Small-molecule inhibitors of P-Rex guanine-nucleotide exchange factors.

P-Rex1 and P-Rex2 are guanine-nucleotide exchange factors (GEFs) that activate Rac small GTPases in response to the stimulation of G protein-coupled receptors and phosphoinositide 3-kinase. P-Rex Rac-GEFs regulate the morphology, adhesion and migration of various cell types, as well as reactive oxygen species production and cell cycle progression. P-Rex Rac-GEFs also have pathogenic roles in the initiation, progression or metastasis of several types of cancer. With one exception, all P-Rex functions are known or assumed to be mediated through their catalytic Rac-GEF activity. Thus, inhibitors of P-Rex Rac-GEF activity would be valuable research tools. We have generated a panel of small-molecule P-Rex inhibitors that target the interface between the catalytic DH domain of P-Rex Rac-GEFs and Rac. Our best-characterized compound, P-Rex inhibitor 1 (PREX-in1), blocks the Rac-GEF activity of full-length P-Rex1 and P-Rex2, and of their isolated catalytic domains, in vitro at low-micromolar concentration, without affecting the activities of several other Rho-GEFs. PREX-in1 blocks the P-Rex1 dependent spreading of PDGF-stimulated endothelial cells and the production of reactive oxygen species in fMLP-stimulated mouse neutrophils. Structure-function analysis revealed critical structural elements of PREX-in1, allowing us to develop derivatives with increased efficacy, the best with an IC50 of 2 µM. In summary, we have developed PREX-in1 and derivative small-molecule compounds that will be useful laboratory research tools for the study of P-Rex function. These compounds may also be a good starting point for the future development of more sophisticated drug-like inhibitors aimed at targeting P-Rex Rac-GEFs in cancer.

Evaluation of post-simulation sonographer students' professional behaviour in the workplace.

INTRODUCTION: In Australia, sonographer's professional identity is traditionally 'caught' from clinical role models. A four-year undergraduate-postgraduate course introduced professional identity education, with simulated practice, to prepare novice sonographer students prior to clinical practice. Preclinical students learnt sonographer professional behaviour, and humanistic attributes, during simulation designed with volunteer peers as standardised patients, educator role-models, immediate feedback, self-reflection, and longitudinal multi-observer assessment. This paper reports on the transfer of learnt professional behaviour and humanistic attributes to clinical practice. METHODS: Professional behaviour evaluations completed by 94 clinical assessors described 174 students' professional behaviour and attributes one month into their initial clinical practice (2015-6). Student performance of each behaviour, and behavioural category, was quantitatively analysed by modelling binomial proportions with logistic regression. RESULTS: Students demonstrated substantial learning transfer to clinical practice, achieving an overall mean score of 'consistent' sonographer professional behaviour and humanistic attributes (mean score of equal to or >3/4), one month into clinical practice. Professional behaviours varied in transferability, with 'response to patient's questions' showing least efficacy (P < 0.05). Increased deliberate practice with educator role-models improved transfer efficacy significantly (P < 0.001). CONCLUSION: Preclinical application of theory to simulated practice, using standardised patients, educator role-models, immediate feedback, and multi-observer assessment, facilitated substantial transfer of sonographer professional behaviour and attributes to clinical practice. The efficacy of transfer varied but improved with increased deliberate practice and feedback. IMPLICATIONS FOR PRACTICE: The incorporation of preclinical professional behaviour education with simulated practice into the core curriculum of sonographer courses is recommended for the formation of sonographer professional identity, improved clinical outcomes and increased patient safety during the early stages of ultrasound education.

Neutron imaging of an operational dilution refrigerator.

The invention of the 3He/4He dilution refrigerator opened a new chapter in experimental ultra-low temperature physics. Dilution refrigerators became essential for providing ultra-low temperature environments for nuclear demagnetisation experiments, superconducting-qubit quantum processors and highly sensitive bolometers used in fundamental physics experiments. Development of dilution refrigeration technology requires thorough understanding of the quantum mechanical processes that take place in liquid helium at ultra-low temperatures. For decades the quantum fluids research community provided valuable information to engineers and designers involved in the development of advanced dilution refrigerators. However, the lack of methods that allow the measurement of physical parameters of liquid helium during the operation of a dilution refrigerator was hindering development of the technology. Here we show direct imaging of an operational dilution refrigerator using neutron radiography. This allows direct observation of the dilution process in 3He/4He mixtures and opens an opportunity for direct measurement of the 3He concentration. We observe the refrigerator behaviour in different regimes, such as continuous circulation and single shot, and show that our method allows investigation of various failure modes. Our results demonstrate that neutron imaging applied to the study of dilution refrigeration processes can provide essential information for developers of ultra-low temperature systems. We expect that neutron imaging will become instrumental in the research and development of advanced dilution refrigerators.

Principles of environmentally-sustainable anaesthesia: a global consensus statement from the World Federation of Societies of Anaesthesiologists.

The Earth's mean surface temperature is already approximately 1.1°C higher than pre-industrial levels. Exceeding a mean 1.5°C rise by 2050 will make global adaptation to the consequences of climate change less possible. To protect public health, anaesthesia providers need to reduce the contribution their practice makes to global warming. We convened a Working Group of 45 anaesthesia providers with a recognised interest in sustainability, and used a three-stage modified Delphi consensus process to agree on principles of environmentally sustainable anaesthesia that are achievable worldwide. The Working Group agreed on the following three important underlying statements: patient safety should not be compromised by sustainable anaesthetic practices; high-, middle- and low-income countries should support each other appropriately in delivering sustainable healthcare (including anaesthesia); and healthcare systems should be mandated to reduce their contribution to global warming. We set out seven fundamental principles to guide anaesthesia providers in the move to environmentally sustainable practice, including: choice of medications and equipment; minimising waste and overuse of resources; and addressing environmental sustainability in anaesthetists' education, research, quality improvement and local healthcare leadership activities. These changes are achievable with minimal material resource and financial investment, and should undergo re-evaluation and updates as better evidence is published. This paper discusses each principle individually, and directs readers towards further important references.

Factors influencing the rating of sonographer students' clinical performance.

INTRODUCTION: Little is known about the factors influencing clinical supervisor-assessors' ratings of sonographer students' performance. This study identifies these influential factors and relates them to professional competency standards, with the aim of raising awareness and improving assessment practice. METHODS: This study used archived written comments from 94 clinical assessors describing 174 sonographer students' performance one month into their initial clinical practice (2015-6). Qualitative mixed method analysis revealed factors influencing assessor ratings of student performance and provided an estimate of the valency, association, and frequency of these factors. RESULTS: Assessors provided written comments for 93 % (n = 162/174) of students. Comments totaled 7190 words (mean of 44 words/student). One-third of comment paragraphs were wholly positive, two-thirds were equivocal. None were wholly negative. Thematic analysis revealed eleven factors, and eight sub-factors, influencing assessor impressions of five dimensions of performance. Of the factors mentioned, 84.6 % (n = 853/1008) related to professional competencies. While 15.4 % (n = 155/1008) were unrelated to competencies, instead reflecting humanistic factors such as student motivation, disposition, approach to learning, prospects and impact on supervisor and staff. Factors were prioritised and combined independently, although some associated. CONCLUSION: Clinical assessors formed impressions based on student performance, humanistic behaviours and personal qualities not necessarily outlined in educational outcomes or professional competency standards. Their presence, and interrelations, impact success in clinical practice, through their contribution to, and indication of, competence. IMPLICATIONS FOR PRACTICE: Sonographer student curricula and assessor training should raise awareness of the factors influencing performance ratings and judgement of clinical competence, particularly the importance of humanistic factors. Inclusion of narrative comments, multiple assessors, and broad performance dimensions would enhance clinical assessment of sonographer student performance.

The role of the sonographer - An investigation into the scope of practice for the sonographer internationally.

INTRODUCTION: There is global variance in the role of a practicing sonographer. Literature examining global sonographic roles and scope of practice is limited, despite the international applicability of ultrasound imaging. This study aimed to examine the common and divergent features of a practicing sonographer internationally, and their impact upon the development of a global standard of practice. METHODS: An ethically approved mixed-methods online survey was conducted. The purposive sample included all 75 current elected council members of the ISRRT [International Society of Radiographers and Radiological Technologists], an international professional organisation. RESULTS: Thirty-six individuals from at least 32 different countries responded, reflecting the sonography profession in all four ISRRT regions. The results suggest that sonographer education requirements differ widely, from on the job training (16%, 6/36) to undergraduate or postgraduate schooling (44%, 16/36). Registration and accreditation bodies were present in the jurisdiction of 41% (14/34) and 35% (12/33) of respondents respectively, though many were voluntary, physician-focused or non-specific to sonographers. Five of 11 (45%) respondents suggested that the sonographer-radiologist relationship is individual-dependent, and not primarily positive or negative. Ten of 28 (36%) suggested that other professionals do not know the role of the sonographer. CONCLUSION: The majority of ISRRT council member respondents believe that an international scope of practice could benefit and be implemented in their jurisdiction (26/28, 93% and 22/33, 67%). The key advantages noted were standardisation of education and improved professional mobility. However, lack of sonographer education and radiologist acceptance are important potential barriers. IMPLICATIONS FOR PRACTICE: An international scope of practice could be beneficial and implementable in most ISRRT jurisdictions. Professional mobility and education standardization are the primary advantages. Insufficient sonographer education and physician acceptance are the key potential obstacles.

Trends in 30-day readmissions following hospitalisation for heart failure by sex, socioeconomic status and ethnicity.

Background: Reducing the high patient and economic burden of early readmissions after hospitalisation for heart failure (HF) has become a health policy priority of recent years. Methods: An observational study linking Hospital Episode Statistics to socioeconomic and death data in England (2002-2018). All first hospitalisations with a primary discharge code for HF were identified. Quasi-poisson models were used to investigate trends in 30-day readmissions by age, sex, socioeconomic status and ethnicity. Findings: There were 698,983 HF admissions, median age 81 years [IQR 14].In-hospital deaths reduced by 0.7% per annum (pa), whilst additional deaths at 30-days remained stable at 5%. Age adjusted 30-day readmissions (21% overall), increased by 1.4% pa (95% CI 1.3-1.5). Readmissions for HF (6%) and 'other cardiovascular disease (CVD)' (3%) remained stable, but readmissions for non-CVD causes (12%) increased at a rate of 2.6% (2.4-2.7) pa. Proportions were similar by sex but trends diverged by ethnicity. Black groups experienced an increase in readmissions for HF (1.8% pa, interaction-p 0.03) and South Asian groups had more rapidly increasing readmission rates for non-CVD causes (interaction-p 0.04). Non-CVD readmissions were also more prominent in the least (15%; 15-15) compared to the most affluent group (12%; 12-12). Strongest predictors for HF readmission were Black ethnicity and chronic kidney disease, whilst cardiac procedures were protective. For non-CVD readmissions, strongest predictors were non-CVD comorbidities, whilst cardiologist care was protective. Interpretation: In HF, despite readmission reduction policies, 30-day readmissions have increased, impacting the least affluent and ethnic minority groups the most. Funding: NIHR.

Association of working shifts, inside and outside of healthcare, with severe COVID-19: an observational study.

BACKGROUND: Health and key workers have elevated odds of developing severe COVID-19; it is not known, however, if this is exacerbated in those with irregular work patterns. We aimed to investigate the odds of developing severe COVID-19 in health and shift workers. METHODS: We included UK Biobank participants in employment or self-employed at baseline (2006-2010) and with linked COVID-19 data to 31st August 2020. Participants were grouped as neither a health worker nor shift worker (reference category) at baseline, health worker only, shift worker only, or both, and associations with severe COVID-19 investigated in logistic regressions. RESULTS: Of 235,685 participants (81·5% neither health nor shift worker, 1·4% health worker only, 16·9% shift worker only, and 0·3% both), there were 580 (0·25%) cases of severe COVID-19. The odds of severe COVID-19 was higher in health workers (adjusted odds ratio: 2·32 [95% CI: 1·33, 4·05]; shift workers (2·06 [1·72, 2·47]); and in health workers who worked shifts (7·56 [3·86, 14·79]). Being both a health worker and a shift worker had a possible greater impact on the odds of severe COVID-19 in South Asian and Black and African Caribbean ethnicities compared to White individuals. CONCLUSIONS: Both health and shift work (measured at baseline, 2006-2010) were independently associated with over twice the odds of severe COVID-19 in 2020; the odds were over seven times higher in health workers who work shifts. Vaccinations, therapeutic and preventative options should take into consideration not only health and key worker status but also shift worker status.

Evaluation of students' clinical performance post-simulation training.

INTRODUCTION: Traditionally in Australia, sonographer skills are learnt on patients in clinical practice. A four-year undergraduate-postgraduate course introduced ultrasound simulation to prepare novice sonographer students for interaction with patients. Second-year students learnt psychomotor and patient-sonographer communication skills during simulation using commercial ultrasound machines and volunteer year-group peers as standardised patients. This paper reports on the transfer of the ultrasound skills learnt in simulation to clinical practice. METHODS: Clinical performance evaluations were completed by 94 supervisors involved in the initial clinical practice of 174 post-simulation second-year students over a two-year period (2015-2016). Student performance of each component skill, and skill category, was analysed by modelling binomial proportions with logistic regression. RESULTS: Students demonstrated substantial transfer of learnt ultrasound skills to achieve a mean of advanced beginner competence (mean score of equal to or >3/5) in complex psychomotor and patient-sonographer communication skills, as measured one month into clinical practice. Knowledge and skill components, or sub-tasks, varied significantly (P < 0.001) in transferability. Scanning tasks in general, particularly the skill of 'extending the examination', transferred with significantly (P < 0.001) less efficacy than pre-exam, instrumentation, post-exam, and additional tasks. Skill transfer improved significantly (P < 0.001) following increased deliberate practice with tutor feedback. CONCLUSION: Preclinical simulation, using standardised patients, clearly stated objectives to manage cognitive load and immediate tutor feedback, facilitated substantial transfer of ultrasound skills to clinical practice. The efficacy of skill transfer varied but improved with increased deliberate practice and feedback quality. IMPLICATIONS FOR PRACTICE: The incorporation of preclinical simulation into the core curriculum of sonographer courses is recommended to improve student performance, reduce the burden on clinical staff and increase patient safety during the early stages of ultrasound education.

Medial Branch Blocks for Diagnosis of Facet Joint Pain Etiology and Use in Chronic Pain Litigation.

A commonly disputed medicolegal issue is the documentation of the location, degree, and anatomical source of an injured plaintiff's ongoing pain, particularly when the painful region is in or near the spine, and when the symptoms have arisen as result of a relatively low speed traffic crash. The purpose of our paper is to provide health and legal practitioners with strategies to identify the source of cervical pain and to aid triers of fact (decision makers) in reaching better informed conclusions. We review the medical evidence for the applications and reliability of cervical medial branch nerve blocks as an indication of painful spinal facets. We also present legal precedents for the legal admissibility of the results of such diagnostic testing as evidence of chronic spine pain after a traffic crash. Part of the reason for the dispute is the subjective nature of pain, and the fact that medical documentation of pain complaints relies primarily on the history given by the patient. A condition that can be documented objectively is chronic cervical spine facet joint pain, as demonstrated by medial branch block (injection). The diagnostic accuracy of medial branch blocks has been extensively described in the scientific medical literature, and evidence of facet blocks to objectively document chronic post-traumatic neck pain has been accepted as scientifically reliable in courts and tribunals in the USA, Canada and the United Kingdom. We conclude that there is convincing scientific medical evidence that the results of cervical facet blocks provide reliable objective evidence of chronic post-traumatic spine pain, suitable for presentation to an adjudicative decision maker.

Assessing the impact of country culture on the socio-cultural practice of radiography.

INTRODUCTION: Diagnostic radiography is a deceptively similar occupation regardless of country and yet there are wide varieties of scopes of practice, levels of autonomy, respect and understanding of what a radiographer does. METHODS: A socio-cultural comparative ethnographic study was carried out in seven culturally diverse countries observing and interviewing radiographers in one regional hospital in each country. The thick descriptions collected were thematically analysed. This article describes the comparison between work culture and country culture between the seven countries using the analytic device of Hofstede's cultural dimensions. RESULTS: The results demonstrate a wide disparity between countries, in importance of hierarchy, acceptance of individuality, ability to work autonomously and strength of country specific cultural norms. The impact of the country culture on the practice of radiography is manifested through variations in education, scope of practice, and level of recognition within the healthcare spectrum. CONCLUSION: These findings offer insight into the socio-cultural practice of radiography through an ethnographic cultural-specific lens and provide some explanations for the barriers evidenced currently to global recognition of standards and scopes of practice. IMPLICATIONS FOR PRACTICE: The study introduced empirical evidence into a subject matter hitherto unexplored in a global comparative manner, and creates an opportunity to improve the recognition of radiographers by creating a foundation of research upon which to build further more targeted studies.

The use of near peer teachers in the radiography program at Monash University.

INTRODUCTION: This research investigated the perceptions of fourth year students as near peer (NP) teachers, and second year NP learners during a pathology unit in the Bachelor of Medical Imaging and Radiation Sciences at Monash University. METHODS: A systematic review of literature was undertaken to inform the research design. Semi-structure pre- and post-teaching interviews were conducted with four NP teachers. An online survey was conducted with 50 second year NP learners. Quantitative data was analysed using Microsoft Excel. Interview data and 64 free text comments in the online survey were analysed using NVivo. RESULTS: NP students felt there were significant benefits being involved in the NP program, including an explanation of concepts and complementary teaching to lecturers. Three of the free text comments outlined a negative perception, although in each case the comment related to the student's individual learning style rather than being negative against the program. CONCLUSION: The benefits to learners in a pathology course was consistent to those identified within the literature. Students perceived benefits in terms of content delivery, interaction and communication. Recommendations were made about the organisation and design for future cohorts.

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.

Cell specific microvesicles vary with season and disease predisposition in healthy and previously laminitic ponies.

Microvesicles are small (up to 1 µm) vesicles found in plasma and other bodily fluids. They are recognised as part of the normal system of inter-cellular communication but altered numbers are also used as biomarkers of disease. Microvesicles have not been studied in detail in the horse but may be relevant to diseases such as laminitis. Identification of equine cell specific microvesicles was performed by developing a panel of cross reactive antibodies to use in flow cytometry to detect microvesicles of platelet, leucocyte and endothelial origin in plasma from healthy ponies and those predisposed to laminitis. The total number and proportion of microvesicles from the different cell types varied with season and there were more annexin V positive endothelial MV in non laminitic ponies compared to previously laminitic ponies. Development of this antibody panel and the technique for measuring microvesicles in the horse opens a new field for further investigation of these important structures in equine health and disease.

Neutrophil Extracellular Traps in Plasma from Dogs with Immune-mediated Hemolytic Anemia.

BACKGROUND: Neutrophil extracellular traps (NETs) are part of the innate immune response and are essential in local pathogen control, but are associated with pathological inflammation, organ damage, autoimmunity, and thrombosis. Immune-mediated hemolytic anemia (IMHA) is a pro-inflammatory, prothrombotic disease associated with high mortality. HYPOTHESIS/OBJECTIVES: Neutrophil extracellular traps (NETs) are a feature of the inflammatory process in dogs with IMHA. The objective of the study was to evaluate plasma from dogs with IMHA for the presence of 2 indirect markers and 1 direct marker of NETs. ANIMALS: Healthy client-owned dogs (56) and hospitalized dogs with IMHA (n = 35). METHODS: Prospective study. Plasma samples for all dogs were evaluated for cell-free DNA using a fluorescence assay, histone-DNA (hisDNA) complex using an ELISA, and citrullinated histone H3 (specific for NETosis) using Western blot. Reference intervals were generated using plasma from healthy dogs. RESULTS: In dogs with IMHA, cell-free DNA concentration was above the reference interval in 17% of samples with a median (range) of 1.0 µg/mL (0.1-17.3), and hisDNA concentration was above the reference interval in 94% of samples with a median (range) of 30.7 × pooled normal plasma (PNP; 0.6-372.1). Western blot for citrullinated histone H3 identified detectable bands in 84% samples from dogs with IMHA. CONCLUSIONS AND CLINICAL IMPORTANCE: The assay for cell-free DNA detected evidence of NETs in fewer dogs than did the other approaches. Excessive NETs appears to be a feature of IMHA in dogs and contributions to the prothrombotic state deserve further study.

Humanitarianism in surgery.

PURPOSE: Humanitarianism is by definition a moral of kindness, benevolence and sympathy extended to all human beings. In our view as surgeons working in underserved countries, humanitarianism means performing the best operation in the best possible circumstances with high income country (HIC) results and training in-country surgeons to do the same. Hernia Repair for the Underserved (HRFU), a not for profit organization, is developing a long term public health initiative for hernia surgery in Western Hemisphere countries. We report the progress of HRFUs methods to render humanitarian care. METHODS: In a collaborative effort, Creighton University and the Institute for Latin American Concern developed an outpatient surgery site for hernia surgery in Santiago, Dominican Republic. Based on this experience, we developed a sustainable care model by recruiting American and European Hernia Society expert surgeons, staff members they recommended, building relationships with local and industry partners, and selecting local surgeons to be trained in mesh hernioplasty. HRFU then extended the care model to other Western Hemisphere countries. RESULTS: Between 2004 and 2015, the HRFU elective hernia morbidity and mortality rates for 2052 hernia operations were 0.7 and 0%, respectively. This is consistent with outcomes from HICs and confirms the feasibility of a public health initiative based on the principles of the Preferential Option for the Poor. CONCLUSIONS: HRFU has recorded HIC morbidity and mortality rates for hernia surgery in low and middle income countries and has initiated a new surgical training model for sustainability of effect.

Development of an international comorbidity education framework.

CONTEXT: The increasing number of people living with multiple chronic conditions in addition to an index condition has become an international healthcare priority. Health education curricula have been developed alongside single condition frameworks in health service policy and practice and need redesigning to incorporate optimal management of multiple conditions. AIM: Our aims were to evaluate current teaching and learning about comorbidity care amongst the global population of healthcare students from different disciplines and to develop an International Comorbidity Education Framework (ICEF) for incorporating comorbidity concepts into health education. METHODS: We surveyed nursing, medical and pharmacy students from England, India, Italy and Sweden to evaluate their understanding of comorbidity care. A list of core comorbidity content was constructed by an international group of higher education academics and clinicians from the same disciplines, by searching current curricula and analysing clinical frameworks and the student survey data. This list was used to develop the International Comorbidity Education Framework. RESULTS: The survey sample consisted of 917 students from England (42%), India (48%), Italy (8%) and Sweden (2%). The majority of students across all disciplines said that they lacked knowledge, training and confidence in comorbidity care and were unable to identify specific teaching on comorbidities. All student groups wanted further comorbidity training. The health education institution representatives found no specific references to comorbidity in current health education curricula. Current clinical frameworks were used to develop an agreed list of core comorbidity content and hence an International Comorbidity Education Framework. CONCLUSIONS: Based on consultation with academics and clinicians and on student feedback we developed an International Comorbidity Education Framework to promote the integration of comorbidity concepts into current healthcare curricula.