Arthralgia in midlife Singaporean women: the Integrated Women's Health Program (IWHP).

OBJECTIVE: Arthralgia is a common menopausal complaint in midlife women, and its causes remain unclear. We examined the prevalence of menopausal arthralgia with various factors including sleep quality, depression/anxiety, muscle strength and physical performance among midlife Singaporean women. METHODS: The Integrated Women's Health Program (IWHP) comprised 1120 healthy, community-dwelling women of Chinese, Malay or Indian ethnicities (aged 45-69 years) attending well-women clinics at the National University Hospital, Singapore. Sociodemographic, menopausal, reproductive and health data were obtained with validated questionnaires. Muscle strength, physical performance and dual-energy X-ray absorptiometry were measured. Women with moderate to very severe symptoms using the Menopause Rating Scale were classified as having arthralgia. Multivariable logistic regression analyses examined risk factors for arthralgia. RESULTS: One-third of the participants reported arthralgia, and 12.7%, 16.2% and 71.2% were in the premenopausal, perimenopausal and postmenopausal period, respectively. Menopausal symptoms, such as vaginal dryness (adjusted odds ratio [aOR]: 2.64, 95% confidence interval [CI]: 1.64, 4.24) and physical/mental exhaustion (aOR: 2.83, 95% CI: 1.79, 4.47), were independent risk factors for arthralgia. Poor muscle strength (aOR: 2.20, 95% CI: 1.29, 3.76), obesity (aOR: 1.94, 95% CI: 1.13, 3.32) and rheumatoid arthritis (aOR: 7.73, 95% CI: 4.47, 13.36) were also independently associated with arthralgia after adjustment for confounders. CONCLUSIONS: Arthralgia in midlife Singaporean women was associated with menopausal symptoms of vaginal dryness and physical and mental exhaustion. Women with poor muscle strength were more likely to experience menopausal arthralgia.

Toxicity and human health assessment of an alcohol-to-jet (ATJ) synthetic kerosene developed under an international agreement with Sweden.

Alcohol-to-jet (ATJ) Synthetic Kerosene with Aromatics (SKA) fuels are produced by dehydration and refining of alcohol feed stocks. ATJ SKA fuel known as SB-8 was developed by Swedish Biofuels as a cooperative agreement between Sweden and AFRL/RQTF. SB-8 including standard additives was tested in a 90-day toxicity study with male and female Fischer 344 rats exposed to 0, 200, 700, or 2000 mg/m3 fuel in an aerosol/vapor mixture for 6 hr/day, 5 days/week. Aerosols represented 0.04 and 0.84% average fuel concentration in 700 or 2000 mg/m3 exposure groups. Examination of vaginal cytology and sperm parameters found no marked changes in reproductive health. Neurobehavioral effects were increased rearing activity (motor activity) and significantly decreased grooming (functional observational battery) in 2000 mg/m3 female rats. Hematological changes were limited to elevated platelet counts in 2000 mg/m3 exposed males. Minimal focal alveolar epithelial hyperplasia with increased number of alveolar macrophages was noted in some 2000 mg/m3 males and one female rat. Additional rats tested for genotoxicity by micronucleus (MN) formation did not detect bone marrow cell toxicity or alterations in number of MN; SB-8 was not clastogenic. Inhalation results were similar to effects reported for JP-8. Both JP-8 and SB fuels were moderately irritating under occlusive wrapped conditions but slightly irritating under semi-occlusion. Exposure to SB-8, alone or as 50:50 blend with petroleum-derived JP-8, is not likely to enhance adverse human health risks in the military workplace.

Safety and efficacy of teriparatide treatment for severe osteoporosis in patients with Duchenne muscular dystrophy.

Osteoporosis is a major concern in patients with Duchenne muscular dystrophy. In this novel study of teriparatide treatment in 6 patients with severe osteoporosis, bone health (fractures, vertebral morphometry, and DXA) remained stable, with no adverse events. These findings will help inform future osteoporosis research in this challenging population. INTRODUCTION: Despite standard therapy with vitamin D and bisphosphonates (BP), many patients with Duchenne muscular dystrophy (DMD) continue to sustain fragility fractures due to long-term glucocorticoid treatment and limited mobility. We aimed to evaluate the safety and efficacy of teriparatide for the treatment of severe osteoporosis in adolescent and young adult patients with DMD. METHODS: We prospectively treated 6 patients with DMD who had severe osteoporosis with teriparatide 20 mcg subcutaneously daily for 1-2 years. Inclusion criteria were long-term glucocorticoid therapy, and severe osteoporosis despite treatment with BP, or intolerance to BP. We examined long bone and vertebral fracture outcomes, including vertebral morphometry measures, bone mineral density and content, bone formation markers, safety indices, and adverse events. RESULTS: The mean age at teriparatide start was 17.9 years (range 13.9-22.1 years). All 6 patients were on daily glucocorticoids (mean ± SD; duration 10.9 ± 2.5 years) and 5 were non-ambulatory. Five patients had been treated with BP for 7.9 ± 4.2 years. All had vertebral and a history of long bone fragility fractures at baseline. Vertebral heights and Genant fracture grading remained stable. Long bone fracture rate appeared to decrease (from 0.84/year to 0.09/year); one patient sustained a long bone fracture at 6 months of treatment. Trajectories for change in bone mineral density and content were not different post- vs. pre-teriparatide. Procollagen type 1 amino-terminal propeptide (P1NP) increased, while laboratory safety indices remained stable and non-concerning. No adverse events were observed. CONCLUSION: In six patients with DMD treated with teriparatide for severe osteoporosis, we observed stable bone health and modest increases in P1NP, without safety concerns. Further studies are needed to better understand teriparatide efficacy for treatment of osteoporosis in patients with DMD.

Identification of novel candidate autoantibodies in Alzheimer's disease.

BACKGROUND AND PURPOSE: Accumulated failures in Alzheimer's disease (AD) clinical trials have highlighted an urgent need to identify additional biomarkers involved in AD. Recently, mounting evidence reported that autoantibodies are ubiquitous in human sera. However, it is unknown whether autoantibodies are upregulated in amyloid-tau biomarker-confirmed AD. METHODS: A total of 40 subjects with mild dementia (Clinical Dementia Rating = 1) were stratified into AD (n = 16) and non-AD (n = 24) groups according to their cerebrospinal fluid levels of tau and Aß42 . Their sera were collected and analyzed using a microarray containing > 1600 potential human autoantigens. Autoantibodies that were present exclusively in the AD group were identified and selected using the penetrance-based fold change method with the following criteria: penetrance fold change(AD)  ≥ 2, frequency(AD)  ≥ 15% and frequency(non-AD)  = 0%. RESULTS: All controls and samples passed the quality control criteria and were further used for biomarker analysis. Six autoantibodies with elevated responses to the following autoantigens were found exclusively in the AD group: nucleosome assembly protein 1-like 3 (31.3%, 5/16 subjects) and microtubule-associated protein 4, pantothenic acid kinase 3, phosphoinositide-3-kinase regulatory subunit 1, protein tyrosine phosphatase type IVA member 1 and SRY (sex-determining region Y)-box 15 (all 18.8%, 3/16 subjects). CONCLUSIONS: Although some identified autoantigens are linked to AD and cognitive dysfunction, the increased autoantibody levels have not been reported in AD. Autoantibodies may provide deeper insights into the pathogenesis of AD and serve as diagnostic biomarkers; their corresponding antigens can be further studied to assess their potential as therapeutic targets.

Pulmonary granulomas in a patient with positive ANCA and history of tuberculosis: case report.

BACKGROUND: Granulomatous polyangiitis (GPA) is a rare multisystem autoimmune disease of unknown aetiology that is pathologically characterised by necrotising vasculitis, tissue necrosis and granulomatous inflammation, typically in the presence of anti-neutrophil cytoplasmic antibodies (ANCA). However infectious diseases may induce high titre ANCA and mimic vasculitis. Tuberculosis may share many clinical features with GPA including fever, arthralgia, granulomatous inflammation and pulmonary lesions and patients. CASE PRESENTATION: A 39 year old patient was admitted with ocular irritation and redness, arthralgia and multiple new pulmonary lesions. The past medical history was significant for two episodes of tuberculosis previously requiring prolonged treatment. ANCA antibodies were positive and CT showed multiple pulmonary lesions including cavitatory lesions. After extensive investigation, the patient was treated for GPA with high dose immune suppression with good clinical response. CONCLUSIONS: Here we review the diagnostic considerations between differentiating GPA and tuberculosis in patients from endemic regions. It is recommended that biopsies of lung lesions, sputum microscopy and multidisciplinary team input are sought as part of the workup when these two differentials are being considered.

Drain-free parotidectomy: a pilot study using ARTISS fibrin sealant.

PURPOSE: Parotidectomy is the definitive procedure for diagnosis and treatment of most parotid masses but, due to the risk of haematoma and seroma formation, has traditionally included a drain. The drain itself comes with its own risks and, in most hospitals, the need for overnight admission, which has significant cost implications (Mallon et al. Ann R Coll Surg Engl 95(4):258-262; 2013). Fibrin glue, with its haemostatic and adhesive properties, reduces the risk of collection or haematoma and therefore may negate the need for a drain. This is the first study to look at the use of ARTISS as an alternative to drains in parotidectomy. METHODS: We performed a retrospective study of all the patients who underwent a partial parotidectomy over a 4-year period from 2014 until 2018 under the same senior surgeon. Patients were divided into those that had a drain and those that had ARTISS. Their operative record, inpatient notes and clinic letters were reviewed to record information regarding length of stay, histology, complications and recurrence. RESULTS: A total of 34 patients were identified; 17 ARTISS and 17 drain patients. We showed that the mean length of stay improved significantly from 1.6 days with the drain to 0.5 days with ARTISS (Fig. 1) but without a difference in complication rate (Fig. 2), which was 5/17 (29%) in each group. CONCLUSIONS: In conclusion, parotidectomy can be undertaken safely as a day-case procedure with the application of ARTISS. This new approach to parotid surgery not only offers less morbidity for patients but also positive financial revenue for public health institutions.

Clinical outcome of head and neck cancer patients: a comparison between ENT patients referred via the 2 weeks wait pathway and alternative routes in the UK health system.

2 weeks wait (2ww) referral was intended to improve cancer outcomes in the UK. However, a previous study found that 2ww failed to detect early stage head and neck cancer. There is no current study to examine the survival outcome of head and neck cancer patients diagnosed on 2ww and non-2ww pathways. The aim of this study is to compare the outcome of cancer patients diagnosed on these pathways. We performed a retrospective review of head and neck cancer patients diagnosed between 2009 and 2013 in the ENT Department at Mid-Yorkshire NHS Hospitals Trust. Gender, age, disease staging, treatment modalities, route of referrals along with survival data were documented. Survival analysis was performed for 2ww and non-2ww cancer patients. There were 4123 patients referred on 2ww during the study period. 147 patients were diagnosed with cancers on 2ww and 89 patients were diagnosed on non-2ww. There were no statistical differences in clinical staging (p = 0.416) and overall survival (p = 0.376) between 2ww and non-2ww patients. This study failed to demonstrate a better overall survival in head and neck cancer patients diagnosed on 2ww pathway within the ENT cohort. Current referral system needs to be refined to improve the survival outcome in head and neck cancer patients.

Inferior vena cava and intra-cardiac invasion of hepatocellular carcinoma: a rare but catastrophic complication.

Intra-cardiac extension of hepatocellular carcinoma (HCC) is an uncommon but serious condition related to poor prognosis. We report a 57-year-old male diagnosed with HCC with intra-cardiac extension into the right atrium at presentation. There were no symptoms related to cardiac involvement and intra-cardiac extension was incidentally noted on radiological imaging. He was offered palliative treatment and succumbed to his disease within 50 days of first diagnosis.

Comparative evaluation of three new commercial immunoassays for anti-Müllerian hormone measurement.

STUDY QUESTION: How do the three new anti-Müllerian hormone (AMH) assay methods, manufactured by Beckman Coulter, Roche and Ansh Labs compare with each other and with the Gen II assay? SUMMARY ANSWER: The three new AMH assays are well correlated among themselves and with the Gen II assay, although differences in calibration do exist. WHAT IS KNOWN ALREADY: The Gen II assay has been the mainstay method for AMH measurement in the past few years. Recently, a few new AMH measurement methods have come to the market. STUDY DESIGN, SIZE, DURATION: This was a prospective assay evaluation performed on 178 human serum samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMH concentration was measured in residual serum samples donated by female patients in a reproductive medicine centre. The three new assay methods were tested in parallel and the numerical values obtained were compared among themselves and with those obtained by the Gen II assay. The assay stability upon different sample storage conditions, intra-assay and inter-assay precision, linearity and dilution recovery, and diagnostic performance for polycystic ovary syndrome (PCOS) of the three new AMH assay methods were also compared. MAIN RESULTS AND THE ROLE OF CHANCE: AMH values measured by the Gen II kit and the three new assay methods have good correlations (R > 0.9 for all pairwise correlations). Values measured by the Ansh Labs assay were significantly higher, whereas those by the Roche assay were significantly lower, than those from the Gen II and Beckman-Coulter automated assays (P < 0.05). AMH values were significantly different when measured on the fresh and frozen-thawed serum sample (at -20oC and -80oC) for all three new methods (P < 0.05), but the magnitude of difference was very small with the Beckman-Coulter automated assay and Roche assay. The intra-assay coefficients of variation (CVs) were 0.7-2.2%, 0.5-1.4%, and 1.4-5.4% for the Beckman-Counter automated, Roche and Ansh Labs assays, respectively. Their inter-assay CVs were 0.9-2.5%, 0.7-1.9%, and 6.2-13.5%, respectively. All three new assay methods showed acceptable linearity, and provided excellent discrimination of PCOS from controls. LIMITATIONS, REASONS FOR CAUTION: The precision and dilution linearity experiments involved a small sample size, although these were not the primary outcome measures and have been properly evaluated in previous publications. The study was not designed or powered for determining diagnostic cut-off values. WIDER IMPLICATIONS OF THE FINDINGS: The results demonstrate that the three new AMH assay methods are all valid methods to be adopted in the field of reproduction and are a basis for further work on their clinical application. STUDY FUNDING/COMPETING INTERESTS: The authors have no competing interest to declare. The execution of this study was funded by the Department of Obstetrics and Gynaecology, The University of Hong Kong.

The association between clinical periodontal parameters and free haem concentration within the gingival crevicular fluid: a pilot study.

OBJECTIVES: To investigate the concentration of local free haem in gingival crevicular fluid at periodontally healthy compared with diseased sites in relation to clinical periodontal parameters. The second objective is to investigate for any correlation between smoking and haem concentration. MATERIAL AND METHODS: Clinical parameters were recorded for two healthy and two diseased sites from 22 patients with untreated periodontitis. Gingival crevicular fluid samples were collected from the same sites. Haem assay analysis was undertaken to determine haem concentration at these sites. RESULTS: Gingival crevicular fluid haem concentration was higher at periodontally diseased sites compared to healthy sites (mean 46.6 ± 70.6 nM in healthy vs. 1116.6 ± 2007.0 nM in diseased sites, p < 0.001) and positively correlated with probing pocket depth, attachment level and radiographic bone loss. Gingival crevicular fluid haem concentration was higher in non-smokers compared with smokers. However, no significant difference in correlation between haem concentration and clinical parameters were seen between smokers and non-smokers (p > 0.3). CONCLUSION: The higher concentration of gingival crevicular fluid haem at diseased compared with healthy sites indicates that there is an association between increased levels of local free haem and periodontal disease. This may be through the pro-inflammatory actions of free haem. Further study on a larger scale is required to determine the influence of smoking between haem concentration and clinical parameters.

Optimizing the Soft Tissue Triangle, Alar Margin Furrow, and Alar Ridge Aesthetics: Analysis and Use of the Articulate Alar Rim Graft.

The alar lobule, alar margin, and soft triangle facet are receiving more attention in the literature as critical elements to address both preoperatively and during rhinoplasty. We have found that the use of the articulated alar rim graft (AARG) corrects deficiencies in these areas as well as provides mechanical stability to the external valve. In this article, we describe indications for AARG, describe in detail the procedure for AARG placement, and highlight the transformation AARGs can achieve in two illustrated case studies.

Multilocus DNA sequencing of the whiskey fungus reveals a continental-scale speciation pattern.

Baudoinia was described to accommodate a single species, B. compniacensis. Known as the 'whiskey fungus', this species is the predominant member of a ubiquitous microbial community known colloquially as 'warehouse staining' that develops on outdoor surfaces subject to periodic exposure to ethanolic vapours near distilleries and bakeries. Here we examine 19 strains recovered from environmental samples near industrial settings in North America, South America, the Caribbean, Europe and the Far East. Molecular phylogenetic analysis of a portion of the nucLSU rRNA gene confirms that Baudoinia is a monophyletic lineage within the Teratosphaeriaceae (Capnodiales). Multilocus phylogenetic analysis of nucITS rRNA (ITS1-5.8S-ITS2) and partial nucLSU rRNA, beta-tubulin (TUB) and elongation factor 1-alpha (TEF1) gene sequences further indicates that Baudoinia consists of five strongly supported, geographically patterned lineages representing four new species (viz. Baudoinia antilliensis, B. caledoniensis, B. orientalis and B. panamericana).

Background matching ability and the maintenance of a colour polymorphism in the red devil cichlid.

The evolution and maintenance of colour polymorphisms remains a topic of considerable research interest. One key mechanism thought to contribute to the coexistence of different colour morphs is a bias in how conspicuous they are to visual predators. Although individuals of many species camouflage themselves against their background to avoid predation, differently coloured individuals within a species may vary in their capacity to do so. However, to date, very few studies have explicitly investigated the ability of different colour morphs to plastically adjust their colouration to match their background. The red devil (Amphilophus labiatus) is a Neotropical cichlid fish with a stable colour polymorphism, with the gold morph being genetically dominant and having a myriad of documented advantages over the dark morph. However, gold individuals are much rarer, which may be related to their heightened conspicuousness to would-be predators. Here, we tested the ability of differently coloured individuals to phenotypically adjust the shade of their body colour and patterns to match their background. In particular, we filmed dark, gold and mottled (a transitioning phase from dark to gold) individuals under an identical set-up on light vs. dark-coloured substrates. We found that, in contrast to individuals of the dark morph, gold and mottled individuals were less capable of matching their body colouration to their background. As a result, gold individuals appeared to be more conspicuous. These results suggest that a difference in background matching ability could play an important role in the maintenance of colour polymorphisms.

Management of paediatric otogenic cerebral venous sinus thrombosis: a systematic review.

BACKGROUND: Otogenic paediatric cerebral venous sinus thrombosis (CVST) is rare but has potential clinical sequelae. Its management has long been debated mainly concerning the role of surgery and the use of anticoagulant therapy. OBJECTIVE OF REVIEW: To review the current literature and examine the medical and surgical management of paediatric otogenic CVST and its clinical and radiological outcome. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: The electronic databases (MEDLINE, EMBASE, Cochrane) were searched from inception to November 2014 using text words 'cerebral venous sinus thrombosis OR cerebral venous thrombosis OR lateral sinus thrombosis OR sigmoid sinus thrombosis' AND 'otogenic OR mastoiditis OR otitis media' AND 'children OR paediatric OR pediatric'. EVALUATION METHOD: Inclusion criteria were applied by two reviewers and data extraction was carried out. The type of otological surgery (conservative versus extensive) and the use of anticoagulants with their clinical and radiological outcomes were tabulated. RESULTS: Thirty-six studies (15 case reports and 21 case series) were included with a total of 190 patients. A total of 92.1% of patients underwent otological surgery, and 69.5% had conservative surgery and 30.5% extensive otological surgery. Anticoagulants were used in 59%. A total of 79.2% of patients were reported to have had a good clinical outcome. Within this group, 56% had conservative surgery and anticoagulants. Follow-up scans were documented in 61.6% of patients and complete recanalisation was observed in 51%. Complete recanalisation was observed in 47% of those who had been anticoagulated and 55% of those who received no anticoagulation. CONCLUSIONS: Conservative otological surgery with the combination of anticoagulation was the most common treatment modality found in the group of patients with good clinical outcome. However, given the current low level of evidence, a multicentre collaborative study is needed to help establish the optimum surgical approach and the role of anticoagulation in managing paediatric otogenic CVST.

Methods to obtain protein concentrates from jumbo squid (Dosidicus gigas) and evaluation of their functionality.

Jumbo squid is an important fishery resource in Mexico, and its muscle is lean and white and it has a very low price in the market. It is abundant, but with little or nothing added value, therefore is necessary to search alternatives of processing. Due to muscle characteristics, the aim of this study was to obtain protein concentrates using different methods. They were obtained by means of acidic (acid protein concentrates) and alkaline (alkaline protein concentrates) dissolution. Moreover, a protein concentrate was obtained by direct isoelectric precipitation and by the traditional method (neutral protein concentrates). The yield with better results was alkaline protein concentrates (63.58 ± 1.8%). The gel hardness was significantly different (p < 0.05), especially for the alkaline protein concentrates. The acid protein concentrates, isoelectric precipitation and alkaline protein concentrates were better with regard to the neutral protein concentrates, concerning the emulsifying and foaming properties. The protein concentrates by means of alkaline dissolution gave a better gelling property, but all the processes had the potential to obtain protein with emulsifying and foaming properties.

A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza a and B infections.

BACKGROUND: It is unclear if higher-dose oseltamivir provides benefit beyond the standard dose in influenza patients who require hospitalization. METHODS: A prospective intervention study was performed in 2 acute care general hospitals in Hong Kong over 4 seasonal peaks (2010-2012). Adults (≥18 years) with laboratory-confirmed influenza (85 A/H3N2, 34 A/H1N1pdm09, 36 B) infections who presented within 96 hours were recruited. Study regimen of either 150 mg or 75 mg oseltamivir twice daily for 5 days was allocated by site, which was switched after 2 seasons. Subjects with preexisting renal impairment (creatinine clearance, 40-60 mL/minute) received 75 mg oseltamivir twice daily. Viral clearance by day 5 and clinical responses were compared between groups. Plasma steady-state trough oseltamivir carboxylate (OC) concentration was measured by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Altogether, 41 and 114 patients received 150 mg and 75 mg twice-daily oseltamivir, respectively; their enrollment characteristics (mean age, 61 ± 18 vs 66 ± 16 years) and illness severity were comparable. Trough OC levels were higher in the 150-mg group (501.0 ± 237.0 vs 342.6 ± 192.7 ng/mL). There were no significant differences in day 5 viral RNA (44.7% vs 40.2%) or culture negativity (100.0% vs 98.1%), RNA decline rate, and durations of fever, oxygen supplementation, and hospitalization. Results were similar when analyzed by study arm (all cases and among those without renal impairment). Subanalysis of influenza B patients showed faster RNA decline rate (analysis of variance, F = 4.14; P = .05) and clearance (day 5, 80.0% vs 57.1%) with higher-dose treatment. No oseltamivir resistance was found. Treatments were generally well tolerated. CONCLUSIONS: We found no additional benefit of higher-dose oseltamivir treatment in adults hospitalized with influenza A, but an improved virologic response in influenza B. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT01052961.

Analgesia nociception index: evaluation as a new parameter for acute postoperative pain.

BACKGROUND: A means of identifying the presence and severity of pain that is not reliant on the subjective assessment of pain is desirable whenever a patient self-rating of pain cannot be easily obtained (e.g. sedated patients, very young children, individuals with learning difficulties). The heart rate variability based analgesia nociception index (ANI) has been proposed to reflect different levels of acute pain. The aim of this study was to compare ANI scores with a numeric rating scale (NRS, 0-10) based on self-assessment of pain in the recovery room. METHODS: One hundred and twenty patients after non-emergency surgery were included. On arrival in the post-anaesthesia care unit (PACU) and subsequently at 5 min intervals, patients were asked to rate their level of pain on a 0-10 NRS. ANI values 0-100 points (low values indicating higher levels of pain) were recorded simultaneously. RESULTS: Eight hundred and sixteen pain ratings from 114 patients were included in the analysis. A small but statistically significant negative correlation was found between ANI and the NRS scores (ρ=-0.075; P=0.034). A small but significant difference in ANI was found comparing the extremes of pain [mean (se): NRS 0: 63 (1.4) vs NRS 6-10: 59 (1.4); P=0.027]. However, a receiver-operating analysis testing the value of ANI to distinguish between NRS 0 and NRS 6-10 revealed only low sensitivity and specificity. CONCLUSION: ANI did not reflect different states of acute postoperative pain measured on a NRS scale after adult sevoflurane-based general anaesthesia.