A quantitative evaluation of aerosol generation during awake tracheal intubation.

Aerosol-generating procedures are medical interventions considered high risk for transmission of airborne pathogens. Tracheal intubation of anaesthetised patients is not high risk for aerosol generation; however, patients often perform respiratory manoeuvres during awake tracheal intubation which may generate aerosol. To assess the risk, we undertook aerosol monitoring during a series of awake tracheal intubations and nasendoscopies in healthy participants. Sampling was undertaken within an ultraclean operating theatre. Procedures were performed and received by 12 anaesthetic trainees. The upper airway was topically anaesthetised with lidocaine and participants were not sedated. An optical particle sizer continuously sampled aerosol. Passage of the bronchoscope through the vocal cords generated similar peak median (IQR [range]) aerosol concentrations to coughing, 1020 (645-1245 [120-48,948]) vs. 1460 (390-2506 [40-12,280]) particles.l-1 respectively, p = 0.266. Coughs evoked when lidocaine was sprayed on the vocal cords generated 91,700 (41,907-166,774 [390-557,817]) particles.l-1 which was significantly greater than volitional coughs (p < 0.001). For 38 nasendoscopies in 12 participants, the aerosol concentrations were relatively low, 180 (120-525 [0-9552]) particles.l-1 , however, five nasendoscopies generated peak aerosol concentrations greater than a volitional cough. Awake tracheal intubation and nasendoscopy can generate high concentrations of respiratory aerosol. Specific risks are associated with lidocaine spray of the larynx, instrumentation of the vocal cords, procedural coughing and deep breaths. Given the proximity of practitioners to patient-generated aerosol, airborne infection control precautions are appropriate when undertaking awake upper airway endoscopy (including awake tracheal intubation, nasendoscopy and bronchoscopy) if respirable pathogens cannot be confidently excluded.

Patient characteristics and predictors of mortality in 470 adults admitted to a district general hospital in England with Covid-19.

Understanding risk factors for death from Covid-19 is key to providing good quality clinical care. We assessed the presenting characteristics of the 'first wave' of patients with Covid-19 at Royal Oldham Hospital, UK and undertook logistic regression modelling to investigate factors associated with death. Of 470 patients admitted, 169 (36%) died. The median age was 71 years (interquartile range 57-82), and 255 (54.3%) were men. The most common comorbidities were hypertension (n = 218, 46.4%), diabetes (n = 143, 30.4%) and chronic neurological disease (n = 123, 26.1%). The most frequent complications were acute kidney injury (AKI) (n = 157, 33.4%) and myocardial injury (n = 21, 4.5%). Forty-three (9.1%) patients required intubation and ventilation, and 39 (8.3%) received non-invasive ventilation. Independent risk factors for death were increasing age (odds ratio (OR) per 10 year increase above 40 years 1.87, 95% confidence interval (CI) 1.57-2.27), hypertension (OR 1.72, 95% CI 1.10-2.70), cancer (OR 2.20, 95% CI 1.27-3.81), platelets <150 × 103/µl (OR 1.93, 95% CI 1.13-3.30), C-reactive protein ≥100 µg/ml (OR 1.68, 95% CI 1.05-2.68), >50% chest radiograph infiltrates (OR 2.09, 95% CI 1.16-3.77) and AKI (OR 2.60, 95% CI 1.64-4.13). There was no independent association between death and gender, ethnicity, deprivation level, fever, SpO2/FiO2, lymphopoenia or other comorbidities. These findings will inform clinical and shared decision making, including use of respiratory support and therapeutic agents.

Two-Dimensional Culture Systems to Enable Mechanics-Based Assays for Stem Cell-Derived Cardiomyocytes.

Well-controlled 2D cell culture systems advance basic investigations in cell biology and provide innovative platforms for drug development, toxicity testing, and diagnostic assays. These cell culture systems have become more advanced in order to provide and to quantify the appropriate biomechanical and biochemical cues that mimic the milieu of conditions present in vivo. Here we present an innovative 2D cell culture system to investigate human stem cell-derived cardiomyocytes, the muscle cells of the heart responsible for pumping blood throughout the body. We designed our 2D cell culture platform to control intracellular features to produce adult-like cardiomyocyte organization with connectivity and anisotropic conduction comparable to the native heart, and combined it with optical microscopy to quantify cell-cell and cell-substrate mechanical interactions. We show the measurement of forces and displacements that occur within individual cells, between neighboring cells, and between cells and their surrounding matrix. This system has broad potential to expand our understanding of tissue physiology, with particular advantages for the study of the mechanically active heart. Furthermore, this technique should prove valuable in screening potential drugs for efficacy and testing for toxicity.

Expression of a Constitutively Active Human Insulin Receptor in Hippocampal Neurons Does Not Alter VGCC Currents.

Memory and cognitive decline are the product of numerous physiological changes within the aging brain. Multiple theories have focused on the oxidative, calcium, cholinergic, vascular, and inflammation hypotheses of brain aging, with recent evidence suggesting that reductions in insulin signaling may also contribute. Specifically, a reduction in insulin receptor density and mRNA levels has been implicated, however, overcoming these changes remains a challenge. While increasing insulin receptor occupation has been successful in offsetting cognitive decline, alternative molecular approaches should be considered as they could bypass the need for brain insulin delivery. Moreover, this approach may be favorable to test the impact of continued insulin receptor signaling on neuronal function. Here we used hippocampal cultures infected with lentivirus with or without IRß, a constitutively active, truncated form of the human insulin receptor, to characterize the impact continued insulin receptor signaling on voltage-gated calcium channels. Infected cultures were harvested between DIV 13 and 17 (48 h after infection) for Western blot analysis on pAKT and AKT. These results were complemented with whole-cell patch-clamp recordings of individual pyramidal neurons starting 96 h post-infection. Results indicate that while a significant increase in neuronal pAKT/AKT ratio was seen at the time point tested, effects on voltage-gated calcium channels were not detected. These results suggest that there is a significant difference between constitutively active insulin receptors and the actions of insulin on an intact receptor, highlighting potential alternate mechanisms of neuronal insulin resistance and mode of activation.

Ultrahigh molecular weight polyethylene/graphene oxide nanocomposites: Wear characterization and biological response to wear particles.

In the field of total joint replacements, polymer nanocomposites are being investigated as alternatives to ultrahigh molecular weight polyethylene (UHMWPE) for acetabular cup bearings. The objective of this study was to investigate the wear performance and biocompatibility of UHMWPE/graphene oxide (GO) nanocomposites. This study revealed that low concentrations of GO nanoparticles (0.5 wt %) do not significantly alter the wear performance of UHMWPE. In contrast, the addition of higher concentrations (2 wt %) led to a significant reduction in wear. In terms of biocompatibility, UHMWPE/GO wear particles did not show any adverse effects on L929 fibroblast and PBMNC viability at any of the concentrations tested over time. Moreover, the addition of GO to a UHMWPE matrix did not significantly affect the inflammatory response to wear particles. Further work is required to optimize the manufacturing processes to improve the mechanical properties of the nanocomposites and additional biocompatibility testing should be performed to understand the potential clinical application of these materials. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 183-190, 2018.

Managing anaesthetic provision for global disasters.

The numbers of people affected by large-scale disasters has increased in recent decades. Disasters produce a huge burden of surgical morbidity at a time when the affected country is least able to respond. For this reason an international disaster response is often required. For many years this disaster response was not coordinated. The response consisted of what was available not what was needed and standards of care varied widely producing a healthcare lottery for the affected population. In recent years the World Health organisation has initiated the Emergency Medical Team programme to coordinate the response to disasters and set minimum standards for responding teams. Anaesthetists have a key role to play in Level 2 Surgical Field Hospitals. The disaster context produces a number of logistical challenges that directly impact on the anaesthetist requiring adaptation of anaesthetic techniques from their everyday practice. The context in which they will be working and the wider scope of practice that will be expected from them in the field mandates that deploying anaesthetists should be trained for disaster response. There have been significant improvements in recent years in the speed of response, equipment availability, coordination and training for disasters. Future challenges include increasing local disaster response capacity, agreeing international standards for training and improving data collection to allow for future research and improvement in disaster response. The goal of this review article is to provide an understanding of the disaster context and what logistical challenges it provides. There has been a move during the last decade from a globally uncoordinated, unregulated response, with no consensus on standards, to a globally coordinated response through the World Health Organisation (WHO). A classification system for responding Emergency Medical Teams (EMTs) and a set of agreed minimum standards has been defined. This review outlines the scope of the role of the anaesthetist in a Level 2 field hospital and some of the challenges that this scope and context present. It focuses mainly on natural disasters, but also outline some of the differences encountered in responding to other global disasters such as conflict and infectious outbreaks, and concludes with some of the challenges for the future.

Enhanced recovery after surgery (ERAS) for head and neck oncology patients.

OBJECTIVES: To describe the development of an enhanced recovery after surgery (ERAS) protocol for people undergoing surgery for head and neck cancer. DESIGN: Service improvement project. PARTICIPANTS: Head and neck oncology patients. METHODS: The programme was developed in a series of structured meetings over a 6-month period. Stakeholders included oral and maxillofacial surgeons, otolaryngologists, anaesthetists, dieticians, physiotherapists, speech and language therapists (SALT) and nursing staff. Based on evidence within current literature and a consensus among the group, an ERAS programme for head and neck surgery patients was formulated. A 12-month study of compliance with the ERAS programme was undertaken from February 2014 to January 2015. RESULTS: The process has resulted in the realisation of a head and neck ERAS programme. Key elements include a patient diary, nutritional optimisation, avoiding tracheostomy when possible, goal-directed fluid therapy intra-operatively and a specific head and neck postoperative pain management protocol. Overall compliance was high. Important areas showed lower levels of compliance - only 55% of people were given an explanation of the ERAS programme preoperatively, 75% took preoperative carbohydrate drinks, 10% had individualised goal-directed fluid therapy, and 7% were mobilised in the first 24 h after surgery. The mean length of hospital stay was 14.55 days (sd 7.48). CONCLUSIONS: The ERAS programme developed is now embedded in the care pathway for people undergoing head and neck cancer surgery in our unit. The mean length of hospital stay has reduced since the introduction of the programme.

The Rak/Frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor.

Src is the founding member of a diverse family of intracellular tyrosine kinases, and Src has a key role in promoting cancer growth, in part, through its association with receptor tyrosine kinases. However, some Src-related proteins have widely divergent physiological roles, and these proteins include the Rak/Frk tyrosine kinase (Frk stands for Fyn-related kinase), which inhibits cancer cell growth and suppresses tumorigenesis. Rak/Frk phosphorylates and stabilizes the Pten tumor suppressor, protecting it from degradation, and Rak/Frk associates with the retinoblastoma (Rb) tumor suppressor. However, the role of Rak/Frk in receptor-mediated signaling is largely unknown. Here, we demonstrate that Rak/Frk associates with epidermal growth factor receptor (EGFR), increasing in activity and EGFR binding after EGF stimulation, when it decreases the pool of EGFR present at the plasma membrane. EGFR-Rak binding is direct, requires the SH2 and SH3 domains of Rak/Frk for efficient complex formation and is not dependent on the Grb2 adaptor protein. EGFR mutations are associated with increased EGFR activity and tumorigenicity, and we found that Rak/Frk associates preferentially with an EGFR exon 19 mutant, EGFRΔ747-749/A750P, compared with wild-type EGFR. Furthermore, Rak/Frk inhibited mutant EGFR phosphorylation at an activating site and dramatically decreased the levels of EGFRΔ747-749/A750P from the plasma membrane. Taken together, the results suggest that Rak/Frk inhibits EGFR signaling in cancer cells and has elevated activity against EGFR exon 19 mutants.

Symmetry, chirality and crystalline tendency: the polymorphism of triacylglycerols.

The physical properties of foods containing fat are often dependent on the polymorphism of the constituent triacylglycerols (TAG). This is illustrated by the favourable physical and sensory properties associated with the ß' form for margarine and butter and the ß(V) form for chocolate. Recent investigations have revealed that the stereochemistry of TAG molecules has a profound influence on their polymorphism. For instance, a pure enantiomer of TAG (sn-10:0-10:0-16:0) was ß'-tending while the corresponding racemic mixture (rac-10:0-10:0-16:0) was ß-tending. In addition, the binary phase diagram for mixtures of the two enantiomers, sn-10:0-10:0-16:0 and sn-16:0-10:0-10:0, showed the formation of a eutectic (metastable ß'-form conglomerate) and a molecular compound (stable ß-form racemic compound). At heart, these differences in polymorph and crystalline tendency stem from differences in the stereochemistry of the unit cell -i.e. both enantiomers in the ß unit cell, one enantiomer in the ß' unit cell. Information on the relative stereochemical arrangement of molecules within the unit cell is also available from the crystallographic space group. This information (determined by X-ray diffraction) is available for a number of ß- and ß'-tending, chiral and achiral TAG systems. Like crystalline tendency (discussed previously), space group data indicates that the unit cell for TAG in the ß' polymorph contains only one stereoisomer whereas the unit cell for TAG in the ß polymorph contains both stereoisomers (conformers in achiral and enantiomers in chiral systems). Therefore, based on the current data, the stereochemical arrangement of TAG molecules in the unit cell is associated with the polymorphic form of the solid - both stereoisomers in the ß form and one stereoisomer in the ß' form. This perspective clearly explains the observed differences in polymorphic behavior for enantiopure and racemic TAG including the ß'-stability of enantiopure systems. As a result, the current descriptive mechanism for TAG polymorphism is vastly improved when the stereochemical orientation of the constituent TAG molecules is considered.

Pre-operative urinary cathepsin D is associated with survival in patients with renal cell carcinoma.

BACKGROUND: No circulating markers are routinely used for renal cancer. The objective of this pilot study was to investigate whether conditioned media (CM) from renal cancer cell lines contains potential biomarkers that, when measured in clinical fluids, have diagnostic or prognostic utility. METHODS: Comparative 2D PAGE profiling of CM from renal cell carcinoma (RCC) and normal renal cultures identified cathepsin D that was subsequently validated in urine samples from 239 patients and healthy and benign disease subjects. RESULTS: Urinary cathepsin D was found to be significantly associated with overall (OS) (hazard ratio, HR, 1.33, 95%CI [1.09-1.63], P=0.005) and cancer-specific survival (HR 1.36, 95%CI [1.07-1.74], P=0.013) in RCC patients on univariate analysis. An optimal cut point (211 ng ml(-1) micromolCr(-1)) around which to stratify patients by OS was determined. Five-year OS equal to/above and below this value was 47.0% (95%CI 35.4%, 62.4%) and 60.9% (48.8%, 76.0%), respectively. On multivariable analysis using pre-operative variables, cathepsin D showed some evidence of independent prognostic value for OS (likelihood ratio test P-value=0.056) although requiring further validation in larger patient numbers with sufficient statistical power to determine independent significance. CONCLUSION: These data establish an important proof of principle and show the potential of proteomics-based studies. Cathepsin D may be of value as a pre-operative urinary biomarker for RCC, alone or in combination.

Ketamine.

Ketamine is a very versatile inexpensive drug and plays an invaluable role in the developing world. In regions where access and funding for a wider range of drugs is problematic, its broad range of clinical applications is ideal. Its good safety profile and ease of storage makes it ideal for use in areas where refrigerators, complex monitoring, electricity and oxygen may all be in short supply or unreliable. Ketamine is also finding increasing use in both the acute and chronic pain settings and research is still ongoing into a potential neuroprotective effect for ketamine in brain injury.

Rapid analysis of acylglycerols in low molecular weight milk fat fractions.

A suitable analytical method was required to facilitate development of an industrial-scale short-path distillation (SPD) process. Short-path distillation produces milk fat distillates (MFD) enriched in low molecular weight milk fat components-viz. free fatty acids, monoacylglycerols, diacylglycerols, cholesterol and low molecular weight triacylglycerols. In this case, solid-phase extraction (SPE) was considered a better alternative than thin-layer chromatography for separating polar and apolar lipid components in MFD samples due to its speed and near-complete recoveries. Solid-phase extraction of MFDs yielded two fractions, both of which are sufficiently pure for subsequent analysis by gas chromatography. This procedure provided rapid and complete chemical characterization (including mass balances) of low-molecular weight milk-fat fractions.

Testing the effect of including oral health in general health checks for elderly patients in medical practice--a randomized controlled trial.

AIM: To test the feasibility and effectiveness of an oral health referral process for elderly patients (aged 75 years or over) attending a preventive health check (PHC) with their general medical practitioner. OBJECTIVES: To evaluate the effectiveness of the process in increasing dental attendance at baseline and 6 months after the intervention. To identify key characteristics of those who accepted an oral health visit (OHV). To determine the proportion of people attending the OHV who required treatment and subsequently attended a dentist. SETTING: Three general medical practices in east Cheshire, UK. DESIGN: A randomized controlled trial. METHOD: Elderly patients attending their general medical practice for PHCs were randomly assigned to a test group, who were invited to attend for an OHV, and to a control group, who received no intervention. Six months after the PHC the effectiveness of the process was measured. RESULTS: Some 50% of those invited for an OHV accepted. Those accepting were more likely to be edentulous, wear dentures or have a current oral health problem, than those declining. Regression analysis showed the best predictors of acceptance to be having a current dental problem or pain and not having a regular dentist. The mean time since their last dental visit was 8.1 years which was significantly longer than those declining the OHV. 63% of individuals attending the OHV were assessed as having a realistic treatment need and 70% of those referred went on to complete the course of treatment. In the test group a highly significant increase in reported dental visiting was found at sixth month evaluation. The primary care staff were happy to include the dental checklist and felt it was a valuable addition to the PHC. CONCLUSIONS: The offer of an OHV was taken up most readily by those with current oral problems, or pain and those with no regular dentist. The inclusion of a dental checklist within the PHC for elderly patients together with help with arranging a dental appointment shows promise as a way of ensuring the dental needs of this group are met.

Validity and Reliability of the Alcohol Expectancy Questionnaire-Adolescent, Brief.

The purpose of this study was to evaluate a brief version of the Alcohol Expectancy Questionnaire-Adolescent (AEQ-A; Brown, Christiansen, & Goldman, 1987). The original AEQ-A was reduced to seven items (called the AEQ-AB). Principal Components Analysis (PCA) was performed and two factors emerged (General Positive Effects and Potential Negative Effects) accounting for 46% of the variance. Internal consistencies are comparable to those of the original AEQ-A (0.50). Scales correlate with criterion variables such as average drinks per week and average number of drinks per heavy drinking day (p < 0.05). It is concluded that this questionnaire may be useful to clinicians providing brief assessment and intervention. Cross-validation in other samples and other settings is recommended.

Multiple sites of impingement of a tracheal tube as it is advanced over a fibreoptic bronchoscope or tracheal tube introducer in anaesthetized, paralysed patients.

Impingement of the tracheal tube on upper airway structures occurs commonly during advancement over a fibreoptic bronchoscope or introducer. In this descriptive study a fibrescope was used to assess the site and mechanism of tracheal tube impingement during advancement over a variety of fibreoptic bronchoscopes and introducers during orotracheal intubation in anaesthetized adults. The effect of the 90 degree counterclockwise rotation manoeuvre in overcoming impingement was also assessed. We recorded impingement at the right arytenoid, left arytenoid, epiglottis, interarytenoid tissue and the left pyriform fossa. Our study found a wider range of sites at which impingement may occur than in previous studies. We also found that when 90 degree counterclockwise rotation of the tip of the tracheal tube was achieved, the impingement was reliably overcome.

The dorsal raphe nucleus in schizophrenia: a post mortem study of 5-hydroxytryptamine neurones.

The 5-hydroxytryptamine (5-HT, serotonin) system has been implicated in the pathophysiology and treatment of schizophrenia. In this study, we addressed the hypothesis that a deficit of 5-HT neurones, either inherited or acquired, is central to the developmental pathology of the disorder. We examined putative 5-HT neurones of the dorsal raphe nucleus (DRN) in post mortem, formalin-fixed tissue from 15 schizophrenic patients and 20 control subjects matched for age and gender. No significant difference was detected between these groups in the number or size (cross-sectional area or diameter) of tryptophan-hydroxylase-immunoreactive cell profiles viewed in transverse sections collected from the level of the trochlear decussation to the emergence of the trigeminal nerve. Profile number was not affected by age, gender, side of the brainstem (left or right) or post mortem interval; however, time in formalin correlated negatively with the number of neurones counted. Moreover, a significant negative correlation was detected between time in formalin and the levels of immunoreaction product (optical density), which in turn correlated positively with our profile counts. A positive correlation was found between the age of subjects and our estimates of cell size. Our results do not support the proposal that an abnormality in the number and/or size of DRN 5-HT neurones is central to the aetiopathology of schizophrenia.

The locus coeruleus in schizophrenia: a postmortem study of noradrenergic neurones.

Despite evidence for an abnormality of noradrenergic function in schizophrenia, it remains unclear whether the number of noradrenergic neurones is normal in patients with the disorder. In postmortem, formalin-fixed tissue from 15 schizophrenic patients and 18 controls matched for age and gender, we made estimates of the number and size of tyrosine-hydroxylase-immunoreactive cells in the locus coeruleus (LC). No significant difference was detected between these groups in the cross-sectional area or diameter of immunoreactive cell profiles. Profile number was not significantly affected by gender, side of the brainstem (left or right), postmortem interval or time in formalin; however, the levels of immunoreaction product (optical density) correlated significantly with our profile counts, which were lower on average in the schizophrenic group. When optical density was included as a covariate in our comparison (a repeated-measures analysis of variance) of schizophrenic and control cases, we found no difference between these groups in the number of neurones counted. An age-related decrease in profile number was detected, but no effect of age on our estimates of cell size was apparent. Our results highlight the importance of accounting for potential confounding variables, including variations in the quality of immunostaining, in investigations of this type. The findings presented here concur with previous studies suggesting that noradrenergic dysfunction in schizophrenia is not associated with an anatomical abnormality at the level of the LC.

Ventilation of a model lung using various cricothyrotomy devices.

In this study we developed a model lung to compare the effectiveness of ventilation using four different cricothyrotomy devices. The Ravussin 13G cannula (VBM Medical), the Quicktrach cannula 4 mm ID (VBM Medical), the Melker cannula 6 mm ID (Cook) and a cuffed tracheal tube 6 mm ID were used in turn to ventilate the model lung through a cricothyrotomy over a range of upper airway resistances. The 6 mm cuffed tracheal tube provided consistently good ventilation independent of upper airway resistance. The 6 mm ID Melker device provided at least reasonable and at best very good ventilation, whatever the patency of the upper airway. The Ravussin cannula could ventilate well with the jet ventilator with low upper airway resistance but could not ventilate at all with complete upper airway obstruction. The Quicktrach performed poorly with low upper airway resistance but well with increased upper airway resistance. With its easier insertion, fewer complications compared to a surgical cricothyrotomy, and the ability to use it with a standard anaesthetic circuit, the authors feel that the 6 mm Melker canula is the technique of choice for emergency trans-tracheal ventilation.

A postmortem study of the mediodorsal nucleus of the thalamus in schizophrenia.

Four studies have reported that the mediodorsal nucleus of the thalamus (MD) is smaller and contains fewer neurons in schizophrenia. The MD is a key node in a circuit proposed to be dysfunctional in the disorder. However, one study did not find a MD volume loss in schizophrenia, and all the studies to date are relatively small. Given the importance of establishing unequivocally the presence of MD pathology, we have carried out a study of the volume and number of neurons in the left and right MD in 21 patients with schizophrenia and 27 healthy comparison subjects. We also measured the size of MD neurons, and estimated total thalamic volume. We found no difference in the volume of the MD, the number of MD neurons, or the size of MD neurons in either hemisphere in schizophrenia. Neither was total thalamic volume altered. There are no obvious methodological or clinical factors to explain our failure to replicate the finding of MD involvement in schizophrenia. Hence our negative observations, in the largest sample yet investigated, cast doubt on the robustness and/or the generalisability of MD neuropathology in schizophrenia.