Tempering hope with realism. Induced pluripotent stem cells in regenerative medicine

• Since their discovery in 2007, human induced pluripotent stem (iPS) cells have been widely championed as the future for regenerative medicine. • By differentiating iPS cells into specialised cells for transplantation, it may be possible to replace diseased cells and “cure” patients of various chronic degenerative conditions, including Parkinson’s disease. • Such putative iPS cell-based therapies would avoid the need to procure transplantable cells from (and in the process, destroy) human embryos, and could be administered to patients without immunosuppressive therapy. • In reality, however, the optimism surrounding iPS cell research has outpaced progress to date and likely emanates, in part, from the “moral panic” surrounding human embryo research. • At such an early stage of development, questions remain about whether iPS cells are strictly equivalent to human embryonic stem cells as a source of transplantable cells. The Heerey Committee considered this point in its recent review of the Commonwealth legislation governing embryo research and human cloning and its Report (tabled in federal Parliament in July 2011) recommended that embryonic stem cell research should continue in Australia. • In addition, there are many ethical issues which will need to be considered when enrolling vulnerable patients in trials of iPS cell therapy given the uncertain benefits and risks involved. • In the rush to embrace iPS cell therapy, there is a real risk that the public may overrate the benefits and expect imminent translation to the clinic

Accountability and efficiency in the public sector : the role of the Auditor-General

As the influence and pervasiveness of the State has increased, there has been a growing concern that governments and their advisors should be held accountable, not only for the regularity of their actions, but also for the wisdom of their decisions and their management of scarce resources. What is required are procedures for demanding accountability for the legality of expenditure as well as for departmental efficiency and for programme effectiveness. The role of the Auditor-General is examined in the light of these requirements. It is argued that his effectiveness will depend on how broadly his mandate is defined, both in terms of the number of agencies audited and the degree of sophistication of the techniques employed; his independence from the administration; and his ability to publicise his findings and communicate his criticisms to Parliament. It is suggested that the ability of the Auditor-General to develop a wide-ranging efficiency and effectiveness audit has been constrained by restrictive norms about the role of the legislature in the analysis of executive programmes; staffing and analytical impediments; and because such an audit would fundamentally alter the distribution of power between competing political actors. This leads to the conclusion that a fully efficient and accountable public sector may only be possible if governments can be convinced that this would be in their own interests

Safety and feasibility of sublingual microcirculation assessment in the emergency department for civilian and military patients with traumatic haemorrhagic shock: a prospective cohort study

OBJECTIVES: Sublingual microcirculatory monitoring for traumatic haemorrhagic shock (THS) may predict clinical outcomes better than traditional blood pressure and cardiac output, but is not usually performed until the patient reaches the intensive care unit (ICU), missing earlier data of potential importance. This pilot study assessed for the first time the feasibility and safety of sublingual video-microscopy for THS in the emergency department (ED), and whether it yields useable data for analysis. SETTING: A safety and feasibility assessment was undertaken as part of the prospective observational MICROSHOCK study; sublingual video-microscopy was performed at the UK-led Role 3 medical facility at Camp Bastion, Afghanistan, and in the ED in 3 UK Major Trauma Centres. PARTICIPANTS: There were 15 casualties (2 military, 13 civilian) who presented with traumatic haemorrhagic shock with a median injury severity score of 26. The median age was 41; the majority (n=12) were male. The most common injury mechanism was road traffic accident. PRIMARY AND SECONDARY OUTCOME MEASURES: Safety and feasibility were the primary outcomes, as measured by lack of adverse events or clinical interruptions, and successful acquisition and storage of data. The secondary outcome was the quality of acquired video clips according to validated criteria, in order to determine whether useful data could be obtained in this emergency context. RESULTS: Video-microscopy was successfully performed and stored for analysis for all patients, yielding 161 video clips. There were no adverse events or episodes where clinical management was affected or interrupted. There were 104 (64.6%) video clips from 14 patients of sufficient quality for analysis. CONCLUSIONS: Early sublingual microcirculatory monitoring in the ED for patients with THS is safe and feasible, even in a deployed military setting, and yields videos of satisfactory quality in a high proportion of cases. Further investigations of early microcirculatory behaviour in this context are warranted. TRIAL REGISTRATION NUMBER: NCT02111109

Pain assessment tools in paediatric palliative care: A systematic review of psychometric properties and recommendations for clinical practice

Background: Assessing pain in infants, children and young people with life-limiting conditions remains a challenge due to diverse patient conditions, types of pain and often a reduced ability or inability of patients to communicate verbally. Aim: To systematically identify pain assessment tools that are currently used in paediatric palliative care and examine their psychometric properties and feasibility and make recommendations for clinical practice. Design: A systematic literature review and evaluation of psychometric properties of pain assessment tools of original peer-reviewed research published from inception of data sources to April 2021. Data sources: PsycINFO via ProQuest, Web of Science Core, Medline via Ovid, EMBASE, BIOSIS and CINAHL were searched from inception to April 2021. Hand searches of reference lists of included studies and relevant reviews were performed. Results: From 1168 articles identified, 201 papers were selected for full-text assessment. Thirty-four articles met the eligibility criteria and we examined the psychometric properties of 22 pain assessment tools. Overall, the Faces Pain Scale-Revised (FPS-R) had high cross-cultural validity, construct validity (hypothesis testing) and responsiveness; while the Faces, Legs, Activity, Cry and Consolability (FLACC) scale and Paediatric Pain Profile (PPP) had high internal consistency, criterion validity, reliability and responsiveness. The number of studies per psychometric property of each pain assessment tool was limited and the methodological quality of included studies was low. Conclusion: Balancing aspects of feasibility and psychometric properties, the FPS-R is recommended for self-assessment, and the FLACC scale/FLACC Revised and PPP are the recommended observational tools in their respective age groups

Dilatation in the femoral vascular bed does not cause retrograde relaxation of the iliac artery in the anaesthetized pig

Aim:  We tested the hypothesis that dilatation of a feeding artery may be elicited by transmission of a signal through the tissue of the arterial wall from a vasodilated peripheral vascular bed. Methods:  In eight pentobarbital anaesthetized pigs, acetylcholine (ACh, an endothelium-dependent vasodilator) was injected intra-arterially above (upstream) and below (downstream) a test segment of the left iliac artery, the diameter of which was measured continuously by sonomicrometry. Results:  Under control conditions, ACh injections upstream and downstream of the test segment caused dilatation. Downstream injection dilated the peripheral arterioles, resulting in increased blood flow and proximal dilatation. This is a shear stress, nitric oxide (NO)-dependent response. The experiment was then repeated after applying a stenosis to prevent the increased flow caused by downstream injection of ACh; the stenosis was placed either above the site of diameter measurement to allow retrograde conduction, or below that site to prevent distally injected ACh reaching the measurement site. Under these conditions, downstream injection of ACh had a minimal effect on the shear stress of the test segment with no increase in test segment diameter. This was not due to endothelial damage or dysfunction as injection of ACh upstream still caused a large increase in test segment diameter. Conclusions:  Our results indicate that dilatation of the feeding artery of a vasodilated bed is caused by increased shear stress within the feeding artery and not via a signal transmitted through the arterial wall from below

Delivery of supported self-management in remote asthma reviews: A systematic rapid realist review

Background: The COVID-19 pandemic forced health care systems globally to adapt quickly to remote modes of health care delivery, including for routine asthma reviews. A core component of asthma care is supporting self-management, a guideline-recommended intervention that reduces the risk of acute attacks, and improves asthma control and quality of life. Objective: We aimed to explore context and mechanisms for the outcomes of clinical effectiveness, acceptability and safety of supported self-management delivery within remote asthma consultations. Design: The review followed standard methodology for rapid realist reviews. An External Reference Group (ERG) provided expert advice and guidance throughout the study. We systematically searched four electronic databases and, with ERG advice, selected 18 papers that explored self-management delivery during routine asthma reviews. Setting, Participants and Intervention: Health care professional delivery of supported self-management for asthma patients during remote (specifically including telephone and video) consultations. Main Outcome Measures: Data were extracted using Context-Mechanism-Outcome (C-M-O) configurations and synthesised into overarching themes using the PRISMS taxonomy of supported self-management as a framework to structure the findings. Results: The review findings identified how support for self-management delivered remotely was acceptable (often more acceptable than in-person consultations), and was a safe and effective alternative to face-to-face reviews. In addition, remote delivery of supported self-management was associated with; increased patient convenience, improved access to and attendance at remote reviews, and offered continuity of care. Discussion: Remote delivery of supported self-management for asthma was generally found to be clinically effective, acceptable, and safe with the added advantage of increasing accessibility. Remote reviews could provide the core content of an asthma review, including remote completion of asthma action plans. Conclusion: Our findings support the option of remote delivery of routine asthma care for those who have this preference, and offer healthcare professionals guidance on embedding supported self-management into remote asthma reviews. Patient and Public Contribution: Patient and public contribution was provided by a representative of the Asthma UK Centre for Applied Research (AUKCAR) patient and public involvement (PPI) group. The PPI representative reviewed the findings, and feedback and comments were considered. This lead to further interpretations of the data which were included in the final manuscript

Prospective observational study to examine health-related quality of life and develop models to predict long-term patient-reported outcomes 6 months after hospital discharge with blunt thoracic injuries.

OBJECTIVE: This study aimed to examine the long-term outcomes and health-related quality of life in patients with blunt thoracic injuries over 6 months from hospital discharge and develop models to predict long-term patient-reported outcomes. DESIGN: A prospective observational study using longitudinal survey design. SETTING: The study recruitment was undertaken at 12 UK hospitals which represented diverse geographical locations and covered urban, suburban and rural areas across England and Wales. PARTICIPANTS: 337 patients admitted to hospital with blunt thoracic injuries were recruited between June 2018-October 2020. METHODS: Participants completed a bank of two quality of life surveys (Short Form-12 (SF-12) and EuroQol 5-Dimensions 5-Levels) and two pain questionnaires (Brief Pain Inventory and painDETECT Questionnaire) at four time points over the first 6 months after discharge from hospital. A total of 211 (63%) participants completed the outcomes data at 6 months after hospital discharge. OUTCOMES MEASURES: Three outcomes were measured using pre-existing and validated patient-reported outcome measures. Outcomes included: Poor physical function (SF-12 Physical Component Score); chronic pain (Brief Pain Inventory Pain Severity Score); and neuropathic pain (painDETECT Questionnaire). RESULTS: Despite a trend towards improving physical functional and pain at 6 months, outcomes did not return to participants perceived baseline level of function. At 6 months after hospital discharge, 37% (n=77) of participants reported poor physical function; 36.5% (n=77) reported a chronic pain state; and 22% (n=47) reported pain with a neuropathic component. Predictive models were developed for each outcome highlighting important data collection requirements for predicting long-term outcomes in this population. Model diagnostics including calibration and discrimination statistics suggested good model fit in this development cohort. CONCLUSIONS: This study identified the recovery trajectories for patients with blunt thoracic injuries over the first 6 months after hospital discharge and present prognostic models for three important outcomes which after external validation could be used as clinical risk stratification scores