Randomised controlled trial of analgesia for the management of acute severe pain from traumatic injury: study protocol for the paramedic analgesia comparing ketamine and morphine in trauma (PACKMaN).

BACKGROUND: Prehospital analgesia is often required after traumatic injury, currently morphine is the strongest parenteral analgesia routinely available for use by paramedics in the United Kingdom (UK) when treating patients with severe pain. This protocol describes a multi-centre, randomised, double blinded trial comparing the clinical and cost-effectiveness of ketamine and morphine for severe pain following acute traumatic injury. METHODS: A two arm pragmatic, phase III trial working with two large NHS ambulance services, with an internal pilot. Participants will be randomised in equal numbers to either (1) morphine or (2) ketamine by IV/IO injection. We aim to recruit 446 participants over the age of 16 years old, with a self-reported pain score of 7 or above out of 10. Randomised participants will receive a maximum of 20 mg of morphine, or a maximum of 30 mg of ketamine, to manage their pain. The primary outcome will be the sum of pain intensity difference. Secondary outcomes measure the effectiveness of pain relief and overall patient experience from randomisation to arrival at hospital as well as monitoring the adverse events, resource use and cost-effectiveness outcomes. DISCUSSION: The PACKMAN study is the first UK clinical trial addressing the clinical and cost-effectiveness of ketamine and morphine in treating acute severe pain from traumatic injury treated by NHS paramedics. The findings will inform future clinical practice and provide insights into the effectiveness of ketamine as a prehospital analgesia. TRIAL REGISTRATION: ISRCTN, ISRCTN14124474. Registered 22 October 2020, https://www.isrctn.com/ISRCTN14124474.

Long-term trends in particulate matter from wood burning in the United Kingdom: Dependence on weather and social factors.

Particulate matter from wood burning emissions (Cwood) was quantified at five locations in the United Kingdom (UK), comprising three rural and two urban sites between 2009 and 2021. The aethalometer method was used. Mean winter Cwood concentrations ranged from 0.26 µg m-3 (in rural Scotland) to 1.30 µg m-3 (London), which represented on average 4% (in rural environments) and 5% (urban) of PM10 concentrations; and 8% of PM2.5. Concentrations were greatest in the evenings in winter months, with larger evening concentrations in the weekends at the urban sites. Random-forest (RF) machine learning regression models were used to reconstruct Cwood concentrations using both meteorological and temporal explanatory variables at each site. The partial dependency plots indicated that temperature and wind speed were the meteorological variables explaining the greatest variability in Cwood, with larger concentrations during cold and calm conditions. Peaks of Cwood concentrations took place during and after events that are celebrated with bonfires. These were Guy Fawkes events in the urban areas and on New Year's Day at the rural sites; the later probably related to long-range transport. Time series were built using the RF. Having removed weather influences, long-term trends of Cwood were estimated using the Theil Sen method. Trends for 2015-2021 were downward at three of the locations (London, Glasgow and rural Scotland), with rates ranging from -5.5% year-1 to -2.5% year-1. The replacement of old fireplaces with lower emission wood stoves might explain the decrease in Cwood especially at the urban sites The two rural sites in England observed positive trends for the same period but this was not statistically significant.

Physicochemical characteristics of droplet interface bilayers.

Droplet interface bilayer (DIB) is a lipid bilayer formed when two lipid monolayer-coated aqueous droplets are brought in contact within an oil phase. DIBs, especially post functionalization, are a facile model system to study the biophysics of the cell membrane. Continued advances in enhancing and functionalizing DIBs to be a faithful cell membrane mimetic requires a deep understanding of the physicochemical characteristics of droplet interface bilayers. In this review, we provide a comprehensive overview of the current scientific understanding of DIB characteristics starting with the key experimental frameworks for DIB generation, visualization and functionalization. Subsequently we report experimentally measured physical, electrical and transport characteristics of DIBs across physiologically relevant lipids. Advances in simulations and mathematical modelling of DIBs are also discussed, with an emphasis on revealing principles governing the key physicochemical characteristics. Finally, we conclude the review with important outstanding questions in the field.

Dewetting characteristics of contact lenses coated with wetting agents.

HYPOTHESIS: Although wetting agents have been developed to limit tear film dewetting over contact lenses, systematic analyses correlating wetting agent properties to mechanisms of the tear film destabilization are not readily available. Clarifying destabilization characteristics across key physio-chemical variables will provide a rational basis for identifying optimal wetting agents. EXPERIMENTS: We employ an in-house, in vitro platform to comprehensively evaluate drainage and dewetting dynamics of five wetting agents across seventeen different formulations and two model tear film solutions. We consider the film thickness evolution, film thickness at breakup, dewetted front propagation, and develop correlations to contact angle to compare the samples. FINDINGS: Zwitterionic wetting agents effectively stabilize the tear film by reducing the film thickness at the onset of dewetting, and delaying the propagation of dewetted regions across the lens. Furthermore, tuning wetting agent surface concentrations and utilizing binary mixtures of wetting agents can enhance wetting characteristics. Finally, despite disparities in wetting agent molecular properties, the time to dewet 50% of the lens scales linearly with the product of the receding contact angle and contact angle hysteresis. Hence, we fundamentally establish the importance of minimizing the absolute contact angle and contact angle hysteresis for effective wetting performance.

Surface energy and separation mechanics of droplet interface phospholipid bilayers.

Droplet interface bilayers are a convenient model system to study the physio-chemical properties of phospholipid bilayers, the major component of the cell membrane. The mechanical response of these bilayers to various external mechanical stimuli is an active area of research because of its implications for cellular viability and the development of artificial cells. In this article, we characterize the separation mechanics of droplet interface bilayers under step strain using a combination of experiments and numerical modelling. Initially, we show that the bilayer surface energy can be obtained using principles of energy conservation. Subsequently, we subject the system to a step strain by separating the drops in a step-wise manner, and track the evolution of the bilayer contact angle and radius. The relaxation time of the bilayer contact angle and radius along with the decay magnitude of the bilayer radius were observed to increase with each separation step. By analysing the forces acting on the bilayer and the rate of separation, we show that the bilayer separates primarily through the peeling process with the dominant resistance to separation coming from viscous dissipation associated with corner flows. Finally, we explain the intrinsic features of the observed bilayer separation by means of a mathematical model comprising the Young-Laplace equation and an evolution equation. We believe that the reported experimental and numerical results extend the scientific understanding of lipid bilayer mechanics, and that the developed experimental and numerical tools offer a convenient platform to study the mechanics of other types of bilayers.

Estimating Local Cellular Density in Glioma Using MR Imaging Data.

BACKGROUND AND PURPOSE: Increased cellular density is a hallmark of gliomas, both in the bulk of the tumor and in areas of tumor infiltration into surrounding brain. Altered cellular density causes altered imaging findings, but the degree to which cellular density can be quantitatively estimated from imaging is unknown. The purpose of this study was to discover the best MR imaging and processing techniques to make quantitative and spatially specific estimates of cellular density. MATERIALS AND METHODS: We collected stereotactic biopsies in a prospective imaging clinical trial targeting untreated patients with gliomas at our institution undergoing their first resection. The data included preoperative MR imaging with conventional anatomic, diffusion, perfusion, and permeability sequences and quantitative histopathology on biopsy samples. We then used multiple machine learning methodologies to estimate cellular density using local intensity information from the MR images and quantitative cellular density measurements at the biopsy coordinates as the criterion standard. RESULTS: The random forest methodology estimated cellular density with R 2 = 0.59 between predicted and observed values using 4 input imaging sequences chosen from our full set of imaging data (T2, fractional anisotropy, CBF, and area under the curve from permeability imaging). Limiting input to conventional MR images (T1 pre- and postcontrast, T2, and FLAIR) yielded slightly degraded performance (R2 = 0.52). Outputs were also reported as graphic maps. CONCLUSIONS: Cellular density can be estimated with moderate-to-strong correlations using MR imaging inputs. The random forest machine learning model provided the best estimates. These spatially specific estimates of cellular density will likely be useful in guiding both diagnosis and treatment.

Single bubble and drop techniques for characterizing foams and emulsions.

The physics of foams and emulsions has traditionally been studied using bulk foam/emulsion tests and single film platforms such as the Scheludko cell. Recently there has been a renewed interest in a third class of techniques that we term as single bubble/drop tests, which employ isolated whole bubbles and drops to probe the characteristics of foams and emulsions. Single bubble and drop techniques provide a convenient framework for investigating a number of important characteristics of foams and emulsions, including the rheology, stabilization mechanisms, and rupture dynamics. In this review we provide a comprehensive discussion of the various single bubble/drop platforms and the associated experimental measurement protocols including the construction of coalescence time distributions, visualization of the thin film profiles and characterization of the interfacial rheological properties. Subsequently, we summarize the recent developments in foam and emulsion science with a focus on the results obtained through single bubble/drop techniques. We conclude the review by presenting important venues for future research.

Bubble Coalescence at Wormlike Micellar Solution-Air Interfaces.

Surfactants in aqueous solutions self-assemble in the presence of salt, to form long, flexible, wormlike micelles (WLM). WLM solutions exhibit viscoelastic properties and are used in many applications, such as for cosmetic products, drag reduction, and hydraulic fracturing. Understanding the coalescence stability of bubbles in WLM solutions is important for the development of WLM based products that require a stable dispersion of bubbles. In this paper, we investigate the thin film drainage dynamics leading up to the coalescence of bubbles at flat WLM solution-air interfaces. The salts and surfactant type and concentrations were chosen so as to have the viscoelastic properties of the tested WLM solutions span over 2 orders of magnitude in moduli and relaxation times. The various stages in drainage and coalescence, the formation of a thick region at the apex (a dimple), the thinning and washout of this dimple, and the final stages of drainage before rupture, are modified by the viscoelasticity of the wormlike micellar solutions. As a result of the unique viscoelastic properties of the WLM solutions, we also observe a number of interesting fluid dynamic phenomena during the drainage processes including elastic recoil, thin film ripping, and single-step terminal drainage.

Hyperspectral imaging for dynamic thin film interferometry.

Dynamic thin film interferometry is a technique used to non-invasively characterize the thickness of thin liquid films that are evolving in both space and time. Recovering the underlying thickness from the captured interferograms, unconditionally and automatically is still an open problem. Here we report a compact setup employing a snapshot hyperspectral camera and the related algorithms for the automated determination of thickness profiles of dynamic thin liquid films. The proposed technique is shown to recover film thickness profiles to within 100 nm of accuracy as compared to those profiles reconstructed through the manual color matching process. Subsequently, we discuss the characteristics and advantages of hyperspectral interferometry including the increased robustness against imaging noise as well as the ability to perform thickness reconstruction without considering the absolute light intensity information.

Imaging-Based Algorithm for the Local Grading of Glioma.

BACKGROUND AND PURPOSE: Gliomas are highly heterogeneous tumors, and optimal treatment depends on identifying and locating the highest grade disease present. Imaging techniques for doing so are generally not validated against the histopathologic criterion standard. The purpose of this work was to estimate the local glioma grade using a machine learning model trained on preoperative image data and spatially specific tumor samples. The value of imaging in patients with brain tumor can be enhanced if pathologic data can be estimated from imaging input using predictive models. MATERIALS AND METHODS: Patients with gliomas were enrolled in a prospective clinical imaging trial between 2013 and 2016. MR imaging was performed with anatomic, diffusion, permeability, and perfusion sequences, followed by image-guided stereotactic biopsy before resection. An imaging description was developed for each biopsy, and multiclass machine learning models were built to predict the World Health Organization grade. Models were assessed on classification accuracy, Cohen κ, precision, and recall. RESULTS: Twenty-three patients (with 7/9/7 grade II/III/IV gliomas) had analyzable imaging-pathologic pairs, yielding 52 biopsy sites. The random forest method was the best algorithm tested. Tumor grade was predicted at 96% accuracy (κ = 0.93) using 4 inputs (T2, ADC, CBV, and transfer constant from dynamic contrast-enhanced imaging). By means of the conventional imaging only, the overall accuracy decreased (89% overall, κ = 0.79) and 43% of high-grade samples were misclassified as lower-grade disease. CONCLUSIONS: We found that local pathologic grade can be predicted with a high accuracy using clinical imaging data. Advanced imaging data improved this accuracy, adding value to conventional imaging. Confirmatory imaging trials are justified.

Foam stability in filtered lubricants containing antifoams.

Lubricant formulations are filtered to remove deleterious particulate matter. An unintended consequence of this important process is the detrimental effect of fine filtration on the foaming performance of lubricants with antifoam additives. Here we outline a method to study this phenomenon in detail by probing the coalescence stability of single bubbles in filtered antifoam laden lubricants. Initially, we establish the validity of Garrett's hypothesis for the tested antifoam laden lubricants. Subsequently, we show that the bubble stability in filtered lubricants are positively correlated to the number of filtration cycles - with the most dramatic changes in bubble stability accompanying the initial few cycles of filtration. Further, we show that post filtration, the stability of bubbles in lubricants is inversely correlated to the pore size of the filter and the volume fraction of antifoam in the lubricant prior to filtration. The results also reveal that in the presence of antifoam additives, the bubble coalescence times span multiple Rayleigh distributions. We also provide visual evidence that shows the tested antifoams employ a bridging-stretching mechanism to rupture non-aqueous foams. Finally, a simple probabilistic model is introduced that helps in analyzing the distribution of coalescence times of single bubbles to obtain insights into the volume fraction of antifoams in the lubricant. We believe these results are valuable in guiding the design of lubricants with robust and superior foaming performance.

The performance of the World Rugby Head Injury Assessment Screening Tool: a diagnostic accuracy study.

BACKGROUND: Off-field screening tools, such as the Sports Concussion Assessment Tool (SCAT), have been recommended to identify possible concussion following a head impact where the consequences are unclear. However, real-life performance, and diagnostic accuracy of constituent sub-tests, have not been well characterized. METHODS: A retrospective cohort study was performed in elite Rugby Union competitions between September 2015 and June 2018. The study population comprised consecutive players identified with a head impact event undergoing off-field assessments with the World Rugby Head Injury Assessment (HIA01) screening tool, an abridged version of the SCAT3. Off-field screening performance was investigated by evaluating real-life removal-from-play outcomes and determining the theoretical diagnostic accuracy of the HIA01 tool, and individual sub-tests, if player-specific baseline or normative sub-test thresholds were strictly applied. The reference standard was clinically diagnosed concussion determined by serial medical assessments. RESULTS: One thousand one hundred eighteen head impacts events requiring off-field assessments were identified, resulting in 448 concussions. Real-life removal-from-play decisions demonstrated a sensitivity of 76.8% (95% CI 72.6-80.6) and a specificity of 86.6% (95% CI 83.7-89.1) for concussion (AUROC 0.82, 95% CI 0.79-0.84). Theoretical HIA01 tool performance worsened if pre-season baseline values (sensitivity 89.6%, specificity 33.9%, AUROC 0.62, p < 0.01) or normative thresholds (sensitivity 80.4%, specificity 69.0%, AUROC 0.75, p < 0.01) were strictly applied. Symptoms and clinical signs were the HIA01 screening tool sub-tests most predictive for concussion; with immediate memory and tandem gait providing little additional diagnostic value. CONCLUSIONS: These findings support expert recommendations that clinical judgement should be used in the assessment of athletes following head impact events. Substitution of the tandem gait and 5-word immediate memory sub-tests with alternative modes could potentially improve screening tool performance.

PM2.5 on the London Underground.

INTRODUCTION: Despite the London Underground (LU) handling on average 2.8 million passenger journeys per day, the characteristics and potential health effects of the elevated concentrations of metal-rich PM2.5 found in this subway system are not well understood. METHODS: Spatial monitoring campaigns were carried out to characterise the health-relevant chemical and physical properties of PM2.5 across the LU network, including diurnal and day-to-day variability and spatial distribution (above ground, depth below ground and subway line). Population-weighted station PM2.5 rankings were produced to understand the relative importance of concentrations at different stations and on different lines. RESULTS: The PM2.5 mass in the LU (mean 88 µg m-3, median 28 µg m-3) was greater than at ambient background locations (mean 19 µg m-3, median 14 µg m-3) and roadside environments in central London (mean 22 µg m-3, median 14 µg m-3). Concentrations varied between lines and locations, with the deepest and shallowest submerged lines being the District (median 4 µg m-3) and Victoria (median 361 µg m-3 but up to 885 µg m-3). Broadly in agreement with other subway systems around the world, sampled LU PM2.5 comprised 47% iron oxide, 7% elemental carbon, 11% organic carbon, and 14% metallic and mineral oxides. Although a relationship between line depth and air quality inside the tube trains was evident, there were clear influences relating to the distance from cleaner outside air and the exchange with cabin air when the doors open. The passenger population-weighted exposure analysis demonstrated a method to identify stations that should be prioritised for remediation to improve air quality. CONCLUSION: PM2.5 concentrations in the LU are many times higher than in other London transport Environments. Failure to include this environment in epidemiological studies of the relationship between PM2.5 and health in London is therefore likely to lead to a large exposure misclassification error. Given the significant contribution of underground PM2.5 to daily exposure, and the differences in composition compared to urban PM2.5, there is a clear need for well-designed studies to better understand the health effects of underground exposure.

Ablation of water drops suspended in asphaltene/heptol solutions due to spontaneous emulsification.

Complex molecules from crude oil, such as asphaltenes, can adsorb onto oil/water interfaces. This creates a viscoelastic network that may cause difficulties in oil recovery and oil spills. In addition to stabilization of oil/water emulsions, they may also cause the spontaneous formation of micron-sized droplets. Here, we investigate spontaneous emulsification in the presence of asphaltenes, probing parameters that may affect this phenomenon by observing isolated drops of water immersed in asphaltene/hydrocarbon solutions within a co-flow microfluidic device. The results indicate that the initial internal pressure of the drop strongly influences the rate at which the drop will shrink due to spontaneous emulsification. In addition, the viscoelastic skin formation by the asphaltenes inhibits increases in this pressure that normally accompanies a decrease in drop radius. Understanding this spontaneous emulsification has implications not only for the oil industry, but also to the cosmetics, foods, medical, and pharmaceutical industries.

The DiPEP study: an observational study of the diagnostic accuracy of clinical assessment, D-dimer and chest x-ray for suspected pulmonary embolism in pregnancy and postpartum.

OBJECTIVE: To identify clinical features associated with pulmonary embolism (PE) diagnosis and determine the accuracy of decision rules and D-dimer for diagnosing suspected PE in pregnant/postpartum women DESIGN: Observational cohort study augmented with additional cases. SETTING: Emergency departments and maternity units at eleven prospectively recruiting sites and maternity units in the United Kingdom Obstetric Surveillance System (UKOSS) POPULATION: 324 pregnant/postpartum women with suspected PE and 198 pregnant/postpartum women with diagnosed PE METHODS: We recorded clinical features, elements of clinical decision rules, D-dimer measurements, imaging results, treatments and adverse outcomes up to 30 days MAIN OUTCOME MEASURES: Women were classified as having PE on the basis of imaging, treatment and adverse outcomes by assessors blind to clinical features and D-dimer. Primary analysis was limited to women with conclusive imaging to avoid work-up bias. Secondary analyses included women with clinically diagnosed or ruled out PE. RESULTS: The only clinical features associated with PE on multivariate analysis were age (odds ratio 1.06; 95% confidence interval 1.01-1.11), previous thrombosis (3.07; 1.05-8.99), family history of thrombosis (0.35; 0.14-0.90), temperature (2.22; 1.26-3.91), systolic blood pressure (0.96; 0.93-0.99), oxygen saturation (0.87; 0.78-0.97) and PE-related chest x-ray abnormality (13.4; 1.39-130.2). Clinical decision rules had areas under the receiver-operator characteristic curve ranging from 0.577 to 0.732 and no clinically useful threshold for decision-making. Sensitivities and specificities of D-dimer were 88.4% and 8.8% using a standard threshold and 69.8% and 32.8% using a pregnancy-specific threshold. CONCLUSIONS: Clinical decision rules and D-dimer should not be used to select pregnant or postpartum women with suspected PE for further investigation. Clinical features and chest x-ray appearances may have counter-intuitive associations with PE in this context. TWEETABLE ABSTRACT: Clinical decision rules and D-dimer are not helpful for diagnosing pregnant/postpartum women with suspected PE.

Fulminant descending mediastinitis secondary to infectious mononucleosis.

Descending mediastinitis is a rare, life-threatening condition caused by contiguous spread of oropharyngeal or cervical infection into the mediastinum. Infectious mononucleosis generally results in a self-limited illness characterized by fever, pharyngitis and lymphadenopathy. We present an exceptional case of an 18-year-old with infectious mononucleosis complicated by progressive bacterial superinfection and fulminant descending mediastinitis. After resuscitation, broad spectrum antibiotics, critical care support and definitive surgical management, they made a full recovery.

Evaporation-induced foam stabilization in lubricating oils.

Foaming in liquids is ubiquitous in nature. Whereas the mechanism of foaming in aqueous systems has been thoroughly studied, nonaqueous systems have not enjoyed the same level of examination. Here we study the mechanism of foaming in a widely used class of nonaqueous liquids: lubricant base oils. Using a newly developed experimental technique, we show that the stability of lubricant foams can be evaluated at the level of single bubbles. The results obtained with this single-bubble technique indicate that solutocapillary flows are central to lubricant foam stabilization. These solutocapillary flows are shown to originate from the differential evaporation of multicomponent lubricants-an unexpected result given the low volatility of nonaqueous liquids. Further, we show that mixing of some combinations of different lubricant base oils, a common practice in the industry, exacerbates solutocapillary flows and hence leads to increased foaming.

Normosmic idiopathic hypogonadotrophic hypogonadism due to a rare KISS1R gene mutation.

Hypogonadotrophic hypogonadism is due to impaired or reduced gonadotrophin secretion from the pituitary gland. In the absence of any anatomical or functional lesions of the pituitary or hypothalamic gland, the hypogonadotrophic hypogonadism is referred to as idiopathic hypogonadotrophic hypogonadism (IHH). We present a case of a young lady born to consanguineous parents who was found to have IHH due to a rare gene mutation. Learning points: The genetic basis of a majority of cases of IHH remains unknown.IHH can have different clinical endocrine manifestations.Patients can present late to the healthcare service because of unawareness and stigmata associated with the clinical features.Family members of affected individuals can be affected to varying degrees.

Sport concussion assessment tool-Third edition normative reference values for professional Rugby Union players.

OBJECTIVES: To establish normative reference data for the SCAT3 in professional Rugby Union players. DESIGN: A cross sectional study in professional Rugby Union players competing in national and international professional competitions between 2015 and 2016. METHODS: The SCAT3 was administered pre-season or prior to tournaments. Data was collected electronically using a custom tablet application. SCAT3 subcomponents distributions were described and normative ranges determined using percentile cut-offs for average, unusually low/high, and extremely low/high scores. The association between player characteristics and performance in SCAT3 subcomponents was also investigated in exploratory analyses. RESULTS: A total of 3611 professional Rugby Union players were included. The most common baseline symptom was fatigue (14%). The symptom score median (md) was 0 (interquartile range (IQR)=0-1). Symptom severity md was 0 (IQR=0-1). The md of the SAC score was 28 (IQR=26-29). The md of the MBESS was 2 (IQR=0-4). The Tandem gait md was 11.1s (IQR=10.0-12.7s). Upper limb coordination was normal in 98.4%. Younger age and lower educational level were associated with worse performance on delayed recall and reverse month sub-components of the SCAT3 (p<0.0001). No statistically significant differences in SCAT3 subcomponents were evident across gender. CONCLUSIONS: Representative normative reference values for the SCAT3 among professional Rugby Union players are provided. Baseline performance on concentration and delayed recall tests may be lower in younger athletes or in those with lower educational level.