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The ferroelectric switching phenomenon has been investigated on a BaTiO3 supercell in the tetragonal state using a first-principles density functional theory. The study shows that a consecutive reversal of polarization via switching of adjacent elementary unit cells is energetically more favourable than the single domain switching. The results thus explain the energetic rationality for the domain wall formation in an ideal structure without the presence of any microscopic non-uniformity. The analysis of individual domain wall energy densities suggests that it is not a constant quantity. The coercive field values for switching different domains have been computed, which identifies the nucleation and propagation phases of domain wall motion. [ABSTRACT FROM AUTHOR]

Background: Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)-like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson's disease (PD)., Objective: The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls., Methods: We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson's Disease Rating Scale (mUPDRS) was measured at baseline and T60., Results: tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity., Conclusions: tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Sulforaphane (SFN) is a dietary isothiocyanate, derived from glucoraphanin, present in cruciferous vegetables belonging to the Brassica genus. It is a biologically active phytochemical that acts as a nuclear factor erythroid 2-related factor 2 (Nrf2) inducer. Thus, it has been reported to have multiple protective functions including anticancer responses and protection against a toxic agent's action., Purpose: The present work systematically reviewed and synthesised the protective properties of sulforaphane against a toxic agent. This review reveals the mechanism of the action of SFN in each organ or system., Methods: The PRISMA guideline was followed in this sequence: researched literature, organised retrieved documents, abstracted relevant information, assessed study quality and bias, synthesised data, and prepared a comprehensive report. Searches were conducted on Science Direct and PubMed using the keywords "Sulforaphane" AND ("protective effects" OR "protection against")., Results: Reports showed that liver and the nervous system are the target organs on which attention was focused, and this might be due to the key role of oxidative stress in liver and neurodegenerative diseases. However, protective activities have also been demonstrated in the lungs, heart, immune system, kidneys, and endocrine system. SFN exerts its protective effects by activating the Nrf2 pathway, which enhances antioxidant defenses and reduces oxidative stress. It also suppresses inflammation by decreasing interleukin production. Moreover, SFN inhibits apoptosis by preventing caspase 3 cleavage and increasing Bcl2 levels. Overall, SFN demonstrates multifaceted mechanisms to counteract the adverse effects of toxic agents., Conclusion: SFN has potential clinical applications as a chemoprotective agent. Nevertheless, more studies are necessary to set the safe doses of SFN in humans., 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 © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Recently, our group developed a synergistic brain drug delivery method to achieve simultaneous transcranial hyperthermia and localized blood-brain barrier opening via MR-guided focused ultrasound (MRgFUS). In a rodent model, we demonstrated that the ultrasound power required for transcranial MRgFUS hyperthermia was significantly reduced by injecting microbubbles (MBs). However, the specific mechanisms underlying the power reduction caused by MBs remain unclear. The present study aims to elucidate the mechanisms of MB-enhanced transcranial MRgFUS hyperthermia through numerical studies using the finite element method. The microbubble acoustic emission (MAE) and the viscous dissipation (VD) were hypothesized to be the specific mechanisms. Acoustic wave propagation was used to model the FUS propagation in the brain tissue, and a bubble dynamics equation for describing the dynamics of MBs with small shell thickness was used to model the MB oscillation under FUS exposures. A modified bioheat transfer equation was used to model the temperature in the rodent brain with different heat sources. A theoretical model was used to estimate the bubble shell's surface tension, elasticity, and viscosity losses. The simulation reveals that MAE and VD caused a 40.5% and 52.3% additional temperature rise, respectively. Compared with FUS only, MBs caused a 64.0% temperature increase, which is consistent with our previous animal experiments. Our investigation showed that MAE and VD are the main mechanisms of MB-enhanced transcranial MRgFUS hyperthermia., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation technique capable of manipulating both cortical and subcortical structures with high precision. Conducting experiments involving humans necessitates careful planning of acoustic and thermal simulations. This planning is essential to adjust for bone interference with the ultrasound beam's shape and trajectory and to ensure TUS parameters meet safety requirements. T1- and T2-weighted, along with zero-time echo (ZTE) magnetic resonance imaging (MRI) scans with 1 mm isotropic resolution, are acquired (alternatively computed tomography x-ray (CT) scans) for skull reconstruction and simulations. Target and trajectory mapping are performed using a neuronavigational platform. SimNIBS is used for the initial segmentation of the skull, skin, and brain tissues. Simulation of TUS is carried over with the BabelBrain tool, which uses the ZTE scan to produce synthetic CT images of the skull to be converted into acoustic properties. We use a phased array ultrasound transducer with electrical steering capabilities. Z-steering is adjusted to ensure that the target depth is reached. Other transducer configurations are also supported in the planning tool. Thermal simulations are run to ensure temperature and mechanical index requirements are within the acoustic guidelines for TUS in human subjects as recommended by the FDA. During TUS delivery sessions, a mechanical arm assists in the movement of the transducer to the required location using a frameless stereotactic localization system.

Background: Patients with chronic diffuse sclerosing osteomyelitis/tendoperiostitis (DSO/TP) of the mandible may complain about facial asymmetry as a result of mandibular deformity, one of the characteristics of DSO/TP of the mandible. If the disease is fully extinguished, remodelling surgery could be performed to treat complaints of facial asymmetry. This study reports the results of remodelling surgery with three-dimensional (3D) designed- and -printed patient-specific surgical guides., Material and Methods: 3D printed guides were designed and manufactured by using mirroring of the contralateral non-affected mandible. Subsequently, the surgical procedure was performed under general anaesthesia using these surgical guides., Results: Four patients (all female) aged 15 (±2.8) years were included. They all complained about facial asymmetry and were planned for surgery with patient-specific surgical guides. Three of those surgeries were performed, of which two patients were satisfied with the result and the other patient is planned for re-surgery because of persistent aesthetical complaints. The last patient cancelled her surgery, because she eventually accepted her asymmetry with the help of a psychologist., Conclusions: The use of patient-specific surgical guides in remodelling surgery of the mandible could enable a more predictable and symmetrical outcome, which could minimise the chance for re-surgery and could increase patient satisfaction. Furthermore, it could minimise the chance of iatrogenic damage to the inferior alveolar nerve.

Magnetic resonance-guided focused ultrasound (MRgFUS) is one of the newest surgical treatments for essential tremor (ET). During this procedure, a lesion is created within the thalamus to mitigate tremor. Targeting is done using a combination of stereotaxy, MR tractography, and sublesional heating, with tremor assessed during the procedure to gauge therapeutic effectiveness. Currently, tremor assessments are done qualitatively, but this approach requires the tremor change to be above a subjective threshold and provides no objective record of surgical tremor progression. Here, the authors present and demonstrate an MR-compatible accelerometer with custom MATLAB analysis code and graphical user interface to record, visualize, and quantify tremor in near real-time. Results can be exported and saved for future review. This method was used in 20 surgeries, with patients experiencing a 50.7% (95% CI -64.1% to -37.3%) improvement in the treated limb per the Clinical Rating Scale for Tremor. This method does not interrupt the surgery and is quantitative. As research on optimizing MRgFUS treatment for ET continues-for example, the refinement of targeting during sublesional sonications-such quantifying and recording of tremor changes will provide rapid and objective feedback.

Propyl-propane thiosulfonate (PTSO), an antioxidant organosulfur compound present in the genus Allium , has become a potential natural additive for food and feed, as well as a possible biopesticide for pest control in plants. A toxicological assessment is necessary to verify its safety for livestock, consumers, and the environment. As part of the risk assessment of PTSO, this study was designed to explore its potential reproductive toxicity in mice following the OECD 416 guideline. The investigation spans two generations to comprehensively evaluate potential reproductive, teratogenic, and hereditary effects. A total of 80 CD1 mice per sex and generation were subjected to PTSO exposure during three phases (premating, gestation, and lactation). This evaluation encompassed three dose levels: 14, 28, and 55 mg PTSO/kg b.w./day, administered through the feed. No clinical changes or mortality attributed to the administration of PTSO were observed in the study. Some changes in the body weight and food consumption were observed, but not related to sex or in a dose-dependent manner. The two parental generations (F0, F1) exhibited normal reproductive performance, and the offspring (F1 and F2) were born without any abnormalities. The serum sexual hormone levels (progesterone -P-, testosterone -T-, estradiol -E2-, follicular stimulating hormone -FSH-, and luteinizing hormone -LH-) were in a normal range. Although significant changes were observed in the sperm analysis in the case of F0 group, no variation was found for F1 group, and no alterations in fertility were recorded either. The absolute organ weights and relative organ weight/body weight and organ weight/brain weight ratios, and the complete histopathological study, showed no significant alterations in males and females for all the generations considered. Considering all the results obtained, PTSO is not considered a reproductive or developmental toxicant in mice under the assayed conditions. These results support the good safety profile of PTSO for its potential application in the agrifood sector.

Background: Non-invasive brain stimulation techniques such as transcranial magnetic stimulation and transcranial direct current stimulation hold promise for inducing brain plasticity. However, their limited precision may hamper certain applications. In contrast, Transcranial Ultrasound Stimulation (TUS), known for its precision and deep brain targeting capabilities, requires further investigation to establish its efficacy in producing enduring effects for treating neurological and psychiatric disorders., Objective: To investigate the enduring effects of different pulse repetition frequencies (PRF) of TUS on motor corticospinal excitability., Methods: T1-, T2-weighted, and zero echo time magnetic resonance imaging scans were acquired from 21 neurologically healthy participants for neuronavigation, skull reconstruction, and the performance of transcranial ultrasound and thermal modelling. The effects of three different TUS PRFs (10, 100, and 1000 Hz) with a constant duty cycle of 10 % on corticospinal excitability in the primary motor cortex were assessed using TMS-induced motor evoked potentials (MEPs). Each PRF and sham condition was evaluated on separate days, with measurements taken 5-, 30-, and 60-min post-TUS., Results: A significant decrease in MEP amplitude was observed with a PRF of 10 Hz (p = 0.007), which persisted for at least 30 min, and with a PRF of 100 Hz (p = 0.001), lasting over 60 min. However, no significant changes were found for the PRF of 1000 Hz and the sham conditions., Conclusion: This study highlights the significance of PRF selection in TUS and underscores its potential as a non-invasive approach to reduce corticospinal excitability, offering valuable insights for future clinical applications., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The biaxial method consists of the utilization of orthogonal electric fields in single-element piezoceramics both in transmission and reception. This study demonstrates the application of the biaxial method to broadband transducers. We developed a three-element biaxial transducer array to demonstrate the feasibility of biaxial method in imaging applications. Finite element analysis was used to model the response of a single transducer element. An electric characterization was performed at each transducer element to determine their driving frequency. Each transducer was driven at 6.25 MHz and tested in different phases to determine the phase that produced the maximum pressure amplitude and shortest pulsewidth. Both simulations and experimental results showed that the acoustic pressure and half-pulsewidth followed a sinusoidal response as a function of the difference in phase applied to the lateral electrodes, as it has been described in our previous work. An imaging test was performed by placing a 0.36-mm diameter nylon wire 20 mm away from the transducer while driving and receiving each element with different combinations of conventional and biaxial driving. By applying a biaxial rephasing at the receiving electrodes during the data analysis, we obtained a maximum reduction in the axial resolution from 4.6 to 1.3 mm and signal-to-noise ratio (SNR) improvements from 15.2 to 24.4 dB, when compared to conventional driving.

Introduction: Pelvic recurrences from rectal cancer present a challenging clinical scenario. Hyperthermia represents an innovative treatment option in combination with concurrent chemoradiation to enhance therapeutic effect. We provide the initial results of a prospective single center feasibility study (NCT02528175) for patients undergoing rectal cancer retreatment using concurrent chemoradiation and mild hyperthermia with MR-guided high intensity focused ultrasound (MR-HIFU)., Methods: All patients were deemed ineligible for salvage surgery and were evaluated in a multidisciplinary fashion with a surgical oncologist, radiation oncologist and medical oncologist. Radiation was delivered to a dose of 30.6 Gy in 1.8 Gy per fraction with concurrent capecitabine. MR-HIFU was delivered on days 1, 8 and 15 of concurrent chemoradiation. Our primary objective was feasibility and toxicity., Results: Six patients (total 11 screened) were treated with concurrent chemoradiation and mild hyperthermia with MR-HIFU. Tumor size varied between 3.1-16.6 cm. Patients spent an average of 228 min in the MRI suite and sonication with the external transducer lasted an average of 35 min. There were no complications on the day of the MR-HIFU procedure and all acute toxicities (no grade >/=3 toxicities) resolved after completion of treatment. There were no late grade >/=3 toxicities., Conclusion: Mild hyperthermia with MR-HIFU, in combination with concurrent chemoradiation for appropriately selected patients, is safe for localized pelvic recurrences from rectal cancer. The potential for MR-HIFU to be applied in the recurrent setting in rectal cancer treatment requires further technical development and prospective evaluation.

The organosulfur compound propyl-propane thiosulfonate (PTSO), mainly found in Allium cepa, has a promising use in the agrifood industry. To confirm its safety for livestock, consumers, and environment, toxicological assessment is needed. In this regard, endocrine-disrupting chemicals (EDCs) are in the spotlight of research. Therefore, as part of the risk assessment of PTSO, in the present work, an in vivo study was performed in mice exposed to PTSO to investigate its potential reproductive toxicity considering fertility, genetic and endocrine endpoints. Five-weeks-old CD1 mice (80 males, 80 females) were exposed for 11 or 16 weeks (males or females, respectively) to different doses of PTSO (0, 14, 28 and 55 mg PTSO/kg b.w./day; 20 animals per group and sex) through the food pellets. No clinical observations or mortality and no changes in absolute organ weights and relative organ weights/body weight or brain ratios occurred during the study. The estrous cycle did not undergo any significant toxicologically relevant change. Most of the sex hormones displayed normal values. Some alterations in the expression of some genes related to reproduction is only observed in females, but they do not appear to have consequences in the development of sex organs. Docking results showed the impossibility of stable binding to estrogen and androgen receptors. Considering all the results obtained, the safe profile of PTSO can be confirmed for different agrifood applications at the conditions assayed., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Biaxial driving can more efficiently convert electrical power to forward acoustic power in piezoelectric materials, and the interaction between the orthogonal electric fields can produce a combination of extensional and shear deformations as a function of the phase difference between them to allow dynamic steering of the beam with a single-element. In this study, we demonstrate for the first time the application of a single-element biaxially driven ring transducer in vivo for blood-brain barrier opening in mice, and compare it to that achieved with a conventional single-element highly focused (F# = 0.7) spherical transducer operating at a similar frequency. Transcranial focused ultrasound (0.45 MPa, 10 ms pulse length, 1 Hz repetition frequency, 30 s duration) was applied bilaterally to mice with a 40 μ l/kg bolus of Definity TM microbubbles, employing either a single-element biaxial ring (1.482 MHz, 10 mm inner diameter, 13.75 mm outer diameter) or spherical (1.5 MHz, 35 mm diameter, F# = 0.7; RK50, FUS Instruments) transducer on each side. Follow-up MRI scans (T1 pre- and post- 0.2 mmol/kg Gd injection, T2) were acquired to assess blood-brain barrier opening volume and potential damage. Compared to blood-brain barrier opening achieved with a conventional single-element spherical focused transducer, the opening volume achieved with a single-element biaxial ring transducer was 35% smaller ( p = 0.002) with a device of a ring diameter of 40% the aperture size. Axial refocusing was further demonstrated with the single-element biaxial ring transducer, yielding a 1.63 mm deeper, five-fold larger opening volume ( p = 0.048) relative to its small-focus mode. The biaxial ring transducer achieved a more localized opening compared to the spherical focused transducer under the same parameters, and further enabled dynamic axial refocusing with a single-element transducer with a smaller fabrication footprint., (Creative Commons Attribution license.)

Biaxial driving is a new driving technique that allows the steering of the ultrasound field generated by a single-element piezoceramic transducer. Because of their natural axisymmetric geometry, ultrasound generation with ring transducers can take advantage of the biaxial driving to change the focus of the beam generated by this type of transducer using only two driving signals. In this study, we applied the biaxial driving technique into a single-element PZT ring transducer operating at 500 kHz to produce a change in size and position of the focal spot while using the 1st (482 kHz), 3rd (1.362 MHz) and 5th (2.62 MHz) harmonic excitation. The transducer had a thickness of 2.85 mm, an inner diameter of 9.75 mm and a ring width of 2.0 mm, and two pairs of electrodes as required for biaxial driving. Simulation and experimental results showed that both the focal area and the distance at which the focal area centre was located changed as a function of the phase and power difference between the two driving signals. Experimental results showed that the focal area could be reduced from 31.6 mm 2 (conventional driving) to 3.4 mm 2 (89 % reduction) when using the first harmonic excitation. For the third harmonic, the focal area could be reduced from 4.0 mm 2 (conventional driving) to 3.3 mm 2 (17.5 % reduction). For the fifth harmonic, the focal area could be reduced from 1.7 mm 2 (conventional driving) to 1 mm 2 (41.7 % reduction). Results also demonstrated the centre of the focus could be displaced between 3.0 mm and 9.3 mm from the surface of the transducer when using the first harmonic, between 7.3 mm and 8.4 mm at the third harmonic, and between 4.9 mm and 8.2 mm at the fifth harmonic. The reduction in the focus area, as well as the possibility to displace the focus dynamically will be advantageous for preclinical applications of focused ultrasound, especially on drug delivery and neuromodulation studies in small rodents., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationship which may be considered as potential competing interests: Laura Curiel, Samuel Pichardo, and Sagid Alberto Delgado Amparano have patent Systems and methods for controlling directional properties of ultrasound transducers via biphasic actuation, pending., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Propyl-propane-thiosulfonate (PTSO) is an organosulfur compound found inAllium spp. Due to its antioxidant and antimicrobial activities, PTSO has been proposed for applications in the agri-food sector, such as feed additive. However, its use with commercial purposes depends on its toxicity evaluation. The present work aimed to perform a pilot-study of toxicokinetic profile of PTSO combining in silico and in vitro techniques, important steps in the risk assessment process. In silico ecotoxicity studies were also performed considering the importance of the environmental impact of the compound before its commercial use. First, an analytical method has been developed and validated to determine the original compound and its metabolites by ultra-performance liquid chromatography-tandem mass spectrometry. The phase I and II metabolism of PTSO was predicted using Meta-Pred Web Server. For the phase I metabolism, rat (male and female) and human liver microsomes were incubated with PTSO and NADPH regeneration system. Furthermore, in the phase II, microsomes were incubated with PTSO and glutathione or uridine 5'- diphosphoglucuronic acid. The analysis revealed the presence of propylpropane thiosulfinate (PTS) originated by redox reaction in phase I, and two conjugates from the phase II: S-propylmercaptoglutathione (GSSP) and S-propylmercaptocysteine (CSSP). Additionally, considering the environmental fate of PTSO and its metabolites, the ADME parameters and the potential ecotoxicity were also predicted using in silico softwares. The results of the ecotoxicity in silico study evidenced that the metabolism induced the formation of detoxified metabolites from the parent compound, except for dimercaprol and 3-mercaptopropane1,2-diol. Further in vivo assays are needed to confirm this prediction., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antonio Cascajosa-Lira reports financial support was provided by Spanish Ministerio de Universidades (FPU2019-01247). Silvia Pichardo reports financial support was provided by Junta de Andalucía (Project P18-TP-2147). Ana M. Camean reports financial support was provided by Junta de Andalucía (Project P18-TP-2147)., (Copyright © 2023. Published by Elsevier Inc.)

BabelBrain is an open-source standalone graphic-user-interface application designed for studies of neuromodulation using transcranial-focused ultrasound (FUS). It calculates the transmitted acoustic field in the brain tissue, taking into account the distortion effects caused by the skull barrier. The simulation is prepared using scans from magnetic resonance imaging (MRI) and, if available, computed tomography (CT) and zero-echo time MRI scans. It also calculates the thermal effects based on a given ultrasound regime, such as the total duration of exposure, the duty cycle, and acoustic intensity. The tool is designed to work in tandem with neuronavigation and visualization software, such as 3-DSlicer. It uses image processing to prepare domains for ultrasound simulation and uses the BabelViscoFDTD library for transcranial modeling calculations. BabelBrain supports multiple GPU backends, including Metal, OpenCL, and CUDA, and works on all major operating systems including Linux, macOS, and Windows. This tool is particularly optimized for Apple ARM64 systems, which are common in brain imaging research. The article presents the modeling pipeline used in BabelBrain and a numerical study where different methods of acoustic properties mapping were tested to select the best method that can reproduce the transcranial pressure transmission efficiency reported in the literature.

Objective . Focused ultrasound (FUS) neuromodulation non-invasively alters brain activity, likely via acoustic radiation force with dynamics of the pulse repetition frequency (PRF). PRF impacts neuromodulation as well as indirect auditory activation, a confound linked to skull vibrations. This study aimed to minimize these vibrations, by adjusting and randomizing PRF, and determine their impact on FUS-induced motor activity. We hypothesized that: the skull would vibrate most at a specific PRF; randomizing PRF would reduce skull vibrations without affecting motor responses; and FUS would yield motor activity while actuator-induced skull vibrations would not. Approach . Three objectives were studied in parallel using C57Bl/6 mice ( n = number of mice used per objective). First, skull vibration amplitude, measured as a percentage of maximum amplitude per treatment, was recorded via contact microphone over a range of PRFs to assess the PRF-dependency of skull vibrations ( n = 19). Vibrations were then compared between random and fixed PRFs ( n = 15). Lastly, motor responses were compared between fixed 1.5 kHz PRF FUS, random PRF FUS, air-puff stimulation, sham stimulation, and vibration induction via piezoelectric actuator ( n = 30). Main Results. The study found amplitude peaked at 1.51 kHz (88.1 ± 11.5%), significantly higher than at 0.54 kHz (75.5 ± 15.1%; p = 0.0149). Random PRF reduced amplitude by 4.2% ( p = 0.0181). Motor response rates to actuator-induced skull vibrations at the PRF (5.73 ± 6.96%) and its third harmonic (22.9 ± 22.7%) were not significantly different than sham (14.1 ± 11.6%), but lower than FUS (70.2 ± 16.3%; p < 0.0001). Significance . Based on these results, PRF near 0.5 kHz may best avoid skull vibrations, while random PRF could be utilized to slightly reduce vibration amplitude. The results also suggested that skull vibrations likely do not significantly impact motor responses to FUS neuromodulation., (Creative Commons Attribution license.)

Background: Mild hyperthermia has been demonstrated to improve the efficacy of chemotherapy, radiation, and immunotherapy in various cancer types. One localized, non-invasive method of administering mild hyperthermia is magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU). However, challenges for ultrasound such as beam deflection, refraction and coupling issues may result in a misalignment of the HIFU focus and the tumor during hyperthermia. Currently, the best option is to stop the treatment, wait for the tissue to cool, and redo the treatment planning before restarting the hyperthermia. This current workflow is both time-consuming and unreliable., Purpose: An adaptive targeting algorithm was developed for MRgHIFU controlled hyperthermia treatments for cancer therapeutics. This algorithm executes in real time while hyperthermia is being administered to ensure that the focus is within our target region. If a mistarget is detected, the HIFU system will electronically steer the focus of the HIFU beam to the correct target. The goal of this study was to quantify the accuracy and precision of the adaptive targeting algorithm's ability to correct a purposely misplanned hyperthermia treatment in real-time using a clinical MRgHIFU system., Methods: A gelatin phantom with acoustic properties matched to the average speed of sound in human tissue was used to test the adaptive targeting algorithm's accuracy and precision. The target was purposely offset 10 mm away from the focus at the origin, in four orthogonal directions, allowing the algorithm to correct for this mistarget. In each direction, 10 data sets were collected for a total sample size of 40. Hyperthermia was administered with a target temperature set at 42°C. The adaptive targeting algorithm was run during the hyperthermia treatment and 20 thermometry images were collected after the beam steering occurred. The location of the focus was quantified by calculating the center of heating on the MR thermometry data., Results: The average calculated trajectory passed to the HIFU system was 9.7 mm ± 0.4 mm where the target trajectory was 10 mm. The accuracy of the adaptive targeting algorithm after the beam steering correction was 0.9 mm and the precision was 1.6 mm., Conclusion: The adaptive targeting algorithm was implemented successfully and was able to correct the 10 mm mistargets with high accuracy and precision in gelatin phantoms. The results demonstrate the capability to correct the MRgHIFU focus location during controlled hyperthermia., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Biaxial transducers are an emerging technology that can steer generated ultrasound waves using a single piezoceramic component. Simulations have also shown that biaxial transducers can passively estimate the direction of arrival (DOA) of sound waves when operating in the receive mode. This research seeks to experimentally verify biaxial directivity estimates and establish directivity as an independent parameter detected by biaxial transducers. Three cuboid ( 3.84×3.84×5.92 mm) biaxial piezoceramics with two pairs of orthogonal electrodes (one pair applied laterally and one pair applied in the polling direction) were manufactured and characterized. Each transducer was placed in a water tank where an independent hemispherical source was attached to a moveable arm and operated at 250 kHz. Terminal voltages were recorded for 81 source positions in a plane parallel to the transducer's front face and at a depth of approximately 9 cm. Collection was repeated three times per transducer to ensure reproducibility. In silico results were compared with the experimental results. Two derived metrics were then calculated using both the forward and lateral terminal voltages: the phase difference and amplitude ratio. Biaxial transducers demonstrate an ability to estimate the DOA of incident sound waves, independently of any time-of-flight (TOF) information. The phase difference and amplitude ratio complement each other to provide statistically significant and repeatable estimates over a range of 48° (from -24° to +24°). These results can be used to augment a variety of medical, geophysical, and industrial passive ultrasound imaging techniques.

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time imaging and acoustic energy modulation, this modality enables precise temperature control within a defined area. Many thermal applications are being explored with this noninvasive, nonionizing technology, such as hyperthermia generation, to release drugs from thermosensitive liposomal carriers. These drugs can include chemotherapies such as doxorubicin, for which targeted release is desired due to the dose-limiting systemic side effects, namely cardiotoxicity. Doxorubicin is a mainstay for treating a variety of malignant tumors and is commonly used in relapsed or recurrent rhabdomyosarcoma (RMS). RMS is the most common solid soft tissue extracranial tumor in children and young adults. Despite aggressive, multimodal therapy, RMS survival rates have remained the same for the past 30 years. To explore a solution for addressing this unmet need, an experimental protocol was developed to evaluate the release of thermosensitive liposomal doxorubicin (TLD) in an immunocompetent, syngeneic RMS mouse model using MRgHIFU as the source of hyperthermia for drug release.

Objective . Focused ultrasound (FUS) use with and without microbubbles (MB) for investigation of the blood-nerve barrier (BNB) within the peripheral nervous system (PNS) has been performed in this study. We evaluate the feasibility of BNB opening in a rodent sciatic nerve model by direct vision FUS treatment and provide preliminary results of magnetic resonance guided FUS (MRgFUS). Approach . Twenty rodent bilateral sciatic nerves were investigated. Rodents were treated using a benchtop FUS system to directly visualize nerve FUS studies. Definity MB, Evans blue dye (EB) and latex micro beads were injected during studies. Selected animals underwent further compound muscle action potential (CMAP) studies. Sonication peak pressure (MPa), width, duty-cycle and duration as well as MB concentration were varied to investigate effective pressure threshold. Further preliminary MRgFUS studies were performed on selected animals. Immunohistochemistry and histological analysis under florescent microscopy were performed at termination of experiments to verify treatment outcomes. Main results . Three ultrasound pressures and three microbubble concentrations at a single sonication frequency (476.5 kHz) were performed under direct open targeting. Histological analysis demonstrated nerve internal architecture disruption at 1.2 MPa with 166.7 μ l kg -1 while 0.3 MPa, with 40 μ l kg -1 MB concentration was the lower threshold for consistently observed disruption of the BNB without anatomical microarchitecture disruption. EB leakage was confirmed at the target region in histological evaluation of nerve following MB injection and FUS sonication. Supra-harmonic emissions were detected during FUS exposures following MB injection but not at baseline reference, indicating effective MB response and stable cavitation. CMAP amplitudes showed delayed onset latency and lower amplitudes in sonicated nerves compared to control nerves without evidence of complete conduction block, suggesting a transient BNB disruption, while at lower limit pressure subtle conduction changes were observed. In MRgFUS, targeted nerves demonstrated further contrast agent leak as well as supra-harmonic frequency detection. Significance . Opening of the BNB in the PNS was achieved using FUS and MB in a rodent model. Ongoing work aims to refine FUS parameters for drug delivery into the nerve after experimental transient BNB disruption., (Creative Commons Attribution license.)

Objective: Intraventricular hemorrhage (IVH) is a neurovascular complication due to premature birth that results in blood clots forming within the ventricles. Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) has been investigated as a noninvasive treatment to lyse clots. The authors designed and constructed a robotic MRgHIFU platform to treat the neonatal brain that facilitates ergonomic patient positioning. The clot lysis efficacy of the platform is quantified using a brain phantom and clinical MRI system., Methods: A thermosensitive brain-mimicking phantom with ventricular cavities was developed to test the clot lysis efficacy of the robotic MRgHIFU platform. Whole porcine blood was clotted within the phantom's cavities. Using the MRgHIFU platform and a boiling histotripsy treatment procedure (500 W, 10-msec pulse duration, 1.0% duty cycle, and 40-second duration), the clots were lysed inside the phantom. The contents of the cavities were vacuum filtered, and the remaining mass of the solid clot particles was used to quantify the percentage of clot lysis. The interior of the phantom's cavities was inspected for any collateral damage during treatment., Results: A total of 9 phantoms were sonicated, yielding an average (± SD) clot lysis of 97.0% ± 2.57%. Treatment resulted in substantial clot lysis within the brain-mimicking phantoms that were apparent on postsonication T2-weighted MR images. No apparent collateral damage was observed within the phantom after treatment. The results from the study showed the MRgHIFU platform was successful at lysing more than 90% of a blood clot at a statistically significant level., Conclusions: The robotic MRgHIFU platform was shown to lyse a large percentage of a blood clot with no observable collateral damage. These results demonstrate the platform's ability to induce clot lysis when targeting through simulated brain matter and show promise toward the final application in neonatal patients.

Selective therapeutic hypothermia in the setting of mechanical thrombectomy (MT) is promising to further improve the outcomes of large vessel occlusion stroke. A significant limitation in applying hypothermia in this setting is the lack of real-time non-invasive brain temperature monitoring mechanism. Non-invasive brain temperature monitoring would provide important information regarding the brain temperature changes during cooling, and the factors that might influence any fluctuations. This review aims to provide appraisal of brain temperature changes during stroke, and the currently available non-invasive modalities of brain temperature measurement that have been developed and tested over the past 20 years. We cover modalities including magnetic resonance spectroscopy imaging (MRSI), radiometric thermometry, and microwave radiometry, and the evidence for their accuracy from human and animal studies. We also evaluate the feasibility of using these modalities in the acute stroke setting and potential ways for incorporating brain temperature monitoring in the stroke workflow., Competing Interests: MA received Bair Hugger™ sensors from 3M™ as an educational grant for conduct of a clinical study. He also serves on the scientific advisory board of Palmera Medical, Inc. AD is a consultant for Medtronic, Circle NVI, and NovaSignal. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that would be constructed as a potential conflict of interest., (Copyright © 2022 Horn, Diprose, Pichardo, Demchuk and Almekhlafi.)

Computational models of acoustic wave propagation are frequently used in transcranial ultrasound therapy, for example, to calculate the intracranial pressure field or to calculate phase delays to correct for skull distortions. To allow intercomparison between the different modeling tools and techniques used by the community, an international working group was convened to formulate a set of numerical benchmarks. Here, these benchmarks are presented, along with intercomparison results. Nine different benchmarks of increasing geometric complexity are defined. These include a single-layer planar bone immersed in water, a multi-layer bone, and a whole skull. Two transducer configurations are considered (a focused bowl and a plane piston operating at 500 kHz), giving a total of 18 permutations of the benchmarks. Eleven different modeling tools are used to compute the benchmark results. The models span a wide range of numerical techniques, including the finite-difference time-domain method, angular spectrum method, pseudospectral method, boundary-element method, and spectral-element method. Good agreement is found between the models, particularly for the position, size, and magnitude of the acoustic focus within the skull. When comparing results for each model with every other model in a cross-comparison, the median values for each benchmark for the difference in focal pressure and position are less than 10% and 1 mm, respectively. The benchmark definitions, model results, and intercomparison codes are freely available to facilitate further comparisons.

Objective: Non-invasive methods to enhance drug delivery and efficacy in the brain have been pursued for decades. Focused ultrasound hyperthermia (HT) combined with thermosensitive therapeutics have been demonstrated promising in enhancing local drug delivery to solid tumors. We hypothesized that the presence of microbubbles (MBs) combined with transcranial MR-guided focused ultrasound (MRgFUS) could be used to reduce the ultrasound power required for HT while simultaneously increasing drug delivery by locally opening the blood-brain barrier (BBB)., Methods: Transcranial HT (42 °C, 10 min) was performed in wild-type mice using a small animal MRgFUS system incorporated into a 9.4T Bruker MR scanner, with infusions of saline or Definity MBs with doses of 20 or 100 µl/kg/min (denoted as MB-20 and MB-100). MR thermometry data was continuously acquired as feedback for the ultrasound controller during the procedure., Results: Spatiotemporally precise transcranial HT was achieved in both saline and MB groups. A significant ultrasound power reduction (-45.7%, p = 0.006) was observed in the MB-20 group compared to saline. Localized BBB opening was achieved in MB groups confirmed by CE-T1w MR images. There were no structural abnormalities, edema, hemorrhage, or acutemicroglial activation in all groups, confirmed by T2w MR imaging and histology., Conclusion: Our investigations showed that it is feasible and safe to achieve spatiotemporally precise brain HT at significantly reduced power and simultaneous localized BBB opening via transcranial MRgFUS and MBs., Significance: This study provides a new synergistic brain drug delivery method with clinical translation potential.

Background: A robotic system for Magnetic Resonance guided Focussed Ultrasound (MRgFUS) therapy of tumours in the breast, bone, thyroid, and abdomen was developed., Methods: A special C-shaped structure was designed to be attached to the table of conventional magnetic resonance imaging (MRI) systems carrying 4 computer-controlled motion stages dedicated to positioning a 2.75 MHz spherically focussed transducer relative to a patient placed in the supine position. The developed system was evaluated for its MRI compatibility and heating abilities in agar-based phantoms and freshly excised tissue., Results: Compatibility of the system with a clinical high-field MRI scanner was demonstrated. FUS heating in the phantom was successfully monitored by magnetic resonance thermometry without any evidence of magnetically induced phenomena. Cigar-shaped discrete lesions and well-defined areas of overlapping lesions were inflicted in excised tissue by robotic movement along grid patterns., Conclusions: The developed MRgFUS robotic system was proven safe and efficient by ex-vivo feasibility studies., (© 2022 John Wiley & Sons Ltd.)

Background: Intraventricular hemorrhage (IVH) is one of the most serious neurovascular complications resulting from premature birth. It can result in clotting of blood within the ventricles, which causes a buildup of cerebrospinal fluid that can lead to posthemorrhagic ventricular dilation and posthemorrhagic hydrocephalus. Currently, there are no direct treatments for these blood clots as the standard of care is invasive surgery to insert a shunt. Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) has been investigated as a noninvasive treatment to lyse blood clots. However, current MRgHIFU systems are not suitable in the context of treating IVH in neonates., Purpose: We have developed a robotic MRgHIFU neurosurgical platform designed to treat the neonatal brain. This platform facilitates ergonomic patient positioning and directs treatment through their open anterior fontanelle while providing a larger treatment volume. The platform is based on an MR-compatible robot developed by our group. Further development of the platform has warranted investigation of its targeting ability to assess its feasibility in the neonatal brain. This study aimed to quantify the platform's targeting accuracy, precision, and repeatability using a brain phantom and clinical MRI system., Methods: A thermosensitive brain-mimicking phantom was developed to test the platform's targeting accuracy. Rectangular grid patterns were created with HIFU thermal energy "lesions" in the phantoms by targeting specific coordinate points. The intended target locations were demarcated by inserting carbon fiber rods through a targeting assessment template. Coordinates for the intended and actual targets were derived from T2-weighted MRI scans, and the centroid distance between them was measured. Subsequently, the platform's targeting accuracy was quantified according to equations derived from ISO Standard 9283:1998., Results: HIFU ablation resulted in distinct thermal lesions within the thermosensitive phantoms, which appeared as discrete hypointense regions in T2-weighted MR scans. A total of 127 target points were included in the data analysis, which yielded a targeting accuracy of 0.6 mm and targeting precision of 1.2 mm., Conclusions: The robotic MRgHIFU platform was shown to have a high degree of accuracy, precision, and repeatability. The results demonstrate the platform's functionality when targeting through simulated brain matter. These results serve as an initial verification of the platform targeting ability and showed promise toward the final application in a neonatal brain., (© 2022 American Association of Physicists in Medicine.)

The organosulfur compounds (OSC) extracted from Allium spp. exhibit antibacterial, antifungal, and antioxidant properties. The agri-food industry is taking advantage of these properties by using them as natural feed and food additives. In the present work, an acute and a subchronic 90-days toxicity studies have been conducted for the first time to assess the safety of the OSC propyl-propane-thiosulfinate (PTS). Both studies were carried out following the Organization for Economic Co-operation and Development test guidelines (425 and 408, respectively). The acute study provided a maximum tolerated dose (MTD) of 175 mg/kg and the subchronic study established the Non Observed Adverse Effect Level (NOAEL) ≥ 55 mg/kg body weight (b.w.)/day in both sexes. In addition, the subchronic study performed on rats exposed to 14, 28 and 55 mg/kg b.w./day PTS, revealed no changes in any of the hematological parameters measured as well as no differences in body weight and water/food consumption. However, biochemical parameters were altered in some groups, although they were not biologically significant (Ca 2+ in female rats, and the thyroids hormones T3 and T4 in rat males). Furthermore, the histopathological assessment evidenced no abnormality on the gastrointestinal, respiratory, lymphoid, urinary, circulatory, nervous, musculoskeletal, and reproductive systems., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: COVID-19 is a viral transmissible disease and there is limited evidence on vertical transmission and prevalence of SARS-CoV-2 during pregnancy, birth, and the postnatal period. This descriptive cross-sectional study aimed to evaluate the possible perinatal transmission of SARS-CoV-2 in mothers and neonates in a Mexican population., Methods: A total of 133 nasopharyngeal swab samples from mothers, 131 swab samples from neonates, and 140 colostrum samples were obtained, and the presence of SARS-CoV-2 was determined by qPCR., Results: One in eight asymptomatic 38-39 weeks' pregnant women were positive for the presence of SARS-CoV-2 in nasopharyngeal swabs taken just before delivery; and one in 12 nasopharyngeal swabs collected from neonates immediately after delivery without breast feeding were also positive. It was also determined that one in 47 colostrum/milk samples were positive for the test. In addition, there was no association between positive results and any collected metadata of mothers or newborns., Conclusions: Asymptomatic women carried the SARS-CoV-2 virus during delivery, with perinatal transmission of SARS-CoV-2 to newborns. Since neonates were sampled immediately after birth, the detection of positive cases might be due to infection by the virus in utero., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Propyl-propanethiosulfinate (PTS) is a component of Allium essential oils. This organosulfur molecule can be used as a feed additive to decrease the appearance of bacterial resistances caused by the residues of antibiotics. In previous in vitro genotoxicity studies, contradictory results were reported for PTS. In this work, the in vivo genotoxicity of PTS in male and female rats was assessed for the first time, following OECD (Organisation for Economic Co-operation and Development) guidelines. After oral administration (doses: 5.5, 17.4, and 55.0 mg/kg PTS body weight), a combination of the micronucleus (MN) assay (OECD 474) in bone marrow and the standard and enzyme-modified comet assay (OECD 489) was performed. After necropsy, histopathological studies were also carried out. The results did not show the in vivo genotoxicity of PTS at any doses assayed, revealed by the absence of increased MN, and DNA strand breaks or oxidative DNA damage in the standard and enzyme-modified comet assays. The histopathological study revealed that only the highest dose tested (55.0 mg/kg) in the liver and all dose groups in the stomach presented minimal pathological lesions in the organs studied. Consequently, the present work confirms that PTS is not genotoxic at the doses assayed, and it is a promising natural alternative to synthetic preservatives and antibiotics in animal feed.

Focused ultrasound is an emerging medical technique for transcranial procedures and requires the precise modeling of ultrasound signal propagation through the skull. To verify models, the onset time delay (OTD) between two signals measured at the same spatial location, with and without the presence of a skull in the path of the signal, is compared between simulations and experiments. Current methods to automatically identify OTD use correlation-based algorithms. However, these techniques suffer from poor results caused by signal distortion and low signal-to-noise ratios in experimental signals. In this study, we compare the effectiveness of machine learning (multiple linear regression) to three correlation-based time-delay estimation techniques in estimating the OTD of a signal pair. A sample of 1643 signal pairs, with the center frequencies of either 270 or 836 kHz, had their delays manually identified as a benchmark. Density, thickness, incidence angle, frequency, and x and y offsets from the center were used as predictors. We find that, compared with manual identification, machine learning is 80.4% more accurate than cross correlation across all test signals and is noise-independent through all noise bins. The median of the errors was less than 0.3 periods was observed for signals with a frequency of 270 kHz and less than 1.1 periods for signals with a frequency of 836 kHz, with little estimate bias. Overall, linear multivariable regression is determined to provide the best estimate of the OTD of two signals.

Stilbenes are secondary metabolites of great interest produced by many plant species due to their important bioactive properties. These phytochemicals have become of increasing interest in the wine industry as a natural alternative to sulphur dioxide, which has been associated with human health risks. However, there is still little toxicological information on stilbenes and the results thus far have been contradictory. Considering the key role of genotoxicity in risk assessment and the need to offer safe products in the market, the aim of this study was to assess the mutagenic and genotoxic potential of a stilbene extract with 99% purity (ST-99 extract). A complete series of different in vitro tests (Ames test, micronucleus (MN) test, and standard and enzyme-modified comet assays) was performed before its use as a preservative in wines. The ST-99 extract induces a significant increase of binucleated cells with micronuclei only in presence of the metabolic fraction S9 at the highest concentration assayed. Neither the Ames test nor the comet assay revealed the extract's genotoxic potential. Further studies are necessary, including in vivo assays, to ensure consumer safety before it can be used., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The application of stilbenes in the food industry is being considered because of their biological activities. Piceatannol, pterostilbene and ε-viniferin have awakened the industry's interest. However, before they can be commercialized, we must first guarantee their safety for consumers. The present work reviews the toxicological studies performed with these stilbenes. A wide variety of studies has demonstrated their cytotoxic effects in both cancer and non-cancerous cell lines. In contrast, although DNA damage was detected by some authors, in vitro genotoxic studies on the effects of piceatannol, pterostilbene, and ε-viniferin remain scarce. None of the three reviewed substances have been evaluated using the in vitro tests required by the European Food Safety Authority (EFSA) as the first step in genotoxicity testing. We did not find any study on the toxic effects of these stilbenes in vivo. Thus, more studies are needed to confirm their safe use before they can be authorized as additive in the food industry.

Genotoxic data of substances that could be used as food additives are required by the European Food Safety Authority. In this sense, the use of an extract from grapevine shoots containing a stilbene richness of 99% (ST-99), due to its antioxidant and antibacterial activities, has been proposed as an alternative to sulfur dioxide in wine. The aim of this work was to study, for the first time, the in vivo genotoxic effects produced in rats orally exposed to 90, 180, or 360 mg ST-99/kg body weight at 0, 24, and 45 h. The combination of micronucleus assay in bone marrow (OECD 474) and standard (OECD 489) and enzyme-modified comet assay was used to determine the genotoxicity on cells isolated from stomach, liver, and blood of exposed animals. The ST-99 revealed no in vivo genotoxicity. These results were corroborated by analytical studies that confirm the presence of stilbenes and their metabolites in plasma and tissues. Moreover, to complete these findings, a histopathological study was performed under light microscopy in liver and stomach showing only slight modifications in both organs at the highest concentration used. The present work confirms that this extract is not genotoxic presenting a good profile for its potential application as a preservative in the wine industry.

Previous work has shown that biaxial driving using two phase-offset orthogonal electric fields (propagation and lateral) improves the efficiency of ferroelectric materials by reducing coercivity and, hence, energy dissipation. In the current investigation, we demonstrated the capability of the biaxial method to steer ultrasound waves in single-element piezoceramic transducers made of prismatic lead zirconate titanate (PZT). We conducted finite element analysis simulations for 133 kHz (model 1) and 470 kHz biaxial (model 2) transducers models. We performed experimental validation with biaxially driven single-element transducers (n = 3) operating at an average frequency of 131 kHz with the same characteristics as model 1. For both models, we found non-symmetric steering that was a function of both the phase and power of the second electric field. At a constant electrical power (1 W) on the propagation electrodes, simulations for the 133 kHz model predicted maximal steering of 10.3°, 22.6°, and 30.9° for lateral electrode powers of 0.1 W, 0.5 W, and 1.0 W, respectively. Experimentally, for model 1, the maximal steering was 11.7° ± 1.9°, 23.5° ± 3.5°, and 30.2° ± 4.4° for the lateral electrode powers of 0.1 W, 0.5 W, and 1.0 W, respectively. Simulations for the 470 kHz model predicted maximal steering of 8.8°, 16.1°, and 27° for lateral electrode powers of 0.1 W, 0.5 W, and 1.0 W, respectively. Simulations showed that the cause of the steering asymmetry was a non-uniform shear deformation associated with the slightly off-resonance lateral electric field driving frequency. This is the first demonstration of ultrasound steering using a single-element transducer, which can have important applications for ultrasound focusing with phased arrays., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

The use of stilbenes has been proposed as an alternative to sulfur dioxide in wine. Provided the feasibility from a technological approach, the cytotoxicity of an extract from grapevine shoots containing a stilbene richness of 99% (ST-99 extract) was assessed in the human cell lines HepG2 and Caco-2. In addition, the effects of the main stilbenes found in ST-99, trans-resveratrol and trans-ε-viniferin were studied, as well as its mixture. Similar cytotoxic effects were obtained in the exposures to trans-ε-viniferin, ST-99 and the mixture; however, trans-resveratrol alone exerted less toxicity. When HepG2 cells were exposed to trans-ε-viniferin, ST-99 and the mixture, the mean effective concentration (EC 50 ) were 28.28 ± 2.15, 31.91 ± 1.55 and 29.47 ± 3.54 µg/mL, respectively. However, in the exposure to trans-resveratrol, the EC 50 was higher 50 µg/mL. The morphological study evidenced damage at ultrastructural level in HepG2 cells, highlighting the inhibition of cell proliferation and the induction of apoptosis. The type of interaction produced by trans-ε-viniferin and trans-resveratrol mixtures was assessed by an isobologram analysis using the CalcuSyn software, evidencing an antagonist effect. These data comprise a starting point in the toxicological assessment; further studies are needed in this field to assure the safety of the extract ST-99., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

An increasing number of patients with medication-related osteonecrosis of the jaws (MRONJ) has recently been reported. It is still being debated whether the presence or placement of dental implants can lead to MRONJ, so the aim of this study was to find out whether dental implants are a risk factor for MRONJ. From January 2003-January 2019 180 patients with MRONJ were seen at the Leiden University Medical Center. Luxating moments for the onset of MRONJ were calculated retrospectively. We collected clinical data and details of antiresorptive medication and found 22 patients with both dental implants and MRONJ. In 18 patients the implants were in the region of the MRONJ and they were included in this study, 14 who had had implants before using antiresorptive drugs and four who had had antiresorptive drugs before or at the time that the implants were placed. The median times between the placement of implants and the diagnosis of MRONJ in these two groups were 24 months and 6 months, respectively. Among the 47 implants, 30 were located in the necrotic region, and all 30 were either lost spontaneously or had to be removed during treatment of MRONJ. Our results show an increased risk for developing MRONJ in patients with dental implants. Both peri-implantitis around previously placed implants, and insertion of dental implants, are risk factors. Prevention of peri-implantitis and caution when inserting dental implants in patients who take antiresorptive medication are therefore important., (Copyright © 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Treating chronic diffuse sclerosing osteomyelitis (DSO) is challenging and many treatments have been reported. However, we know of no standard protocol or guidelines. In this systematic review of relevant publications we provide an overview of the different treatments used. We made an electronic search of PubMed, Medline, Embase, Web of Science, and the Cochrane Library databases, for papers that described the treatment of DSO of the mandible. The search yielded 48 papers that applied to all inclusion criteria, resulting in 16 case reports, 13 case series, 18 retrospective clinical cohort studies, and one randomised controlled trial. Reported treatment options included different operations; the use of antibiotics, anti-inflammatories, and antiresorptive medication; conservative treatment; and hyperbaric oxygen. Surgical treatment resulted in a low success rate and was associated with higher morbidity than other treatments. Conservative treatment, and that of bisphosphonates, yielded more promising results, so conservative treatment and bisphosphonates seem to be the most promising therapeutic options. However, because of the high risk of bias, no firm conclusions can be drawn, and larger studies with clear inclusion criteria and specified endpoints are needed., (Copyright © 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)