Bioelectronic medicine最新文献

{"title":"A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms.","authors":"Bashar W Badran,&nbsp;Sarah M Huffman,&nbsp;Morgan Dancy,&nbsp;Christopher W Austelle,&nbsp;Marom Bikson,&nbsp;Steven A Kautz,&nbsp;Mark S George","doi":"10.1186/s42234-022-00094-y","DOIUrl":"https://doi.org/10.1186/s42234-022-00094-y","url":null,"abstract":"<p><strong>Background: </strong>Although the coronavirus disease 19 (COVID-19) pandemic has now impacted the world for over two years, the persistent secondary neuropsychiatric effects are still not fully understood. These \"long COVID\" symptoms, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), can persist for months after infection without any effective treatments. Long COVID involves a complex heterogenous symptomology and can lead to disability and limit work. Long COVID symptoms may be due to sustained inflammatory responses and prolonged immune response after infection. Interestingly, vagus nerve stimulation (VNS) may have anti-inflammatory effects, however, until recently, VNS could not be self-administered, at-home, noninvasively.</p><p><strong>Methods: </strong>We created a double-blind, noninvasive transcutaneous auricular VNS (taVNS) system that can be self-administered at home with simultaneous remote monitoring of physiological biomarkers and video supervision by study staff. Subsequently, we carried out a pilot (n = 13) randomized, sham-controlled, trial with this system for four weeks to treat nine predefined long covid symptoms (anxiety, depression, vertigo, anosmia, ageusia, headaches, fatigue, irritability, brain fog). No in-person patient contact was needed, with informed consent, trainings, ratings, and all procedures being conducted remotely during the pandemic (2020-2021) and equipment being shipped to individuals' homes. This trial was registered on ClinicalTrials.gov under the identifier: NCT04638673 registered November 20, 2020.</p><p><strong>Results: </strong>Four-weeks of at-home self-administered taVNS (two, one-hour sessions daily, delivered at suprathreshold intensities) was feasible and safe. Although our trial was not powered to determine efficacy as an intervention in a heterogenous population, the trends in the data suggest taVNS may have a mild to moderate effect in reducing mental fatigue symptoms in a subset of individuals.</p><p><strong>Conclusions: </strong>This innovative study demonstrates the safety and feasibility of supervised self-administered taVNS under a fully contactless protocol and suggests that future studies can safely investigate this novel form of brain stimulation at-home for a variety of neuropsychiatric and motor recovery applications.</p>","PeriodicalId":72363,"journal":{"name":"Bioelectronic medicine","volume":" ","pages":"13"},"PeriodicalIF":0.0,"publicationDate":"2022-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40636174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delivering transcutaneous auricular neurostimulation (tAN) to improve symptoms associated with opioid withdrawal: results from a prospective clinical trial.","authors":"Carlos F Tirado,&nbsp;Stephanie N Washburn,&nbsp;Alejandro Covalin,&nbsp;Caroline Hedenberg,&nbsp;Heather Vanderpool,&nbsp;Caroline Benner,&nbsp;Daniel P Powell,&nbsp;Melanie A McWade,&nbsp;Navid Khodaparast","doi":"10.1186/s42234-022-00095-x","DOIUrl":"https://doi.org/10.1186/s42234-022-00095-x","url":null,"abstract":"<p><strong>Background: </strong>As pharmacological treatments are the primary option for opioid use disorder, neuromodulation has recently demonstrated efficacy in managing opioid withdrawal syndrome (OWS). This study investigated the safety and effectiveness of transcutaneous auricular neurostimulation (tAN) for managing OWS.</p><p><strong>Methods: </strong>This prospective inpatient trial included a 30-minute randomized, sham-controlled, double-blind period followed by a 5-day open-label period. Adults with physical dependence on opioids were randomized to receive active or sham tAN following abrupt opioid discontinuation. The Clinical Opiate Withdrawal Scale (COWS) was used to determine withdrawal level, and participants were required to have a baseline COWS score ≥ 13 before enrollment. The double-blind period of the study occurred during the first 30-minutes to assess the acute effects of tAN therapy compared to a sham control. Group 1 received active tAN during both the 30-minute double-blind period and the 5-day open-label period. Group 2 received passive sham tAN (no stimulation) during the double-blind period, followed by active tAN during the 5-day open-label period. The primary outcome was change in COWS from baseline to 60-minutes of active tAN (pooled across groups, accounting for 30-minute delay). Secondary outcomes included difference in change in COWS scores between groups after 30-minutes of active or sham tAN, change in COWS scores after 120-minutes of active tAN, and change in COWS scores on Days 2-5. Non-opioid comfort medications were administered during the trial.</p><p><strong>Results: </strong>Across all thirty-one participants, the mean (SD) COWS scores relative to baseline were reduced by 7.0 (4.7) points after 60-minutes of active tAN across both groups (p < 0.0001; Cohen's d = 2.0), demonstrating a significant and clinically meaningful reduction of 45.9%. After 30-minutes of active tAN (Group 1) or sham tAN (Group 2), the active tAN group demonstrated a significantly greater COWS score reduction than the sham tAN group (41.7% vs. 24.1%; p = 0.036). Participants across both groups achieved an average COWS reduction up to 74.7% on Days 2-5.</p><p><strong>Conclusion: </strong>Results demonstrate tAN is a safe and effective non-opioid approach for reducing symptoms of OWS. This study supported an FDA clearance.</p><p><strong>Clinical trial registration: </strong>clinicaltrials.gov/ct2/show/NCT04075214 , Identifier: NCT04075214, Release Date: August 28, 2019.</p>","PeriodicalId":72363,"journal":{"name":"Bioelectronic medicine","volume":" ","pages":"12"},"PeriodicalIF":0.0,"publicationDate":"2022-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9385243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40619224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of waveform shape and electrode material on KiloHertz frequency alternating current block of mammalian peripheral nerve.","authors":"David B Green,&nbsp;Joseph A Kilgore,&nbsp;Shane A Bender,&nbsp;Robert J Daniels,&nbsp;Douglas D Gunzler,&nbsp;Tina L Vrabec,&nbsp;Niloy Bhadra","doi":"10.1186/s42234-022-00093-z","DOIUrl":"https://doi.org/10.1186/s42234-022-00093-z","url":null,"abstract":"<p><strong>Objectives: </strong>KiloHertz frequency alternating current waveforms produce conduction block in peripheral nerves. It is not clearly known how the waveform shape affects block outcomes, and if waveform effects are frequency dependent. We determined the effects of waveform shape using two types of electrodes.</p><p><strong>Materials and methods: </strong>Acute in-vivo experiments were performed on 12 rats. Bipolar electrodes were used to electrically block motor nerve impulses in the sciatic nerve, as measured using force output from the gastrocnemius muscle. Three blocking waveforms were delivered (sinusoidal, square and triangular) at 6 frequencies (10-60 kHz). Bare platinum electrodes were compared with carbon black coated electrodes. We determined the minimum amplitude that could completely block motor nerve conduction (block threshold), and measured properties of the onset response, which is a transient period of nerve activation at the start of block. In-vivo results were compared with computational modeling conducted using the NEURON simulation environment using a nerve membrane model modified for stimulation in the kilohertz frequency range.</p><p><strong>Results: </strong>For the majority of parameters, in-vivo testing and simulations showed similar results: Block thresholds increased linearly with frequency for all three waveforms. Block thresholds were significantly different between waveforms; lowest for the square waveform and highest for triangular waveform. When converted to charge per cycle, square waveforms required the maximum charge per phase, and triangular waveforms the least. Onset parameters were affected by blocking frequency but not by waveform shape. Electrode comparisons were performed only in-vivo. Electrodes with carbon black coatings gave significantly lower block thresholds and reduced onset responses across all blocking frequencies. For 10 and 20 kHz, carbon black coating significantly reduced the charge required for nerve block.</p><p><strong>Conclusions: </strong>We conclude that both sinusoidal and square waveforms at frequencies of 20 kHz or higher would be optimal. Future investigation of carbon black or other high charge capacity electrodes may be useful in achieving block with lower BTs and onsets. These findings will be of importance for designing clinical nerve block systems.</p>","PeriodicalId":72363,"journal":{"name":"Bioelectronic medicine","volume":"8 1","pages":"11"},"PeriodicalIF":0.0,"publicationDate":"2022-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10686806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Threshold adjusted vagus nerve stimulation after asphyxial cardiac arrest results in neuroprotection and improved survival.","authors":"Rishabh C Choudhary, Umair Ahmed, Muhammad Shoaib, Eric Alper, Abdul Rehman, Junhwan Kim, Koichiro Shinozaki, Bruce T Volpe, Sangeeta Chavan, Stavros Zanos, Kevin J Tracey, Lance B Becker","doi":"10.1186/s42234-022-00092-0","DOIUrl":"10.1186/s42234-022-00092-0","url":null,"abstract":"<p><strong>Background: </strong>Vagus nerve stimulation (VNS) has shown therapeutic potential in a variety of different diseases with many ongoing clinical trials. The role of VNS in reducing ischemic injury in the brain requires further evaluation. Cardiac arrest (CA) causes global ischemia and leads to the injury of vital organs, especially the brain. In this study, we investigated the protective effects of customized threshold-adjusted VNS (tVNS) in a rat model of CA and resuscitation.</p><p><strong>Methods: </strong>Sprague-Dawley rats underwent 12 min asphyxia-CA followed by resuscitation. Rats were assigned to either post-resuscitation tVNS for 2 h or no-tVNS (control). tVNS was applied by electrode placement in the left cervical vagus nerve. To optimize a threshold, we used animal's heart rate and determined a 15-20% drop from baseline levels as the effective and physiological threshold for each animal. The primary endpoint was 72 h survival; secondary endpoints included neurological functional recovery, reduction in brain cellular injury (histopathology), cardiac and renal injury parameters (troponin I and creatinine levels, respectively).</p><p><strong>Results: </strong>In comparison to the control group, tVNS significantly improved 72 h survival and brain functional recovery after 12 minutes of CA. The tVNS group demonstrated significantly reduced numbers of damaged neurons in the CA1 hippocampal region of the brain as compared to the control group. Similarly, the tVNS group showed decreased trend in plasma troponin I and creatinine levels as compared to the control group.</p><p><strong>Conclusions: </strong>Our findings suggest that using tVNS for 2 h after 12 minutes of CA attenuates ischemia neuronal cell death, heart and kidney damage, and improves 72 h survival with improved neurological recovery.</p>","PeriodicalId":72363,"journal":{"name":"Bioelectronic medicine","volume":" ","pages":"10"},"PeriodicalIF":0.0,"publicationDate":"2022-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9297561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40607394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific differences in the efficacy of traditional low frequency versus high frequency spinal cord stimulation for chronic pain","authors":"R. Conic, Jacob Caylor, Christina L. Cui, Zabrina Reyes, Eric Nelson, Sopyda Yin, I. Lerman","doi":"10.1186/s42234-022-00090-2","DOIUrl":"https://doi.org/10.1186/s42234-022-00090-2","url":null,"abstract":"","PeriodicalId":72363,"journal":{"name":"Bioelectronic medicine","volume":"71 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90717789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anatomical differences in nociceptor neurons sensitivity","authors":"T. Crosson, S. Talbot","doi":"10.1186/s42234-022-00088-w","DOIUrl":"https://doi.org/10.1186/s42234-022-00088-w","url":null,"abstract":"","PeriodicalId":72363,"journal":{"name":"Bioelectronic medicine","volume":"101 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74236564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrical neurostimulation in glaucoma with progressive vision loss","authors":"C. Erb, Sophie Eckert, Pia Gindorf, Martina Köhler, T. Köhler, Lukas Neuhann, T. Neuhann, Nadja Salzmann, S. Schmickler, J. Ellrich","doi":"10.1186/s42234-022-00089-9","DOIUrl":"https://doi.org/10.1186/s42234-022-00089-9","url":null,"abstract":"","PeriodicalId":72363,"journal":{"name":"Bioelectronic medicine","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82525264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noninvasive spinal neuromodulation mitigates symptoms of idiopathic overactive bladder.","authors":"Hui Zhong,&nbsp;Emilie Liu,&nbsp;Priya Kohli,&nbsp;Laura Perez,&nbsp;V Reggie Edgerton,&nbsp;David Ginsberg,&nbsp;Parag Gad,&nbsp;Evgeniy Kreydin","doi":"10.1186/s42234-022-00087-x","DOIUrl":"https://doi.org/10.1186/s42234-022-00087-x","url":null,"abstract":"<p><strong>Background: </strong>Overactive bladder (OAB) affects 12 to 30% of the world's population. The accompanying urinary urgency, frequency and incontinence can have a profound effect on quality of life, leading to depression, social isolation, avoidance of sexual activity and loss of productivity. Conservative measures such as lifestyle modification and pelvic floor physical therapy are the first line of treatment for overactive bladder. Patients who fail these may go on to take medications, undergo neuromodulation or receive injection of botulinum toxin into the bladder wall. While effective, medications have side effects and suffer from poor adherence. Neuromodulation and botulinum toxin injection are also effective but are invasive and not acceptable to some patients.</p><p><strong>Methods: </strong>We have developed a novel transcutaneous spinal cord neuromodulator (SCONE™^,) that delivers multifrequency electrical stimulation to the spinal cord without the need for insertion or implantation of stimulating electrodes. Previously, multifrequency transcutaneous stimulation has been demonstrated to penetrate to the spinal cord and lead to motor activation of detrusor and external urethral sphincter muscles. Here, we report on eight patients with idiopathic overactive bladder, who underwent 12 weeks of SCONE™ therapy.</p><p><strong>Results: </strong>All patients reported statistically significant clinical improvement in multiple symptoms of overactive bladder, such as urinary urgency, frequency and urge incontinence. In addition, patients reported significant symptomatic improvements as captured by validated clinical surveys.</p><p><strong>Conclusion: </strong>SCONE™ therapy represents the first of its kind therapy to treat symptoms of urgency, frequency and urge urinary incontinence in patients with OAB.</p><p><strong>Trial registration: </strong>The study was listed on clinicaltrials.gov ( NCT03753750 ).</p>","PeriodicalId":72363,"journal":{"name":"Bioelectronic medicine","volume":" ","pages":"5"},"PeriodicalIF":0.0,"publicationDate":"2022-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8941742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40315362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of closed-loop intracortical stimulation on neural activity in brain-injured, anesthetized animals.","authors":"Marta Carè,&nbsp;Alberto Averna,&nbsp;Federico Barban,&nbsp;Marianna Semprini,&nbsp;Lorenzo De Michieli,&nbsp;Randolph J Nudo,&nbsp;David J Guggenmos,&nbsp;Michela Chiappalone","doi":"10.1186/s42234-022-00086-y","DOIUrl":"https://doi.org/10.1186/s42234-022-00086-y","url":null,"abstract":"<p><strong>Background: </strong>Acquired brain injuries, such as stroke, are a major cause of long-term disability worldwide. Intracortical microstimulation (ICMS) can be used successfully to assist in guiding appropriate connections to restore lost sensorimotor integration. Activity-Dependent Stimulation (ADS) is a specific type of closed-loop ICMS that aims at coupling the activity of two different brain regions by stimulating one in response to activity in the other. Recently, ADS was used to effectively promote behavioral recovery in rodent models following a unilateral traumatic brain injury in the primary motor cortex. While behavioral benefits have been described, the neurophysiological changes in spared areas in response to this type of stimulation have not been fully characterized. Here we explored how single-unit spiking activity is impacted by a focal ischemic lesion and, subsequently, by an ADS treatment.</p><p><strong>Methods: </strong>Intracortical microelectrode arrays were implanted in the ipsilesional rostral forelimb area (RFA) to record spike activity and to trigger intracortical microstimulation in the primary somatosensory area (S1) of anaesthetized Long Evans rats. An ischemic injury was induced in the caudal forelimb area through microinjections of Endothelin-1. Activity from both RFA and S1 was recorded and analyzed off-line by evaluating possible changes, either induced by the lesion in the Control group or by stimulation in the ADS group.</p><p><strong>Results: </strong>We found that the ischemic lesion in the motor area led to an overall increase in spike activity within RFA and a decrease in S1 with respect to the baseline condition. Subsequent treatment with ADS increased the firing rate in both RFA and S1. Post-stimulation spiking activity was significantly higher compared to pre-stimulation activity in the ADS animals versus non-stimulated controls. Moreover, stimulation promoted the generation of highly synchronized bursting patterns in both RFA and S1 only in the ADS group.</p><p><strong>Conclusions: </strong>This study describes the impact on single-unit activity in ipsilesional areas immediately following a cortical infarct and demonstrates that application of ADS is effective in altering this activity.</p>","PeriodicalId":72363,"journal":{"name":"Bioelectronic medicine","volume":"8 1","pages":"4"},"PeriodicalIF":0.0,"publicationDate":"2022-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41184382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coarse-graining and the Haar wavelet transform for multiscale analysis.","authors":"William J Bosl, Tobias Loddenkemper, Solveig Vieluf","doi":"10.1186/s42234-022-00085-z","DOIUrl":"10.1186/s42234-022-00085-z","url":null,"abstract":"<p><strong>Background: </strong>Multiscale entropy (MSE) has become increasingly common as a quantitative tool for analysis of physiological signals. The MSE computation involves first decomposing a signal into multiple sub-signal 'scales' using a coarse-graining algorithm.</p><p><strong>Methods: </strong>The coarse-graining algorithm averages adjacent values in a time series to produce a coarser scale time series. The Haar wavelet transform convolutes a time series with a scaled square wave function to produce an approximation which is equivalent to averaging points.</p><p><strong>Results: </strong>Coarse-graining is mathematically identical to the Haar wavelet transform approximations. Thus, multiscale entropy is entropy computed on sub-signals derived from approximations of the Haar wavelet transform. By describing coarse-graining algorithms properly as Haar wavelet transforms, the meaning of 'scales' as wavelet approximations becomes transparent. The computed value of entropy is different with different wavelet basis functions, suggesting further research is needed to determine optimal methods for computing multiscale entropy.</p><p><strong>Conclusion: </strong>Coarse-graining is mathematically identical to Haar wavelet approximations at power-of-two scales. Referring to coarse-graining as a Haar wavelet transform motivates research into the optimal approach to signal decomposition for entropy analysis.</p>","PeriodicalId":72363,"journal":{"name":"Bioelectronic medicine","volume":" ","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2022-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39878604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}