painful and nonpainful electrocutaneous shocks (stimulus type), timed to occur either at systole or at diastole (cardiac phase) in an event-related design. After each trial, participants evaluated their subjective experience. RESULTS: Subjective pain was lower for painful stimuli administered at systole compared with diastole, F(1, 2283) = 4.82, p = 0.03. Individuals with higher baseline BP demonstrated overall lower pain perception, F(1, 2164) = 10.47, p < .0001. Within the brain, painful stimulation activated somatosensory areas, prefrontal cortex, cingulate cortex, posterior insula, amygdala, and the thalamus. Stimuli delivered during systole (concurrent with baroreceptor discharge) activated areas associated with heightened parasympathetic drive. No stimulus type by cardiac phase interaction emerged except for a small cluster located in the right parietal cortex. CONCLUSIONS: We confirm the negative associations between BP and pain, highlighting the antinociceptive impact of baroreceptor discharge. Neural substrates associated with baroreceptor/BP-related hypoalgesia include superior parietal lobule, precentral, and lingual gyrus, regions typically involved in the cognitive aspects of pain experience.

A novel method for the identification of conserved structural patterns in RNA: From small scale to high-throughput applications.

Functional RNA regions are often related to recurrent secondary structure patterns (or motifs), which can exert their role in several different ways, particularly in dictating the interaction with RNA-binding proteins, and acting in the regulation of a large number of cellular processes. Among the available motif-finding tools, the majority focuses on sequence patterns, sometimes including secondary structure as additional constraints to improve their performance. Nonetheless, secondary structures motifs may be concurrent to their sequence counterparts or even encode a stronger functional signal. Current methods for searching structural motifs generally require long pipelines and/or high computational efforts or previously aligned sequences. Here, we present BEAM (BEAr Motif finder), a novel method for structural motif discovery from a set of unaligned RNAs, taking advantage of a recently developed encoding for RNA secondary structure named BEAR (Brand nEw Alphabet for RNAs) and of evolutionary substitution rates of secondary structure elements. Tested in a varied set of scenarios, from small- to large-scale, BEAM is successful in retrieving structural motifs even in highly noisy data sets, such as those that can arise in CLIP-Seq or other high-throughput experiments.

Web-Beagle: a web server for the alignment of RNA secondary structures.

Web-Beagle (http://beagle.bio.uniroma2.it) is a web server for the pairwise global or local alignment of RNA secondary structures. The server exploits a new encoding for RNA secondary structure and a substitution matrix of RNA structural elements to perform RNA structural alignments. The web server allows the user to compute up to 10 000 alignments in a single run, taking as input sets of RNA sequences and structures or primary sequences alone. In the latter case, the server computes the secondary structure prediction for the RNAs on-the-fly using RNAfold (free energy minimization). The user can also compare a set of input RNAs to one of five pre-compiled RNA datasets including lncRNAs and 3' UTRs. All types of comparison produce in output the pairwise alignments along with structural similarity and statistical significance measures for each resulting alignment. A graphical color-coded representation of the alignments allows the user to easily identify structural similarities between RNAs. Web-Beagle can be used for finding structurally related regions in two or more RNAs, for the identification of homologous regions or for functional annotation. Benchmark tests show that Web-Beagle has lower computational complexity, running time and better performances than other available methods.

A novel approach to represent and compare RNA secondary structures.

Structural information is crucial in ribonucleic acid (RNA) analysis and functional annotation; nevertheless, how to include such structural data is still a debated problem. Dot-bracket notation is the most common and simple representation for RNA secondary structures but its simplicity leads also to ambiguity requiring further processing steps to dissolve. Here we present BEAR (Brand nEw Alphabet for RNA), a new context-aware structural encoding represented by a string of characters. Each character in BEAR encodes for a specific secondary structure element (loop, stem, bulge and internal loop) with specific length. Furthermore, exploiting this informative and yet simple encoding in multiple alignments of related RNAs, we captured how much structural variation is tolerated in RNA families and convert it into transition rates among secondary structure elements. This allowed us to compute a substitution matrix for secondary structure elements called MBR (Matrix of BEAR-encoded RNA secondary structures), of which we tested the ability in aligning RNA secondary structures. We propose BEAR and the MBR as powerful resources for the RNA secondary structure analysis, comparison and classification, motif finding and phylogeny.

Impact of capped and uncapped abandoned leads on the heating of an MR-conditional pacemaker implant.

PURPOSE: To assess the risk of radiofrequency (RF)-induced heating in patients with MR-conditional pacemaker (PM) systems, in the presence of another lead abandoned from a previous implant. METHODS: Four commercial pacemaker leads were placed beside a MR-conditional PM system, inside a human trunk simulator. The phantom has been exposed to the RF generated by a 64 MHz body bird-cage coil (whole-body specific absorption rate [SAR] = 1 W/kg) and the induced heating was measured at the tip of the abandoned lead and of the MR-conditional implant. Configurations that maximize the coupling between the RF field and the leads have been tested, as well as realistic implant positions. RESULTS: Abandoned leads showed heating behaviors that strongly depend on the termination condition (abandoned-capped or saline exposed) and on the lead path (left or right positioning). Given a whole-body SAR = 1 W/kg, a maximum temperature rise of 17.6°C was observed. The presence of the abandoned lead modifies the RF-heating profile of the MR-conditional implant: either an increase or a decrease in the induced heating at its lead tip can occur, mainly depending on the relative position of the two leads. Variations ranging from -63% to +69% with respect to the MR-conditional system alone were observed. CONCLUSION: These findings provide experimental evidence that the presence of an abandoned lead poses an additional risk for the patient implanted with a MR-conditional PM system. Our results support the current PM manufacturers' policy of conditioning the MR compatibility of their systems to the absence of abandoned leads (including leads from MR-conditional implants). From a clinical point of view, in such cases, the decision whether to perform the exam shall be based upon a risk/benefit evaluation, as in the case of conventional PM systems.

An optically coupled sensor for the measurement of currents induced by MRI gradient fields into endocardial leads.

OBJECT: The gradient fields generated during magnetic resonance imaging (MRI) procedures have the potential to induce electrical current on implanted endocardial leads. Whether this current can result in undesired cardiac stimulation is unknown. MATERIALS AND METHODS: This paper provides a detailed description of how to construct an optically coupled sensor for the measurement of gradient-field-induced currents into endocardial leads. The system is based on a microcontroller that works as analog-to-digital converter and sends the current signal acquired from the lead to an optical high-speed, light-emitting diode transmitter. A plastic fiber guides the light outside the MRI chamber to a photodiode receiver and then to an acquisition board connected to a PC laptop. RESULTS: The performance of the system has been characterized in terms of power consumption (8 mA on average), sampling frequency (20.5 kHz), measurement range (-12.8 to 10.3 mA) and resolution (22.6 µA). Results inside a 3 T MRI scanner are also presented. CONCLUSIONS: The detailed description of the current sensor could permit more standardized study of MRI gradient current induction in pacemaker systems. Results show the potential of gradient currents to affect the pacemaker capability of triggering a heartbeat, by modifying the overall energy delivered by the stimulator.

Risk Assessment for Workers with Wearable Medical Devices Exposed to Electromagnetic Fields.

ABSTRACT: The exponential diffusion of wearable medical devices (WMD) in recent years has involved people of all ages, including workers. Workers who use WMDs should be considered at a particular risk from electromagnetic fields, and in accordance with EU Directive 2013/35/EU, they require an individual risk assessment. Currently, there is no international standard that provides specific guidance on how to perform such a risk assessment. This paper focuses on the effects of electromagnetic fields on WMDs and does not consider the direct effects on human body tissues. It aims to offer practical recommendations to employers and/or health physicists for the risk assessment of workers with WMDs. Focusing on EU countries, we first describe the requirements outlined by the technical standard for the electromagnetic compatibility (EMC) of medical electrical equipment EN 60601-1-2. Then, some general guidelines on how to perform the risk assessment are provided. The assessment can be conducted by comparing the field values measured in the workplace with the immunity test levels specified in the technical standards of medical electrical equipment. If the measured values are lower than the immunity test levels indicated in the standard and the distance from the electromagnetic source is greater than the distance used by the manufacturer during the EMC (electromagnetic compatibility) tests (typically 30 cm), the risk for the worker may be considered acceptable. However, if the measured values exceed the immunity test levels or the distance criteria, a specific evaluation based on a case-by-case analysis is required.

Personalized Antiarrhythmic Therapy Using a Self-Managed Daily-ECG Device.

A 50-year-old Caucasian man arrived at the emergency department presenting paucisymptomatic atrial fibrillation. Once discharged after the appropriate treatments, the patient continued to have paucisymptomatic episodes. For this reason, he was provided with the Cardionica device which made it possible to better investigate the type of arrhythmic episodes, in order to tailor his therapy and to finally restore a normal sinus rhythm in the patient.

Pacemakers, Implantable Defibrillators, and 5G Technology: What We Need to Know.

ABSTRACT: Pacemakers (PM) and implantable cardioverter defibrillators (ICD) are active implantable medical devices (AIMD) needed in case of cardiac arrhythmias. Given their potentially life-sustaining nature, the interaction between any source of electromagnetic field and these AIMDs is an ongoing concern of patients, industry, and regulators. According to the current regulatory framework, the required immunity of PM and ICD provides a reasonable unperturbed behavior in the presence of cell phones and base stations that use pre-5G technologies. PM/ICD international standards do not consider some peculiar characteristics of 5G technology and some of the 5G technology frequency bands (those above 3 GHz), since these frequencies are considered not to add risks to the AIMD functioning. Here we analyze the theoretical issues about the interference between 5G technology and PM/ICD and propose an experimental approach to perform a measurement campaign.

5G Service and Pacemakers/Implantable Defibrillators: What Is the Actual Risk?

Rapidly growing worldwide, 5G service is expected to deeply change the way we communicate, connect and share data. It encompasses the whole spectrum of new technology, infrastructure and mobile connectivity, and will touch not only every sector in the industry, but also many aspects of our everyday life. Although the compliance with international regulations provides reasonable protection to public health and safety, there might be specific issues not fully covered by the current technical standards. Among the aspects that shall be carefully considered, there is the potential interference that can be induced on medical devices, and in particular on implantable medical devices that are critical for the patient's life, such as pacemakers and implantable defibrillators. This study aims to assess the actual risk that 5G communication systems pose to pacemakers and implantable defibrillators. The setup proposed by the ISO 14117 standard was adapted to include 5G characteristic frequencies of 700 MHz and 3.6 GHz. A total number of 384 tests were conducted. Among them, 43 EMI events were observed. Collected results reveal that RF hand-held transmitters operating in these two frequency bands do not pose additional risk compared to pre-5G bands and that the safety distance of 15 cm typically indicted by the PM/ICD manufacturer is still able to guarantee the patient's safety.

Single-cell multi-scale footprinting reveals the modular organization of DNA regulatory elements.

Cis-regulatory elements control gene expression and are dynamic in their structure, reflecting changes to the composition of diverse effector proteins over time1-3. Here we sought to connect the structural changes at cis-regulatory elements to alterations in cellular fate and function. To do this we developed PRINT, a computational method that uses deep learning to correct sequence bias in chromatin accessibility data and identifies multi-scale footprints of DNA-protein interactions. We find that multi-scale footprints enable more accurate inference of TF and nucleosome binding. Using PRINT with single-cell multi-omics, we discover wide-spread changes to the structure and function of candidate cis-regulatory elements (cCREs) across hematopoiesis, wherein nucleosomes slide, expose DNA for TF binding, and promote gene expression. Activity segmentation using the co-variance across cell states identifies "sub-cCREs" as modular cCRE subunits of regulatory DNA. We apply this single-cell and PRINT approach to characterize the age-associated alterations to cCREs within hematopoietic stem cells (HSCs). Remarkably, we find a spectrum of aging alterations among HSCs corresponding to a global gain of sub-cCRE activity while preserving cCRE accessibility. Collectively, we reveal the functional importance of cCRE structure across cell states, highlighting changes to gene regulation at single-cell and single-base-pair resolution.

Role of the lead structure in MRI-induced heating: In vitro measurements on 30 commercial pacemaker/defibrillator leads.

MRI-induced heating on endocardial leads is a serious concern for the safety of patients with implantable pacemakers or cardioverter-defibrillator. The lead heating depends on many factors and its amount is largely variable. In this study, we investigated the role of those structural properties of the lead that are reported on the accompanying documents of the device: (1) fixation modality (active vs. passive); (2) number of electrodes (unipolar vs. bipolar); (3) length; (4) tip surface; and (5) tip and ring resistance. In vitro temperature and specific absorption rate measurements on 30 leads (27 pacemakers, three implantable cardioverter-defibrillator leads) exposed to the radiofrequency field typical of a 1.5 T MRI scanner are presented. The data show that each lead has its own attitude to radiofrequency-induced heating and that the information that is available in the accompanying documents of the pacemaker is not sufficient to explain such attitude. Even if combined with that of the implant geometry, this information is still not sufficient to estimate the amount of heating due to the exposure to the radiofrequency field during MRI examination.

Daily distribution of atrial arrhythmic episodes in sick sinus syndrome patients: implications for atrial arrhythmia monitoring.

AIMS: Disorders such as paroxysmal atrial fibrillation (AF) and atrial tachyarrhythmias (AT) are difficult to investigate because of their intermittent, and sometimes asymptomatic, nature. The aim of this study was to investigate the daily temporal distribution of AT/AF episodes--onset and occurrence--by analysing data from 250 pacemaker-implanted, brady-tachy syndrome patients who have been enrolled in the Burden II Study. METHODS AND RESULTS: Data were analysed accounting for the mode switch list which includes date, time, and duration of each mode switch episode. Chi-squared tests for goodness of fit were used to determine whether AT/AF episode were uniformly distributed. The population analysed in the present study suggests the occurrence of a circadian rhythm of paroxysmal AF episodes, similar to that described for other cardiovascular diseases, with clustering of events in the morning from 08:00 and (to a lesser degree) in the afternoon (03:00 to 18:00). The relative risk of AT/AF onset is 13% higher during daytime, 40% lower at night (P < 0.000001). CONCLUSION: The use of monitoring devices based on daily electrocardiogram (ECG) recording could be optimized with these data, thus increasing the probability to detect AT/AF episodes.

Mapping European research networks providing health data: results from the InfAct Joint Action on health information.

BACKGROUND: Research networks offer multidisciplinary expertise and promote information exchange between researchers across Europe. They are essential for the European Union's (EU) health information system as providers of health information and data. The aim of this mapping exercise was to identify and analyze EU research networks in terms of health data collection methods, quality assessment, availability and accessibility procedures. METHODS: A web-based search was performed to identify EU research networks that are not part of international organizations (e.g., WHO-Europe, OECD) and are involved in collection of data for health monitoring or health system performance assessment. General characteristics of the research networks (e.g., data sources, representativeness), quality assessment procedures, availability and accessibility of health data were collected through an ad hoc extraction form. RESULTS: Fifty-seven research networks, representative at national, international or regional level, were identified. In these networks, data are mainly collected through administrative sources, health surveys and cohort studies. Over 70% of networks provide information on quality assessment of their data collection procedures. Most networks share macrodata through articles and reports, while microdata are available from ten networks. A request for data access is required by 14 networks, of which three apply a financial charge. Few networks share data with other research networks (8/49) or specify the metadata-reporting standards used for data description (9/49). CONCLUSIONS: Improving health information and availability of high quality data is a priority in Europe. Research networks could play a major role in tackling health data and information inequalities by enhancing quality, availability, and accessibility of health data and data sharing across European networks.

Health data collection methods and procedures across EU member states: findings from the InfAct Joint Action on health information.

BACKGROUND: Health-related data are collected from a variety of sources for different purposes, including secondary use for population health monitoring (HM) and health system performance assessment (HSPA). Most of these data sources are not included in databases of international organizations (e.g., WHO, OECD, Eurostat), limiting their use for research activities and policy making. This study aims at identifying and describing collection methods, quality assessment procedures, availability and accessibility of health data across EU Member States (MS) for HM and HSPA. METHODS: A structured questionnaire was developed and administered through an online platform to partners of the InfAct consortium form EU MS to investigate data collections applied in HM and HSPA projects, as well as their methods and procedures. A descriptive analysis of the questionnaire results was performed. RESULTS: Information on 91 projects from 18 EU MS was collected. In these projects, data were mainly collected through administrative sources, population health interview or health examination surveys and from electronic medical records. Tools and methods used for data collection were mostly mandatory reports, self-administered questionnaires, or record linkage of various data sources. One-third of the projects shared data with EU research networks and less than one-third performed quality assessment of their data collection procedures using international standardized criteria. Macrodata were accessible via open access and reusable in 22 projects. Microdata were accessible upon specific request and reusable in 15 projects based on data usage licenses. Metadata was available for the majority of the projects, but followed reporting standards only in 29 projects. Overall, compliance to FAIR Data principles (Findable, Accessible, Interoperable, and Reusable) was not optimal across the EU projects. CONCLUSIONS: Data collection and exchange procedures differ across EU MS and research data are not always available, accessible, comparable or reusable for further research and evidence-based policy making. There is a need for an EU-level health information infrastructure and governance to promote and facilitate sharing and dissemination of standardized and comparable health data, following FAIR Data principles, across the EU.

Workers with Cardiac AIMD Exposed to EMF: Methods and Case Studies for Risk Analysis in the Framework of the European Regulations.

Workers with cardiac active implantable medical devices (AIMD), such as a pacemaker (PM) or an implantable defibrillator (ICD), are considered by the occupational health and safety regulation framework as a particularly sensitive risk group that must be protected against the dangers caused by the interference of electromagnetic field (EMF). In this paper, we first describe the general methodology that shall be followed for the risk assessment of employees with a cardiac AIMD exposed to EMF, according to the EU regulation, and in particular to the EN 50527-2-1:2016 and 50527-2-2:2018 standards. Then, three case studies related to specific EMF sources are presented, to better describe how the initial analysis of the risk assessment can be performed in practice, and to understand if a further specific risk assessment analysis is required or not.