Otolaryngology & Head and Neck Surgery

Rib cartilage in Asian rhinoplasty: new trends Purpose of review Costal cartilage has many advantages over other grafting materials because of its large quantity and high biocompatibility. As a result, it has been considered as a good option for Asian rhinoplasty. However, costal cartilage is difficult to use and is associated with a high complication rate. To avoid the disadvantages and complications of costal cartilage graft, several techniques have been proposed in the literature. This review addresses the conventional uses of costal cartilage in Asian rhinoplasty and recent updates. Recent findings Different techniques have been reported for Asian rhinoplasty using costal cartilage. Solid-block costal cartilage and diced cartilage with or without wrapping materials are widely used for dorsal augmentation. Many different grafting techniques for the tip and septal reconstruction have been reported by numerous surgeons. When using costal cartilage graft, surgeons should pay attention to both graft complications, such as warping or infection, and donor-site morbidity. Several strategies have recently been developed to avoid these complications. Summary This article summarises grafting options for Asian rhinoplasty using costal cartilage and possible complications. This information may assist with proper selection of appropriate techniques for harvesting, carving and grafting costal cartilage. Correspondence to Yong Ju Jang, MD, PhD, Professor, Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. Tel: +82 2 3010 3710; fax: +82 2 489 2773; e-mail: jangyj@amc.seoul.kr Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Oral Oncology

1. CorrespondenceNo access

   Why refer possible oral cancer to the dentist for assessment?

   Javier Fernández-Feijoo, Marta Fernández-Varela, Márcio Diniz-Freitas, Pedro Diz-Dios, Jacobo Limeres-Posse

   In Press, Corrected Proof, Available online 14 May 2019

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2. select article The interest of sequential treatment with immune check point inhibitors followed chemotherapy: A case report

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   The interest of sequential treatment with immune check point inhibitors followed chemotherapy: A case report

   Matthieu Lasserre, Charlotte Domblides, Marine Gross-goupil, Alain Ravaud, Amaury Daste

   In Press, Corrected Proof, Available online 8 May 2019

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3. select article Myoepithelial carcinoma with rhabdoid features in the maxillary sinus: Immunohistochemical and in situ hybridization analysis of a rare case

   CorrespondenceAbstract only

   Myoepithelial carcinoma with rhabdoid features in the maxillary sinus: Immunohistochemical and in situ hybridization analysis of a rare case

   Heitor Albergoni Silveira, Luciana Yamamoto Almeida, Cassiano Francisco Weege Nonaka, Pollianna Muniz Alves, ... Jorge Esquiche León

   In Press, Corrected Proof, Available online 30 April 2019

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   Abstract

   Myoepithelial carcinomas of the head and neck are often located in the major salivary glands, notably in the parotid glands, being less frequent in the minor salivary glands. Noteworthy, myoepithelial carcinoma in the maxillary sinus is extremely rare. In fact, only five cases have been previously published to date. Here, we present, for the first time, a detailed immunohistochemical and in situ hybridization analysis of a SMARCB1 (INI-1)-intact myoepithelial carcinoma with rhabdoid features, expanding the histopathological spectrum of high-grade sinonasal carcinomas.

4. select article Corrigendum to "Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma" [Oral Oncol. 86 (2018) 278–287]

   ErratumFull text access

   Corrigendum to "Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma" [Oral Oncol. 86 (2018) 278–287]

   D.J. Hartman, F.S. Ahmed, R.L. Ferris, D.L. Rimm, L. Pantanowitz

   In Press, Corrected Proof, Available online 30 April 2019

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5. select article Regression and long-term control after radiotherapy of carotid body paraganglioma – Are these still issues?

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   Regression and long-term control after radiotherapy of carotid body paraganglioma – Are these still issues?

   Federico Ampil

   In Press, Corrected Proof, Available online 30 April 2019

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6. select article Concurrent oropharyngeal squamous cell carcinomas in couples

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   Concurrent oropharyngeal squamous cell carcinomas in couples

   Prashanth Panta, Mukund Seshadri

   In Press, Corrected Proof, Available online 25 April 2019

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7. select article Tooth mobility: A plausible predictor of bony margins

   CorrespondenceNo access

   Tooth mobility: A plausible predictor of bony margins

   Sameep S. Shetty, Vishal Rao, Akshay Kudpaje, Premalatha Shetty

   In Press, Corrected Proof, Available online 24 April 2019

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8. select article Sanctuary site central nervous system relapse-refractory DLBCL responding to nivolumab and lenalidomide

   CorrespondenceAbstract only

   Sanctuary site central nervous system relapse-refractory DLBCL responding to nivolumab and lenalidomide

   Irappa V. Madabhavi, Swaroop Revannasiddaiah, Malay S. Sarkar, Mitul G. Modi

   In Press, Corrected Proof, Available online 19 April 2019

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   Abstract

   Despite improvement in survival in diffuse large B-cell lymphoma (DLBCL) with the introduction of rituximab, central nervous system (CNS) relapse continues to represent a clinical challenge. In diffuse large B-cell lymphoma (DLBCL), the incidence of CNS relapse is only ∼5% in unselected cohorts. Immunotherapy is the treatment that either boosts the patient's own immune system or uses man-made versions of the normal parts of the immune system to kill lymphoma cells or slow their growth. We are presenting a thirty-eight year old man who, presented with neck nodes, axillary nodes, altered sensorium, abnormal body movements, unconsciousness, weight loss and, fever, with a past history of DLBCL in May 2008, treated with 6 cycles of CHOP and completed in November 2008. After 9 years in April 2018, the patient developed similar symptoms and treated with salvage chemotherapy with R-DHAP which was completed in September 2018. Post-treatment PET-CT showed partial metabolic response and we started external beam radiotherapy to initial bulky disease. After completion of radiotherapy, the patient was very reluctant for any type of therapy and went home. After one month he presented to us with persistent vomiting, abnormal body movements and, altered sensorium. On examination, his Glasgow Coma Scale (GCS) was E2V3M2 and he was admitted in Intensive Care Unit. The patient was managed with mannitol, dexamethasone, antiepileptics, antibiotics and other supportive care medicines. His brain magnetic resonance imaging (MRI) was showing multiple heterogeneously enhancing lesions with surrounding vasogenic oedema and his cerebrospinal fluid analysis was positive for malignant cells. He was managed with triple intrathecal chemotherapy with methotrexate 12 mg, Cytarabine 50 mg, and Hydrocortisone 50 mg along with other supportive care medicines, and after 4–5 days he regained consciousness and he was able to talk and understand verbal commands. In view of improvement in general condition and performance status, we started biweekly triple intra-thecal therapy, and Inj. Nivolumab 3 mg per kg q 2 weekly. From the second cycle, we started Lenalidomide 10 mg once a day for 21 days with 7 days gap along with 2 weekly nivolumab and biweekly triple IT chemotherapy. After one month his CSF analysis was negative for malignant cells. Now he is on regular treatment with weekly IT chemotherapy, 2 weekly nivolumab and 3 weeks on and one week off lenalidomide. After 2 months of treatment, his MRI Brain was showing. At the time of submission of this article, he has completed the fifth cycle of immunotherapy and two cycles of lenalidomide. He was able to manage his daily ADL and able to walk with a stick. The patient tolerated immunotherapy, triple IT therapy and lenalidomide very well without much intolerable side effects. Therefore, we concluded that nivolumab and lenalidomide was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory sanctuary site CNS B- cell lymphomas. Additional studies of Nivolumab and lenalidomide in these diseases are ongoing.

9. select article Human papillomavirus (HPV) vaccine and HPV-related head and neck cancer: What's next?

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   Human papillomavirus (HPV) vaccine and HPV-related head and neck cancer: What's next?

   F. De Felice, A. Polimeni, V. Tombolini

   In Press, Corrected Proof, Available online 5 April 2019

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Anaesthesiology

Propofol intravenous anaesthesia with desflurane compared with desflurane alone on postoperative liver function after living-donor liver transplantation: A randomised controlled trial BACKGROUND Propofol is an anaesthetic that resembles α-tocopherol and it has been suggested that it protects against ischaemia-reperfusion injury in liver transplantation. Living-donor liver transplantation (LDLT) presents an opportunity to test this hypothesis in both donors and recipients. OBJECTIVES We compared clinical outcomes after LDLT following anaesthesia with propofol and desflurane against desflurane alone. DESIGN A prospective, randomised, parallel study. SETTING Single-centre trial, study period June 2014 and May 2017. PATIENTS Sixty-two pairs of adult donors and recipients who underwent LDLT. INTERVENTION Patients were randomised to receive either desflurane balanced anaesthesia or propofol total intravenous anaesthesia combined with desflurane anaesthesia. MAIN OUTCOME MEASURES The primary outcome was peak liver transaminase levels during the first 7 days after surgery. Liver function was assessed at 10 different time-points (before surgery, 1 h after reperfusion, upon arrival in the ICU, and daily until postoperative day 7). Creatinine was measured to evaluate the incidence of acute kidney injury. TNF-α, IL-1β, IL-6 and TGF-β1 were assessed in 31 donors after induction, at hepatectomy and at the end of surgery and in 52 recipients after induction, and 1, 3 and 24 h after reperfusion. RESULTS Peak liver transaminase levels were not significantly different between the two groups. Liver function tests and creatinine were also similar between groups at all time-points. There was no difference in the incidence of postoperative complications, including acute kidney injury. With the exception of higher TNF-α in donors of the Propofol group at hepatectomy (0.60 ± 0.29 vs. 1.03 ± 0.53, P = 0.01) cytokine results were comparable between the two groups. CONCLUSION Despite the simultaneous administration of propofol infusion in both donors and recipients, no improvement in laboratory or surgical outcome was observed after LDLT compared with patients who received desflurane anaesthesia alone. TRIAL REGISTRATION NCT02504138 at clinicaltrials.gov. Correspondence to Young C. Yoo, Department of Anesthesiology and Pain Medicine, Severance Hospital, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea Tel: +82 2 2228 2420; fax: +82 2 2227 7897; e-mail: seaoyster@yuhs.ac © 2019 European Society of Anaesthesiology

Can quantitative sensory tests predict failed back surgery?: A prospective cohort study BACKGROUND Failed back surgery syndrome (FBSS) is a pain condition refractory to therapy, and is characterised by persistent low back pain after spinal surgery. FBSS is associated with severe disability, low quality of life and high unemployment. We are currently unable to identify patients who are at risk of developing FBSS. Patients with chronic low back pain may display signs of central hypersensitivity as assessed by quantitative sensory tests (QST). This can contribute to the risk of developing persistent pain after surgery. OBJECTIVE We tested the hypothesis that central hypersensitivity as assessed by QST predicts FBSS. DESIGN AND SETTING We performed a prospective cohort study in three tertiary care centres with 141 patients scheduled for up to three segment spinal surgery for chronic low back pain due to degenerative changes. PATIENTS Chronic low back pain was defined as at least 3 on a numerical rating scale on most days during the week and with a minimum duration of 3 months. OUTCOMES We defined FBSS as persistent pain, persistent disability or a composite outcome defined as either persistent pain or disability. The primary outcome was persistent pain 12 months after surgery. We applied 14 QST using electrical, pressure and temperature stimulation to predict FBSS and assessed the association of QST with FBSS in multivariable analyses adjusted for sociodemographic, psychological and clinical and surgery-related characteristics. RESULTS None of the investigated 14 QST predicted FBSS, with 95% confidence intervals of crude and adjusted associations of all QST including one as a measure of no association. Results remained robust in all sensitivity and secondary analyses. CONCLUSION The study indicates that assessment of altered central pain processing using current QST is unlikely to identify patients at risk of FBSS and is therefore unlikely to inform clinical decisions. Correspondence to Prof. Michele Curatolo, MD, PhD, Department of Anesthesiology and Pain Medicine, University of Washington, 1959 NE Pacific Street, Box 356540 Seattle, WA 98195-6540, USA Tel: +1 206 543 2568; fax: +1 206 543 2958; e-mail: curatolo@uw.edu Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.ejanaesthesiology.com). © 2019 European Society of Anaesthesiology

Tidal volume challenge to predict fluid responsiveness in the operating room: A prospective trial on neurosurgical patients undergoing protective ventilation BACKGROUND Pulse pressure variation (PPV) and stroke volume variation (SVV) do not predict fluid responsiveness when using a protective ventilation strategy: the use of functional haemodynamic tests can be useful to overcome this limitation. OBJECTIVES We tested the use of a tidal volume challenge (VTC), during 6 ml kg−1 [predicted body weight (PBW)] ventilation, and the end-expiratory occlusion test (EEOT) for prediction of fluid responsiveness. DESIGN An interventional prospective study. SETTING Supine elective neurosurgical patients. INTERVENTIONS The study protocol was, first, the initial EEOT test was performed during baseline 6 ml kg−1 PBW ventilation; second, VTC was performed by increasing the VT up to 8 ml kg−1 PBW and PPV and SVV changes were recorded after 1 min; third, a second EEOT was performed during 8 ml kg−1 PBW ventilation; and VT was reduced back to 6 ml kg−1 PBW and a third EEOT was performed. Finally, a 250 ml fluid challenge was administered over 10 min to identify fluid responders (increase in stroke volume index ≥10%). RESULTS In the 40 patients analysed, PPV and SVV values at baseline and EEOT performed at 6 ml kg−1 PBW did not predict fluid responsiveness. A 13.3% increase in PPV after VTC predicted fluid responsiveness with a sensitivity of 94.7% and a specificity of 76.1%, while a 12.1% increase in SVV after VTC predicted fluid responsiveness with a sensitivity of 78.9% and a specificity of 95.2%. After EEOT performed at 8 ml kg−1 PBW, a 3.6% increase in cardiac index predicted fluid responsiveness with a sensitivity of 89.4% and a specificity of 85.7%, while a 4.7% increase in stroke volume index (SVI) with a sensitivity of 89.4% and a specificity of 85.7%. CONCLUSION The changes in PPV and SVV obtained after VTC are reliable and comparable to the changes in CI and SVI obtained after EEOT performed at 8 ml kg−1 PBW in predicting fluid responsiveness in neurosurgical patients. TRIAL REGISTRATION ACTRN12618000351213. Correspondence to Antonio Messina, MD, PhD, Department of Anaesthesia and Intensive Care Medicine, IRCCS Humanitas, Humanitas University, Via Alessandro Manzoni, 56, Rozzano – Milan 20089, Italy. Tel: +39(0)2 8224 8282; e-mail: mess81rc@gmail.com Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.ejanaesthesiology.com). © 2019 European Society of Anaesthesiology

Effect of pre-operative oral carbohydrate loading on recovery after day-case cholecystectomy: A randomised controlled trial BACKGROUND Pre-operative carbohydrate loading has been shown to reduce pre-operative discomfort and postoperative nausea and vomiting in general surgical patients. Few studies have considered day-case surgery. OBJECTIVE The aim of this prospective randomised study was to determine whether pre-operative carbohydrate loading enhanced recovery after day-case cholecystectomy. DESIGN A randomised controlled trial. SETTING Secondary care in a district general and a university hospital in Finland between 2013 and 2016. PATIENTS A total of 113 patients American Society of Anesthesiologists physical status I or II aged 18 to 70 undergoing day-case cholecystectomy were included in the study. Exclusion criteria were bleeding or coagulation disorders, BMI more than 40 kg m−2, dementia, insulin-treated diabetes, migraine, Meniere's disease or a history of alcohol or drug abuse. INTERVENTION The carbohydrate-rich drink group received oral carbohydrate (200 ml) 2 to 3 h before surgery, and the control (fasting) group fasted from midnight according to standard protocol. MAIN OUTCOME MEASURES Visual analogue scales (VAS) were used to score six forms of discomfort: the need for analgesia and antiemetics, the time to drinking, eating and first mobilisation after surgery and the time to discharge. Any hospital re-admission was also recorded. RESULTS The highest VAS scores were seen for mouth dryness and tiredness 2 h after surgery in the fasting group. There were no significant differences in any VAS scores between the study groups. No differences in time to mobilisation, need for pain or antiemetic medication or time to discharge were seen between the groups. CONCLUSION Compared with overnight fasting, pre-operative carbohydrate loading did not significantly enhance peri-operative well being or recovery in patients undergoing day-case cholecystectomy. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT03757208. Correspondence to Heli Helminen, Senior Physician, Department of Surgery, Seinäjoki Central Hospital, Hanneksenrinne 7, 60220 Seinäjoki, Finland Tel: +358 64155888; e-mail: heli.helminen@epshp.fi © 2019 European Society of Anaesthesiology

Deep neuromuscular blockade improves surgical conditions during gastric bypass surgery for morbid obesity: A randomised controlled trial BACKGROUND There is a controversy in the literature whether deep compared with moderate neuromuscular block (NMB) improves surgical conditions for laparoscopic surgery. OBJECTIVES The primary outcome measure was to examine whether switching from moderate to deep NMB improves surgical conditions for laparoscopic surgery in the obese; secondary outcome measures were changes in intra-abdominal pressure, time required to perform the gastrojejunal anastomosis and peri-operative surgical complications. DESIGN A single-centre, randomised controlled study. Each patient was taken as their own control and examined twice: at the first evaluation (E1), all patients had a moderate NMB, thereafter patients were randomised to deep or moderate block and a second evaluation (E2) was performed within 10 min. Patients with excellent rating at E1 were excluded from E2, as their surgical condition could not be further improved. SETTING University Hospital France. PATIENTS Patients undergoing laparoscopic gastric bypass surgery under general anaesthesia were included. Main exclusion criteria were hypersensitivity to the drugs used and absence of written informed consent. INTERVENTIONS According to the group assignment, patients received bolus doses of rocuronium or 0.9% saline. MAIN OUTCOME MEASURES Surgical conditions were assessed with a 4-point rating scale. Intra-operative adverse events were assessed with the Kaafarani-classification and postoperative complications with the Clavien-Dindo classification. RESULTS Eighty-nine patients were initially included and data from 85 could be assessed at E1; surgical rating was excellent in 20, good in 35, acceptable in 18, poor in 12. After excluding those with an excellent rating, the remaining 65 patients were randomly assigned to deep or moderate block. At E2, an improvement of surgical conditions was observed in 29 out of 34 patients with deep block and in four out of 31 with moderate block; P < 0.0001. Poor surgical conditions were more frequently associated with surgical complications (61.5 versus 15.3%; P < 0.001). CONCLUSION Switching from moderate to deep block improves surgical conditions. Poor surgical conditions were associated with a higher incidence of surgical complications. TRIAL REGISTRATION NCT02118844 (www.clinicaltrial.gov). Correspondence to Prof. Thomas Fuchs-Buder, University de Lorraine, CHRU Nancy, Brabois University Hospital, Department of Anesthesiology & Critical Care, 7 allée du Morvan, Vandoeuvre-les-Nancy 54511, France; E-mail: t.fuchs-buder@chru-nancy.fr © 2019 European Society of Anaesthesiology

A randomised controlled pragmatic trial of acupressure therapy on quality of recovery after surgery BACKGROUND Acupressure therapy is associated with favourable efficacies on postoperative nausea, pain and sleep disturbance, although the quality of the evidence is generally low. No randomised clinical trial has yet assessed the effect of acupressure on postoperative quality of recovery (QoR). OBJECTIVE The objective was to study acupressure efficacy on patient-reported postoperative recovery. DESIGN We conducted a single centre, three-group, blind, randomised controlled, pragmatic trial assessing acupressure therapy on the PC6, LI4 and HT7 acupoints. PATIENTS Postoperative patients expected to stay in hospital at least 2 days after surgery. INTERVENTIONS In the acupressure group, pressure was applied for 6 min (2 min per acupoint), three times a day after surgery for a maximum of 2 postoperative days during the hospital stay. In the sham group, extremely light touch was applied to the acupoints. The third group did not receive any touch. MAIN OUTCOME MEASURES The primary outcome was the change in the QoR, using the QoR-15 questionnaire, between postoperative days 1 and 3. Key secondary outcomes included patients' satisfaction, postoperative nausea and vomiting, pain score and opioid (morphine equivalent) consumption. Assessors for the primary and secondary endpoints were blind to the group allocation. RESULTS Overall, 163 patients were randomised (acupressure n=55, sham n=53, no intervention n=55). The mean (SD) postoperative change in QoR-15 did not differ statistically (P = 0.27) between the acupressure, sham and no intervention groups: 15.2 (17.8), 14.2 (21.9), 9.2 (21.7), respectively. Patient satisfaction (on a 0 to 10 scale) was statistically different (P = 0.01) among these three groups: 9.1 (1.5), 8.4 (1.6) and 8.2 (2.2), respectively. Changes in pain score and morphine equivalent consumption were not significantly different between the groups. CONCLUSION Two days of postoperative acupressure therapy (up to six treatments) did not significantly improve patient QoR, postoperative nausea and vomiting, pain score or opioid consumption. Acupressure, however, was associated with improved patient satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02762435. Correspondence to Eric Noll, MD, PhD, Department of Anesthesiology and Intensive Care, Hôpitaux Universitaires de Strasbourg, Avenue Molière, 67098 Strasbourg, France Tel: +33 3 88127076; fax: +33 3 88127074; e-mail: eric.noll@chru-strasbourg.fr © 2019 European Society of Anaesthesiology

Initial end-tidal carbon dioxide as a predictive factor for return of spontaneous circulation in nonshockable out-of-hospital cardiac arrest patients: A last straw to cling to? BACKGROUND Early outcome prediction in out-of-hospital cardiac arrest is still a challenge. End-tidal carbon dioxide (ETCO2) has been shown to be a reliable parameter to reflect the quality of cardiopulmonary resuscitation and the chance of return of spontaneous circulation (ROSC). OBJECTIVES This study assessed the validity of early capnography as a predictive factor for ROSC and survival in out-of-hospital cardiac arrest victims with an underlying nonshockable rhythm. DESIGN Retrospective observational study. SETTING/PATIENTS During a 2-year observational period, data from 2223 out-of-hospital cardiac arrest victims within the city of Vienna were analysed. The focus was on the following patients: age more than 18 years, an underlying nonshockable rhythm, and advanced airway management within the first 15 min of advanced life support with subsequent capnography. INTERVENTION No specific intervention was set in this observational study. MAIN OUTCOME MEASURES The first measured ETCO2, assessed immediately after placement of an advanced airway, was used for further analysis. The primary outcome was defined as sustained ROSC, and the secondary outcome was 30-day survival. RESULTS A total of 526 patients met the inclusion criteria. These were stratified into three groups according to initial ETCO2 values (<20, 20 to 45, >45 mmHg). Baseline data and resuscitation factors were similar among all groups. The odds of sustained ROSC and survival were significantly higher for patients presenting with higher values of initial ETCO2 (>45 mmHg): 3.59 [95% CI, 2.19 to 5.85] P = 0.001 and 5.02 [95% CI, 2.25 to 11.23] P = 0.001, respectively. On the contrary ETCO2 levels less than 20 mmHg were associated with significantly poorer outcomes. CONCLUSION Patients with a nonshockable out-of-hospital cardiac arrest who presented with higher values of initial ETCO2 had an increased chance of sustained ROSC and survival. This finding could help decision making as regards continuation of resuscitation efforts. Correspondence to Michael Poppe, Universitätsklinik für Notfallmedizin, Medizinische Universität Wien, Währinger Gürtel 18–20/6D, 1090 Wien, Austria Tel: +43 14040019640; fax: +43 14040019650; e-mail: michael.poppe@meduniwien.ac.at © 2019 European Society of Anaesthesiology

Effect of pretreatment with magnesium sulphate on the duration of intense and deep neuromuscular blockade with rocuronium: A randomised controlled trial BACKGROUND Magnesium sulphate is an important adjuvant drug in multimodal anaesthesia. In combination with rocuronium it can enhance neuromuscular blockade (NMB). Limited data exist concerning the effect of magnesium sulphate on the duration of deep or intense NMB and the period of no response. OBJECTIVE(S) To determine the role of magnesium sulphate on the duration of rocuronium-induced deep and intense NMB, and the period of no response to nerve stimulation. DESIGN A randomised controlled trial. SETTING A public tertiary care hospital, Rio de Janeiro, Brazil, from February 2017 to March 2018. PATIENTS All patients between 18 and 65 years of age scheduled to undergo elective otorhinolaryngological surgery, with a BMI between 18.5 and 24.9 kg m−2 and an American Society of Anesthesiologists physical status classification of I or II. INTERVENTION(S) Before induction of anaesthesia 60 patients were pretreated with an intravenous infusion of either 100 ml 0.9% saline (saline group), or 60 mg kg−1 magnesium sulphate (magnesium group). After loss of consciousness, a bolus of rocuronium (0.6 mg kg−1) was administered. Neuromuscular function was measured by TOF-Watch SX monitor. MAIN OUTCOME MEASURES The primary and secondary outcomes were the duration of the period of no response to nerve stimulation and intense and deep NMB, respectively. An additional outcome was the NMB onset time. RESULTS Median [IQR] durations of deep NMB were 20.3 [12.0 to 35.4] and 18.3 [11.2 to 26.3] min in the magnesium and saline groups, respectively (P = 0.18). Median durations of intense NMB were 21.7 [0.0 to 32.2] min and 0.0 [0.0 to 6.2] min (P = 0.001) in the magnesium and saline groups, respectively. Median durations of the period of no response were 40.8 [51.4 to 36.0] min and 28.0 [21.9 to 31.6] min (P = 0.0001) in the magnesium and saline groups, respectively. CONCLUSION Magnesium sulphate increased both the duration of intense NMB and the period of no response. The duration of deep NMB was similar in the magnesium sulphate group and saline group. TRIAL REGISTRATION ClinicalTrials.gov; identifier: NCT02989272. Correspondence to Angelo J. Queiroz Rangel Micuci, Department of Anesthesiology, Bonsucesso Federal Hospital (Hospital Federal de Bonsucesso), Rio de Janeiro, Brazil E-mail: angelojorgemicuci@gmail.com © 2019 European Society of Anaesthesiology

Ultrasound as a new tool in the assessment of airway difficulties BACKGROUND Prediction of difficult mask ventilation (DMV) is as challenging as difficult laryngoscopy. Ultrasound could be a helpful tool in the prediction of these difficulties. OBJECTIVES The purpose of this study was to evaluate the ability of pre-operative ultrasound assessment of neck anatomy in predicting DMV and difficult laryngoscopy in patients undergoing during elective surgery requiring tracheal intubation. DESIGN Prospective, single blind, observational study. SETTING Operating theatre of a teaching hospital in Italy from April 2018 to July 2018. PATIENTS A total of 194 patients aged more than 18 years, without neck masses, previous thyroid surgery or tracheotomy undergoing general anaesthesia and tracheal intubation for elective ear, nose and throat-surgery were included in the study. OUTCOME MEASURES Ultrasound distances were recorded with a linear 6 to 13 MHz ultrasound transducer: measurements included the minimum distance from the thyroid isthmus to skin surface, the minimum distance from the hyoid bone to skin surface (DSHB), the minimum distance from skin to anterior commissure of the vocal cords, the minimum distance from skin to trachea at the level of the jugular notch and the distance from skin to epiglottis midway. The degree of DMV and difficult laryngoscopy was quantified. RESULTS The mean (SD) of DSHB was 0.88 (0.3) cm in the easy mask ventilation group, 1.4 (0.19) cm in DMV group. The mean of DSHB and of the other ultrasound distances increased according to the DMV and difficult laryngoscopy level. The DSHB was correlated with an increase in the risk for DMV (0.61 [IQR 0.5 to 0.69]). DMV groups were associated with a greater ultrasound-measured DSHB. CONCLUSION The prospective observational study confirms the relationship between ultrasound assessment of the anterior soft tissues of the neck and difficult laryngoscopy and DMV. DSHB and the other distances extend the available evidence, not only for difficult laryngoscopy but also for DMV. TRIAL REGISTRATION Clinicaltrials.gov. identified NCT03592758. Correspondence to Francesco Alessandri, MD, Department of Anaesthesia and Intensive Care Medicine, Sapienza University of Rome, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy Tel: +39 064 997 8007; e-mail: francesco.alessandri@uniroma1.it © 2019 European Society of Anaesthesiology

Necessity to depict difficult neck anatomy for training of cricothyroidotomy: A pilot study evaluating two surgical devices on a new hybrid training model BACKGROUND Everyone dealing with airway emergencies must be able to accomplish cricothyroidotomy, which cannot be trained in real patients. Training models are necessary. OBJECTIVE To evaluate the suitability of a hybrid training model combining synthetic and porcine parts to depict variable neck anatomy. DESIGN Model-based comparative trial. SETTING Armed Forces Hospital Ulm, Germany, August 2018. INTERVENTION On four anatomical neck variations (long slim/long obese/short slim/short obese) we performed two surgical approaches to cricothyroidotomy (SurgiCric II vs. ControlCricTM). PARTICIPANTS Forty-eight volunteers divided into two groups based on their personal skill level: beginners group and proficient performers group. MAIN OUTCOME MEASURES Time to completion was recorded for each procedure. Once the operator had indicated completion, the correct anatomical tube placement was confirmed by dissection and structures were inspected for complications. Primary outcomes were successful tracheal placement of an airway tube and time needed to achieve a patent airway. Secondary outcome was assessment of complications. RESULTS Overall, 384 procedures were performed. Median time to completion was 74 s. In total, 284 procedures (74%) resulted in successful ventilation. Time to completion was longer in short obese than in long slim and the risk of unsuccessful procedures was increased in short obese compared with long slim. Even if ControlCric resulted in faster completion of the procedure, its use was less successful and had an increased risk of complications compared with SurgiCric II. Proficient performers group performed faster but had an increased risk of injuring the tracheal wall compared with beginners group. CONCLUSION Participants had difficulties in performing cricothyroidotomy in obese models, but various and difficult anatomical situations must be expected in airway management and therefore must be taught. A new hybrid model combining porcine and synthetic materials offers the necessary conditions for the next step in training of surgical airway procedures. TRIAL REGISTRATION The study was performed without human tissue or living animals, and was therefore exempted from ethical review by the University of Ulm Ethical Committee, Germany (Chairperson Prof Dr C. Lenk) on 9 August 2018. Hence a protocol number was not attributed. Correspondence to Bjoern Hossfeld, LtCol., Department of Anaesthesiology, Intensive Care Medicine, Emergency Medicine and Pain Therapy, Federal Armed Forces Hospital, Oberer Eselsberg 40, 89081 Ulm, Germany Tel: +49 731 1710 26501; e-mail: bjoern.hossfeld@uni-ulm.de © 2019 European Society of Anaesthesiology

Toxicology

Functional transepithelial transport measurements to detect nephrotoxicity in vitro using the RPTEC/TERT1 cell line Abstract The kidney is a frequent target for organ-specific toxicity as a result of its primary function in controlling body fluids, for example, via resorption of amino acids, peptides, nutrients, ions, xenobiotics and water from the primary urine as well as excretion of metabolic waste products and hydrophilic and amphiphilic xenobiotics. Compounds exhibiting dose-limiting nephrotoxicity include drugs from highly diverse classes and chemical structures, e.g., antibiotics (gentamicin), chemotherapeutics (cisplatin), immunosuppressants (cyclosporine A and tacrolimus) or bisphosphonates (zoledronate). All of these compounds elicit nephrotoxicity primarily by injuring renal proximal tubule epithelial cells (RPTECs). However, prediction of a compound's nephrotoxic potential in humans to support early unmasking of risk-bearing drug candidates remains an unmet challenge, mainly due to the complex kidney anatomy as well as pronounced inter- and intraspecies differences and lack of relevant and validated human in vitro models. Accordingly, we used the recently established human RPTEC/TERT1 cell line to carry out toxicity studies with a focus on impairment of functional characteristics, i.e., transepithelial electrical resistance (TEER), vectorial transport of water, cations, and anions. Results were compared to real-time cytotoxicity assessments using cellular impedance (xCELLigence assay) and the routine cell viability readout (MTT). As expected, most toxins caused exposure time- and concentration-dependent cytotoxicity. However, for some compounds (cyclosporine A and tacrolimus), transport processes were strongly impaired in absence of a concomitant decrease in cell viability. In conclusion, these data demonstrate that functional parameters are important, highly sensitive and meaningful additional readouts for nephrotoxicity assessment in human renal proximal tubule epithelial cells.

Role of microglial activation and neuroinflammation in neurotoxicity of acrylamide in vivo and in vitro Abstract Acrylamide, a soft electrophile, is widely used in the industry and laboratories, and also contaminates certain foods. Neurotoxicity and neurodegenerative effects of acrylamide have been reported in humans and experimental animals, although the underlying mechanism remains obscure. Activation of microglia and neuroinflammation has been demonstrated in various neurodegenerative diseases as well as other pathologies of the brain. The present study aimed to investigate the role of microglial activation and neuroinflammation in acrylamide neurotoxicity. Male 10-week-old Wistar rats were exposed to acrylamide by gavage at 0, 0.2, 2, or 20 mg/kg BW, once per day for 5 weeks. The results showed that 5-week exposure to acrylamide induced inflammatory responses in the cerebral cortex, evident by upregulated mRNA and protein expression of pro-inflammatory cytokines IL-1β, IL-6, and IL-18. Acrylamide also induced activation of microglia, indicated by increased expression of microglial markers, CD11b and CD40, and increased CD11b/c-positive microglial area and microglial process length. In vitro studies using BV-2 microglial cells confirmed microglial inflammatory response, as evident by time- (0–36 h; 50 μM) and dose- (0–500 μM; 24 h) dependent increase in mRNA expression of IL-1β and IL-18, as well as the inflammatory marker iNOS. Furthermore, acrylamide-induced upregulation of pro-inflammatory cytokines was mediated through the NLRP3 inflammasome pathway, as evident by increased expression of NLRP3, caspase 1, and ASC in the rat cerebral cortex, and by the inhibitory effects of NLRP3 inflammasome inhibitor on the acrylamide-induced upregulation of NLRP3, caspase 1, IL-1β, and IL-18 in BV-2 microglia.

Forensic evidence of sulfur mustard exposure in real cases of human poisoning by detection of diverse albumin-derived protein adducts Abstract We present the forensic analyses of plasma samples of human victims exposed to sulfur mustard (SM) in a crisis region in the Middle East in 2015. A few hours after exposure, poisoned persons showed typical signs and symptoms of percutaneous SM exposure including erythema and later on blisters and hardly healing skin wounds. Blood samples were collected 15 days after poisoning to be analyzed for the presence of long-lived protein-adduct biomarkers to verify SM poisoning. We applied a novel bioanalytical toolbox targeting four human serum albumin-derived biomarkers that were made accessible after plasma proteolysis. These adducts contained the SM-specific hydroxyethylthioethyl moiety either bound to the thiol group of a cysteine residue (C34*) or to the side-chain carboxylic group of a glutamic acid residue (E230*). Peptide biomarkers were produced from plasma of the victims using proteinase K (C34*PF), pronase (C34*P) and pepsin (AE230*VSKL and LQQC34*PFEDHVKL) for enzymatic protein cleavage. Separation and detection were carried out by selective micro-liquid chromatography–electrospray ionization high-resolution tandem mass spectrometry (µLC–ESI MS/HR MS). In addition to this site-specific adduct detection, a general approach after alkaline hydrolysis of the plasma protein fraction was applied. Liberated thiodiglycol (TDG) was derivatized with heptafluorobutyric anhydride and detected by gas chromatography–electron ionization mass spectrometry (GC–EI MS). The different bioanalytical methods yielded congruent results confirming SM poisoning for all patients who showed clinical signs and symptoms. This is the first time that real cases of SM poisoning were confirmed and presented by such a broad compilation of protein-derived biomarkers.

Selecting the dose metric in reverse dosimetry based QIVIVE

Behavioural and metabolomic changes from chronic dietary exposure to low-level deoxynivalenol reveal impact on mouse well-being Abstract The mycotoxin deoxynivalenol (DON) has a high global prevalence in grain-based products. Biomarkers of exposure are detectable in most humans and farm animals. Considering the acute emetic and chronic anorexigenic toxicity of DON, maximum levels for food and feed have been implemented by food authorities. The tolerable daily intake (TDI) is 1 µg/kg body weight (bw)/day for the sum of DON and its main derivatives, which was based on the no-observed adverse-effect level (NOAEL) of 100 µg DON/kg bw/day for anorexic effects in rodents. Chronic exposure to a low-DON dose can, however, also cause inflammation and imbalanced neurotransmitter levels. In the present study, we therefore investigated the impact of a 2-week exposure at the NOAEL in mice by performing behavioural experiments, monitoring brain activation by c-Fos expression, and analysing changes in the metabolomes of brain and serum. We found that DON affected neuronal activity and innate behaviour in both male and female mice. Metabolite profiles were differentiable between control and treated mice. The behavioural changes evidenced at NOAEL reduce the safety margin to the established TDI and may be indicative of a risk for human health.

Naturally occurring bisphenol F in plants used in traditional medicine Abstract Bisphenol F (BPF, 4-[(4-hydroxyphenyl)methyl]phenol) is a bisphenol that is structurally similar to bisphenol A (BPA). In response to consumer concern towards BPA, industry has started to substitute BPA for BPF and other bisphenol analogues in the production of epoxy resins and coatings for various applications. In 2016, it was reported that commercially sold mustard contained naturally occurring BPF. Here, the existing literature was reviewed to investigate whether other natural sources of BPF among edible plants exist, including their impact on human exposure to BPF. Coeloglossum viride var. bracteatum (rhizome), Galeola faberi (rhizome), Gastrodia elata (rhizome), Xanthium strumarium (seeds) and Tropidia curculioides (root) were found to contain naturally occurring BPF. Botanical extracts from these plants are used in traditional Chinese medicine. The highest values of BPF were recorded for G. elata and T. curculioides. Information on precise doses of the plant extracts used is scarce; however, for G. elata, also known as Tian Ma and available in powder form, a daily exposure of BPF from this source could theoretically amount up to 4.5 µg/kg body weight per day (based on a 70 kg body weight). Therefore, herbal products used in traditional Chinese medicine should be considered as a potential source contributing to the overall human exposure when assessing endocrine-active bisphenolic compounds.

Minor structural modifications of bisphenol A strongly affect physiological responses of HepG2 cells Abstract Bisphenols represent a large group of structurally similar compounds. In contrast to bisphenol A (BPA) and bisphenol S (BPS), however, toxicological data are usually scarce, thus making bisphenols an ideal candidate for read-across assessments. BPA, bisphenol C (BPC) and a newly synthesized bisphenol A/C (BPA/C) differ only by one methyl group attached to the phenolic ring. Their EC50 values for cytotoxicity and logPOW values are comparable. However, the estrogenic activities of these bisphenols are not comparable and among this group only BPC leads to a decrease of the mitochondrial membrane potential and ATP concentration in HepG2 cells. Conversely, the cell division rate was decreased by BPS, BPA, BPC and BPA/C at 10% toxicity (EC10). At lower concentrations, only BPC significantly affected proliferation. The pro-inflammatory cytokines TGFB1 and TNFwere significantly upregulated by BPC only, while SPP1 was upregulated by BPA, BPA/C and BPS. BPC led to the release of cytochrome c from mitochondria, indicating that this compound is capable of inducing apoptosis. In conclusion, the read-across approach revealed non-applicable in the case of the various structurally and physicochemically comparable bisphenols tested in this study, as the presence of one or two additional methyl group(s) attached at the phenol ring profoundly affected cellular physiology.

Integration of epidemiological findings with mechanistic evidence in regulatory pesticide risk assessment: EFSA experiences Abstract Toxicological risk assessment of plant protection products (PPP) is currently carried out with the principal input from regulatory toxicology studies following OECD test guidelines, with little input from epidemiological data. An EFSA-commissioned systematic review of pesticide epidemiological studies (Ntzani et al. in Literature review on epidemiological studies linking exposure to pesticides and health effects. EFSA supporting publication 2013:EN-497, 2013) revealed statistically significant associations, among others, between pesticide exposures, and Parkinson's disease and childhood leukemia. Thereafter, EFSA launched a project with a mandate for the plant protection products and their residues (PPR) Panel to set the ground for the use of epidemiological data in the risk assessment of pesticides, as requested by Regulation (EC) 1107/2009. The project culminated with the publication of two EFSA's scientific opinions on the potential contribution of experimental investigations and epidemiological studies in PPP risk assessment and with the scientific conference held on 20 November 2017, in Parma, Italy. The application of modern methodologies in exposure assessment, toxicology and epidemiology would improve the pesticide risk assessment process and support a mechanistic shift for the integration of these three disciplines under a novel paradigm in risk assessment. The application of the adverse outcome pathway (AOP) conceptual framework to this approach would contribute to gain insight into the biological plausibility of a hazard identified in epidemiological or experimental studies and would inform an Integrated Approach to Testing and Assessment (IATA) within a regulatory context.