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Background: The extravascular implantable cardioverter-defibrillator (ICD) has a single lead implanted substernally to enable pause-prevention pacing, antitachycardia pacing, and defibrillation energy similar to that of transvenous ICDs. The safety and efficacy of extravascular ICDs are not yet known.Methods: We conducted a prospective, single-group, nonrandomized, premarket global clinical study involving patients with a class I or IIa indication for an ICD, all of whom received an extravascular ICD system. The primary efficacy end point was successful defibrillation at implantation. The efficacy objective would be met if the lower boundary of the one-sided 97.5% confidence interval for the percentage of patients with successful defibrillation was greater than 88%. The primary safety end point was freedom from major system- or procedure-related complications at 6 months. The safety objective would be met if the lower boundary of the one-sided 97.5% confidence interval for the percentage of patients free from such complications was greater than 79%.Results: A total of 356 patients were enrolled, 316 of whom had an implantation attempt. Among the 302 patients in whom ventricular arrhythmia could be induced and who completed the defibrillation testing protocol, the percentage of patients with successful defibrillation was 98.7% (lower boundary of the one-sided 97.5% confidence interval [CI], 96.6%; P<0.001 for the comparison with the performance goal of 88%); 299 of 316 patients (94.6%) were discharged with a working ICD system. The Kaplan-Meier estimate of the percentage of patients free from major system- or procedure-related complications at 6 months was 92.6% (lower boundary of the one-sided 97.5% CI, 89.0%; P<0.001 for the comparison with the performance goal of 79%). No major intraprocedural complications were reported. At 6 months, 25 major complications were observed, in 23 of 316 patients (7.3%). The success rate of antitachycardia pacing, as assessed with generalized estimating equations, was 50.8% (95% CI, 23.3 to 77.8). A total of 29 patients received 118 inappropriate shocks for 81 arrhythmic episodes. Eight systems were explanted without extravascular ICD replacement over the 10.6-month mean follow-up period.Conclusions: In this prospective global study, we found that extravascular ICDs were implanted safely and were able to detect and terminate induced ventricular arrhythmias at the time of implantation. (Funded by Medtronic; ClinicalTrials.gov number, NCT04060680.). [ABSTRACT FROM AUTHOR]

Background: Substernal lead placement of the extravascular implantable cardioverter-defibrillator (EV ICD) permits both defibrillation at thresholds similar to those seen with transvenous ICDs and effective antitachycardia pacing (ATP), while avoiding the vasculature and associated complications. The global Pivotal study has shown the EV ICD system to be safe and effective through 6 months, but long-term experience has yet to be published. We aim to report the performance and safety of the EV ICD system throughout the study., Methods: The EV ICD Pivotal study was a prospective, global, single-arm, pre-market clinical study. Individuals with a class I or IIa indication for a single-chamber ICD per guidelines were enrolled. Freedom from major system- or procedure-related complications, as well as appropriate and inappropriate therapy rates, were assessed through 3 years using the Kaplan-Meier method. Anti-tachycardia pacing success was calculated using simple proportions., Results: An implant was attempted in 316 patients [25.3% female, 53.8±13.1 years old, 81.6% primary prevention, LVEF 38.9%±15.4%]. Of 299 patients with a successful implant, 24 experienced 82 spontaneous arrhythmic episodes that were appropriately treated with either ATP only (38, 46.3%), shock only (34, 41.5%), or both (10, 12.2%) for a Kaplan-Meier-estimated rate of first any appropriate therapy of 9.2% at 3 years. Antitachycardia pacing was successful in 77.1% (37/48) of episodes, and ATP usage significantly increased from discharge to last follow-up visit (P<0.0001). Shock therapy was successful in 100% (27/27) of discrete, spontaneous ventricular arrhythmias. The inappropriate shock rates at 1 and 3 years were 9.8% and 17.5%, respectively, with P-wave oversensing the predominant cause. No major intraprocedural complications were reported and the estimated freedom from system- or procedure-related major complications was 91.9% at 1 year and 89.0% at 3 years. The most common major complications were lead dislodgement (10 events; n=9 patients, 2.8%), postoperative wound or device pocket infection (n=8, 2.5%), and device inappropriate shock delivery (n=4, 1.3%). Twenty-four system revisions were performed as a result of major complications related to the EV ICD system or procedure., Conclusions: From implant to study completion, the EV ICD Pivotal study demonstrated that a single integrated system with an extravascular lead placed in the substernal space maintains high ATP success, effective defibrillation, and a consistent safety profile.

Aims: The extravascular implantable cardioverter-defibrillator (EV ICD) has been shown to be safe and effective for patients at risk of sudden cardiac death, but little is known about EV ICD lead removal in humans. This analysis aimed to characterize the EV ICD lead removal experience thus far., Methods and Results: This was a retrospective analysis of lead removals from the EV ICD Pilot, Pivotal, and Continued Access Studies. Patients with a successful EV ICD implant who underwent lead removal were included. The main objective was lead removal success. Ancillary objectives included characterizing technique used, procedure complications, and reimplantation status. An EV ICD system was successfully implanted in 347 patients across the 3 studies (25.9% female; 53.4 ± 13.3 years; left ventricular ejection fraction: 39.7 ± 15.9). Of these patients, 29 (8.4%) underwent lead removal with a mean lead dwell time of 12.6 ± 14.3 months (0.2-58.4). The main reason for lead removal was lead dislodgement (n = 9, 31.0%). Lead removal was successful in 27/29 (93.1%) cases [100% (19/19) success rate <1 year and 80% (8/10) success rate >1 year post-implant]. Simple traction was used in 22/26 (84.6%) and extraction tools in 4/26 (15.4%) successful cases where technique was known. No complications were reported for any of the removal procedures. All 11 EV ICD reimplant attempts were successful., Conclusion: Complete removal of the EV ICD lead was successful in 93.1% of cases, and simple traction was sufficient in most instances. Based on these results, lead removal from the substernal space was safe and achievable up to 3 years post-implant., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Here we present a fusiform, partially thrombosed, previously ruptured aneurysm in the posterior cerebral artery that was treated with parent vessel sacrifice after a micro-WADA and micro-balloon test occlusion (video 1). These aneurysms pose treatment challenges due to their deep location, morphology, and potentially eloquent distal supply.1 2 Primary coiling, stent assisted coiling, or microsurgical clipping are often not viable options, whereas flow diversion, parent vessel sacrifice,3 or trapping with bypass are usually employed. Pharmacological provocative testing via a micro-WADA4 5 with or without a micro-balloon test occlusion is critical to establish whether the territory at risk has functional eloquence, although specific reports for using these techniques are limited. We describe the patient presentation, initial treatment attempt and failure, and our protocol for performing a micro-WADA/balloon test occlusion test.neurintsurg;jnis-2024-022058v1/V1F1V1Video 1 Micro wada for PCA aneurysm., Competing Interests: Competing interests: IJA: consultant for Balt, Rapid Medical, Imperative Care, IschemaView, Von Medical, and Remedy Robotics; equity in Hyperion, Von Medical, and Remedy Robotics; and grant funding from CNS Foundation. RMS: research supported by NREF, Joe Niekro Foundation, Brain Aneurysm Foundation, Bee Foundation, and National Institutes of Health (R01NS111119-01A1 and UL1TR002736, KL2TR002737) through the Miami Clinical and Translational Science Institute, from the National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH; unrestricted research grant, consulting, and teaching agreement with Medtronic; consulting and teaching agreement with Penumbra, Abbott, InNeuroCo, and Cerenovus., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Human temporal bones (HTBs) are invaluable resources for the study of otologic disorders and for evaluating novel treatment approaches. Given the high costs and technical expertise required to collect and process HTBs, there has been a decline in the number of otopathology laboratories. Our objective is to encourage ongoing study of HTBs by outlining the necessary steps to establish a pipeline for collection and processing of HTBs. In this methods manuscript, we: (1) provide the design of a temporal bone plug sawblade that can be used to collect specimens from autopsy donors; (2) establish that decalcification time can be dramatically reduced from 9 to 3 months if ethylenediaminetetraacetic acid is combined with microwave tissue processing and periodic bone trimming; (3) show that serial sections of relatively-rapidly decalcified HTBs can be successfully immunostained for key inner ear proteins; (4) demonstrate how to drill down a HTB to the otic capsule within a few hours so that subsequent decalcification time can be further reduced to only weeks. We include photographs and videos to facilitate rapid dissemination of the developed methods. Collected HTBs can be used for many purposes, including, but not limited to device testing, imaging studies, education, histopathology, and molecular studies. As new technology develops, it is imperative to continue studying HTBs to further our understanding of the cellular and molecular underpinnings of otologic disorders., Competing Interests: The 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 © 2023 Sagi, Kosaraju, Moore, Mulders, Solyali, Ma, Regula, Hooper and Stankovic.)

Objective: Super-refractory status epilepticus (SRSE) has high rates of morbidity and mortality. Few published studies have investigated neurostimulation treatment options in the setting of SRSE. This systematic literature review and series of 10 cases investigated the safety and efficacy of implanting and activating the responsive neurostimulation (RNS) system acutely during SRSE and discusses the rationale for lead placement and selection of stimulation parameters., Methods: Through a literature search (of databases and American Epilepsy Society abstracts that were last searched on March 1, 2023) and direct contact with the manufacturer of the RNS system, 10 total cases were identified that utilized RNS acutely during SE (9 SRSE cases and 1 case of refractory SE [RSE]). Nine centers obtained IRB approval for retrospective chart review and completed data collection forms. A tenth case had published data from a case report that were referenced in this study. Data from the collection forms and the published case report were compiled in Excel., Results: All 10 cases presented with focal SE: 9 with SRSE and 1 with RSE. Etiology varied from known lesion (focal cortical dysplasia in 7 cases and recurrent meningioma in 1) to unknown (2 cases, with 1 presenting with new-onset refractory focal SE [NORSE]). Seven of 10 cases exited SRSE after RNS placement and activation, with a time frame ranging from 1 to 27 days. Two patients died of complications due to ongoing SRSE. Another patient's SE never resolved but was subclinical. One of 10 cases had a device-related significant adverse event (trace hemorrhage), which did not require intervention. There was 1 reported recurrence of SE after discharge among the cases in which SRSE resolved up to the defined endpoint., Conclusions: This case series offers preliminary evidence that RNS is a safe and potentially effective treatment option for SRSE in patients with 1-2 well-defined seizure-onset zone(s) who meet the eligibility criteria for RNS. The unique features of RNS offer multiple benefits in the SRSE setting, including real-time electrocorticography to supplement scalp EEG for monitoring SRSE progress and response to treatment, as well as numerous stimulation options. Further research is indicated to investigate the optimal stimulation settings in this unique clinical scenario.

Tumor necrosis factor-alpha (TNFα) may promote neuroinflammation prompting tinnitus. This retrospective cohort study evaluated whether anti-TNFα therapy influences incident tinnitus risk among adults with autoimmune disorders and no baseline tinnitus selected from a US electronic health records database (Eversana; 1 January 2010-27 January 2022). Patients with anti-TNFα had ≥90-day history pre-index (first autoimmune disorder diagnosis) and ≥180-day follow-up post-index. Random samples ( n = 25,000) of autoimmune patients without anti-TNFα were selected for comparisons. Tinnitus incidence was compared among patients with or without anti-TNFα therapy, overall and among at-risk age groups or by anti-TNFα category. High-dimensionality propensity score (hdPS) matching was used to adjust for baseline confounders. Compared with patients with no anti-TNFα, anti-TNFα was not associated with tinnitus risk overall (hdPS-matched HR [95% CI]: 1.06 [0.85, 1.33]), or between groups stratified by age (30-50 years: 1 [0.68, 1.48]; 51-70 years: 1.18 [0.89, 1.56]) or anti-TNFα category (monoclonal antibody vs. fusion protein: 0.91 [0.59, 1.41]). Anti-TNFα was not associated with tinnitus risk among those treated for ≥6 months (hdPS-matched HR [95% CI]: 0.96 [0.69, 1.32]) or ≥12 (1.03 [0.71, 1.5]), or those with RA (1.16 [0.88, 1.53]). Thus, in this US cohort study, anti-TNFα therapy was not associated with tinnitus incidence among patients with autoimmune disorders.

With a rising population and increasing concern for food security, food loss and waste (FLW) has become a critical challenge to global sustainability. This paper, drawing on multi-stakeholder theory, aims to empirically identify the key determinants influencing the reduction of FLW in Indian agri-food supply chains (AFSCs) for ensuring food security. A structured questionnaire was used to collect responses from the various stakeholders of the AFSC and then the exploratory factor analysis technique was used to summarize the items into underlying determinants of reduction of FLW in Indian AFSC for ensuring food security. The results of this study reveal that (1) government support, (2) supply chain partnerships, (3) technological support, (4) consumer attitude and (5) top management commitment are the key determinants in the given context. All the stakeholders of AFSC must be aware of these key determinants affecting the reduction of FLW. They must work collaboratively to make a difference by preventing and managing FLW as it is everyone's responsibility to work towards food security.

Background: Previous studies demonstrated that accelerometer-based, mechanically timed atrioventricular synchrony (AVS) is feasible using a leadless ventricular pacemaker., Objective: The purpose of this study was to determine the performance of a leadless ventricular pacemaker with accelerometer-based algorithms that provide AVS pacing., Methods: AccelAV was a prospective, single-arm study to characterize AVS in patients implanted with a Micra AV, which uses the device accelerometer to mechanically detect atrial contractions and promote VDD pacing. The primary objective was to characterize resting AVS at 1 month in patients with complete atrioventricular block (AVB) and normal sinus function., Results: A total of 152 patients (age 77 ± 11 years; 48% female) from 20 centers were enrolled and implanted with a leadless pacemaker. Among patients with normal sinus function and complete AVB (n = 54), mean resting AVS was 85.4% at 1 month, and ambulatory AVS was 74.8%. In the subset of patients (n = 20) with programming optimization, mean ambulatory AVS was 82.6%, representing a 10.5% improvement (P <.001). Quality of life as measured by the EQ-5D-3L (EuroQol Five-Dimensions Three-Level questionnaire) improved significantly from preimplant to 3 months (P = .031). In 37 patients with AVB at both 1 and 3 months, mean AVS during rest did not differ (86.1% vs 84.1%; P = .43). There were no upgrades to dual-chamber devices or cardiac resynchronization therapy through 3 months., Conclusion: Accelerometer-based mechanical atrial sensing provided by a leadless pacemaker implanted in the right ventricle significantly improves quality of life in a select cohort of patients with AV block and normal sinus function. AVS remained stable through 3 months, and there were no system upgrades to dual-chamber pacemakers., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objective: Super-refractory status epilepticus (SRSE) is a neurologic emergency with high mortality and morbidity. Although medical algorithms typically are effective, when they do fail, options may be limited, and neurosurgical intervention should be considered., Methods: We report a case of SRSE treated acutely with responsive neurostimulation (RNS) and focal surgical resection after intracranial monitoring. We also conducted a systematic review of the literature for neurosurgical treatment of SRSE (e.g., neurostimulation). Only published manuscripts were considered., Results: Our patient's seizure semiology consisted of left facial twitching with frequent evolution to bilateral tonic-clonic convulsions. Stereoelectroencephalography and grid monitoring identified multiple seizure foci. The patient underwent right RNS placement with cortical strip leads over the lateral primary motor and premotor cortex as well as simultaneous right superior temporal and frontopolar resection. Status epilepticus resolved 21 days after surgical resection and placement of the RNS. The systematic review revealed 15 case reports describing 17 patients with SRSE who underwent acute neurosurgical intervention. There were 3 patients with SRSE with RNS placement as a single modality, all of whom experienced cessation of SE. Four patients with SRSE received vagus nerve stimulation (3 as a single modality and 1 with combined corpus callosotomy), of whom 1 had SE recurrence at 2weeks. Two patients with SRSE received deep brain stimulation, and the remaining 8 underwent surgical resection; none had recurrence of SE., Conclusions: RNS System placement with or without resection can be a viable treatment option for select patients with SRSE. Early neurosurgical intervention may improve seizure outcomes and reduce complications., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Sensorineural hearing loss (SNHL), which typically arises from the inner ear, is the most common sensory deficit worldwide. The traditional method for studying pathophysiology underlying human SNHL involves histological processing of the inner ear from temporal bones collected during autopsy. Histopathological analysis is destructive and limits future use of a given specimen. Non-destructive strategies for the study of the inner ear are urgently needed to fully leverage the utility of each specimen because access to human temporal bones is increasingly difficult and these precious specimens are required to uncover disease mechanisms and to enable development of new devices. We highlight the potential of reversible iodine staining for micro-computed tomography imaging of the human inner ear. This approach provides reversible, high-resolution visualization of intracochlear structures and is becoming more rapid and accessible., Competing Interests: The 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., (© 2022 Bommakanti, Iyer, Sagi, Brown, Ma, Gonzales and Stankovic.)

Abstract: Sensorineural hearing loss (SNHL) is the most common sensory deficit, disabling nearly half a billion people worldwide. The cochlear implant (CI) has transformed the treatment of patients with SNHL, having restored hearing to more than 800,000 people. The success of CIs has inspired multidisciplinary efforts to address the unmet need for personalized, cellular-level diagnosis, and treatment of patients with SNHL. Current limitations include an inability to safely and accurately image at high resolution and biopsy the inner ear, precluding the use of key structural and molecular information during diagnostic and treatment decisions. Furthermore, there remains a lack of pharmacological therapies for hearing loss, which can partially be attributed to challenges associated with new drug development. We highlight advances in diagnostic and therapeutic strategies for SNHL that will help accelerate the push toward precision medicine. In addition, we discuss technological improvements for the CI that will further enhance its functionality for future patients. This report highlights work that was originally presented by Dr. Stankovic as part of the Dr. John Niparko Memorial Lecture during the 2021 American Cochlear Implant Alliance annual meeting., Competing Interests: The author discloses no conflicts of interest., (Copyright © 2022, Otology & Neurotology, Inc.)

The fibroblast growth factor 2 (FGF2) is a member of the FGF family which is involved in key biological processes including development, cellular proliferation, wound healing, and angiogenesis. Although the utility of the FGF family as therapeutic agents has attracted attention, and FGF2 has been studied in several clinical contexts, there remains an incomplete understanding of the molecular and clinical function of FGF2 in the auditory system. In this review, we highlight the role of FGF2 in inner ear development and hearing protection and present relevant clinical studies for tympanic membrane (TM) repair. We conclude by discussing the future implications of FGF2 as a potential therapeutic agent., Competing Interests: The 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 Jeong, Bojkovic, Sagi and Stankovic.)

Objective: To identify and report novel variants in the TMPRSS3 gene and their clinical manifestations related to hearing loss as well as intervention outcomes. This information will be helpful for genetic counseling and treatment planning for these patients. Methods: Literature review of previously reported TMPRSS3 variants was conducted. Reported variants and associated clinical information was compiled. Additionally, cohort data from 18 patients, and their families, with a positive result for TMPRSS3 -associated hearing loss were analyzed. Genetic testing included sequencing and copy number variation (CNV) analysis of TMPRSS3 and the Laboratory for Molecular Medicine's OtoGenome-v1, -v2, or -v3 panels. Clinical data regarding patient hearing rehabilitation was interpreted along with their genetic testing results and in the context of previously reported cochlear implant outcomes in individuals with TMPRSS3 variants. Results: There have been 87 previously reported TMPRSS3 variants associated with non-syndromic hearing loss in more than 20 ancestral groups worldwide. Here we report occurrences of known variants as well as one novel variant: deletion of Exons 1-5 and 13 identified from our cohort of 18 patients. The hearing impairment in many of these families was consistent with that of previously reported patients with TMPRSS3 variants (i.e., typical down-sloping audiogram). Four patients from our cohort underwent cochlear implantation. Conclusion: Bi-allelic variants of TMPRSS3 are associated with down-sloping hearing loss regardless of ancestry. The outcome following cochlear implantation in patients with variants of TMPRSS3 is excellent. Therefore, cochlear implantation is strongly recommended for hearing rehabilitation in these patients., Competing Interests: The 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 Moon, Grant, Sagi, Rehm and Stankovic.)

Pain is a major comorbidity of sickle cell disease (SCD). Patients with SCD may suffer from both acute and chronic pain. Acute pain is caused by recurrent and unpredictable episodes of vaso-occlusive crises (VOC), whereas the exact etiology of chronic pain is still unknown. Opioids are the mainstay for pain treatment, but the opioid epidemic has significantly altered access to prescription opioids and has brought concerns over their long-term use into the forefront, which have negatively impacted the treatment of sickle pain. Opioids remain potent analgesics but growing opioid-phobia has led to the realization of an unmet need to develop nonopioid therapies that can provide relief for severe sickle pain. This realization has contributed to the approval of 3 different drugs by the Food and Drug Administration (FDA) for the treatment of SCD, particularly to reduce VOC and/or have an impact on the pathobiology of SCD. In this review, we outline the challenges and need for validation of side-effects of opioids and provide an update on the development of mechanism-based translational therapies, specifically targeting pain in SCD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: MARVEL 2 assessed the efficacy of mechanical atrial sensing by a ventricular leadless pacemaker, enabling a VDD pacing mode. The behavior of the enhanced MARVEL 2 algorithm during variable atrio-ventricular conduction (AVC) and/or arrhythmias has not been characterized and is the focus of this study., Methods: Of the 75 patients enrolled in the MARVEL 2 study, 73 had a rhythm assessment and were included in the analysis. The enhanced MARVEL 2 algorithm included a mode-switching algorithm that automatically switches between VDD and ventricular only antibradycardia pacing (VVI)-40 depending upon AVC status., Results: Forty-two patients (58%) had persistent third degree AV block (AVB), 18 (25%) had 1:1 AVC, 5 (7%) had variable AVC status, and 8 (11%) had atrial arrhythmias. Among the 42 patients with persistent third degree AVB, the median ventricular pacing (VP) percentage was 99.9% compared to 0.2% among those with 1:1 AVC. As AVC status changed, the algorithm switched to VDD when the ventricular rate dropped less than 40 bpm. During atrial fibrillation (AF) with ventricular response greater than 40 bpm, VVI-40 mode was maintained. No pauses longer than 1500 ms were observed. Frequent ventricular premature beats reduced the percentage of AV synchrony. During AF, the atrial signal was of low amplitude and there was infrequent sensing., Conclusion: The mode switching algorithm reduced VP in patients with 1:1 AVC and appropriately switched to VDD during AV block. No pacing safety issues were observed during arrhythmias., (© 2021 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Objective: Gamma Knife radiosurgery (GKRS) is an established surgical option for the treatment of trigeminal neuralgia (TN), particularly for high-risk surgical candidates and those with recurrent pain. However, outcomes after three or more GKRS treatments have rarely been reported. Herein, the authors reviewed outcomes among patients who had undergone three or more GKRS procedures for recurrent TN., Methods: The authors conducted a multicenter retrospective analysis of patients who had undergone at least three GKRS treatments for TN between July 1997 and April 2019 at two different institutions. Clinical characteristics, radiosurgical dosimetry and technique, pain outcomes, and complications were reviewed. Pain outcomes were scored on the Barrow Neurological Institute (BNI) scale, including time to pain relief (BNI score ≤ III) and recurrence (BNI score > III)., Results: A total of 30 patients were identified, including 16 women and 14 men. Median pain duration prior to the first GKRS treatment was 10 years. Three patients (10%) had multiple sclerosis. Time to pain relief was longer after the third treatment (p = 0.0003), whereas time to pain recurrence was similar across each of the successive treatments (p = 0.842). Complete or partial pain relief was achieved in 93.1% of patients after the third treatment. The maximum pain relief achieved after the third treatment was significantly better among patients with no prior percutaneous procedures (p = 0.0111) and patients with shorter durations of pain before initiation of GKRS therapy (p = 0.0449). New or progressive facial sensory dysfunction occurred in 29% of patients after the third GKRS treatment and was reported as bothersome in 14%. One patient developed facial twitching, while another experienced persistent lacrimation. No statistically significant predictors of adverse effects following the third treatment were found. Over a median of 39 months of follow-up, 77% of patients maintained complete or partial pain relief. Three patients underwent a fourth GKRS treatment, including one who ultimately received five treatments; all of them reported sustained pain relief at the extended follow-up., Conclusions: The authors describe the largest series to date of patients undergoing three or more GKRS treatments for refractory TN. A third treatment may produce outcomes similar to those of the first two treatments in terms of long-term pain relief, recurrence, and adverse effects.

Background: The feasibility and outcomes of concomitant atrioventricular node ablation (AVNA) and leadless pacemaker implant are not well studied. We report outcomes in patients undergoing Micra implant with concomitant AVNA., Methods: Patients undergoing AVNA at the time of Micra implant from the Micra Transcatheter Pacing (IDE) Study, Continued Access (CA) study, and Post-Approval Registry (PAR) were included in the analysis and compared to Micra patients without AVNA. Baseline characteristics, acute and follow-up outcomes, and electrical performance were compared between patients with and without AVNA during the follow-up period., Results: A total of 192 patients (mean age 77.4 ± 8.9 years, 72% female) underwent AVNA at the time of Micra implant and were followed for 20.4 ± 15.6 months. AVNA patients were older, more frequently female, and tended to have more co-morbid conditions compared with non-AVNA patients (N = 2616). Implant was successful in 191 of 192 patients (99.5%). The mean pacing threshold at implant was 0.58 ± 0.35 V and remained stable during follow-up. Major complications within 30 days occurred more frequently in AVNA patients than non-AVNA patients (7.3% vs. 2.0%, p < .001). The risk of major complications through 36-months was higher in AVNA patients (hazard ratio: 3.81, 95% confidence interval: 2.33-6.23, p < .001). Intermittent loss of capture occurred in three AVNA patients (1.6%), all were within 30 days of implant and required system revision. There were no device macrodislodgements or unexpected device malfunctions., Conclusion: Concomitant AVN ablation and leadless pacemaker implant is feasible. Pacing thresholds are stable over time. However, patient comorbidities and the risk of major complications are higher in patients undergoing AVNA., (© 2021 The Authors. Journal of Cardiovascular Electrophysiology Published by Wiley Periodicals LLC.)

Treatment of severe chronic and acute pain in sickle cell disease (SCD) remains challenging due to the interdependence of pain and psychosocial modulation. We examined whether modulation of the descending pain pathway through an enriched diet and companionship could alleviate pain in transgenic sickle mice. Mechanical and thermal hyperalgesia were reduced significantly with enriched diet and/or companionship. Upon withdrawal of both conditions, analgesic effects observed prior to withdrawal were diminished. Serotonin (5-hydroxytryptamine, 5-HT) was found to be increased in the spinal cords of mice provided both treatments. Additionally, 5-HT production improved at the rostral ventromedial medulla and 5-HT accumulated at the dorsal horn of the spinal cord of sickle mice, suggesting the involvement of the descending pain pathway in the analgesic response. Modulation of 5-HT and its effect on hyperalgesia was also investigated through pharmaceutical approaches. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, showed a similar anti-nociceptive effect as the combination of diet and companionship. Depletion of 5-HT through p-chlorophenylalanine attenuated the anti-hyperalgesic effect of enriched diet and companionship. More significantly, improved diet and companionship enhanced the efficacy of a sub-optimal dose of morphine for analgesia in sickle mice. These findings offer the potential to reduce opioid use without pharmacological interventions to develop effective pain management strategies.

With the outbreak of COVID-19 (coronavirus disease 2019) as a global pandemic, various of its neurological manifestations have been reported. We report a case of a 54-year-old male with new-onset seizure who tested positive for severe acute respiratory syndrome coronavirus 2 from a nasopharyngeal swab sample. Investigative findings, which included contrast-enhancing right posterior temporal lobe T2-hyperintensity on brain magnetic resonance imaging, right-sided lateralized periodic discharges on the electroencephalogram, and elevated protein level on cerebrospinal fluid analysis, supported the diagnosis of possible encephalitis from COVID-19 infection. The findings in this case are placed in the context of the existing literature.

Pain in Sickle Cell Disease (SCD) is a major comorbidity and unique with acute pain due to recurrent and episodic vaso-occlusive crises as well as chronic pain, which can span an individual's entire life. Opioids are the mainstay treatment for pain in SCD. Due to recent health crises raised by adverse effects including deaths from opioid use, pain management in SCD is adversely affected. Cannabis and its products are most widely used for pain in multiple conditions and also by patients with SCD on their own. With the availability of "Medical Cannabis" and approval to use cannabis as medicine across majority of States in the United States as well as over-the-counter preparations, cannabis products are being used increasingly for SCD. The reliability of many of these products remains questionable, which poses a major health risk to the vulnerable individuals seeking pain relief. Therefore, this review provides up to date insights into available categories of cannabis-based treatment strategies, their mechanism of action and pre-clinical and clinical outcomes in SCD. It provides evidence for the benefits and risks of cannabis use in SCD and cautions about the unreliable and unvalidated products that may be adulterated with life-threatening non-cannabis compounds.

Background: The MARVEL (Micra Atrial TRacking Using a Ventricular AccELerometer) 2 study assessed the efficacy of atrioventricular (AV) synchronous pacing with a Micra leadless pacemaker. Average atrioventricular synchrony (AVS) was 89.2%. Previously, low amplitude of the Micra-sensed atrial signal (A4) was observed to be a factor of low AVS., Objective: The purpose of this study was to identify predictors of A4 amplitude and high AVS., Methods: We analyzed 64 patients enrolled in MARVEL 2 who had visible P waves on electrocardiogram for assessing A4 amplitude and 40 patients with third-degree AV block for assessing AVS at rest. High AVS was defined as >90% correct atrial-triggered ventricular pacing. The association between clinical factors and echocardiographic parameters with A4 amplitude was investigated using a multivariable model with lasso variable selection. Variables associated with A4 amplitude together with premature ventricular contraction burden, sinus rate, and sinus rate variability (standard deviation of successive differences of P-P intervals [SDSD]) were assessed for association with AVS., Results: In univariate analysis, low A4 amplitude was inversely related to atrial function assessed by E/A ratio and e'/a' ratio, and was directly related to atrial contraction excursion (ACE) and atrial strain (Ɛa) on echocardiography (all P ≤.05). The multivariable lasso regression model found coronary artery bypass graft history, E/A ratio, ACE, and Ɛa were associated with low A4 amplitude. E/A ratio and SDSD were multivariable predictors of high AVS, with >90% probability if E/A <0.94 and SDSD <5 bpm., Conclusion: Clinical parameters and echocardiographic markers of atrial function are associated with A4 signal amplitude. High AVS can be predicted by E/A ratio <0.94 and low sinus rate variability at rest., (Copyright © 2020 The Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Sickle cell disease (SCD) is a hemoglobinopathy affecting multiple organs and featuring acute and chronic pain. Purkinje cell damage and hyperalgesia have been demonstrated in transgenic sickle mice. Purkinje cells are associated with movement and neural function which may influence pain. We hypothesized that Purkinje cell damage and/or chronic pain burden provoke compensatory gait changes in sickle mice. We found that Purkinje cells undergoe increased apoptosis as shown by caspase-3 activation. Using an automated gait measurement system, MouseWalker, we characterized spatiotemporal gait characteristics of humanized transgenic BERK sickle mice in comparison to control mice. Sickle mice showed alteration in stance instability and dynamic gait parameters (walking speed, stance duration, swing duration and specific swing indices). Differences in stance instability may reflect motor dysfunction due to damaged Purkinje cells. Alterations in diagonal and all stance indices indicative of hesitation during walking may originate from motor dysfunction and/or arise from fear and/or anticipation of movement-evoked pain. We also demonstrate that stance duration, diagonal swing indices and all stance indices correlate with both mechanical and deep tissue hyperalgesia, while stance instability correlates with only deep tissue hyperalgesia. Therefore, objective analysis of gait in SCD may provide insights into neurological impairment and pain states., (Copyright © 2020 Kiven, Wang, Aich, Argueta, Lei, Sagi, Tennakoon, Bedros, Lambrecht and Gupta.)

Objective: The objective was to study latency to first event among patients with psychogenic nonepileptic seizures compared (PNES) to epileptic seizures (ES) in an epilepsy monitoring unit (EMU). Introduction: PNES are common imitators of ES. This study investigates latency to first event in patients with PNES compared to patients with ES. Methods: We performed a retrospective chart review of patients admitted to our EMU from March 2016 to October 2017. We identified patients with PNES and ES. Patients with other nonepileptic events and mixed PNES (epilepsy plus PNES) were excluded. Patient demographics, baseline seizure frequency, length of EMU stay and time from admission to first event were recorded. Results: In total, 111 patients with PNES and 121 patients with ES were included. The mean age (in years) was 42 and 38, respectively. The average baseline seizure frequency was four times higher in the PNES group than the ES group. Greater than half (52%) of the patients with PNES and about one third (38%) of the patients with ES had an event within the first 24 hours. The average time to first event was 20.88 hours for the PNES group and 30.99 hours for the ES group ( p <0.01). The median latency to first event was 14 hours for the PNES group and 23 hours for the ES group. The average length of EMU stay was significantly longer in the ES group (70.82 hours) than the PNES group (53.95 hours). Conclusion: The average time to first event is shorter for PNES than in ES. In patients with high pre-EMU clinical suspicion for PNES, relatively shorter EMU monitoring (24 to 48 hours) can confirm diagnosis. This phenomenon might improve cost-effectiveness of EMU monitoring in patients with PNES., Competing Interests: FUNDING:No funding was provided for this study. DISCLOSURES:The authors have no conflicts of interest relevant to the content of this article., (Copyright © 2020. Matrix Medical Communications. All rights reserved.)

Ectopic cerebellar tissue has only been described in isolated case reports, with only two reported cases in adult patients. We report the case of a 63-year-old woman with progressive, medically refractory headaches. A scan showed an intraosseous lesion of the midline occipital bone. Surgical resection of the soft tissue lesion was undertaken. Her headaches ceased postoperatively. Histopathological analysis revealed cerebellar cortical tissue with a surrounding meningothelial cell layer, characteristic of cerebellar ectopia. This is the second reported case of an intraosseous location of this lesion, and only the third case described in an adult patient. Our findings illustrate a rare cause of headaches and support the therapeutic roles of surgical treatment for this extremely rare condition., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare.

Importance: Sickle cell disease (SCD) is characterized by chronic pain and episodic acute pain caused by vasoocclusive crises, often requiring high doses of opioids for prolonged periods. In humanized mouse models of SCD, a synthetic cannabinoid has been found to attenuate both chronic and acute hyperalgesia. The effect of cannabis on chronic pain in adults with SCD is unknown., Objective: To determine whether inhaled cannabis is more effective than inhaled placebo in relieving chronic pain in adults with SCD., Design, Setting, and Participants: This pilot randomized clinical trial included participants with SCD with chronic pain admitted to a single inpatient clinical research center for 2 separate 5-day stays from August 2014 to April 2017. Participants inhaled either vaporized cannabis (4.4% Δ-9-tetrahydrocannabinol to 4.9% cannabidiol) 3 times daily or vaporized placebo cannabis. Pain and pain interference ratings using the Brief Pain Inventory were assessed throughout each 5-day period. Participants with SCD and chronic pain on stable analgesics were eligible to enroll. A total of 90 participants were assessed for eligibility; 56 participants were deemed ineligible, and 34 participants were enrolled. Of these, 7 participants dropped out before randomization. Of 27 randomized participants, 23 completed both treatment arms of the crossover study and were included in the final per protocol analysis. Data analysis was completed in June 2019, with the sensitivity analysis conducted in April 2020., Interventions: Inhalation of vaporized cannabis plant (4.4% Δ-9-tetrahydrocannbinol to 4.9% cannabidiol) or placebo cannabis plant using a vaporizer 3 times daily for 5 days., Main Outcomes and Measures: Daily pain assessed with visual analog scale and Brief Pain Inventory., Results: A total of 23 participants (mean [SD] age, 37.6 [11.4] years; 13 [56%] women) completed the trial. The mean (SD) difference in pain rating assessment between the cannabis and placebo groups was -5.3 (8.1) for day 1, -10.9 (7.0) for day 2, -16.5 (9.2) for day 3, -8.9 (6.7) for day 4, and -8.2 (8.1) for day 5; however, none of these differences were statistically significant. There was no statistically significant mean (SD) difference in pain interference ratings between cannabis and placebo between days 1 and 5 for interference in general activities (day 1: 0.27 [0.35]; day 5: -1.0 [0.5]), walking (day 1: 0.14 [0.73]; day 5: -0.87 [0.63]), sleep (day 1: 0.59 [0.74]; day 5: -1.3 [0.8]), or enjoyment (day 1: 0.23 [0.69]; day 5: -0.91 [0.48]), but there was a statistically significant mean (SD) difference in decrease in interference with mood (day 1: 0.96 [0.59]; day 5: -1.4 [0.6]; P = .02). No differences in treatment-related adverse effects were observed. Use of concomitant opioids was similar during both treatment periods., Conclusions and Relevance: This randomized clinical trial found that, compared with vaporized placebo, vaporized cannabis did not statistically significantly reduce pain and associated symptoms, except interference in mood, in patients with SCD with chronic pain., Trial Registration: ClinicalTrials.gov Identifier: NCT01771731.

•We present a case of squamous cell carcinoma causing cortical venous thrombosis (CoVT)•This is the first case of an invasive scalp lesion causing CoVT and brain hemorrhage•Some cases of CoVT may be managed conservatively•Recurrent, invasive squamous cell carcinoma remains therapeutically challenging., (© 2020 The Author(s).)

Sickle cell disease (SCD) is a genetic disorder characterized by hemolysis, end-organ damage, inflammation, and pain. Recurrent and unpredictable episodes of acute pain due to vaso-occlusive crises are a unique feature of SCD. Many patients also develop lifelong chronic pain. Opioids are the primary method of pain treatment in SCD; however, continued use is associated with several adverse effects. Integrative approaches to treating pain in SCD are increasingly being explored to prevent the side effects associated with opioids. In this review, we highlight the mechanisms of pain in SCD and describe mechanism-based integrative approaches for treating pain., Competing Interests: Declaration of Competing Interest Kalpna Gupta: Fera Pharmaceuticals LLC: Consultancy, Honoraria; Tautona Group: Consultancy, Honoraria; Novartis advisory group: Honoraria; CSL Behring, honoraria; Grifols, Research Grant; 1910 Genetics, Resaerch Grant. All other authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)