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Objective: Non-invasive brain stimulation (NIBS) methodologies, such as transcranial electric (tES) are increasingly employed for therapeutic, diagnostic, or research purposes. The concurrent presence of active/passive implants can pose safety risks, affect the NIBS delivery, or generate confounding signals. A systematic investigation is required to understand the interaction mechanisms, quantify exposure, assess risks, and establish guidance for NIBS applications., Approach: We used measurements, simplified generic, and detailed anatomical modeling to: (i) systematically analyze exposure conditions with passive and active implants, considering local field enhancement, exposure dosimetry, tissue heating and neuromodulation, capacitive lead current injection, low-impedance pathways between electrode contacts, and insulation damage; (ii) identify risk metrics and efficient prediction strategies; (iii) quantify these metrics in relevant exposure cases and (iv) identify worst case conditions. Various aspects including implant design, positioning, scar tissue formation, anisotropy, and frequency were investigated., Results: At typical tES frequencies, local enhancement of dosimetric exposure quantities can reach up to one order of magnitude for deep brain stimulation (DBS) and stereoelectroencephalography implants (more for elongated passive implants), potentially resulting in unwanted neuromodulation that can confound results but is still 2-3 orders of magnitude lower than active DBS. Under worst-case conditions, capacitive current injection in the active implants' lead can produce local exposures of similar magnitude as the passive field enhancement, while capacitive pathways between contacts are negligible. Above 10 kHz, applied current magnitudes increase, necessitating consideration of tissue heating. Furthermore, capacitive effects become more prominent, leading to current injection that can reach DBS-like levels. Adverse effects from abandoned/damaged leads in direct electrode vicinity cannot be excluded., Significance: Safety related concerns of tES application in the presence of implants are systematically identified and explored, resulting in specific and quantitative guidance and establishing basis for safety standards. Furthermore,several methods for reducing risks are suggested while acknowledging the limitations(see Sec. 4.5)., (Creative Commons Attribution license.)

The growing use of adjuvants in the fast-paced formulation of new vaccines has created an unprecedented need for meaningful analytical assays that deliver reliable quantitative data from complex adjuvant and adjuvant-antigen mixtures. Due to their complex chemical and physical properties, method development for the separation of vaccine adjuvants is considered a highly challenging and laborious task. Reversed-phase liquid chromatography (RPLC) is among the most important tests in the (bio)pharmaceutical industry for release and stability indicating measurements including adjuvant content, identity, and purity profile. However, the time constraints of developing "on-demand" robust quantitative methods prior to each change in formulation can easily lead to sample analysis becoming a bottleneck in vaccine development. Herein, a simple and efficient generic analytical framework capable of chromatographically resolving the most commonly used non-aluminum-based adjuvants across academic and industrial sectors is introduced. This was designed to seek a more proactive approach for fast-paced assay development endeavors that evolved from extensive stationary phase screening in conjunction with multifactorial in silico simulations of adjuvant retention time (RT) as a function of gradient time, temperature, organic modifier blending, and buffer concentration. The multifactorial retention models yield 3D resolution maps with excellent baseline separation of all adjuvants in a single run, which was found to be very accurate, with differences between experimental and simulated retention times of less than 1%. The analytical framework described here also includes the introduction of a more versatile approach to method development by introducing a dynamic RT database for adjuvants covering the entire library of adjuvants with broad mechanisms of action across numerous vaccine formulations with excellent linearity, accuracy, precision, and specificity. The power of this framework was also demonstrated with numerous analytical assays that can be generated rapidly from simulations guiding vaccine processes in the development of new adjuvant formulations. Analytical assay in this work covers content, purity profile by LC with diode array detector (DAD) and charged aerosol detector (CAD), and component identification by LC with mass spectrometry (MS) across complex vaccine formulations, including the use of surfactants ( e.g. , polysorbates) as well as their separation from adjuvant targets., Competing Interests: The authors declare no competing financial interest., (© 2024 Merck & Co., Inc. Rahway, NJ, USA and its affiliates. Published by American Chemical Society.)

The sense of agency refers to the feeling of controlling one's actions and their effects on the external environment. Here, we tested how the physiological process of aging affects the agency experience by taking advantage of a validated ecological experimental paradigm and exploring the different dimensions of agency. We tested 60 young and older adults during active and passive movements, causing, after a variable time delay, an external sensorial event. We collected overt agency judgments (i.e., explicit agency dimension), and we measured the perceived compression of the time interval between the active/passive movements and outcomes (to quantify the intentional binding phenomenon, an implicit index of agency). Our results indicate that the sense of agency significantly changes across the adult life span, with older participants exhibiting a reduced sense of agency, both at the explicit and implicit level. Crucially, the temporal dimension of the action outcome did not affect their agency experience. We suggest that elderly adults are more reliant on internal predictions, making them less sensitive to cognitive biases and external manipulations. We discuss these results in the domain of neurocognitive models of motor control, with reference to how aging affects the weighting process of predictive and sensory signals for efficient sensorimotor integration., (© 2024. The Author(s).)

Objective . Spinal cord stimulation (SCS) is a well-established treatment for managing certain chronic pain conditions. More recently, it has also garnered attention as a means of modulating neural activity to restore lost autonomic or sensory-motor function. Personalized modeling and treatment planning are critical aspects of safe and effective SCS (Rowald and Amft 2022 Front. Neurorobotics 16 983072, Wagner et al 2018 Nature 563 65-71). However, the generation of spine models at the required level of detail and accuracy requires time and labor intensive manual image segmentation by human experts. This study aims to develop a maximally automated segmentation routine capable of producing high-quality anatomical models, even with limited data, to facilitate safe and effective personalized SCS treatment planning. Approach . We developed an automated image segmentation and model generation pipeline based on a novel convolutional neural network (CNN) architecture trained on feline spinal cord magnetic resonance imaging data. The pipeline includes steps for image preprocessing, data augmentation, transfer learning, and cleanup. To assess the relative importance of each step in the pipeline and our choice of CNN architecture, we systematically dropped steps or substituted architectures, quantifying the downstream effects in terms of tissue segmentation quality (Jaccard index and Hausdorff distance) and predicted nerve recruitment (estimated axonal depolarization). Main results . The leave-one-out analysis demonstrated that each pipeline step contributed a small but measurable increment to mean segmentation quality. Surprisingly, minor differences in segmentation accuracy translated to significant deviations (ranging between 4% and 13% for each pipeline step) in predicted nerve recruitment, highlighting the importance of careful workflow design. Additionally, transfer learning techniques enhanced segmentation metric consistency and allowed generalization to a completely different spine region with minimal additional training data. Significance . To our knowledge, this work is the first to assess the downstream impacts of segmentation quality differences on neurostimulation predictions. It highlights the role of each step in the pipeline and paves the way towards fully automated, personalized SCS treatment planning in clinical settings., (Creative Commons Attribution license.)

Purpose: Radiofrequency (RF) exposure during MR examination is limited by IEC 60601-2-33 to prevent thermal hazards to patients. These limits are also the basis to derive the maximum induced field for the demonstration of MR safety of implants per ISO/TS 10974 (2018). One limit is the head-averaged specific absorption rate (SAR), for which the head extent is defined differently by MR and implant vendors. The purpose of this technical note is to inform MR safety stakeholders on the sensitivity of safety evaluations due to different head extent definitions., Methods: RF distributions from the validated MRIxViP exposure libraries of 12 high-resolution human anatomical models were scaled to the normative SAR limits for different definitions of the head extent to compare the corresponding induced SAR and electric (E-)field levels., Results: The definitions of the head extent used by major implant vendors and defined in ISO/TS 10974 (2018) are larger than those introduced in IEC 60601-2-33 (2022), resulting in lower RF head exposure by up to 2.4 dB (factor 1.7). Other proposed definitions of the head result in intermediate values., Conclusion: The different head extents result in different maximum RF exposures affecting the risk assessment by up to a factor of 1.7. The results of this study can be used to estimate the additional uncertainty in safety assessments. Future revisions of MR standards should eliminate this inconsistency., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background and Aims: The dialysate magnesium (Mg) concentration is a major determinant of Mg balance in hemodialysis. This study aimed to assess the systemic variations of total (tMg) and ionized Mg (iMg) during a dialysis session using acetate or citrate fluids and 0.5 or 0.75 mM Mg., Materials and Methods: 134 patients in maintenance hemodialysis were assigned to a dialysis session with 4 different dialysates: acetate fluid with 0.5 mM Mg (1) or 0.75 mM Mg (2), citrate fluid with 0.5 mM Mg (3) or 0.75 mM Mg (4). Ionized form was measured by direct ion-selective electrode., Results: A Mg loss was observed in both acetate (0.12 and 0.08 mmol/L) and citrate (0.13 and 0.14 mmol/L for tMg and iMg, respectively) fluid groups containing 0.5 mM Mg. The use of acetate and citrate dialysates with 0.75 mM Mg led to a significant median intra-dialytic increase of 0.15 and 0.08 mmol/L for tMg, respectively. A significant augmentation in iMg concentration with acetate (0.11 mmol/L) but not with citrate dialysate (0.02 mmol/L) was observed., Conclusion: While a dialysate Mg concentration at 0.5 mM leads to a negative balance, increasing the concentration to 0.75 mM significantly raises post-dialysis circulating Mg. Monitoring of iMg should allow a personalized prescription in dialysate Mg., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Deep brain stimulation (DBS) via implanted electrodes is used worldwide to treat patients with severe neurological and psychiatric disorders. However, its invasiveness precludes widespread clinical use and deployment in research. Temporal interference (TI) is a strategy for non-invasive steerable DBS using multiple kHz-range electric fields with a difference frequency within the range of neural activity. Here we report the validation of the non-invasive DBS concept in humans. We used electric field modeling and measurements in a human cadaver to verify that the locus of the transcranial TI stimulation can be steerably focused in the hippocampus with minimal exposure to the overlying cortex. We then used functional magnetic resonance imaging and behavioral experiments to show that TI stimulation can focally modulate hippocampal activity and enhance the accuracy of episodic memories in healthy humans. Our results demonstrate targeted, non-invasive electrical stimulation of deep structures in the human brain., (© 2023. The Author(s).)

Objective . Craniospinal compliance (CC) is an important metric for the characterization of space-occupying neurological pathologies. CC is obtained using invasive procedures that carry risks for the patients. Therefore, noninvasive methods for acquiring surrogates of CC have been proposed, most recently based on changes in the head's dielectric properties during the cardiac cycle. Here, we have tested whether changes in body position, which are known to influence CC, are reflected in a capacitively acquired signal (hereinafter referred to as W) originating from dynamic changes of the head's dielectric properties. Approach . eighteen young healthy volunteers were included in the study. After 10 min in supine position, subjects were tilted head-up (HUT), back to 0° (horizontal, control), and then head-down (HDT). Metrics related to cardiovascular action were extracted from W, including AMP, the peak-to-valley amplitude of the cardiac modulation of W. Computational electromagnetic simulations were performed to probe the association between intracranial volume change and W. Main results . AMP decreased during HUT (0°: 2869 ± 597 arbitrary units (au); +75°: 2307 ± 490 au, P = 0.002) and increased during HDT (-30°: 4403 ± 1428 au, P < 0.0001). The same behavior was predicted by the electromagnetic model. Significance . tilting affects the distribution of CC between cranial and spinal compartments. Cardiovascular action induces compliance-dependent oscillatory changes in the intracranial fluid composition, which causes corresponding variations in the head's dielectric properties. These manifest as increasing AMP with decreasing intracranial compliance, which suggests that W may contain information related to CC, and that it might be possible to derive CC surrogates therefrom., (Creative Commons Attribution license.)

Background and Aims: Muscle mass (MM) impairment observed in facioscapulohumeral muscular dystrophy (FSHD) may bias estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcreat). eGFR based on cystatin C (eGFRcys), produced by all nucleated cells, should be an interesting alternative. Main objectives were to compare eGFRcreat and eGRFcys for chronic kidney disease (CKD) staging and for annual eGFR evolution. Secondary objective was to analyse creatinine, cystatin C with measured MM., Material and Methods: During 4 years, 159 FSHD patients having one or more creatinine and cystatin C measurements (total samples: n = 379), with MM determination by bio-impedancemetry during their follow-up were included. eGFR were determined with CKD-Epi and EKFC equations., Results: On first examination samples, mean eGFRcys was significantly lower than mean eGFRcreat of 25.5 and 17.9 ml/min/1.73 m 2 using CKD-Epi and EKFC equations, respectively. 53.5% (CKD-Epi) and 59.1% (EKFC) of agreement were obtained when using eGFRcys instead of eGFRcreat with reclassifications occurring mainly towards more severe stages. Age was correlated with cystatin C but not with creatinine, MM was correlated with creatinine but not with cystatin C. eGFR decreases > 1 ml/min/1.73 m 2 were more important when using eGFRcys instead of eGFRcreat (CKD-Epi: 37.5 vs 15.4%, p < 0.001; EKFC: 34.6 vs 20.2%, p < 0.01)., Conclusion: Cystatin C which is independent of MM appears as a promising candidate biomarker for CKD diagnosis and follow-up in FSHD patient., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Transvenous lead extractions are increasingly performed for malfunction or infection of cardiac implantable electronic devices, but they harvest a potential for complications and suboptimal success. Apart from multicenter registries and reports from highly experienced single centers, the outcome in individual newly developing high-volume centers starting a lead extraction program is less well established. We aimed to evaluate the clinical and radiological success and complication rate at our center, having started a lead extraction program less than a decade ago., Methods: We retrospectively analyzed patients who underwent transvenous lead extraction at the University Hospital Zurich from 2013 to 2021 regarding success as well as complications and compared our results to previously reported outcome rates., Results: A total of 346 patients underwent 350 transvenous lead extractions from January 2013 to December 2021. Combined radiological success was achieved in 97.7% and clinical success in 96.0% of interventions. Procedure-related major complications occurred in 13 patients (3.7%). Death within 30 days after transvenous lead extractions occurred in 13 patients (3.7%), with a procedure-related mortality of 1.4% (five patients)., Summary: Transvenous lead extractions in newly developing high-volume centers can be performed with high clinical and radiological success rates, but procedure-related major complications may affect a relevant number of patients. Compared to large single or multicenter registries of experienced centers, the success rate may be lower and the complication rate higher in centers newly starting with lead extraction, which may have important implications for patient selection, procedural planning, proctoring, and safety measures., Competing Interests: Daniel Hofer reports educational grants, consultant or speaker fees, and fellowship support from Abbott, Medtronic, Biotronik, Boston Scientific, Biosense Webster, Novartis, Bayer, Pfizer, and Spectranetics. Alexander Breitenstein has received consultant and/or speaker fees from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Bristol-Myers Squibb, Cook Medical, Daiichi Sankyo, Medtronic, Pfizer, and Spectranetics/Philipps. Jan Steffel has received consultant and/or speaker fees from Abbott, Alexion, Astra-Zeneca, Bayer, Berlin-Chemie, Biosense Webster, Biotronik, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Medscape, Medtronic, Menarini, Merck/MSD, Organon, Pfizer, Saja, Servier, andWebMD. He reports ownership of CorXL and Swiss EP. Steffel has received grant support through his former institution from Abbott, Bayer Healthcare, BiosenseWebster, Biotronik, Boston Scientific, Daiichi Sankyo, and Medtronic. Sasse reports educational grants from Biotronik.

Bacterial infection remains as one of the major healthcare issues, despite significant scientific and medical progress in this field. Infection by Streptococcus Pneumoniae (S. Pneumoniae) can cause pneumonia and other serious infectious diseases, such as bacteremia, sinusitis and meningitis. The pneumococcal capsular polysaccharides (CPS) that constitute the outermost layer of the bacterial cell are the main immunogens and protect the pathogen from host defense mechanisms. Over 90 pneumococcal CPS serotypes have been identified, among which more than 30 can cause invasive pneumococcal diseases that could lead to morbidity and mortality. Multivalent pneumococcal vaccines have been developed to prevent diseases caused by S. Pneumoniae. These vaccines employ either purified pneumococcal CPSs or protein conjugates of these CPSs to generate antigen-specific immune responses for patient protection. Serotype-specific quantitation of these polysaccharides (Ps) antigen species are required for vaccine clinical dosage, product release and quality control. Herein, we have developed an antibody-enhanced high-performance liquid chromatography (HPLC) assay for serotype-specific quantitation of the polysaccharide contents in multivalent pneumococcal conjugate vaccines (PCVs). A fluorescence-labeled multiplex assay format has also been developed. This work laid the foundation for a serotype-specific antigen assay format that could play an important role for future vaccine research and development., (© 2023. Merck & Co., Inc., Rahway, NJ USA and its affiliates.)

Objective . Regulators require that wireless power transfer (WPT) systems and other strong magnetic field sources are compliant with the basic restrictions (BR) defined as the limits of the fields induced in the human body, i.e. the induced electric field/current density/specific absorption rate limits. This can be achieved by demonstrating compliance with the reference levels (RL) defined in air without the human body, i.e. the incident electric/magnetic field limits. Local sources, such as WPT transmitters, generate non-uniform fields that can locally exceed the RL while the induced fields are still well below the BR. In these cases, robust compliance with BR can be demonstrated, generally requiring a large number of simulations. In this study, we proposed an efficient evaluation using a homogeneous phantom and applying a coverage factor to account for the local field enhancements caused by the dielectric contrasts of the highly inhomogeneous human tissues. Approach . The generally applicable coverage factors were derived from a statistical analysis of the field enhancements observed on four magnetic near-field sources placed at different separation distances (2-80 mm) and locations on the back of 12 anatomical models. The field enhancements were characterized by the ratios between the peak induced fields in the anatomical models and those in the homogeneous half-space phantom ( ϵ r = 55, σ = 0.75 S m -1 , ρ = 1,000 kg m -3 ) at the same distance. Main results . The resulting 99th percentile coverage factors range from 1 and 9 depending on the dosimetric quantity. Significance . The use of these coverage factors reduces the compliance testing effort from hundreds of simulations to only one, and makes experimental testing feasible without the support of simulations. The study also demonstrates that running only a few use-case simulations with anatomical models may underestimate the exposure by more than 10 dB., (© 2023 Institute of Physics and Engineering in Medicine.)

Objective: The clinical management of several neurological disorders benefits from the assessment of intracranial pressure and craniospinal compliance. However, the associated procedures are invasive in nature. Here, we aimed to assess whether naturally occurring periodic changes in the dielectric properties of the head could serve as the basis for deriving surrogates of craniospinal compliance noninvasively., Methods: We designed a device and electrodes for noninvasive measurement of periodic changes of the dielectric properties of the human head. We characterized the properties of the device-electrode-head system by measurements on healthy volunteers, by computational modeling, and by electromechanical modeling. We then performed hyperventilation testing to assess whether the measured signal is of intracranial origin., Results: Signals obtained with the device on volunteers showed characteristic cardiac and respiratory modulations. Signal oscillations can be attributed primarily to changes in resistive properties of the head during cardiac and respiratory cycles. Reduction of end-tidal CO 2 , through hyperventilation, resulted in a decrease in the signal amplitude associated with cardiovascular action., Conclusion: Given the higher CO 2 reactivity of intracranial vessels compared to extracranial ones, the results of hyperventilation testing suggest that the acquired signal is, in part, of intracranial origin., Significance: If confirmed in larger cohorts, our observations suggest that noninvasive capacitive acquisition of changes in the dielectric properties of the head could be used to derive surrogates of craniospinal compliance.

Monitoring intracranial pressure (ICP) and craniospinal compliance (CC) is frequently required in the treatment of patients suffering from craniospinal diseases. However, current approaches are invasive and cannot provide continuous monitoring of CC. Dynamic exchange of blood and cerebrospinal fluid (CSF) between cranial and spinal compartments due to cardiac action transiently modulates the geometry and dielectric properties of the brain. The resulting impedance changes can be measured and might be usable as a non-invasive CC surrogate. A numerically robust and computationally efficient approach based on the reciprocity theorem was developed to compute dynamic impedance changes resulting from small geometry and material property changes. The approach was successfully verified against semi-analytical benchmarks, before being combined with experimental brain pulsation data to study the information content of the impedance variation. The results indicate that the measurable signal is dominated by the pulsatile displacement of the cortical brain surface, with minor contributions from the ventricular surfaces and from changes in brain perfusion. Different electrode setups result in complementary information. The information content from the investigated three electrode pairs was employed to successfully infer subject-specific brain pulsation and motion features. This suggests that non-invasive CC surrogates based on impedance monitoring could be established., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andreas Spiegelberg is applicant and inventor of the patent application DE102018100697A1 and several dependent international applications. Vartan Kurtcuoglu is inventor and the University of Zurich applicant of the same patent applications., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study investigates the absorption of the induced E-field in homogeneous biological tissue exposed to highly localized field sources in proximity of the body, such as the charged tips of antennas, where E-field coupling dominates. These conditions are relevant for compliance testing of modern mobile phones where exposure is evaluated at small separation between radiators and the body. We derive an approximation that characterizes the decay of the induced E-field in the tissue as a function of distance. The absorption is quantified in terms of the local specific absorption rate (SAR) at the tissue surface as a function of the charge at the antenna tip. The approximation is based on the analytical evaluation of the E-fields of a charged disk under quasi-static conditions. We validate this approximation using full-wave simulations of dipoles. We demonstrate that the coupling mechanism of the E-field is dominated by the perpendicular field component and that wave propagation need not be considered for the characterization of the exposure. The surface SAR decreases approximately with the fourth power of the distance and with the square of the ratio of the permittivities of the tissue and free-space. The approximation predicts the induced maximum E-field with an accuracy of better than 1.5 dB. © 2022 Bioelectromagnetics Society., (© 2022 Bioelectromagnetics Society.)

Background: Point-of-care testing (POCT) provides shorter turn-around times and, in many cases, potentially improves medical decision making. The AQT90 FLEX® benchtop immunoanalyzer (Radiometer Medical ApS, Copenhagen, Denmark) allows for the determination of beta-human chorionic gonadotropin (βhCG) in 18 min. The main aim of this study was to evaluate the impact of measuring βhCG using the AQT90 analyzer in the gynecology emergency department (ED) compared to the standard practice of using central laboratory blood testing on the patient length of stay (LOS). Methods: The evaluation consisted of two parts. The first one, conducted in the central laboratory, focused on the analytical performances of the AQT βhCG assay. The second one, conducted in the ED, aimed at determining the impact of POCT βhCG implementation on the timeframe in which ED patients require βhCG assessment. Results: The within-lab imprecisions at the mean values of 17 and 287 IU/L were 2.7% and 3.7%, respectively. Using Deming regression (n = 60), the following equation was obtained in the central lab: AQT90 βhCG = 1.1 Roche βhCG—12.9 (r = 0.997). The implementation of POCT βhCG in the ED significantly reduced patient LOS (145 (90−212) min vs. 205 (155−265) with and without AQT90, respectively, p < 0.001). At the 2 IU/L decision level, a 99.7% agreement with the Roche assay was reported (kappa statistics, 0.99). Conclusions: We confirm that the analytical qualities of the AQT 90 were in line with those obtained in the central lab. The implementation of the POCT βhCG is associated with a shorter LOS in the ED due to the faster availability of the results and the faster decision-making possibilities.

Background: The use of cardiac implantable electronic devices (CIEDs) to treat tachy- and bradyarrhythmia has significantly increased over the past decades. Consequently, transvenous lead extractions (TLE) have been performed more frequently, particularly in the treatment of device infection or malfunction. We aimed to evaluate the development of procedure indications and cardiovascular risk factors of patients undergoing TLE over time. Materials and methods: 277 TLE cases from 2013 to 2020 performed at the University Hospital Zurich were included in this retrospective analysis. Patient charts and follow-up letters were screened for procedure indication and cardiovascular risk factors to evaluate trends over time. Results: 502 leads were extracted in 273 patients. The main indications for TLE remained lead dysfunction (48.7%) and infection (31.4%) throughout the investigated period; however, infections were less and device upgrade more frequently encountered indications for TLE over time. Mean patient age at the time of TLE (64.0 ± 0.9 in the entire sample) decreased over time, while the incidence of chronic kidney disease (33.6%), heart failure (48.6%), or diabetes mellitus (22%) demonstrated an increasing trend. Conclusions: The main indications for TLE remain device malfunction and infection, while device upgrade was increasingly encountered as an indication for TLE in recent years. Over time, patients undergoing TLE were increasingly younger and more often presented with cardiovascular risk factors.

Epidural electrical stimulation (EES) targeting the dorsal roots of lumbosacral segments restores walking in people with spinal cord injury (SCI). However, EES is delivered with multielectrode paddle leads that were originally designed to target the dorsal column of the spinal cord. Here, we hypothesized that an arrangement of electrodes targeting the ensemble of dorsal roots involved in leg and trunk movements would result in superior efficacy, restoring more diverse motor activities after the most severe SCI. To test this hypothesis, we established a computational framework that informed the optimal arrangement of electrodes on a new paddle lead and guided its neurosurgical positioning. We also developed software supporting the rapid configuration of activity-specific stimulation programs that reproduced the natural activation of motor neurons underlying each activity. We tested these neurotechnologies in three individuals with complete sensorimotor paralysis as part of an ongoing clinical trial ( www.clinicaltrials.gov identifier NCT02936453). Within a single day, activity-specific stimulation programs enabled these three individuals to stand, walk, cycle, swim and control trunk movements. Neurorehabilitation mediated sufficient improvement to restore these activities in community settings, opening a realistic path to support everyday mobility with EES in people with SCI., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Healthy tissue hotspots are a main limiting factor in administering deep hyperthermia cancer therapy. We propose an optimization scheme that uses time-multiplexed steering (TMPS) among minimally correlated (nearly) Pareto-optimal solutions to suppress hotspots without reducing tumor heating. Furthermore, tumor heating homogeneity is maximized, thus reducing toxicity and avoiding underexposed tumor regions, which in turn may reduce recurrence., Materials and Methods: The novel optimization scheme combines random generation of steering parameters with local optimization to efficiently identify the set of (Pareto-) optimal solutions of conflicting optimization goals. To achieve simultaneous suppression of hotspots, multiple steering parameter configurations with minimally correlated hotspots are selected near the Pareto front and combined in TMPS. The performance of the novel scheme was compared with that of a multi-goal Genetic Algorithm for a range of simulated treatment configurations involving a modular applicator heating a generic tumor situated in the bladder, cervix, or pelvic bone. SAR cumulative histograms in tumor and healthy tissue, as well as hotspot volumes are used as metrics., Results: Compared to the non-TMPS optimization, the proposed scheme was able to reduce the peak temperature in healthy tissue by 0.2 °C-1.0 °C (a thermal dose reduction by at least 26%) and, importantly, the hotspot volume above 42 °C in healthy tissue by 41%-86%. At the same time, tumor heating homogeneity was maintained or improved., Conclusions: The extremely rapid optimization (5 s for TMPS part, on a standard PC) permits closed-loop treatment reoptimization during treatment administration, and empowers physicians with a selection of optimal treatment scenarios reflecting different weighting of conflicting treatment goals.

Fifth generation networks (5G) will be associated with a partial shift to higher carrier frequencies, including wavelengths comparable in size to insects. This may lead to higher absorption of radio frequency (RF) electromagnetic fields (EMF) by insects and could cause dielectric heating. The yellow fever mosquito (Aedes aegypti), a vector for diseases such as yellow and dengue fever, favors warm climates. Being exposed to higher frequency RF EMFs causing possible dielectric heating, could have an influence on behavior, physiology and morphology, and could be a possible factor for introduction of the species in regions where the yellow fever mosquito normally does not appear. In this study, the influence of far field RF exposure on A. aegypti was examined between 2 and 240 GHz. Using Finite Difference Time Domain (FDTD) simulations, the distribution of the electric field in and around the insect and the absorbed RF power were found for six different mosquito models (three male, three female). The 3D models were created from micro-CT scans of real mosquitoes. The dielectric properties used in the simulation were measured from a mixture of homogenized A. aegypti. For a given incident RF power, the absorption increases with increasing frequency between 2 and 90 GHz with a maximum between 90 and 240 GHz. The absorption was maximal in the region where the wavelength matches the size of the mosquito. For a same incident field strength, the power absorption by the mosquito is 16 times higher at 60 GHz than at 6 GHz. The higher absorption of RF power by future technologies can result in dielectric heating and potentially influence the biology of this mosquito., Competing Interests: The authors have declared that no competing interests exist.

Several recent theoretical dosimetric studies above 6 GHz apply generic layered skin models. For this frequency range, new experimental phantoms for over-the-air performance of wireless devices were proposed that simulate the impedance matching effects of the stratum corneum layer (SCL) with a low-loss coating layer. The aim of this study was to verify the skin models by comparing their reflection coefficients S 11 with measurements of 37 human volunteers (21 males, 16 females, 5-80 years) at 21 body locations (10 at palm, 11 at arm/face) with different SCL thicknesses, using waveguides covering frequencies from 40 to 110 GHz. Such measurements were also carried out with the phantom material. The statistical analysis showed strong evidence that S 11 depends on the SCL thickness and no evidence that S 11 depends on sex. The measured S 11 values for thin and thick skin can be represented by SCL layers of 15 and 140 μm, respectively. These values correspond well to the assumptions of previous studies. (The cohort did not include volunteers doing heavy manual work.) The phantom material mimics the matching effect of the SCL with deviations from the waveguide measurements of less than 0.85 dB (22%), which confirms the suitability of layered phantoms to represent the electromagnetic reflection/absorption of human skin. © 2021 Bioelectromagnetics Society., (© 2021 Bioelectromagnetics Society.)

Purpose: The risks of RF-induced heating of active implantable medical device (AIMD) leads during MR examinations must be well understood and realistically assessed. In this study, we evaluate the potential additional risks of broken and abandoned (cut) leads., Methods: First, we defined a generic AIMD with a metallic implantable pulse generator (IPG) and a 100-cm long lead containing 1 or 2 wires. Next, we numerically estimated the deposited in vitro lead-tip power for an intact lead, as well as with wire breaks placed at 10 cm intervals. We studied the effect of the break size (wire gap width), as well as the presence of an intact wire parallel to the broken wire, and experimentally validated the numeric results for the configurations with maximum deposited in vitro lead-tip power. Finally, we performed a Tier 3 assessment of the deposited in vivo lead-tip power for the intact and broken lead in 4 high resolution virtual population anatomic models for over 54,000 MR examination scenarios., Results: The enhancement of the deposited lead-tip power for the broken leads, compared to the intact lead, reached 30-fold in isoelectric exposure, and 16-fold in realistic clinical exposures. The presence of a nearby intact wire, or even a nearby broken wire, reduced this enhancement factor to <7-fold over the intact lead., Conclusion: Broken and abandoned leads can pose increased risk of RF-induced lead-tip heating to patients undergoing MR examinations. The potential enhancement of deposited in vivo lead-tip power depends on location and type of the wire break, lead design, and clinical routing of the lead, and should be carefully considered when performing risk assessment for MR examinations and MR conditional labeling., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Sarcopaenia, defined as a decline in both muscle mass and function, has been recognized as a major determinant of poor outcome in haemodialysis (HD) patients. It is generally assumed that sarcopaenia is driven by muscle atrophy related to protein-energy wasting. However, dynapaenia, defined as weakness without atrophy, has been characterized by a different disease phenotype from sarcopaenia. The aim of this study was to compare the characteristics and prognosis of sarcopaenic and dynapaenic patients among a prospective cohort of chronic HD (CHD) patients., Methods: Two hundred and thirty-two CHD patients were enrolled from January to July 2016 and then followed prospectively until December 2018. At inclusion, weakness and atrophy were, respectively, evaluated by maximal voluntary force (MVF) and creatinine index (CI). Sarcopaenia was defined as the association of weakness and atrophy (MVF and CI below the median) while dynapaenia was defined as weakness not related to atrophy (MVF below the median, and CI above the median)., Results: From a total of 187 prevalent CHD patients [65% of men, age 65.3 (49.7-82.0) years], 44 died during the follow-up period of 23.7 (12.4-34.9) months. Sarcopaenia and dynapaenia were observed in 33.7 and 16% of the patients, respectively. Compared with patients with sarcopaenia, patients with dynapaenia were younger and with a lower Charlson score. In contrast, mortality rate was similar in both groups (38 and 27%, respectively). After adjustment for age, sex, lean tissue index, serum albumin, high-sensitivity C-reactive protein (hs-CRP), haemoglobin (Hb), normalized protein catabolic rate (nPCR), dialysis vintage and Charlson score, only patients with dynapaenia were at increased risk of death [hazard ratio (HR) = 2.99, confidence interval 1.18-7.61; P = 0.02]., Conclusions: Screening for muscle functionality is highly warranted to identify patients with muscle functional impairment without muscle atrophy. In contrast to sarcopaenia, dynapaenia should appear as a phenotype induced by uraemic milieu, characterized by young patients with low Charlson score and poor prognosis outcome independently of serum albumin, hs-CRP, Hb, nPCR and dialysis vintage., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Purpose . To characterize and quantify the induced radiofrequency (RF) electric ( E )-fields and B 1+rms fields in patients undergoing magnetic resonance (MR) examinations; to provide guidance on aspects of RF heating risks for patients with and without implants; and to discuss some strengths and limitations of safety assessments in current ISO, IEC, and ASTM standards to determine the RF heating risks for patients with and without implants. Methods . Induced E -fields and B 1+rms fields during 1.5 T and 3 T MR examinations were numerically estimated for high-resolution patient models of the Virtual Population exposed to ten two-port birdcage RF coils from head to feet imaging landmarks over the full polarization space, as well as in surrogate ASTM phantoms. Results . Worst-case B 1+rms exposure greater than 3.5 μ T (1.5 T) and 2 μ T (3 T) must be considered for all MR examinations at the Normal Operating Mode limit. Representative induced E -field and specific absorption rate distributions under different clinical scenarios allow quick estimation of clinical factors of high and reduced exposure. B 1 shimming can cause +6 dB enhancements to E -fields along implant trajectories. The distribution and magnitude of induced E -fields in the ASTM phantom differ from clinical exposures and are not always conservative for typical implant locations. Conclusions. Field distributions in patient models are condensed, visualized for quick estimation of risks, and compared to those induced in the ASTM phantom. Induced E -fields in patient models can significantly exceed those in the surrogate ASTM phantom in some cases. In the recent 19 ε 2 revision of the ASTM F2182 standard, the major shortcomings of previous versions have been addressed by requiring that the relationship between ASTM test conditions and in vivo tangential E -fields be established, e.g. numerically. With this requirement, the principal methods defined in the ASTM standard for passive implants are reconciled with those of the ISO 10974 standard for active implantable medical devices., (Creative Commons Attribution license.)

Low-Intensity Focused Ultrasound Stimulation (LIFUS) holds promise for the remote modulation of neural activity, but an incomplete mechanistic characterization hinders its clinical maturation. Here we developed a computational framework to model intramembrane cavitation (a candidate mechanism) in multi-compartment, morphologically structured neuron models, and used it to investigate ultrasound neuromodulation of peripheral nerves. We predict that by engaging membrane mechanoelectrical coupling, LIFUS exploits fiber-specific differences in membrane conductance and capacitance to selectively recruit myelinated and/or unmyelinated axons in distinct parametric subspaces, allowing to modulate their activity concurrently and independently over physiologically relevant spiking frequency ranges. These theoretical results consistently explain recent empirical findings and suggest that LIFUS can simultaneously, yet selectively, engage different neural pathways, opening up opportunities for peripheral neuromodulation currently not addressable by electrical stimulation. More generally, our framework is readily applicable to other neural targets to establish application-specific LIFUS protocols., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

The introduction of new dosimetric quantities, in particular, epithelial or absorbed power density for frequencies above 6 GHz, in exposure guidelines and safety standards requires the development of new experimental assessment procedures for compliance testing. In this study, we propose to approximate the peak spatial-average absorbed power density (psS ab ) using the same measured data and algorithms that are used for determining the peak spatial-average specific absorption rate psSAR, which is currently limited to frequencies up to 10 GHz. The uncertainty component for the transformation of psSAR to psS ab was evaluated as less than 0.55 dB (13.5%) for any source as close as 0.02 λ from the tissue simulating media. The approach is easy to implement and allows determining compliance with the basic restrictions of the latest safety guidelines. In the next project, we will expand dosimetric probes, phantoms, and procedures for frequencies above 10 GHz. © 2021 Bioelectromagnetics Society., (© 2021 Bioelectromagnetics Society.)

Point of care testing makes it possible to obtain results in an extremely short time. Recently, radiometer has expanded the panel of tests available on its ABL90 FLEX PLUS blood gas analyzer (ABL90) by adding urea and creatinine. The aim of this study was to verify the performance of these new parameters. This included assessment of imprecision, linearity, accuracy by comparison with central laboratory standard assays and interferences. In addition, clinical utility in a dialysis center was evaluated. Within-lab coefficients of variation were close to 2%. The mean and limits of agreement (mean ± 1.96 SD) of the difference between ABL90 and Roche enzymatic assays on cobas 8000 were 0.5 (from -1.4 to 2.3) mmol/L and -0.9 (from -19.5 to 17.8) µmol/L for urea and creatinine, respectively. The ABL90 enzymatic urea and creatinine assays met the acceptance criteria based on biological variation for imprecision and showed good agreement with central laboratory. The two assays were unaffected by hematocrit variation between 20 and 70%, hemolysis and icterus interferences. It should be noted that the relationship between lab methods and ABL90 was conserved even for high pre-dialysis values allowing easy access to dialysis adequacy parameters ( Kt / V ) and muscle mass evaluation (creatinine index). Rapid measurement of creatinine and urea using whole blood specimens on ABL90 appears as a fast and convenient method. Analytical performances were in accordance with our expectations without any significant interferences by hemolysis or icterus.

We present a simulation study investigating the feasibility of electrical impedance tomography (EIT) as a low cost, noninvasive technique for hyperthermia (HT) treatment monitoring and adaptation. Temperature rise in tissues leads to perfusion and tissue conductivity changes that can be reconstructed in 3D by EIT to noninvasively map temperature and perfusion. In this study, we developed reconstruction methods and investigated the achievable accuracy of EIT by simulating HT treatmentlike scenarios, using detailed anatomical models with heterogeneous conductivity distributions. The impact of the size and location of the heated region, the voltage measurement signal-to-noise ratio, and the reference model personalization and accuracy were studied. Results showed that by introducing an iterative reconstruction approach, combined with adaptive prior regions and tissue-dependent penalties, planning-based reference models, measurement-based reweighting, and physics-based constraints, it is possible to map conductivity-changes throughout the heated domain, with an accuracy of around 5% and cm-scale spatial resolution. An initial exploration of the use of multifrequency EIT to separate temperature and perfusion effects yielded promising results, indicating that temperature reconstruction accuracy can be in the order of 1 ∘C. Our results suggest that EIT can provide valuable real-time HT monitoring capabilities. Experimental confirmation in real-world conditions is the next step.

The Data and Resource Center (DRC) of the NIH-funded SPARC program is developing databases, connectivity maps, and simulation tools for the mammalian autonomic nervous system. The experimental data and mathematical models supplied to the DRC by the SPARC consortium are curated, annotated and semantically linked via a single knowledgebase. A data portal has been developed that allows discovery of data and models both via semantic search and via an interface that includes Google Map-like 2D flatmaps for displaying connectivity, and 3D anatomical organ scaffolds that provide a common coordinate framework for cross-species comparisons. We discuss examples that illustrate the data pipeline, which includes data upload, curation, segmentation (for image data), registration against the flatmaps and scaffolds, and finally display via the web portal, including the link to freely available online computational facilities that will enable neuromodulation hypotheses to be investigated by the autonomic neuroscience community and device manufacturers., Competing Interests: AB, MM, and JG have equity interest in SciCrunch.com, a tech startup out of UCSD that develops tools and services for reproducible science, including support for RRIDs. AB is the CEO of SciCrunch.com. ST and MH are company employees of MBF Bioscience, a commercial entity. LG and JW were employed by Blackfynn Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Osanlouy, Bandrowski, de Bono, Brooks, Cassarà, Christie, Ebrahimi, Gillespie, Grethe, Guercio, Heal, Lin, Kuster, Martone, Neufeld, Nickerson, Soltani, Tappan, Wagenaar, Zhuang and Hunter.)

Objective . Low-intensity transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation (NIBS) technique. TUS can reach deeper areas and target smaller regions in the brain than other NIBS techniques, but its application in humans is hampered by the lack of a straightforward and reliable procedure to predict the induced ultrasound exposure. Here, we examined how skull modeling affects computer simulations of TUS. Approach . We characterized the ultrasonic beam after transmission through a sheep skull with a hydrophone and performed computed tomography (CT) image-based simulations of the experimental setup. To study the skull model's impact, we varied: CT acquisition parameters (tube voltage, dose, filter sharpness), image interpolation, segmentation parameters, acoustic property maps (speed-of-sound, density, attenuation), and transducer-position mismatches. We compared the impact of modeling parameter changes on model predictions and on measurement agreement. Spatial-peak intensity and location, total power, and the Gamma metric (a measure for distribution differences) were used as quantitative criteria. Modeling-based sensitivity analysis was also performed for two human head models. Main results . Sheep skull attenuation assignment and transducer positioning had the most important impact on spatial peak intensity (overestimation up to 300%, respectively 30%), followed by filter sharpness and tube voltage (up to 20%), requiring calibration of the mapping functions. Positioning and skull-heterogeneity-structure strongly affected the intensity distribution (gamma tolerances exceeded in>80%, respectively>150%, of the focus-volume in water), necessitating image-based personalized modeling. Simulation results in human models consistently demonstrate a high sensitivity to the skull-heterogeneity model, attenuation tuning, and transducer shifts, the magnitude of which depends on the underlying skull structure complexity. Significance . Our study reveals the importance of properly modeling the skull-heterogeneity and its structure and of accurately reproducing the transducer position. The results raise red flags when translating modeling approaches among clinical sites without proper standardization and/or recalibration of the imaging and modeling parameters., (© 2021 IOP Publishing Ltd.)

Background: Whether soluble urokinase-type plasminogen activator receptor (suPAR) could be a valuable prognostic indicator remains uncertain., Materials & Methods: Patients from STADE-HF (Soluble Suppression of Tumorigenesis-2 as a Help for Management of Diagnosis, Evaluation and Management of Heart Failure) were included for analysis., Results: 95 patients were included. The suPAR level of expression was significantly higher in the group of patients who died at one month (7.90 ± 4.35 ng/ml vs 11.94 ± 6.86 ng/ml; p < 0.05) or 1 year (7.28 ± 4.27 ng/ml vs 11.81 ± 4.88 ng/ml; p < 0.01), but there was no significant difference according to the readmission., Conclusion: High suPAR levels during hospitalization for acute heart failure were highly predictive for the risk of mortality, but not the risk of readmission., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript., (© 2021 Fabien Huet.)

Objectives: Inflammation is a hallmark of heart failure (HF) and among inflammatory biomarkers, the most studied remains the C-reactive protein (CRP). In recent years several biomarkers have emerged, such as sST2 and soluble urokinase-type plasminogen activator receptor (suPAR). This study set out to examine the relative importance of long-time prognostic strength of suPAR and the potential additive information on patient risk with chronic HF in comparison with pronostic value of CRP and sST2., Methods: Demographics, clinical and biological variables were assessed in a total of 182 patients with chronic HF over median follow-up period of 80 months. Inflammatory biomarkers (i.e., CRP, sST2, and suPAR) were performed., Results: In univariate Cox regression analysis age, NYHA class, MAGGIC score and the five biomarkers (N-terminal pro brain natriuretic peptide [NT-proBNP], high-sensitive cardiac troponin T [hs-cTnT], CRP, sST2, and suPAR) were associated with both all-cause and cardiovascular mortality. In the multivariate model, only NT-proBNP, suPAR, and MAGGIC score remained independent predictors of all-cause mortality as well as of cardiovascular mortality. Risk classification analysis was significantly improved with the addition of suPAR particularly for all-cause short- and long-term mortality. Using a classification tree approach, the same three variables could be considered as significant classifier variables to predict all-cause or cardiovascular mortality and an algorithm were reported. We demonstrated the favorable outcome associated with patients with a low MAGGIC score and a low suPAR level by comparison to patients with low MAGGIC score but high suPAR values., Conclusions: The main findings of our study are (1) that among the three inflammatory biomarkers, only suPAR levels were independently associated with 96-month mortality for patients with chronic HF and (2) that an algorithm based on clinical score, a cardiomyocyte stress biomarker and an inflammatory biomarker could help to a more reliable long term risk stratification in heart failure., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

The latest electromagnetic safety guidelines define transmitted or epithelial power density as the basic restriction above 6 GHz. In this note, we derive an approximation for a conservative transmission coefficient for quasi plane wave incidence as a function of the frequency for the normal component of the Poynting vector with respect to the evaluation plane or tissue surface |Sz inc| and for its modulus ||Sinc||. The maximum transmission coefficient for the normal component of the Poynting vector ${\boldsymbol{T}}&#95;{\mathbf{z}}^{\mathbf{max}}$ is 1 independent of tissue composition and frequency. Approximations of ${\boldsymbol{T}}&#95;{\mathbf{total}}^{\mathbf{max}}$ normalized to ||Sinc|| for thin and thick stratum corneum are provided allowing higher exposures. These approximations allow to conservatively demonstrate compliance with basic restrictions when quasi plane-wave conditions are locally satisfied and enhancement effects of standing waves between source and body can be neglected. The reported results are important to regulators and standardization bodies regarding revisions of compliance requirements and safety guidelines., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We present a novel patient-specific fluid-solid-growth framework to model the mechanobiological state of clinically detected intracranial aneurysms (IAs) and their evolution. The artery and IA sac are modeled as thick-walled, non-linear elastic fiber-reinforced composites. We represent the undulation distribution of collagen fibers: the adventitia of the healthy artery is modeled as a protective sheath whereas the aneurysm sac is modeled to bear load within physiological range of pressures. Initially, we assume the detected IA is stable and then consider two flow-related mechanisms to drive enlargement: (1) low wall shear stress; (2) dysfunctional endothelium which is associated with regions of high oscillatory flow. Localized collagen degradation and remodelling gives rise to formation of secondary blebs on the aneurysm dome. Restabilization of blebs is achieved by remodelling of the homeostatic collagen fiber stretch distribution. This integrative mechanobiological modelling workflow provides a step towards a personalized risk-assessment and treatment of clinically detected IAs.

To determine the analytical performance of Novel VITROS BRAHMS Procalcitonin Immunoassay on VITROS 3600 and correlation with BRAHMS PCT sensitive KRYPTOR reference method. Analytical performances including imprecision studies, linearity, limit of detection (LoD) and determination of hemolysis index were performed for VITROS BRAHMS PCT assay. Imprecision was assessed on plasma pool and internal control with 2 levels. The method comparison was performed using 162 plasma obtained from clinical departments. The total imprecision was acceptable and all CV were <5%. The LoD was in accordance with manufacturer's claims. The equation of linearity in the lower range was found to be y  = 1.0014 x - 0.0091, with r 2 = 1. No interference to hemoglobin up to 11 g/L was observed. Correlation studies showed a good correlation between PCT measurements using VITROS BRAHMS PCT assay against KRYPTOR system including for values lower than 2 µg/L. The novel VITROS BRAHMS PCT assay from OrthoClinical Diagnostics shows analytical performances acceptable for clinical use. In addition, the concordance with KRYPTOR method was fine at all clinical cut-offs.

Neuromodulation is a new therapeutic pathway to treat inflammatory conditions by modulating the electrical signalling pattern of the autonomic connections to the spleen. However, targeting this sub-division of the nervous system presents specific challenges in translating nerve stimulation parameters. Firstly, autonomic nerves are typically embedded non-uniformly among visceral and connective tissues with complex interfacing requirements. Secondly, these nerves contain axons with populations of varying phenotypes leading to complexities for axon engagement and activation. Thirdly, clinical translational of methodologies attained using preclinical animal models are limited due to heterogeneity of the intra- and inter-species comparative anatomy and physiology. Here we demonstrate how this can be accomplished by the use of in silico modelling of target anatomy, and validation of these estimations through ex vivo human tissue electrophysiology studies. Neuroelectrical models are developed to address the challenges in translation of parameters, which provides strong input criteria for device design and dose selection prior to a first-in-human trial.

The use of body-worn wireless devices with different communication protocols and rapidly changing exposure scenarios is still multiplying and the need to identify possible health effects of radiofrequency electromagnetic field (RF-EMF) exposure with extremely low-frequency (ELF) modulation envelops. In this study, effects of ELF-modulated 935 MHz RF-EMF on apoptosis, autophagy, oxidative stress and electron exchange in N9 microglial and SH-SY5Y neuroblastoma cells were investigated. Cells were exposed at 4 W/kg or sham-exposed for 2 and 24 h. RF-EMF exposure of both cell types did not alter apoptosis, the number of living cells nor the apoptosis-inducing factor (AIF), irrespective of the exposure duration. RF-EMF exposure for 24, but not for 2 h, increased protein levels of the autophagy marker ATG5, whereas LC3B-I and II and pERK were not altered in both cell types and exposure times investigated. A transient increase in glutathione (GSH), but not hydrogen peroxide and cytochrome c oxidase was found only in SH-SY5Y cells, indicating that short-time RF-EMF at SAR levels accepted by today's safety guidelines might cause autophagy and oxidative stress with the effect being dependent on cell type and exposure duration. Further studies are needed to evaluate possible underlying mechanisms involved in pulse-modulated RF-EMF exposure., Competing Interests: Declaration of Competing Interest All authors disclose any financial and personal relationships with other people or organizations that could inappropriately influence this work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: Inflammation and cardiac remodelling are common and synergistic pathways in heart failure (HF). Emerging biomarkers such as soluble suppression of tumorigenicity 2 (sST2) and growth differentiation factor-15 (GDF-15), which are linked to inflammation and fibrosis process, have been proposed as prognosis factors. However, their potential additive values remain poorly investigated., Methods and Results: Here, we aimed at evaluating inflammatory and remodelling biomarkers to predict both short-term and long-term mortality in a population with chronic HF in comparison with other classical clinical or biological markers (i.e. N terminal pro brain natriuretic peptide, hs-cTnT, C-reactive protein) alone or using meta-analysis global group in chronic HF risk score in a cohort of 182 patients followed during 80 months (interquartile range: 12.3-90.0). Proportional hazard assumption does not hold for sST2 and C-reactive protein, and follow-up was split into short term (less than 1 year), midterm (between 1 and 5 years), and long term (after 5 years). In univariate analysis, C-reactive protein and sST2 were predictive of short-term mortality but not of middle term and long term whereas GDF-15 was predictive of short and mid-term but not of long-term mortality. In a multivariate model after adjustment for meta-analysis global group in chronic HF score including the three markers, only sST2 was predictive of short-term mortality (P = 0.0225), and only GDF-15 was predictive of middle term mortality (P = 0.0375). None of the markers was predictive of long-term mortality., Conclusions: Our results demonstrate that both sST2 and GDF-15 significantly improve the prognosis evaluation of HF patients and suggest that the value of GDF-15 is more sustained overtime and could predict middle term events., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background All general biochemistry instruments allow the measure of hemolysis index (HI), and suppliers provide an acceptable HI for each assay without consideration of the analyte value or its clinical application. Our first objective was to measure the impact of hemolysis degree on plasma biochemical and immunochemical analytes to determine the maximum allowable HI for each of them using four calculation methods as significant bias in comparison to manufacturer's data. The second objective was to assess whether the maximum allowable HI varied according to the analyte values. Methods Twenty analytes were measured in hemolyzate-treated plasma to determine the HI leading to a significant change compared to baseline value. Analytes were assessed at one (3 analytes), two (5 analytes) and three (12 analytes) values according to their sensitivity to hemolysis and their clinical impact. We used four calculation methods as significant limit from baseline value: the total change limit (TCL), the 10% change (10%Δ), the analytical change limit and the reference change value. Results Allowable HI was significantly different according to the threshold chosen for most analytes and was also dependent on the analyte value for alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatine kinase, iron, haptoglobin and high sensitivity troponin T. No hemolysis interference was observed for albumin, creatinine, C-reactive protein, and procalcitonin even at an HI value of 11 g/L. Conclusions This study highlights that TCL is the most appropriate calculation method to determine allowable HI in practice for biochemical and immunochemical parameters using Cobas 8000© from Roche Diagnostics. In addition, different allowable HI were found according to analyte value leading to optimization of resampling to save time in patient care.

An article published in the International Journal of Environmental Research and Public Health compares two types of specific absorption rate measurement systems-a fast system using a time-domain array and a traditional system using probe scanning. While the time-domain array system is analyzed in detail under idealized conditions, the probe-scanning system evaluation used a fixed set of scanning and evaluation parameters that are not fully compliant with the requirements of the published standards. This leads to a false comparison and the incorrect conclusion that time-domain array systems can be theoretically more accurate than probe-scanning systems. We have repeated the analysis applied in the paper using the same raw data but with state-of-the art scanning and evaluation parameters. The results confirm the high accuracy of probe-scanning systems for any field distribution. Due to the high precision, robustness, and reliability of probe-scanning systems, the results of these systems are often referred to as reference results.

Objective: Low-intensity transcranial ultrasound stimulation (TUS) is emerging as a non-invasive brain stimulation technique with superior spatial resolution and the ability to reach deep brain areas. Medical image-based computational modeling could be an important tool for individualized TUS dose control and targeting optimization, but requires further validation. This study aims to assess the impact of the transducer model on the accuracy of the simulations., Approach: Using hydrophone measurements, the acoustic beam of a single-element focused transducer (SEFT) with a flat piezoelectric disc and an acoustic lens was characterized. The acoustic beam was assessed in a homogeneous water bath and after transmission through obstacles (3D-printed shapes and skull samples). The acoustic simulations employed the finite-difference time-domain method and were informed by computed tomography (CT) images of the obstacles. Transducer models of varying complexity were tested representing the SEFT either as a surface boundary condition with variable curvature or also accounting for its internal geometry. In addition, a back-propagated pressure distribution from the first measurement plane was used as source model. The simulations and measurements were quantitatively compared using key metrics for peak location, focus size, intensity and spatial distribution., Main Results: While a surface boundary with an adapted, 'effective' curvature radius based on the specifications given by the manufacturer could reproduce the measured focus location and size in a homogeneous water bath, it regularly failed to accurately predict the beam after obstacle transmission. In contrast, models that were based on a one-time calibration to the homogeneous water bath measurements performed substantially better in all cases with obstacles. For one of the 3D-printed obstacles, the simulated intensities deviated substantially from the measured ones, irrespective of the transducer model. We attribute this finding to a standing wave effect, and further studies should clarify its relevance for accurate simulations of skull transmission., Significance: Validated transducer models are important to ensure accurate simulations of the acoustic beam of SEFTs, in particular in the presence of obstacles such as the skull.

The most recent safety guidelines define basic restrictions for electromagnetic field exposure at frequencies more than 6 GHz in terms of spatial- and time-averaged transmitted power density inside the body. To enable easy-to-perform evaluations in situ, the reference levels for the incident power density were derived. In this study, we examined whether compliance with the reference levels always ensures compliance with basic restrictions. This was evaluated at several distances from different antennas (dipole, loop, slot, patch, and helix). Three power density definitions based on integration of the perpendicular real part of the Poynting vector, the real part of its three vector components, and its modulus were compared for averaging areas of λ 2 /16, 4 cm 2 (below 30 GHz) and 1 cm 2 (30 GHz). In the reactive near-field (d < λ/(2π)), the transmitted power density can be underestimated if an antenna operates at the free space exposure limit. This underestimation may exceed 6 dB (4.0 times) and depends on the field source due to different coupling mechanisms. It is frequency-dependent for fixed-size averaging areas (4 and 1 cm 2 ). At larger distances, transmission can be larger than the theoretical plane-wave transmission coefficient due to backscattering between the body and field source. Using the modulus of the incident Poynting vector yields the smallest underestimation. © 2020 Bioelectromagnetics Society., (© 2020 Bioelectromagnetics Society.)

This study assesses the maximum temperature increase induced by exposure to electromagnetic fields between 6 and 100 GHz using a stratified model of the skin with four or five layers under plane wave incidence. The skin model distinguishes the stratum corneum (SC) and the viable epidermis as the outermost layers of the skin. The analysis identifies the tissue layer structures that minimize reflection and maximize the temperature increase induced by the electromagnetic field. The maximum observed temperature increase is 0.4°C for exposure at the present power density limit for the general population of 10 W m -2 . This result is more than twice as high as the findings reported in a previous study. The reasons for this difference are identified as impedance matching effects in the SC and less conservative thermal parameters. Modeling the skin as homogeneous dermis tissue can underestimate the induced temperature increase by more than a factor of three., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Beta-trace protein (BTP), a low molecular weight protein of 23-29 kDa, has been proposed as a promising biomarker to estimate residual renal function (RRF) in patients on maintenance hemodialysis (HD). Indeed, BTP is cleared by native kidney but not during conventional HD session. By contrast, the removal rate of BTP using convective processes (mainly hemodiafiltration [HDF]) and peritoneal dialysis (PD) has been little or not investigated. Therefore, an aim of this study was to evaluate the impact of dialysis procedures (high-flux HD, on-line post-dilution HDF and PD) on BTP removal in comparison with beta-2 microglobulin (B2M) and cystatin C (CYSC) removals after a single session. In addition, the ability of BTP to predict RRF in PD was assessed. This observational cross-sectional study included a total of 82 stable chronic kidney disease patients, 53 patients were on maintenance dialysis (with n = 26 in HD and n = 27 in HDF) and 29 were on PD. Serum concentrations of BTP, B2M, and CYSC were measured (a) before and after a single dialysis session in HD and HDF anuric patients to calculate reduction percentages, (b) in serum, 24-hour-dialysate and 24-hour-urine in PD patients to compute total, peritoneal, and urinary clearance. RRF was estimated using four equations developed for dialysis patients without urine collection and compared to the mean of the urea and creatinine clearances in PD. The concentrations of the three studied molecules were significantly reduced (P < .001) after dialysis session with significantly higher reduction ratio using HDF compared to HD modality (P < .001): BTP 49.3% vs 17.5%; B2M 82.3% vs 69.7%; CYSC 77.4% vs 66% in HDF and HD, respectively. In non-anuric PD patients, B2M and CYSC were partly removed by peritoneal clearance (72.3% and 57.6% for B2M and CYSC, respectively). By contrast, BTP removal by the peritoneum was negligible and a low bias for the BTP-based equation to estimate RRF (-1.4 mL/min/1.73 m 2 ) was calculated. BTP is significantly removed by high-flux HD or HDF, thereby compromising its use to estimate RRF. By contrast, BTP appears as a promising biomarker to estimate RRF in PD patients since it is not affected by peritoneal clearance, unlike B2M and CYSC, and it is well correlated to RRF., (© 2020 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Electromagnetic (EM) radiofrequency (RF) safety testing of elongated active implantable medical devices (AIMD) during magnetic resonance imaging (MRI) requires an RF response model of the implant to assess a wide range of exposure conditions. The model must be validated using a sufficiently large set of incident tangential electric field ([Formula: see text]) conditions that provide diversified exposure. Until now, this procedure was very time consuming and often resulted in poorly defined [Formula: see text] conditions. In this paper, we propose a test field diversity (TFD) validation method that provides more diverse exposure conditions of high fidelity, thereby decreasing the number of implant routings to be tested. The TFD method is based on the finding that the amplitude and phase of [Formula: see text] along a single lead path in a cylindrical phantom can be sufficiently varied by changing the polarization of the incident 64 and 128 MHz magnetic fields inside standard birdcage test coils. The method is validated, its benefits are demonstrated, and an uncertainty budget is developed. First, the numerically determined field conditions were experimentally verified. The RF transfer function of a 90 cm long spinal cord stimulator was successfully validated with the TFD approach and excitation conditions that cover a > 10 dB dynamic range of RF-heating enhancement factors (for identical trajectory-averaged incident field strength). The new TFD method yields an improved and reliable validation of the AIMD RF response model with low uncertainty, i.e. < 1.5 dB, for both 1.5 and 3.0 T evaluations.

Modulated electromagnetic fields (wEMFs), as generated by modern communication technologies, have raised concerns about adverse health effects. The International Agency for Research on Cancer (IARC) classifies them as "possibly carcinogenic to humans" (Group 2B), yet, the underlying molecular mechanisms initiating and promoting tumorigenesis remain elusive. Here, we comprehensively assess the impact of technologically relevant wEMF modulations on the genome integrity of cultured human cells, investigating cell type-specificities as well as time- and dose-dependencies. Classical and advanced methodologies of genetic toxicology and DNA repair were applied, and key experiments were performed in two separate laboratories. Overall, we found no conclusive evidence for an induction of DNA damage nor for alterations of the DNA repair capacity in cells exposed to several wEMF modulations (i.e., GSM, UMTS, WiFi, and RFID). Previously reported observations of increased DNA damage after exposure of cells to GSM-modulated signals could not be reproduced. Experimental variables, presumably underlying the discrepant observations, were investigated and are discussed. On the basis of our data, we conclude that the possible carcinogenicity of wEMF modulations cannot be explained by an effect on genome integrity through direct DNA damage. However, we cannot exclude non-genotoxic, indirect, or secondary effects of wEMF exposure that may promote tumorigenesis in other ways., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.