Pub Date : 2025-01-22DOI: 10.1016/j.bja.2024.12.004
Usha Gurunathan, Robert L Medcalf, Lily Chiang, Zikou Liu, Xin Liu, Charithani B Keragala, Maria Patricia Hernandez-Mitre, Paul Brady, Steven C Wallis, Jason A Roberts, Daniel Mullany, Harshal Nandurkar, Victoria Eley, Suzanne L Parker
Background: Uncertainty about optimal tranexamic acid (TXA) dosage has led to significant practice variation in hip arthroplasty. We aimed to identify the optimal i.v. dosage of TXA using a population pharmacokinetic/pharmacodynamic (PK/PD) approach in adults undergoing primary elective hip arthroplasty.
Methods: Participants received an i.v. TXA bolus dose of 15 mg kg-1 of total body weight, 30 min before skin incision (maximum dose 1500 mg). Blood samples were collected at baseline, 5 min post-TXA, skin incision, skin closure, and 3, 6, and 24 h post-TXA administration. TXA activity was measured ex vivo using a tissue plasminogen activator-induced clot lysis assay, targeted to achieve 90% maximal antifibrinolysis, based on maximum lysis rate. A nonlinear mixed-effects population PK/PD model was developed. Monte Carlo simulations (n=1000) identified the dosing regimens to achieve the PK/PD target over 24 h.
Results: There were 24 participants (18 females, 6 males), with a median (range) age of 62 (56.5-72) yr and BMI of 31.1 (23.0-41.8) kg m-2. A three-compartment model best described the 24-h data. The 15 mg kg-1 of i.v. bolus maintained TXA concentrations above the PK/PD target of 10 mg L-1 for a median duration of 4.94 h (IQR: 3.76-8.21 h). Of the various simulated regimens, only 30 mg kg-1 of i.v. TXA infusion after this bolus achieved the 24-h PK/PD target in 76-100% of patients, varying with their estimated glomerular function rates.
Conclusions: The PK/PD modelling indicated that 15 mg kg-1 of i.v. TXA bolus followed by a continuous i.v. infusion achieves the 24-h antifibrinolytic target.
Clinical trial registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377339&isClinicalTrial=False (ACTRN12619000670178); registered on May 6, 2019.
{"title":"A pharmacokinetic/pharmacodynamic analysis of intravenous tranexamic acid in adult patients undergoing elective total hip arthroplasty (ORACLE).","authors":"Usha Gurunathan, Robert L Medcalf, Lily Chiang, Zikou Liu, Xin Liu, Charithani B Keragala, Maria Patricia Hernandez-Mitre, Paul Brady, Steven C Wallis, Jason A Roberts, Daniel Mullany, Harshal Nandurkar, Victoria Eley, Suzanne L Parker","doi":"10.1016/j.bja.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.bja.2024.12.004","url":null,"abstract":"<p><strong>Background: </strong>Uncertainty about optimal tranexamic acid (TXA) dosage has led to significant practice variation in hip arthroplasty. We aimed to identify the optimal i.v. dosage of TXA using a population pharmacokinetic/pharmacodynamic (PK/PD) approach in adults undergoing primary elective hip arthroplasty.</p><p><strong>Methods: </strong>Participants received an i.v. TXA bolus dose of 15 mg kg<sup>-1</sup> of total body weight, 30 min before skin incision (maximum dose 1500 mg). Blood samples were collected at baseline, 5 min post-TXA, skin incision, skin closure, and 3, 6, and 24 h post-TXA administration. TXA activity was measured ex vivo using a tissue plasminogen activator-induced clot lysis assay, targeted to achieve 90% maximal antifibrinolysis, based on maximum lysis rate. A nonlinear mixed-effects population PK/PD model was developed. Monte Carlo simulations (n=1000) identified the dosing regimens to achieve the PK/PD target over 24 h.</p><p><strong>Results: </strong>There were 24 participants (18 females, 6 males), with a median (range) age of 62 (56.5-72) yr and BMI of 31.1 (23.0-41.8) kg m<sup>-2</sup>. A three-compartment model best described the 24-h data. The 15 mg kg<sup>-1</sup> of i.v. bolus maintained TXA concentrations above the PK/PD target of 10 mg L<sup>-1</sup> for a median duration of 4.94 h (IQR: 3.76-8.21 h). Of the various simulated regimens, only 30 mg kg<sup>-1</sup> of i.v. TXA infusion after this bolus achieved the 24-h PK/PD target in 76-100% of patients, varying with their estimated glomerular function rates.</p><p><strong>Conclusions: </strong>The PK/PD modelling indicated that 15 mg kg<sup>-1</sup> of i.v. TXA bolus followed by a continuous i.v. infusion achieves the 24-h antifibrinolytic target.</p><p><strong>Clinical trial registration: </strong>https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377339&isClinicalTrial=False (ACTRN12619000670178); registered on May 6, 2019.</p>","PeriodicalId":9250,"journal":{"name":"British journal of anaesthesia","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-20DOI: 10.1016/j.bja.2024.10.042
Anil R Maharaj, Michael C Montana, Christoph P Hornik, Evan D Kharasch
<p><strong>Background: </strong>Patients with obstructive sleep apnoea (OSA) are considered more sensitive to opioids and at increased risk of opioid-induced respiratory depression. Nonetheless, whether OSA treatment (continuous positive airway pressure, CPAP; or bilevel positive airway pressure, BIPAP) modifies this risk remains unknown. Greater opioid sensitivity can arise from altered pharmacokinetics or pharmacodynamics. This preplanned analysis of a previous cohort study of remifentanil clinical effects in OSA tested the null hypothesis that the pharmacokinetics, pharmacodynamics, or both of remifentanil, a representative μ-opioid agonist, are not altered in adults with treated or untreated OSA.</p><p><strong>Methods: </strong>A single-centre, prospective, open-label, cohort study administered a stepped-dose, target-controlled remifentanil infusion (target effect-site concentrations 0.5, 1, 2, 3, 4 ng ml<sup>-1</sup>) to awake adult volunteers (median age 52 yr, range 23-70) without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). Type III (in-home) polysomnography verified OSA. Remifentanil plasma concentrations, end-expired CO<sub>2</sub>, thermal heat tolerance, and pupil diameter (miosis) were assessed. Population pharmacokinetic (clearance, volume of distribution) and pharmacodynamic (miosis, thermal heat tolerance, end-expired CO<sub>2</sub>) models were developed.</p><p><strong>Results: </strong>Remifentanil clearance (median) was 147, 143, and 155 L h<sup>-1</sup> (P=0.472), and volume of distribution was 19.6, 15.5, and 17.7 L (P=0.473) for subjects without OSA, untreated OSA, or treated OSA, respectively. Total body weight was an influential covariate on both remifentanil clearance and central volume of distribution. There were no statistically or clinically significant differences between the three groups in miosis EC<sub>50</sub> or Emax, or the slopes of thermal heat tolerance or end-expired CO<sub>2</sub>vs remifentanil concentration. At a plasma remifentanil concentration of 4 ng ml<sup>-1</sup>, in participants without OSA, with untreated OSA, or with treated OSA, respectively, model-estimated pupil area (12%, 13%, and 17% of baseline, P=0.086), thermal heat tolerance (50°C, 51°C, and 51°C, P=0.218), and end-expired CO<sub>2</sub> (6.3 kPa, 6.4 kPa, and 6.7 kPa, P=0.257) were not statistically different between groups.</p><p><strong>Conclusions: </strong>OSA (untreated or treated) did not influence remifentanil pharmacokinetics or pharmacodynamics (miosis, analgesia, respiratory depression). Results support the null hypothesis that neither pharmacokinetics nor pharmacodynamics of remifentanil, a representative μ-opioid, are altered in adults with treated or untreated OSA. These findings provide a mechanistic explanation for the lack of influence of OSA or OSA treatment on the clinical miotic, sedative, analgesic, or respiratory depressant response to remifentanil in awake adults. The conventional notion that
背景：阻塞性睡眠呼吸暂停（OSA）患者被认为对阿片类药物更敏感，阿片类药物引起呼吸抑制的风险增加。然而，OSA治疗(持续气道正压通气，CPAP；或双水平气道正压通气（BIPAP）是否能改变这种风险尚不清楚。更大的阿片类药物敏感性可由药代动力学或药效学改变引起。对先前一项关于瑞芬太尼在OSA中的临床作用的队列研究的预先分析验证了一个原假设，即瑞芬太尼（一种代表性的μ-阿片受体激动剂）在接受治疗或未接受治疗的OSA成人中，其药代动力学、药效学或两者都没有改变。方法：一项单中心、前瞻性、开放标签、队列研究，对未患OSA （n=20）、未治疗OSA （n=33）或已治疗OSA （n=21）的清醒成年志愿者（中位年龄52岁，范围23-70岁）进行分剂量、目标控制的瑞芬太尼输注（目标效应部位浓度为0.5、1、2、3、4 ng ml-1）。III型（家庭）多导睡眠图证实OSA。评估瑞芬太尼血浆浓度、过期CO2、热耐受性和瞳孔直径（瞳孔缩小）。建立了种群药代动力学（清除率、分布体积）和药效学（体积缩小、热耐热性、过期CO2）模型。结果：无OSA、未治疗OSA和治疗OSA受试者的瑞芬太尼清除率（中位数）分别为147、143和155 L h-1 (P=0.472)，分布容积分别为19.6、15.5和17.7 L （P=0.473）。体重是影响瑞芬太尼清除率和中心分布容积的协变量。三组患者的miosis EC50、Emax、热耐受性斜率、终末CO2vs瑞芬太尼浓度差异均无统计学意义和临床意义。在血浆瑞芬太尼浓度为4 ng ml-1时，无OSA、未治疗OSA或治疗OSA的受试者，模型估计瞳孔面积（基线的12%、13%和17%，P=0.086）、热耐受性（50°C、51°C和51°C， P=0.218）和终止二氧化碳（6.3 kPa、6.4 kPa和6.7 kPa， P=0.257）在组间无统计学差异。结论：OSA（未经治疗或治疗）不影响瑞芬太尼的药代动力学或药效学（缩小、镇痛、呼吸抑制）。结果支持原假设，即治疗或未治疗OSA的成人中，具有代表性的μ-阿片类药物瑞芬太尼的药代动力学和药效学都没有改变。这些发现为OSA或OSA治疗对醒着的成人对瑞芬太尼的临床微生物、镇静、镇痛或呼吸抑制反应缺乏影响提供了机制解释。我们的研究结果不支持OSA改变清醒成人对阿片类药物敏感性的传统观点，因此阿片类药物的剂量可能不需要根据药代动力学或药效学因素进行调整。临床试验注册：ClinicalTrials.gov, NCT02898792, https://clinicaltrials.gov/ct2/show/NCT02898792。首次发布：2016年9月13日。
{"title":"Opioid use in treated and untreated obstructive sleep apnoea: remifentanil pharmacokinetics and pharmacodynamics in adult volunteers.","authors":"Anil R Maharaj, Michael C Montana, Christoph P Hornik, Evan D Kharasch","doi":"10.1016/j.bja.2024.10.042","DOIUrl":"https://doi.org/10.1016/j.bja.2024.10.042","url":null,"abstract":"<p><strong>Background: </strong>Patients with obstructive sleep apnoea (OSA) are considered more sensitive to opioids and at increased risk of opioid-induced respiratory depression. Nonetheless, whether OSA treatment (continuous positive airway pressure, CPAP; or bilevel positive airway pressure, BIPAP) modifies this risk remains unknown. Greater opioid sensitivity can arise from altered pharmacokinetics or pharmacodynamics. This preplanned analysis of a previous cohort study of remifentanil clinical effects in OSA tested the null hypothesis that the pharmacokinetics, pharmacodynamics, or both of remifentanil, a representative μ-opioid agonist, are not altered in adults with treated or untreated OSA.</p><p><strong>Methods: </strong>A single-centre, prospective, open-label, cohort study administered a stepped-dose, target-controlled remifentanil infusion (target effect-site concentrations 0.5, 1, 2, 3, 4 ng ml<sup>-1</sup>) to awake adult volunteers (median age 52 yr, range 23-70) without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). Type III (in-home) polysomnography verified OSA. Remifentanil plasma concentrations, end-expired CO<sub>2</sub>, thermal heat tolerance, and pupil diameter (miosis) were assessed. Population pharmacokinetic (clearance, volume of distribution) and pharmacodynamic (miosis, thermal heat tolerance, end-expired CO<sub>2</sub>) models were developed.</p><p><strong>Results: </strong>Remifentanil clearance (median) was 147, 143, and 155 L h<sup>-1</sup> (P=0.472), and volume of distribution was 19.6, 15.5, and 17.7 L (P=0.473) for subjects without OSA, untreated OSA, or treated OSA, respectively. Total body weight was an influential covariate on both remifentanil clearance and central volume of distribution. There were no statistically or clinically significant differences between the three groups in miosis EC<sub>50</sub> or Emax, or the slopes of thermal heat tolerance or end-expired CO<sub>2</sub>vs remifentanil concentration. At a plasma remifentanil concentration of 4 ng ml<sup>-1</sup>, in participants without OSA, with untreated OSA, or with treated OSA, respectively, model-estimated pupil area (12%, 13%, and 17% of baseline, P=0.086), thermal heat tolerance (50°C, 51°C, and 51°C, P=0.218), and end-expired CO<sub>2</sub> (6.3 kPa, 6.4 kPa, and 6.7 kPa, P=0.257) were not statistically different between groups.</p><p><strong>Conclusions: </strong>OSA (untreated or treated) did not influence remifentanil pharmacokinetics or pharmacodynamics (miosis, analgesia, respiratory depression). Results support the null hypothesis that neither pharmacokinetics nor pharmacodynamics of remifentanil, a representative μ-opioid, are altered in adults with treated or untreated OSA. These findings provide a mechanistic explanation for the lack of influence of OSA or OSA treatment on the clinical miotic, sedative, analgesic, or respiratory depressant response to remifentanil in awake adults. The conventional notion that","PeriodicalId":9250,"journal":{"name":"British journal of anaesthesia","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-20DOI: 10.1016/j.bja.2024.12.007
Kylie S Meacham, Jacob D Schmidt, Yanhua Sun, Mads Rasmussen, Ziyue Liu, David C Adams, Kevin M Backfish-White, Lingzhong Meng
Background: Intravenous antihypertensivedrugs are commonly used in acute care settings, yet their impact on cerebral blood flow (CBF) remains uncertain.
Methods: A systematic review and meta-analysis of 50 studies evaluated the effects of commonly used i.v. antihypertensive agents on CBF in normotensive, hypertensive, and intracranial pathology populations. Meta-analyses used standardised mean differences (SMD), stratified by population type, consciousness state, antihypertensive agent, and CBF measurement method.
Results: Intravenous antihypertensivedrug therapy significantly reduced CBF in normotensive individuals without intracranial pathology (SMD -0.31, 95% confidence interval -0.51 to -0.11), primarily driven by nitroprusside and nitroglycerin in awake subjects (SMD -0.80, 95% confidence interval -1.15 to -0.46), with a median CBF decrease of 14% (interquartile range 13-16%) and a median mean arterial pressure reduction of 17% (interquartile range 9-22%). Other antihypertensives showed no significant effects on CBF in normotensive individuals, nor were changes observed in hypertensive patients or those with intracranial pathology when the median mean arterial pressure reduction was ∼20%. No correlation was found between mean arterial pressure reduction and CBF change, supporting intact cerebral autoregulation. Historical data revealed neurocognitive changes when CBF fell to ∼30 ml 100 g-1 min-1, associated with a 58% mean arterial pressure reduction and a 38% CBF reduction.
Conclusions: Most i.v. antihypertensive agents do not significantly affect CBF in clinical dose ranges; however, nitroprusside and nitroglycerin can reduce CBF under specific clinical conditions. The certainty of evidence remains low. Neurocognitive changes appear to depend on the magnitude of blood pressure and CBF reductions.
{"title":"Impact of intravenous antihypertensive therapy on cerebral blood flow and neurocognition: a systematic review and meta-analysis.","authors":"Kylie S Meacham, Jacob D Schmidt, Yanhua Sun, Mads Rasmussen, Ziyue Liu, David C Adams, Kevin M Backfish-White, Lingzhong Meng","doi":"10.1016/j.bja.2024.12.007","DOIUrl":"https://doi.org/10.1016/j.bja.2024.12.007","url":null,"abstract":"<p><strong>Background: </strong>Intravenous antihypertensivedrugs are commonly used in acute care settings, yet their impact on cerebral blood flow (CBF) remains uncertain.</p><p><strong>Methods: </strong>A systematic review and meta-analysis of 50 studies evaluated the effects of commonly used i.v. antihypertensive agents on CBF in normotensive, hypertensive, and intracranial pathology populations. Meta-analyses used standardised mean differences (SMD), stratified by population type, consciousness state, antihypertensive agent, and CBF measurement method.</p><p><strong>Results: </strong>Intravenous antihypertensivedrug therapy significantly reduced CBF in normotensive individuals without intracranial pathology (SMD -0.31, 95% confidence interval -0.51 to -0.11), primarily driven by nitroprusside and nitroglycerin in awake subjects (SMD -0.80, 95% confidence interval -1.15 to -0.46), with a median CBF decrease of 14% (interquartile range 13-16%) and a median mean arterial pressure reduction of 17% (interquartile range 9-22%). Other antihypertensives showed no significant effects on CBF in normotensive individuals, nor were changes observed in hypertensive patients or those with intracranial pathology when the median mean arterial pressure reduction was ∼20%. No correlation was found between mean arterial pressure reduction and CBF change, supporting intact cerebral autoregulation. Historical data revealed neurocognitive changes when CBF fell to ∼30 ml 100 g<sup>-1</sup> min<sup>-1</sup>, associated with a 58% mean arterial pressure reduction and a 38% CBF reduction.</p><p><strong>Conclusions: </strong>Most i.v. antihypertensive agents do not significantly affect CBF in clinical dose ranges; however, nitroprusside and nitroglycerin can reduce CBF under specific clinical conditions. The certainty of evidence remains low. Neurocognitive changes appear to depend on the magnitude of blood pressure and CBF reductions.</p><p><strong>Systematic review protocol: </strong>PROSPERO (CRD42024511954).</p>","PeriodicalId":9250,"journal":{"name":"British journal of anaesthesia","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-20DOI: 10.1016/j.bja.2024.12.014
Felix Borngaesser, Annika Bald, Ling Zhang, Tina Ramishvili, Stephen J Lorenzen, Michael L Rinke, Simon T Schaefer, Jeffrey Freda, Philipp Fassbender, Raja Thota, Michael E Kiyatkin, Andrew D Racine, Matthias Eikermann
{"title":"Association of a bundle intervention to address fluid shortages with intraoperative fluid use, total fluid balance, and postoperative outcomes.","authors":"Felix Borngaesser, Annika Bald, Ling Zhang, Tina Ramishvili, Stephen J Lorenzen, Michael L Rinke, Simon T Schaefer, Jeffrey Freda, Philipp Fassbender, Raja Thota, Michael E Kiyatkin, Andrew D Racine, Matthias Eikermann","doi":"10.1016/j.bja.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.bja.2024.12.014","url":null,"abstract":"","PeriodicalId":9250,"journal":{"name":"British journal of anaesthesia","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-18DOI: 10.1016/j.bja.2024.12.006
Amour B U Patel,Phillip P W M Bibawy,Juri Ibrahim M Althonayan,Zehra Majeed,Weng L Gan,Tom E F Abbott,Gareth L Ackland
{"title":"Corrigendum to 'Effect of transauricular nerve stimulation on perioperative pain: a single-blind, analyser-masked, randomised controlled trial' (Br J Anaesth 2023; 130: 458-76).","authors":"Amour B U Patel,Phillip P W M Bibawy,Juri Ibrahim M Althonayan,Zehra Majeed,Weng L Gan,Tom E F Abbott,Gareth L Ackland","doi":"10.1016/j.bja.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.bja.2024.12.006","url":null,"abstract":"","PeriodicalId":9250,"journal":{"name":"British journal of anaesthesia","volume":"466 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-17DOI: 10.1016/j.bja.2024.11.027
Annabel Lim,Yasmin Lennie,Zoe Keon-Cohen
{"title":"Ophthalmic regional anaesthesia: ANZCA survey of practice in Australia and New Zealand.","authors":"Annabel Lim,Yasmin Lennie,Zoe Keon-Cohen","doi":"10.1016/j.bja.2024.11.027","DOIUrl":"https://doi.org/10.1016/j.bja.2024.11.027","url":null,"abstract":"","PeriodicalId":9250,"journal":{"name":"British journal of anaesthesia","volume":"22 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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