MRI-based parameter inference for cerebral perfusion modelling in health and ischaemic stroke.

Cerebral perfusion modelling is a promising tool to predict the impact of acute ischaemic stroke treatments on the spatial distribution of cerebral blood flow (CBF) in the human brain. To estimate treatment efficacy based on CBF, perfusion simulations need to become suitable for group-level investigations and thus account for physiological variability between individuals. However, computational perfusion modelling to date has been restricted to a few patient-specific cases. This study set out to establish automated parameter inference for perfusion modelling based on neuroimaging data and thus enable CBF simulations of groups. Magnetic resonance imaging (MRI) data from 75 healthy senior adults were utilised. Brain geometries were computed from healthy reference subjects' T1-weighted MRI. Haemodynamic model parameters were determined from spatial CBF maps measured by arterial spin labelling (ASL) perfusion MRI. Thereafter, perfusion simulations were conducted in 75 healthy cases followed by 150 acute ischaemic stroke cases representing an occlusion and CBF cessation in the left and right middle cerebral arteries. The anatomical fitness of the brain geometries was evaluated by comparing the simulated grey (GM) and white matter (WM) volumes to measurements in healthy reference subjects. Strong positive correlations were found in both tissue types (GM: Pearson's r 0.74, P<0.001; WM: Pearson's r 0.84, P<0.001). Haemodynamic parameter tuning was verified by comparing the total volumetric blood flow rate to the brain in healthy reference subjects and simulations (Pearson's r 0.89, P<0.001). In acute ischaemic stroke cases, the simulated infarct volume using a perfusion-based estimate was 197±25 ml. Computational predictions were in agreement with anatomical and haemodynamic values from the literature concerning T1-weighted, T2-weighted, and phase-contrast MRI measurements in healthy scenarios and acute ischaemic stroke cases. The acute stroke simulations did not capture small infarcts (left tail of the distribution), which could be explained by neglected compensatory mechanisms, e.g. collaterals. The proposed parameter inference method provides a foundation for group-level CBF simulations and for in silico clinical stroke trials which could assist in medical device and drug development.

The footprint of the COVID-19 pandemic in reading performance of students in the U.S. with and without disabilities.

BACKGROUND: Many schools around the world involuntarily began remote learning in March of 2020 as a result of the COVID-19 pandemic, which brought immediate changes and challenges to teaching and learning that are likely to influence student achievement into the foreseeable future. While large numbers of students face difficulties in learning to read under typical conditions, remote learning resulted in substantial deficits in reading outcomes. AIMS: This study aimed to examine the relative impact of the pandemic on reading performance in United States (U.S.) for students with and without disabilities. METHODS: and procedure: In this interpretive analysis, we compared the progress of a large sample of students (n = 219,500) by using the National Assessment of Educational Progress (NAEP) data, in two grade levels (Grades 4 and 8), with and without disabilities, at two time points (2019 and 2022). OUTCOMES AND RESULTS: Statistically significant decreases were identified on the reading outcomes of students in U.S. Students without disabilities experienced a significant decrease in their reading outcomes pre- and post-pandemic, compared to students with disabilities (SWDs). CONCLUSIONS AND IMPLICATIONS: We discuss the effects of the COVID-19 pandemic on students' reading performance and the implications for effective reading instructions in the future.

A multicentre randomised controlled trial of the McGrath™ Mac videolaryngoscope versus conventional laryngoscopy.

Before completion of this study, there was insufficient evidence demonstrating the superiority of videolaryngoscopy compared with direct laryngoscopy for elective tracheal intubation. We hypothesised that using videolaryngoscopy for routine tracheal intubation would result in higher first-pass tracheal intubation success compared with direct laryngoscopy. In this multicentre randomised trial, 2092 adult patients without predicted difficult airway requiring tracheal intubation for elective surgery were allocated randomly to either videolaryngoscopy with a Macintosh blade (McGrath™) or direct laryngoscopy. First-pass tracheal intubation success was higher with the McGrath (987/1053, 94%), compared with direct laryngoscopy (848/1039, 82%); absolute risk reduction (95%CI) was 12.1% (10.9-13.6%). This resulted in a relative risk (95%CI) of unsuccessful tracheal intubation at first attempt of 0.34 (0.26-0.45; p < 0.001) for McGrath compared with direct laryngoscopy. Cormack and Lehane grade ≥ 3 was observed more frequently with direct laryngoscopy (84/1039, 8%) compared with McGrath (8/1053, 0.7%; p < 0.001) No significant difference in tracheal intubation-associated adverse events was observed between groups. This study demonstrates that using McGrath videolaryngoscopy compared with direct laryngoscopy improves first-pass tracheal intubation success in patients having elective surgery. Practitioners may consider using this device as first choice for tracheal intubation.

Strategies and checklist for designing and conducting palliative care research with family carers: EAPC international expert elicitation study.

BACKGROUND: Palliative care services seek to improve the wellbeing of family carers of people living with serious and life-limiting illness. To help achieve this goal, systematic reviews have recommended priority areas for family carer research and the need to improve the quality of study design. Policy makers have also advocated for enhanced family carer support. However, there are specific methodological considerations and challenges in designing and conducting carer research conducted during the course of the serious illness trajectory and in bereavement. AIM: To develop strategies to improve the design and conduct of research with family carers. DESIGN: Expert elicitation study using an adapted version of the 'Identify, Discuss, Estimate and Aggregate' elicitation protocol, supplemented with strategies from peer-reviewed literature. SETTING/PARTICIPANTS: Nine members of the management committee of the European Association for Palliative Care's Reference group on family carer research, comprising international senior research academics in family caregiving. RESULTS: A compilation of recommended strategies and checklist was created to: (a) help researchers plan research involving family carers focussing on: preparation, conduct and dissemination and (b) assist ethics committees and funding bodies to evaluate proposals. CONCLUSIONS: The strategies and checklist for conducting research with family carers may enhance methodologically rigorous research. Consequently, researchers, practitioners and policy makers will not only gain a more comprehensive understanding of the unmet needs of family carers but also promote the development of empirically sound interventions.

An analysis of the experiences of bereaved relatives and health care providers following palliative sedation: a study protocol for a qualitative international multicenter case study.

BACKGROUND: Patients at the end-of-life may experience refractory symptoms of which pain, delirium, vomiting and dyspnea are the most frequent. Palliative sedation can be considered a last resort option to alleviate one or more refractory symptoms. There are only a limited number of (qualitative) studies exploring the experiences of relatives of sedated patients and their health care professionals (HCPs). The aims of this study protocol are: 1) to elicit the experiences of bereaved relatives and health care professionals of patients treated with palliative sedation and 2) to explore the understanding of the decision-making process to start palliative sedation across care settings in 5 European countries. METHODS: This study protocol is part of the larger HORIZON 2020 Palliative Sedation project. Organisational case study methodology will be used to guide the study design. In total, 50 cases will be conducted in five European countries (10 per country). A case involves a semi-structured interview with a relative and an HCP closely involved in the care of a deceased patient who received some type of palliative sedation at the end-of-life. Relatives and health care professionals of deceased patients participating in a linked observational cohort study of sedated patients cared for in hospital wards, palliative care units and hospices will be recruited. The data will be analyzed using a framework analysis approach. The first full case will be analyzed by all researchers after being translated into English using a pre-prepared code book. Afterwards, bimonthly meetings will be organized to coordinate the data analysis. DISCUSSION: The study aims to have a better understanding of the experiences of relatives and professional caregivers regarding palliative sedation and this within different settings and countries. Some limitations are: 1) the sensitivity of the topic may deter some relatives from participation, 2) since the data collection and analysis will be performed by at least 5 different researchers in 5 countries, some differences may occur which possibly makes it difficult to compare cases, but using a rigorous methodology will minimize this risk.

Large differences in the organization of palliative care in nursing homes in six European countries: findings from the PACE cross-sectional study.

BACKGROUND: To be able to provide high-quality palliative care, there need to be a number of organizational structures available in the nursing homes. It is unclear to what extent such structures are actually present in nursing homes in Europe. We aim to examine structural indicators for quality of palliative care in nursing homes in Europe and to evaluate the differences in terms of availability of and access to palliative care, infrastructure for residents and families, multidisciplinary meetings and quality improvement initiatives. METHODS: A PACE cross-sectional study (2015) of nursing homes in Belgium, England, Finland, Italy, the Netherlands and Poland. Nursing homes (N = 322) were selected in each country via proportional stratified random sampling. Nursing home administrators (N = 305) filled in structured questionnaires on nursing home characteristics. Organization of palliative care was measured using 13 of the previously defined IMPACT structural indicators for quality of palliative care covering four domains: availability of and access to palliative care, infrastructure for residents and families, multidisciplinary meetings and quality improvement initiatives. We calculated structural indicator scores for each country and computed differences in indicator scores between the six countries. Pearson's Chi-square test was used to compute the p-value of each difference. RESULTS: The availability of specialist palliative care teams in nursing homes was limited (6.1-48.7%). In Finland, Poland and Italy, specialist advice was also less often available (35.6-46.9%). Up to 49% of the nursing homes did not provide a dedicated contact person who maintained regular contact with the resident and relatives. The 24/7 availability of opioids for all nursing home residents was low in Poland (37.5%). CONCLUSIONS: This study found a large heterogeneity between countries in the organization of palliative care in nursing homes, although a common challenge is ensuring sufficient structural access to specialist palliative care services. Policymakers and health and palliative care organizations can use these structural indicators to identify areas for improvement in the organization of palliative care.

Simulation-based optimisation to quantify heterogeneity of specific ventilation and perfusion in the lung by the Inspired Sinewave Test.

The degree of specific ventilatory heterogeneity (spatial unevenness of ventilation) of the lung is a useful marker of early structural lung changes which has the potential to detect early-onset disease. The Inspired Sinewave Test (IST) is an established noninvasive 'gas-distribution' type of respiratory test capable of measuring the cardiopulmonary parameters. We developed a simulation-based optimisation for the IST, with a simulation of a realistic heterogeneous lung, namely a lognormal distribution of spatial ventilation and perfusion. We tested this method in datasets from 13 anaesthetised pigs (pre and post-lung injury) and 104 human subjects (32 healthy and 72 COPD subjects). The 72 COPD subjects were classified into four COPD phenotypes based on 'GOLD' classification. This method allowed IST to identify and quantify heterogeneity of both ventilation and perfusion, permitting diagnostic distinction between health and disease states. In healthy volunteers, we show a linear relationship between the ventilatory heterogeneity versus age ([Formula: see text]). In a mechanically ventilated pig, IST ventilatory heterogeneity in noninjured and injured lungs was significantly different (p < 0.0001). Additionally, measured indices could accurately identify patients with COPD (area under the receiver operating characteristic curve is 0.76, p < 0.0001). The IST also could distinguish different phenotypes of COPD with 73% agreement with spirometry.

On the Sensitivity Analysis of Porous Finite Element Models for Cerebral Perfusion Estimation.

Computational physiological models are promising tools to enhance the design of clinical trials and to assist in decision making. Organ-scale haemodynamic models are gaining popularity to evaluate perfusion in a virtual environment both in healthy and diseased patients. Recently, the principles of verification, validation, and uncertainty quantification of such physiological models have been laid down to ensure safe applications of engineering software in the medical device industry. The present study sets out to establish guidelines for the usage of a three-dimensional steady state porous cerebral perfusion model of the human brain following principles detailed in the verification and validation (V&V 40) standard of the American Society of Mechanical Engineers. The model relies on the finite element method and has been developed specifically to estimate how brain perfusion is altered in ischaemic stroke patients before, during, and after treatments. Simulations are compared with exact analytical solutions and a thorough sensitivity analysis is presented covering every numerical and physiological model parameter. The results suggest that such porous models can approximate blood pressure and perfusion distributions reliably even on a coarse grid with first order elements. On the other hand, higher order elements are essential to mitigate errors in volumetric blood flow rate estimation through cortical surface regions. Matching the volumetric flow rate corresponding to major cerebral arteries is identified as a validation milestone. It is found that inlet velocity boundary conditions are hard to obtain and that constant pressure inlet boundary conditions are feasible alternatives. A one-dimensional model is presented which can serve as a computationally inexpensive replacement of the three-dimensional brain model to ease parameter optimisation, sensitivity analyses and uncertainty quantification. The findings of the present study can be generalised to organ-scale porous perfusion models. The results increase the applicability of computational tools regarding treatment development for stroke and other cerebrovascular conditions.

A porous circulation model of the human brain for in silico clinical trials in ischaemic stroke.

The advancement of ischaemic stroke treatment relies on resource-intensive experiments and clinical trials. In order to improve ischaemic stroke treatments, such as thrombolysis and thrombectomy, we target the development of computational tools for in silico trials which can partially replace these animal and human experiments with fast simulations. This study proposes a model that will serve as part of a predictive unit within an in silico clinical trial estimating patient outcome as a function of treatment. In particular, the present work aims at the development and evaluation of an organ-scale microcirculation model of the human brain for perfusion prediction. The model relies on a three-compartment porous continuum approach. Firstly, a fast and robust method is established to compute the anisotropic permeability tensors representing arterioles and venules. Secondly, vessel encoded arterial spin labelling magnetic resonance imaging and clustering are employed to create an anatomically accurate mapping between the microcirculation and large arteries by identifying superficial perfusion territories. Thirdly, the parameter space of the problem is reduced by analysing the governing equations and experimental data. Fourthly, a parameter optimization is conducted. Finally, simulations are performed with the tuned model to obtain perfusion maps corresponding to an open and an occluded (ischaemic stroke) scenario. The perfusion map in the occluded vessel scenario shows promising qualitative agreement with computed tomography images of a patient with ischaemic stroke caused by large vessel occlusion. The results highlight that in the case of vessel occlusion (i) identifying perfusion territories is essential to capture the location and extent of underperfused regions and (ii) anisotropic permeability tensors are required to give quantitatively realistic estimation of perfusion change. In the future, the model will be thoroughly validated against experiments.

INFOMATAS multi-center systematic review and meta-analysis individual patient data of dynamic cerebral autoregulation in ischemic stroke.

RATIONALE: Disturbances in dynamic cerebral autoregulation after ischemic stroke may have important implications for prognosis. Recent meta-analyses have been hampered by heterogeneity and small samples. AIM AND/OR HYPOTHESIS: The aim of study is to undertake an individual patient data meta-analysis (IPD-MA) of dynamic cerebral autoregulation changes post-ischemic stroke and to determine a predictive model for outcome in ischemic stroke using information combined from dynamic cerebral autoregulation, clinical history, and neuroimaging. SAMPLE SIZE ESTIMATES: To detect a change of 2% between categories in modified Rankin scale requires a sample size of ∼1500 patients with moderate to severe stroke, and a change of 1 in autoregulation index requires a sample size of 45 healthy individuals (powered at 80%, α = 0.05). Pooled estimates of mean and standard deviation derived from this study will be used to inform sample size calculations for adequately powered future dynamic cerebral autoregulation studies in ischemic stroke. METHODS AND DESIGN: This is an IPD-MA as part of an international, multi-center collaboration (INFOMATAS) with three phases. Firstly, univariate analyses will be constructed for primary (modified Rankin scale) and secondary outcomes, with key co-variates and dynamic cerebral autoregulation parameters. Participants clustering from within studies will be accounted for with random effects. Secondly, dynamic cerebral autoregulation variables will be validated for diagnostic and prognostic accuracy in ischemic stroke using summary receiver operating characteristic curve analysis. Finally, the prognostic accuracy will be determined for four different models combining clinical history, neuroimaging, and dynamic cerebral autoregulation parameters. STUDY OUTCOME(S): The outcomes for this study are to determine the relationship between clinical outcome, dynamic cerebral autoregulation changes, and baseline patient demographics, to determine the diagnostic and prognostic accuracy of dynamic cerebral autoregulation parameters, and to develop a prognostic model using dynamic cerebral autoregulation in ischemic stroke. DISCUSSION: This is the first international collaboration to use IPD-MA to determine prognostic models of dynamic cerebral autoregulation for patients with ischemic stroke.

Time-stretched photonic Doppler velocimetry.

Inertial confinement fusion facilities generate implosions at speeds greater than 100 km/s, and measuring the material velocities is important and challenging. We have developed a new velocimetry technique that uses time-stretched spectral interferometry to increase the measurable velocity range normally limited by the detector bandwidth. In this approach, the signal is encoded on a chirped laser pulse that is stretched in time to reduce the beat frequency before detection. We demonstrate the technique on an imploding liner experiment at the Sandia National Laboratories' Z machine, where beat frequencies in excess of 50 GHz were measured with 20 GHz bandwidth detection.

Association of Anaesthetists: anaesthesia and peri-operative care for Jehovah's Witnesses and patients who refuse blood.

There are approximately 8.5 million Jehovah's Witnesses and around 150,000 live in Great Britain and Ireland. Based on their beliefs and core values, Jehovah's Witnesses refuse blood component transfusion (including red cells, plasma and platelets). They regard non-consensual transfusion as a physical violation. Consent to treatment is at the heart of this guideline. Refusal of treatment by an adult with capacity is lawful. The reasons why a patient might refuse transfusion and the implications are examined. The processes and products that are deemed acceptable or unacceptable to Jehovah's Witnesses are described. When a team is faced with a patient who refuses transfusion, a thorough review of the clinical situation is advocated and all options for treatment should be explored. After discussion, a plan should then be made that is acceptable to the patient and appropriate consent obtained. When agreement cannot be reached between the doctor and the patient, referral for a second opinion should be considered. When the patient is a child, the same strategy should be used but on occasion the clinical team may have to obtain legal help.

Association of Anaesthetists guidelines: cell salvage for peri-operative blood conservation 2018.

The use of cell salvage is recommended when it can be expected to reduce the likelihood of allogeneic (donor) red cell transfusion and/or severe postoperative anaemia. We support and encourage a continued increase in the appropriate use of peri-operative cell salvage and we recommend that it should be available for immediate use 24 h a day in any hospital undertaking surgery where blood loss is a recognised potential complication (other than minor/day case procedures).

Identifying the myogenic and metabolic components of cerebral autoregulation.

Cerebral autoregulation is the term used to describe a number of mechanisms that act together to maintain a near constant cerebral blood flow in response to changes in arterial blood pressure. These mechanisms are complex and known to be affected in a range of cerebrovascular diseases. However, it can be difficult to assign an alteration in cerebral autoregulation to one of the underlying physiological mechanisms without the use of a complex mathematical model. In this paper, we thus set out a new approach that enables these mechanisms to be related to the autoregulation behaviour and hence inferred from experimental measurements. We show that the arteriolar response is a function of just three parameters, which we term the elastic, the myogenic and the metabolic sensitivity coefficients, and that the full vascular response is dependent upon only seven parameters. The ratio of the strengths of the myogenic and the metabolic responses is found to be in the range 2.5 to 5 over a wide range of pressure, indicating that the balance between the two appears to lie within this range. We validate the model with existing experimental data both at the level of an individual vessel and across the whole vasculature, and show that the results are consistent with findings from the literature. We then conduct a sensitivity analysis of the model to demonstrate which parameters are most important in determining the strength of static autoregulation, showing that autoregulation strength is predominantly set by the arteriolar sensitivity coefficients. This new approach could be used in future studies to help to interpret the components of the autoregulation response and how they are affected under different conditions, providing a greater insight into the fundamental processes that govern autoregulation.

Modelling dynamic changes in blood flow and volume in the cerebral vasculature.

The cerebral microvasculature plays a key role in the transport of blood and the delivery of nutrients to the cells that perform brain function. Although recent advances in experimental imaging techniques mean that its structure and function can be interrogated to very small length scales, allowing individual vessels to be mapped to a fraction of 1 µm, these techniques currently remain confined to animal models. In-vivo human data can only be obtained at a much coarser length scale, of order 1 mm, meaning that mathematical models of the microvasculature play a key role in interpreting flow and metabolism data. However, there are close to 10,000 vessels even within a single voxel of size 1 mm3. Given the number of vessels present within a typical voxel and the complexity of the governing equations for flow and volume changes, it is computationally challenging to solve these in full, particularly when considering dynamic changes, such as those found in response to neural activation. We thus consider here the governing equations and some of the simplifications that have been proposed in order more rigorously to justify in what generations of blood vessels these approximations are valid. We show that two approximations (neglecting the advection term and assuming a quasi-steady state solution for blood volume) can be applied throughout the cerebral vasculature and that two further approximations (a simple first order differential relationship between inlet and outlet flows and inlet and outlet pressures, and matching of static pressure at nodes) can be applied in vessels smaller than approximately 1 mm in diameter. We then show how these results can be applied in solving flow fields within cerebral vascular networks providing a simplified yet rigorous approach to solving dynamic flow fields and compare the results to those obtained with alternative approaches. We thus provide a framework to model cerebral blood flow and volume within the cerebral vasculature that can be used, particularly at sub human imaging length scales, to provide greater insight into the behaviour of blood flow and volume in the cerebral vasculature.

Procyanidin A2 in the Australian plant Alectryon oleifolius has anthelmintic activity against equine cyathostomins in vitro.

There is a need to investigate new methods of controlling cyathostomins in horses due to increasing anthelmintic resistance amongst these parasites. In a previous study we identified the Australian plant Alectryon oleifolius as having anthelmintic activity towards cyathostomins. This study aimed to isolate and identify the bioactive compound(s) responsible for all or part of this anthelmintic activity and quantify its activity in vitro. The condensed tannin procyanidin A2 was isolated from the plant through a process of bioassay guided fractionation and identified using 1D and 2D nuclear magnetic resonance spectroscopy and high performance liquid chromatography with mass spectrometry. Procyanidin A2 demonstrated significant anthelmintic activity in larval development assays, completely inhibiting development from egg to third larval stage at concentrations as low as 50µg/mL and having an IC50 value of 12.6µg/mL. Procyanidin A2 also significantly inhibited larval migration at concentrations of 25µg/mL. This study indicates that procyanidin A2 is the principal anthelmintic compound in extracts from A. oleifolius, and further highlights the potential for the use of this plant as a component of cyathostomin control programs in the future.

A model for generating synthetic arterial blood pressure.

A new model capable of simulating many important aspects of human arterial blood pressure (ABP) is proposed. Both data-driven approach and physiological principles have been applied to describe the time series of diastolic, systolic, dicrotic notch and dicrotic peak pressure points. Major static and dynamic features of the model can be prescribed by the user, including heart rate, mean systolic and diastolic pressure, and the corresponding physiological control quantities, such as baroreflex sensitivity coefficient and Windkessel time constant. A realistic ABP generator can be used to compile a virtual database of signals reflecting individuals with different clinical conditions and signals containing common artefacts. The ABP model permits to create a platform to assess a wide range of biomedical signal processing approaches and be used in conjunction with, e.g. Kalman filters to improve the quality of ABP signals.

Cancer-related pain management: A review of knowledge and attitudes of healthcare professionals.

Cancer-related pain (CRP) is common and many patients continue to experience pain in spite of advances in pain management modalities. The lack of knowledge, inadequate assessment of CRP and/or organisational factors, such as lack of time due to heavy workload, can be a barrier to effective pain management of healthcare professionals. The purpose was to examine the evidence with regard to the knowledge and attitudes towards practice of healthcare professionals in relation to CRP management. A search of the literature (1999-2015) was conducted searching databases and journals including CINAHL, MEDLINE, PsycINFO, PubMed, Science Direct and Wiley-Blackwell. The initial search revealed a total of 99 articles and following removal of those that did not meet the inclusion criteria, 19 articles were included in the final review. Recognition of the widespread under treatment of CRP has prompted recent corrective efforts in terms of education from healthcare professionals, however, there is a continuing deficit in healthcare professionals' knowledge with regard to CRP management and indicated that healthcare professionals still have negative attitudes that hinder the delivery of quality care to patients suffering from CRP. Further research on how and where education on this topic should be delivered is required.

Using a bespoke situated digital kiosk to encourage user participation in healthcare environment design.

Involving users through participation in healthcare service and environment design is growing. Existing approaches and toolkits for practitioners and researchers are often paper based involving workshops and other more traditional design approaches such as paper prototyping. The advent of digital technology provides the opportunity to explore new platforms for user participation. This paper presents results from three studies that used a bespoke situated user participation digital kiosk, engaging 33 users in investigating healthcare environment design. The studies, from primary and secondary care settings, allowed participant feedback on each environment and proved a novel, engaging "21st century" way to participate in the appraisal of the design process. The results point toward this as an exciting and growing area of research in developing not just a new method of user participation but also the technology that supports it. Limitations were noted in terms of data validity and engagement with the device. To guide the development of user participation using similar situated digital devices, key lessons and reflections are presented.