A Modular Communicative Leadless Pacing-Defibrillator System.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (ICD) is associated with fewer lead-related complications than a transvenous ICD; however, the subcutaneous ICD cannot provide bradycardia and antitachycardia pacing. Whether a modular pacing-defibrillator system comprising a leadless pacemaker in wireless communication with a subcutaneous ICD to provide antitachycardia and bradycardia pacing is safe remains unknown. METHODS: We conducted a multinational, single-group study that enrolled patients at risk for sudden death from ventricular arrhythmias and followed them for 6 months after implantation of a modular pacemaker-defibrillator system. The safety end point was freedom from leadless pacemaker-related major complications, evaluated against a performance goal of 86%. The two primary performance end points were successful communication between the pacemaker and the ICD (performance goal, 88%) and a pacing threshold of up to 2.0 V at a 0.4-msec pulse width (performance goal, 80%). RESULTS: We enrolled 293 patients, 162 of whom were in the 6-month end-point cohort and 151 of whom completed the 6-month follow-up period. The mean age of the patients was 60 years, 16.7% were women, and the mean (±SD) left ventricular ejection fraction was 33.1±12.6%. The percentage of patients who were free from leadless pacemaker-related major complications was 97.5%, which exceeded the prespecified performance goal. Wireless-device communication was successful in 98.8% of communication tests, which exceeded the prespecified goal. Of 151 patients, 147 (97.4%) had pacing thresholds of 2.0 V or less, which exceeded the prespecified goal. The percentage of episodes of arrhythmia that were successfully terminated by antitachycardia pacing was 61.3%, and there were no episodes for which antitachycardia pacing was not delivered owing to communication failure. Of 162 patients, 8 died (4.9%); none of the deaths were deemed to be related to arrhythmias or the implantation procedure. CONCLUSIONS: The leadless pacemaker in wireless communication with a subcutaneous ICD exceeded performance goals for freedom from major complications related to the leadless pacemaker, for communication between the leadless pacemaker and subcutaneous ICD, and for the percentage of patients with a pacing threshold up to 2.0 V at a 0.4-msec pulse width at 6 months. (Funded by Boston Scientific; MODULAR ATP ClinicalTrials.gov NCT04798768.).

Climate Change, Emerging Vector-Borne Illnesses, and Anesthetic Considerations.

As a result of the widespread prevalence of anesthetic usage, anesthesia-related complications are well studied, ranging from benign postoperative nausea and vomiting to potentially fatal complications, such as paralysis, malignant hyperthermia, and death. However, one intersection that still needs further analysis is the relationship between vector-borne illnesses (VBIs) and anesthetic complications. With the advent of climate change and global warming, what were previously endemic vectors have spread far beyond their typical regions, resulting in the spread of VBI. As the incidence of VBIs rapidly increases in the United States, operations for diagnostic testing, and thus the identification and treatments of these VBIs, have significantly diminished. A literature review was conducted to analyze case reports of patients with VBIs and anesthetic concerns with sources from PubMed and Google Scholar databases, and a wide range of complications were found.

The effects of psychosocial and behavioral interventions on depressive and anxiety symptoms during the COVID-19 pandemic: a systematic review and meta-analysis.

Psychosocial and behavioral interventions have been shown to significantly reduce depressive and anxiety symptoms in different populations. Recent evidence suggests that the mental health of the general population has deteriorated significantly since the start of Coronavirus Disease 2019 (COVID-19) pandemic. We conducted a systematic review and meta-analysis of studies on the therapeutic effects of psychosocial and behavioral interventions on depression and anxiety during the COVID-19 pandemic. We systematically searched six electronic databases between December 2019 and February 2022 including PubMed, PsycINFO, Scopus, Web of Science, CNKI, and Wanfang Data. We included randomized clinical trials of psychosocial and behavioral interventions in individuals with depressive or anxiety symptoms during the COVID-19 outbreak compared to various control conditions. A total of 35 eligible studies with 5457 participants were included. The meta-analysis results showed that psychosocial and behavioral interventions had statistically significant moderate effects on depression [SMD = - 0.73, 95% CI (- 1.01, - 0.45), I2 = 90%] and large effects on anxiety [SMD = - 0.90, 95% CI (- 1.19, - 0.60), I2 = 92%], especially in the general population and COVID-19 survivors. Exercise and cognitive behavioral therapy were found to be the most effective treatments with moderate-to-large effect size for depression and anxiety during the outbreak of COVID-19. We also found the internet-based approach could also achieve almost equally significant effects on depression and anxiety compared with face-to-face traditional approach. Our findings suggest that cognitive behavioral therapy and physical exercise intervention are significantly effective for depression and anxiety related to the COVID-19 pandemic regardless of the delivery modes, and gender differences should be taken into consideration for better implementation of interventions in clinical and community practice.

Longitudinal QTc stability and impact of baseline cardiac rhythm on discharge dose in dofetilide-treated patients.

INTRODUCTION: Dofetilide suppresses atrial fibrillation (AF) in a dose-dependent fashion. The protective effect of AF against QTc prolongation induced torsades de pointe and transient post-cardioversion QTc prolongation may result in dofetilide under-dosing during initiation. Thus, the optimal timing of cardioversion for AF patients undergoing dofetilide initiation to optimize discharge dose remains unknown as does the longitudinal stability of QTc . The purpose of this study was to evaluate the impact of baseline rhythm on dofetilide dosing during initiation and assess the longitudinal stability of QTc-all (Bazzett, Fridericia, Framingham, and Hodges) over time. METHODS: Medical records of patients who underwent preplanned dofetilide loading at a tertiary care center between January 2016 and 2019 were reviewed. RESULTS: A total of 198 patients (66 ± 10 years, 32% female, CHADS2 -Vasc 3 [2-4]) presented for dofetilide loading in either AF (59%) or sinus rhythm (SR) (41%). Neither presenting rhythm, nor spontaneous conversion to SR impacted discharge dose. The cumulative dofetilide dose before cardioversion moderately correlated (r = .36; p = .0001) with discharge dose. Postcardioversion QTc-all prolongation (p < .0001) prompted discharge dose reduction (890 ± 224 mcg vs. 552 ± 199 mcg; p < .0001) in 30% patients. QTc-all in SR prolonged significantly during loading (p < .0001). All patients displayed QTc-all reduction (p < .0001) from discharge to short-term (46 [34-65] days) that continued at long-term (360 [296-414] days) follow-ups. The extent of QTc-all reduction over time moderately correlated with discharge QTc-all (r = .54-0.65; p < .0001). CONCLUSION: Dofetilide initiation before cardioversion is equivalent to initiation during SR. Significant QTc reduction proportional to discharge QTc is seen over time in all dofetilide-treated patients. QTc returns to preloading baseline during follow-up in patients initiated in SR.

Impact of a dedicated atrial fibrillation clinic on diagnosis-to-ablation time.

Background: Outcomes following catheter ablation (CA) for atrial fibrillation (AF) improve as the diagnosis-to-ablation time (DAT) shortens. Use of a protocol-based integrated care model through a dedicated atrial fibrillation clinic (AFC) may serve to standardize treatment pathways and decrease DAT. Objective: To evaluate the DAT and clinical characteristics of patients with AF referred from an AFC vs a conventional electrophysiology clinic (EC). Methods: Retrospective analysis was completed in consecutive patients undergoing index AF ablation at Riverside Methodist Hospital in 2019 with minimum 1 year follow-up. Patients were categorized based off their CA referral source (AFC vs EC) and where the initial visit following index diagnosis of AF occurred (AFC vs EC). Results: A total of 182 patients (mean age 65 years, 64% male) were reviewed. Patients referred from an AFC (21%) had a median DAT of 342 days (interquartile range [IQR], 125-855 days) compared to patients referred from EC (79%) with a median DAT of 813 days (IQR, 241-1444 days; P = .01). Patients with their index visit following AF diagnosis occurring in the AFC (9%) had significantly shorter median DAT (127 days [IQR, 95-188 days]) compared to EC (91%) (789 days [IQR, 253-1503 days]; P = .002). Patients with DAT <1 year had lower AF recurrence than patients with DAT >1 year (P = .04, hazard ratio = 0.58, 95% confidence interval 0.3418-1.000). Conclusion: DAT is a modifiable factor that may affect CA outcomes. Significant reductions in DAT were observed in patients evaluated through a dedicated AF clinic.

Prevention of Cooktop Ignition Using Detection and Multi-Step Machine Learning Algorithms.

This paper presents a study to examine the potential use of machine learning models to build a real-time detection algorithm for prevention of kitchen cooktop fires. Sixteen sets of time-dependent sensor signals were obtained from 60 normal/ignition cooking experiments. A total of 200 000 data instances are documented and analyzed. The raw data are preprocessed. Selected features are generated for time series data focusing on real-time detection applications. Utilizing the leave-one-out cross validation method, three machine learning models are built and tested. Parametric studies are carried out to understand the diversity, volume, and tendency of the data. Given the current dataset, the detection algorithm based on Support Vector Machine (SVM) provides the most reliable prediction (with an overall accuracy of 96.9 %) on pre-ignition conditions. Analyses indicate that using a multi-step approach can further improve overall prediction accuracy. The development of an accurate detection algorithm can provide reliable feedback to intercept ignition of unattended cooking and help reduce fire losses.

P-Flash - A Machine Learning-based Model for Flashover Prediction using Recovered Temperature Data.

Research was conducted to examine the use of Support Vector Regression (SVR) to build a model to forecast the potential occurrence of flashover in a single-floor, multi-room compartment fire. Synthetic temperature data for heat detectors in different rooms were generated, 1000 simulation cases are considered, and a total of 8 million data points are utilized for model development. An operating temperature limitation is placed on heat detectors where they fail at a fixed exposure temperature of 150 °C and no longer provide data to more closely follow actual performance. The forecast model P-Flash (Prediction model for Flashover occurrence) is developed to use an array of heat detector temperature data, including in adjacent spaces, to recover temperature data from the room of fire origin and predict potential for flashover. Two special treatments, sequence segmentation and learning from fitting, are proposed to overcome the temperature limitation of heat detectors in real-life fire scenarios and to enhance prediction capabilities to determine if the flashover condition is met even with situations where there is no temperature data from all detectors. Experimental evaluation shows that P-Flash offers reliable prediction. The model performance is approximately 83 % and 81 %, respectively, for current and future flashover occurrence, considering heat detector failure at 150 °C. Results demonstrate that P-Flash, a new data-driven model, has potential to provide fire fighters real-time, trustworthy, and actionable information to enhance situational awareness, operational effectiveness, and safety for firefighting.

Lead Macrodislodgement of a Subcutaneous Implantable Cardioverter-Defibrillator Results in a Reel Problem.

Lead macrodislodgement is a rare complication of cardiac implantable electronic devices associated with patient-related risk factors. This paper outlines a case of reel syndrome secondary to device manipulation 3 months after subcutaneous implantable cardioverter-defibrillator implantation and describes the challenges with lead macrodislodgement diagnosis, mechanisms, and management. (Level of Difficulty: Beginner.).

Same-day Discharge after Subcutaneous Implantable Cardioverter-defibrillator Implantation is Safe and Cost-effective.

The feasibility and safety of same-day discharge after transvenous implantable cardioverter-defibrillator implantation is well-established. However, subcutaneous ICDs (S-ICDs) are now increasingly being implanted, and the feasibility, safety, and potential cost savings associated with same-day discharge after S-ICD placement has not been widely investigated. In a small cohort of patients (n = 24) who underwent S-ICD implantation at our institution, 54% were successfully discharged on the same day as their implant procedure. Procedure-related complications were not apparent in this sampling and the reduction in health care costs was high, suggesting this protocol has immense benefit in today's health care environment. As such, same-day discharge of S-ICD patients is appropriate to consider and should receive further attention.

Generating Synthetic Sensor Data to Facilitate Machine Learning Paradigm for Prediction of Building Fire Hazard.

Using the zone fire model CFAST as the simulation engine, time series data for building sensors, such as heat detectors, smoke detectors, and other targets at any arbitrary locations in multi-room compartments with different geometric configurations, can be obtained. An automated process for creating inputs files and summarizing model results, CData, is being developed as a companion to CFAST. An example case is presented to demonstrate the use of CData where synthetic data is generated for a wide range of fire scenarios. Three machine learning algorithms: support vector machine (SVM), decision tree (DT), and random forest (RF), are used to develop classification models that can predict the location of a fire based on temperature data within a compartment. Results show that DT and RF have excellent performance on the prediction of fire location and achieve model accuracy in between 93 % and 96 %. For SVM, model performance is sensitive to the size of training data. Additional study shows that results obtained from DT and RT can be used to examine the importance of each input feature. This paper contributes a learning-by-synthesis approach to facilitate the utilization of a machine learning paradigm to enhance situational awareness for fire fighting in buildings.

Iatrogenic Spinal Epidural Hematoma in the Acute Postoperative Period.

BACKGROUND: Spinal epidural hematomas (SEHs) are a rare but serious complication associated with spinal surgery, with an incidence estimated to be as high as 3%. Patients present with back pain and neurologic symptoms, with a typical onset time of several hours to days following surgery. CASE REPORT: A 60-year-old female who underwent cervical spine surgery had negative intraoperative neuromonitoring and no apparent neurologic deficits of the upper extremities immediately postsurgery. On arrival in the postanesthesia care unit, the patient reported a loss of sensation in her lower extremities, prompting the anesthesiology resident to perform a focused neurologic examination. The patient demonstrated 0/5 motor strength in the lower extremities and total loss of sensation to touch and temperature up to the level of T10 bilaterally. She was returned to the operating room, and surgical exploration revealed a cervical SEH. Decompression yielded abrupt return of motor evoked potentials and improvement in somatosensory evoked potentials. CONCLUSION: As the primary clinician in the perioperative period, the anesthesiologist is ideally positioned to be the first to detect any deterioration in a patient's condition. Anesthesiologists should be cognizant of the potential for acute presentation of SEH so that it can be considered in the differential diagnosis.

Human carbonic anhydrase-8 AAV8 gene therapy inhibits nerve growth factor signaling producing prolonged analgesia and anti-hyperalgesia in mice.

Carbonic anhydrase-8 (Car8; murine gene symbol) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates neuronal intracellular calcium release. We previously reported that wild-type Car8 overexpression corrects the baseline allodynia and hyperalgesia associated with calcium dysregulation in the waddle (wdl) mouse due to a 19 bp deletion in exon 8 of the Car8 gene. In this report, we provide preliminary evidence that overexpression of the human wild-type ortholog of Car8 (CA8WT), but not the reported CA8 S100P loss-of-function mutation (CA8MT), inhibits nerve growth factor (NGF)-induced phosphorylation of ITPR1, TrkA (NGF high-affinity receptor), and ITPR1-mediated cytoplasmic free calcium release in vitro. In addition, we show that gene transfer using AAV8-V5-CA8WT viral particles via sciatic nerve injection demonstrates retrograde transport to dorsal root ganglia (DRG) producing prolonged V5-CA8WT expression, pITPR1 and pTrkA inhibition, and profound analgesia and anti-hyperalgesia in male C57BL/6J mice. AAV8-V5-CA8WT-mediated overexpression prevented and treated allodynia and hyperalgesia associated with chronic neuropathic pain produced by the spinal nerve ligation (SNL) model. These AAV8-V5-CA8 data provide a proof-of-concept for precision medicine through targeted gene therapy of NGF-responsive somatosensory neurons as a long-acting local analgesic able to prevent and treat chronic neuropathic pain through regulating TrkA signaling, ITPR1 activation, and intracellular free calcium release by ITPR1.

Clinical Impact of Saline Volume Infused Through Irrigated-Tip Ablation Catheter in Low Acuity Paroxysmal Atrial Fibrillation Ablation Patients.

BACKGROUND: Radio-Frequency ablation (RFA) to achieve pulmonary vein isolation (PVI) remains mainstay therapy for symptomatic paroxysmal atrial fibrillation (PAF). The clinical consequences of large saline infusions during AF ablation have not been systematically studied. We utilized the differential flow-rates of the two commercially available ablation catheters (AC): 'ThermoCool' (TCAC) and 'Surround Flow' (SFAC) from Biosense-Webster to evaluate the clinical impact of the saline infused in the immediate post-ablation period. METHODS: Consecutive charts of PAF patients between 18 and 81 years who underwent RFA procedure at a tertiary care hospital were reviewed. RESULTS: Forty-seven patients were included in the study (33Males, 65±11years, LVEF 58±7% and left atrial diameter 44±7.5mm, 23TCAC-use). The saline volume infused through the AC was significantly higher with TCAC vs SFAC use (1277±316vs697±299 ml; p<0.001), with no difference in volume infused from other sources, total procedure or RFA times (p>0.05). This led to significant increase in post-ablation weight gain (96±23 vs 97.5±24kg; p=0.002), furosemide usage (39% vs 0%; p=0.0006), urine production (120±79 vs 63±31ml/hr; p=0.003) and post-RFA potassium reduction (4.4±0.42 vs 4±0.32mmol/l; p<0.001) with TCAC use. Significant post-RFA reduction in magnesium, calcium and creatinine, associated hyperchloremic metabolic acidosis and a modest QTc prolongation were also observed with use of both ACs albeit only moderate to weakly correlated with saline volume infused through the AC. No clinical adverse outcomes were encountered. CONCLUSIONS: Higher saline-volume infusing AC use in PAF ablation causes significant post-ablation weight gain despite higher furosemide use, larger urine production and associated post-RFA potassium reduction without increasing morbidity in lower acuity patients. Furthermore, an array of post-ablation electrolyte disturbances causes a modest and clinically insignificant QTc prolongation.

Impact of human CA8 on thermal antinociception in relation to morphine equivalence in mice.

Recently, we showed that murine dorsal root ganglion (DRG) Car8 expression is a cis-regulated eQTL that determines analgesic responses. In this report, we show that transduction through sciatic nerve injection of DRG with human wild-type carbonic anhydrase-8 using adeno-associated virus viral particles (AAV8-V5-CA8WT) produces analgesia in naive male C57BL/6J mice and antihyperalgesia after carrageenan treatment. A peak mean increase of about 4 s in thermal hindpaw withdrawal latency equaled increases in thermal withdrawal latency produced by 10 mg/kg intraperitoneal morphine in these mice. Allometric conversion of this intraperitoneal morphine dose in mice equals an oral morphine dose of about 146 mg in a 60-kg adult. Our work quantifies for the first time analgesia and antihyperalgesia in an inflammatory pain model after DRG transduction by CA8 gene therapy.

Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice.

Carbonic anhydrase-8 (Car8 mouse gene symbol) is devoid of enzymatic activity, but instead functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) to regulate this intracellular calcium release channel important in synaptic functions and neuronal excitability. Causative mutations in ITPR1 and carbonic anhydrase-8 in mice and humans are associated with certain subtypes of spinal cerebellar ataxia (SCA). SCA mice are genetically deficient in dorsal root ganglia (DRG) Car8 expression and display mechanical and thermal hypersensitivity and susceptibility to subacute and chronic inflammatory pain behaviors. In this report, we show that DRG Car8 expression is variable across 25 naïve-inbred strains of mice, and this cis-regulated eQTL (association between rs27660559, rs27706398, and rs27688767 and DRG Car8 expression; P < 1 × 10-11) is correlated with nociceptive responses in mice. Next, we hypothesized that increasing DRG Car8 gene expression would inhibit intracellular calcium release required for morphine antinociception and might correlate with antinociceptive sensitivity of morphine and perhaps other analgesic agents. We show that mean DRG Car8 gene expression is directly related to the dose of morphine or clonidine needed to provide a half-maximal analgesic response (r = 0.93, P < 0.00002; r = 0.83, P < 0.0008, respectively), suggesting that greater DRG Car8 expression increases analgesic requirements. Finally, we show that morphine induces intracellular free calcium release using Fura 2 calcium imaging in a dose-dependent manner; V5-Car8 WT overexpression in NBL cells inhibits morphine-induced calcium increase. These findings highlight the 'morphine paradox' whereby morphine provides antinociception by increasing intracellular free calcium, while Car8 and other antinociceptive agents work by decreasing intracellular free calcium. This is the first study demonstrating that biologic variability associated with this cis-eQTL may contribute to differing analgesic responses through altered regulation of ITPR1-dependent calcium release in mice.

Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway.

Calcium dysregulation is causally linked with various forms of neuropathology including seizure disorders, multiple sclerosis, Huntington's disease, Alzheimer's, spinal cerebellar ataxia (SCA) and chronic pain. Carbonic anhydrase-8 (Car8) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates intracellular calcium release fundamental to critical cellular functions including neuronal excitability, neurite outgrowth, neurotransmitter release, mitochondrial energy production and cell fate. In this report we test the hypothesis that Car8 regulation of ITPR1 and cytoplasmic free calcium release is critical to nociception and pain behaviors. We show Car8 null mutant mice (MT) exhibit mechanical allodynia and thermal hyperalgesia. Dorsal root ganglia (DRG) from MT also demonstrate increased steady-state ITPR1 phosphorylation (pITPR1) and cytoplasmic free calcium release. Overexpression of Car8 wildtype protein in MT nociceptors complements Car8 deficiency, down regulates pITPR1 and abolishes thermal and mechanical hypersensitivity. We also show that Car8 nociceptor overexpression alleviates chronic inflammatory pain. Finally, inflammation results in downregulation of DRG Car8 that is associated with increased pITPR1 expression relative to ITPR1, suggesting a possible mechanism of acute hypersensitivity. Our findings indicate Car8 regulates the ITPR1-cytosolic free calcium pathway that is critical to nociception, inflammatory pain and possibly other neuropathological states. Car8 and ITPR1 represent new therapeutic targets for chronic pain.

Glial NF-κB inhibition alters neuropeptide expression after sciatic nerve injury in mice.

We utilized a transgenic mouse model where nuclear factor kappa B (NF-κB) is selectively inhibited in glial fibrillary acidic protein (GFAP) expressing cells. The transgene, GFAP-IκBα-dn, overexpresses a dominant negative form of the inhibitor of NF-κB (IκBα) under the control of the GFAP promoter. In the present work, we sought to understand the impact of glial NF-κB inhibition on the expression of pain mediating sensory neuropeptides galanin and calcitonin gene related peptide (CGRP) in a model of neuropathic pain in mice. Chronic constriction injury (CCI) of the left sciatic nerve was performed on wild type (WT) and GFAP-IκBα-dn transgenic mice. RT-PCR and immunohistological staining were performed in sciatic nerve and/or L4-L5 DRG tissue for galanin, CGRP and macrophage marker CD11b. GFAP-IκBα-dn mice had less mechanical and thermal hyperalgesia compared to WT mice post-CCI. After CCI, we observed galanin upregulation in DRG and sciatic nerve, which was less in GFAP-IκBα-dn mice. CGRP gene expression in the DRG increased transiently on day 1 post-CCI in WT but not in GFAP-IκBα-dn mice, and no evidence of CGRP upregulation in sciatic nerve post-CCI was found. After CCI, upregulation of CD11b in sciatic nerve was less in GFAP-IκBα-dn mice compared to WT mice, indicative of less macrophage infiltration. Our results showed that glial NF-κB inhibition reduces galanin and CGRP expression, which are neuropeptides that correlate with pain behavior and inflammation after peripheral nerve injury.