Exercise rehabilitation following intensive care unit discharge for recovery from critical illness: Executive summary of a Cochrane Collaboration systematic review

Skeletal muscle wasting and weakness are major complications of critical illness and underlie the profound physical and functional impairments experienced by survivors after discharge from the intensive care unit (ICU). Exercise-based rehabilitation has been shown to be beneficial when delivered during ICU admission. This review aimed to determine the effectiveness of exercise rehabilitation initiated after ICU discharge on primary outcomes of functional exercise capacity and health-related quality of life. We sought randomized controlled trials, quasi-randomized controlled trials, and controlled clinical trials comparing an exercise intervention commenced after ICU discharge vs. any other intervention or a control or ‘usual care’ programme in adult survivors of critical illness. Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database, and Cumulative Index to Nursing and Allied Health Literature databases were searched up to February 2015. Dual, independent screening of results, data extraction, and quality appraisal were performed. We included six trials involving 483 patients. Overall quality of evidence for both outcomes was very low. All studies evaluated functional exercise capacity, with three reporting positive effects in favour of the intervention. Only two studies evaluated health-related quality of life and neither reported differences between intervention and control groups. Meta-analyses of data were precluded due to variation in study design, types of interventions, and selection and reporting of outcome measurements. We were unable to determine an overall effect on functional exercise capacity or health-related quality of life of interventions initiated after ICU discharge for survivors of critical illness. Findings from ongoing studies are awaited. Future studies need to address methodological aspects of study design and conduct to enhance rigour, quality, and synthesis.

How can we use systematic reviews to inform clinical practice?

Aims/purpose: Systematic reviews provide the highest quality evidence and inform clinical practice. For patient benefit, it is imperative that nurses keep abreast of evidence-based practice. This presentation highlights where to find systematic reviews and how the information presented can be used to inform care.
Presentation description: Clinical research is increasing at an incredible rate. In the clinical trials database alone, more than 2000 new studies are registered/month and this does not include qualitative studies that do not require registration. Keeping abreast of current evidence can not only be a time consuming process, but can be problematic when studies produce conflicting results. Systematic reviews can be useful for summarizing the increasing amount of knowledge that is gained from scientific papers. In addition, combining individual studies in a meta-analysis increases statistical power, resulting in more precise effect estimates. This presentation draws upon a few systematic reviews relevant to ICU nursing practice, highlights their findings and demonstrates how the information can be used to inform translation of evidence into practice. Additionally, although these reviews include steps to minimize bias, nurses should be aware of some of the biases that may reduce confidence in the findings.
Conclusion: Systematic reviews can be useful tools for informing evidence based practice, although careful interpretation is necessary for understanding their relevance to local practice.

Ambulance Treatment Space Ergonomic Layout

This is the first time a multidisciplinary team has employed an iterative co-design method to determine the ergonomic layout of an emergency ambulance treatment space. This process allowed the research team to understand how treatment protocols were performed and developed analytical tools to reach an optimum configuration towards ambulance design standardisation. Fusari conducted participatory observations during 12-hour shifts with front-line ambulance clinicians, hospital staff and patients to understand the details of their working environments whilst on response to urgent and emergency calls. A simple yet accurate 1:1 mock-up of the existing ambulance was built for detailed analysis of these procedures through simulations. Paramedics were called in to participate in interviews and role-playing inside the model to recreate tasks, how they are performed, the equipment used and to understand the limitations of the current ambulance. The use of Link Analysis distilled 5 modes of use. In parallel, an exhaustive audit of all equipment and consumables used in ambulances was performed (logging and photography) to define space use. These developed 12 layout options for refinement and CAD modelling and presented back to paramedics. The preferred options and features were then developed into a full size test rig and appearance model. Two key studies informed the process. The 2005 National Patient Safety Agency funded study “Future Ambulances” outlined 9 design challenges for future standardisation of emergency vehicles and equipment. Secondly, the 2007 EPSRC funded “Smart Pods” project investigated a new system of mobile urgent and emergency medicine to treat patients in the community. A full-size mobile demonstrator unit featuring the evidence-based ergonomic layout was built for clinical tests through simulated emergency scenarios. Results from clinical trials clearly show that the new layout improves infection control, speeds up treatment, and makes it easier for ambulance crews to follow correct clinical protocols.

“Medical bag for General Practice” Just in Case: redesigning the doctor’s bag (2012)

This research addressed practice related problems from a medico-legal perspective and aims to provide a working tool that aids GPs to comply with best practice protocols. The resulting bag was developed in collaboration with General Practitioners, clinicians and members of the Medical Defense Union. Using proven methods developed within the Healthcare & Patient Safety Lab (e.g. DOME, Ambulance) to establish an evidence-based brief, this research used task, equipment and consumables analysis to determine minimum requirements and preferred layouts for task optimisation. The research established that clinicians require three distinct functions in their workspace: laying out, organisation and information retrieval. Feedback from clinicians indicates that this working tool allows them to access information and equipment wherever they may be and suggests an improvement from current practice. The research is now into a second year where the design of the bag will be refined and tested. Lifestyle and demographic changes such as the ageing population and increased prevalence of chronic diseases require more consistent standards of primary care, and care that is well coordinated and integrated (Imison, et al., 2011). Many guidelines exist relating to general practice and the doctor’s bag (NSLMC, 2008, RACGP, 2010, RCGP, 2008 and Hiramanek, 2004), however there is no standard in the UK that regulates the shape and materials of the bag or its contents. Doctors may use any sort of vessel to transport their equipment and consumables to a patient’s location. Furthermore, treating a patient in their own home, outside an ideal clinical environment, presents its own complications. A looks-like, works-like bag prototype and information system that will be used in clinical trials, the results of which will determine the manufacturing of a new, standardised bag for clinical treatment used by members of the Medical Defence Union.

Clinical Research and Standard of Care — An Unresolved Question?

Ever since the 1996 revision of the Declaration of Helsinki, the World Medical Association has attempted to address ethical and scientific concerns of its diverse stakeholders for Articles 33 (use of placebo) and 34 (posttrial provisions), most recently in 2013. Both are inextricably linked to standard of care, an essential element of any comparative, interventional clinical trial. But has this now 20-year-long ethical debate truly been put to rest? The choice of standard of care in clinical trials remains a complex issue, particularly for comparative trials conducted in emerging countries.

Curricular training report: clinical studies coordination in a clinical research organization vs an investigational site perspective

This report describes my experience of nine months as a trainee of a CRO (Eurotrials, Scientific Consultants), as well as a trainee of a clinical research site (Clinical Academic Center – Braga, Association). This document describes the European framework about clinical research and the Portuguese situation compared to similar countries. The activities developed during this internship are also described. These activities are divided in two phases. The first one occurred in Eurotrials, Scientific Consultants, a CRO specialized in clinical research and scientific advice. The first weeks were dedicated to intensive self-training needed to perform CTA tasks. These tasks included qualification, initiation and monitoring activities related to clinical trials, as well as the development of a quality management system. The second phase took place on 2CA-Braga, a clinical research center located in Hospital of Braga. Clinical studies coordination was the main focus of this second phase of my internship, as well as negotiation of clinical studies agreements. I had also the opportunity to participate in “1as Jornadas de Investigação Clínica e Inovação” (1st Clinical Investigation and Innovation Conference) organized by 2CA-Braga. Globally, this internship was a great opportunity to get knowledge and experience in the implementation and management of clinical trials, in a CRO and clinical research site perspectives. These two perspectives provided an interesting overview about the scientific needs of different players involved in clinical research. To conclude, this internship strengthened the knowledge acquired from my academic background, which make me able to face and overcome new challenges in the clinical research area.

Do Editorial Policies Support Ethical Research? A Thematic Text Analysis of Author Instructions in Psychiatry Journals

Introduction: According to the Declaration of Helsinki and other guidelines, clinical studies should be approved by a research ethics committee and seek valid informed consent from the participants. Editors of medical journals are encouraged by the ICMJE and COPE to include requirements for these principles in the journal's instructions for authors. This study assessed the editorial policies of psychiatry journals regarding ethics review and informed consent. Methods and Findings: The information given on ethics review and informed consent and the mentioning of the ICMJE and COPE recommendations were assessed within author's instructions and online submission procedures of all 123 eligible psychiatry journals. While 54% and 58% of editorial policies required ethics review and informed consent, only 14% and 19% demanded the reporting of these issues in the manuscript. The TOP-10 psychiatry journals (ranked by impact factor) performed similarly in this regard. Conclusions: Only every second psychiatry journal adheres to the ICMJE's recommendation to inform authors about requirements for informed consent and ethics review. Furthermore, we argue that even the ICMJE's recommendations in this regard are insufficient, at least for ethically challenging clinical trials. At the same time, ideal scientific design sometimes even needs to be compromised for ethical reasons. We suggest that features of clinical studies that make them morally controversial, but not necessarily unethical, are analogous to methodological limitations and should thus be reported explicitly. Editorial policies as well as reporting guidelines such as CONSORT should be extended to support a meaningful reporting of ethical research.

How Psychiatry Journals Support the Unbiased Translation of Clinical Research. A Cross-Sectional Study of Editorial Policies

Introduction: Reporting guidelines (e. g. CONSORT) have been developed as tools to improve quality and reduce bias in reporting research findings. Trial registration has been recommended for countering selective publication. The International Committee of Medical Journal Editors (ICMJE) encourages the implementation of reporting guidelines and trial registration as uniform requirements (URM). For the last two decades, however, biased reporting and insufficient registration of clinical trials has been identified in several literature reviews and other investigations. No study has so far investigated the extent to which author instructions in psychiatry journals encourage following reporting guidelines and trial registration. Method: Psychiatry Journals were identified from the 2011 Journal Citation Report. Information given in the author instructions and during the submission procedure of all journals was assessed on whether major reporting guidelines, trial registration and the ICMJE's URM in general were mentioned and adherence recommended. Results: We included 123 psychiatry journals (English and German language) in our analysis. A minority recommend or require 1) following the URM (21%), 2) adherence to reporting guidelines such as CONSORT, PRISMA, STROBE (23%, 7%, 4%), or 3) registration of clinical trials (34%). The subsample of the top-10 psychiatry journals (ranked by impact factor) provided much better but still improvable rates. For example, 70% of the top-10 psychiatry journals do not ask for the specific trial registration number. Discussion: Under the assumption that better reported and better registered clinical research that does not lack substantial information will improve the understanding, credibility, and unbiased translation of clinical research findings, several stakeholders including readers (physicians, patients), authors, reviewers, and editors might benefit from improved author instructions in psychiatry journals. A first step of improvement would consist in requiring adherence to the broadly accepted reporting guidelines and to trial registration.

Assessment of the quality of sample labelling for clinical research

Objective: To assess the quality of the labels for clinical trial samples through current regulations, and to analyze its potential correlation with the specific characteristics of each sample. Method: A transversal multicenter study where the clinical trial samples from two third level hospitals were analyzed. The eleven items from Directive 2003/94/EC, as well as the name of the clinical trial and the dose on the label cover, were considered variables for labelling quality. The influence of the characteristics of each sample on labelling quality was also analyzed. Outcome: The study included 503 samples from 220 clinical trials. The mean quality of labelling, understood as the proportion of items from Appendix 13, was of 91.9%. Out of these, 6.6% did not include the name of the sample in the outer face of the label, while in 9.7% the dose was missing. The samples with clinical trial-type samples presented a higher quality (p < 0.049), blinding reduced their quality (p = 0.017), and identification by kit number or by patient increased it (p < 0.01). The promoter was the variable which introduced the highest variability into the analysis. Conclusions: The mean quality of labelling is adequate in the majority of clinical trial samples. The lack of essential information in some samples, such as the clinical trial code and the period of validity, is alarming and might be the potential source for dispensing or administration errors.

Five-year review of an international clinical research-training program

The exponential increase in clinical research has profoundly changed medical sciences. Evidence that has accumulated in the past three decades from clinical trials has led to the proposal that clinical care should not be based solely on clinical expertise and patient values, and should integrate robust data from systematic research. As a consequence, clinical research has become more complex and methods have become more rigorous, and evidence is usually not easily translated into clinical practice. Therefore, the instruction of clinical research methods for scientists and clinicians must adapt to this new reality. To address this challenge, a global distance-learning clinical research-training program was developed, based on collaborative learning, the pedagogical goal of which was to develop critical thinking skills in clinical research. We describe and analyze the challenges and possible solutions of this course after 5 years of experience (2008-2012) with this program. Through evaluation by students and faculty, we identified and reviewed the following challenges of our program: 1) student engagement and motivation, 2) impact of heterogeneous audience on learning, 3) learning in large groups, 4) enhancing group learning, 5) enhancing social presence, 6) dropouts, 7) quality control, and 8) course management. We discuss these issues and potential alternatives with regard to our research and background.

TRIB2 in human AML: a biological and clinical investigation

Acute myeloid leukemia (AML) involves the proliferation, abnormal survival and arrest of cells at a very early stage of myeloid cell differentiation. The biological and clinical heterogeneity of this disease complicates treatment and highlights the significance of understanding the underlying causes of AML, which may constitute potential therapeutic targets, as well as offer prognostic information. Tribbles homolog 2 (Trib2) is a potent murine oncogene capable of inducing transplantable AML with complete penetrance. The pathogenicity of Trib2 is attributed to its ability to induce proteasomal degradation of the full length isoform of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα p42). The role of TRIB2 in human AML cells, however, has not been systematically investigated or targeted. Across human cancers, TRIB2 oncogenic activity was found to be associated with its elevated expression. In the context of AML, TRIB2 overexpression was suggested to be associated with the large and heterogeneous subset of cytogenetically normal AML patients. Based upon the observation that overexpression of TRIB2 has a role in cellular transformation, the effect of modulating its expression in human AML was examined in a human AML cell line that expresses high levels of TRIB2, U937 cells. Specific suppression of TRIB2 led to impaired cell growth, as a consequence of both an increase in apoptosis and a decrease in cell proliferation. Consistent with these in vitro results, TRIB2 silencing strongly reduced progression of the U937 in vivo xenografts, accompanied by detection of a lower spleen weight when compared with mice transplanted with TRIB2- expressing control cells. Gene expression analysis suggested that TRIB2 modulates apoptosis and cell-cycle sensitivity by influencing the expression of a subset of genes known to have implications on these phenotypes. Furthermore, TRIB2 was found to be expressed in a significant subset of AML patient samples analysed. To investigate whether increased expression of this gene could be afforded prognostic significance, primary AML cells with dichotomized levels of TRIB2 transcripts were evaluated in terms of their xenoengraftment potential, an assay reported to correlate with disease aggressiveness observed in humans. A small cohort of analysed samples with higher TRIB2 expression did not associate with preferential leukaemic cell engraftment in highly immune-deficient mice, hence, not predicting for an adverse prognosis. However, further experiments including a larger cohort of well characterized AML patients would be needed to clarify TRIB2 significance in the diagnostic setting. Collectively, these data support a functional role for TRIB2 in the maintenance of the oncogenic properties of human AML cells and suggest TRIB2 can be considered a rational therapeutic target. Proteasome inhibition has emerged as an attractive target for the development of novel anti-cancer therapies and results from translational research and clinical trials support the idea that proteasome inhibitors should be considered in the treatment of AML. The present study argued that proteasome inhibition would effectively inhibit the function of TRIB2 by abrogating C/EBPα p42 protein degradation and that it would be an effective pharmacological targeting strategy in TRIB2-positive AMLs. Here, a number of cell models expressing high levels of TRIB2 were successfully targeted by treatment with proteasome inhibitors, as demonstrated by multiple measurements that included increased cytotoxicity, inhibition of clonogenic growth and anti-AML activity in vivo. Mechanistically, it was shown that block of the TRIB2 degradative function led to an increase of C/EBPα p42 and that response was specific to the TRIB2-C/EBPα axis. Specificity was addressed by a panel of experiments showing that U937 cells (express detectable levels of endogenous TRIB2 and C/EBPα) treated with the proteasome inhibitor bortezomib (Brtz) displayed a higher cytotoxic response upon TRIB2 overexpression and that ectopic expression of C/EBPα rescued cell death. Additionally, in C/EBPα-negative leukaemia cells, K562 and Kasumi 1, Brtz-induced toxicity was not increased following TRIB2 overexpression supporting the specificity of the compound on the TRIB2-C/EBPα axis. Together these findings provide pre-clinical evidence that TRIB2- expressing AML cells can be pharmacologically targeted with proteasome inhibition due, in part, to blockage of the TRIB2 proteolytic function on C/EBPα p42. A large body of evidence indicates that AML arises through the stepwise acquisition of genetic and epigenetic changes. Mass spectrometry data has identified an interaction between TRIB2 and the epigenetic regulator Protein Arginine Methyltransferase 5 (PRMT5). Following assessment of TRIB2‟s role in AML cell survival and effective targeting of the TRIB2-C/EBPα degradation pathway, a putative TRIB2/PRMT5 cooperation was investigated in order to gain a deeper understanding of the molecular network in which TRIB2 acts as a potent myeloid oncogene. First, a microarray data set was interrogated for PRMT5 expression levels and the primary enzyme responsible for symmetric dimethylation was found to be transcribed at significantly higher levels in AML patients when compared to healthy controls. Next, depletion of PRMT5 in the U937 cell line was shown to reduce the transformative phenotype in the high expressing TRIB2 AML cells, which suggests that PRMT5 and TRIB2 may cooperate to maintain the leukaemogenic potential. Importantly, PRMT5 was identified as a TRIB2-interacting protein by means of a protein tagging approach to purify TRIB2 complexes from 293T cells. These findings trigger further research aimed at understanding the underlying mechanism and the functional significance of this interplay. In summary, the present study provides experimental evidence that TRIB2 has an important oncogenic role in human AML maintenance and, importantly in such a molecularly heterogeneous disease, provides the rational basis to consider proteasome inhibition as an effective targeting strategy for AML patients with high TRIB2 expression. Finally, the identification of PRMT5 as a TRIB2-interacting protein opens a new level of regulation to consider in AML. This work may contribute to our further understanding and therapeutic strategies in acute leukaemias.

MRI indices of functional recovery following intracerebral implantation of a human neural stem cell line in a pre-clinical model of ischaemic stroke

Stem cell therapy for ischaemic stroke is an emerging field in light of an increasing number of patients surviving with permanent disability. Several allogenic and autologous cells types are now in clinical trials with preliminary evidence of safety. Some clinical studies have reported functional improvements in some patients. After initial safety evaluation in a Phase 1 study, the conditionally immortalised human neural stem cell line CTX0E03 is currently in a Phase 2 clinical trial (PISCES-II). Previous pre-clinical studies conducted by ReNeuron Ltd, showed evidence of functional recovery in the Bilateral Asymmetry test up to 6 weeks following transplantation into rodent brain, 4 weeks after middle cerebral artery occlusion. Resting-state fMRI is increasingly used to investigate brain function in health and disease, and may also act as a predictor of recovery due to known network changes in the post-stroke recovery period. Resting-state methods have also been applied to non-human primates and rodents which have been found to have analogous resting-state networks to humans. The sensorimotor resting-state network of rodents is impaired following experimental focal ischaemia of the middle cerebral artery territory. However, the effects of stem cell implantation on brain functional networks has not previously been investigated. Prior studies assessed sensorimotor function following sub-cortical implantation of CTX0E03 cells in the rodent post-stroke brain but with no MRI assessments of functional improvements. This thesis presents research on the effect of sub-cortical implantation of CTX0E03 cells on the resting- state sensorimotor network and sensorimotor deficits in the rat following experimental stroke, using protocols based on previous work with this cell line. The work in this thesis identified functional tests of appropriate sensitivity for long-term dysfunction suitable for this laboratory, and investigated non-invasive monitoring of physiological variables required to optimize BOLD signal stability within a high-field MRI scanner. Following experimental stroke, rats demonstrated expected sensorimotor dysfunction and changes in the resting-state sensorimotor network. CTX0E03 cells did not improve post-stroke functional outcome (compared to previous studies) and with no changes in resting-state sensorimotor network activity. However, in control animals, we observed changes in functional networks due to the stereotaxic procedure. This illustrates the sensitivity of resting-state fMRI to stereotaxic procedures. We hypothesise that the damage caused by cell or vehicle implantation may have prevented functional and network recovery which has not been previously identified due to the application of different functional tests. The findings in this thesis represent one of few pre-clinical studies in resting-state fMRI network changes post-stroke and the only to date applying this technique to evaluate functional outcomes following a clinically applicable human neural stem cell treatment for ischaemic stroke. It was found that injury caused by stereotaxic injection should be taken into account when assessing the effectiveness of treatment.

Systematic reviews as a tool for planning and interpreting trials

Background Systematic reviews followed by ameta-analysis are carried out in medical research to combine the results of two or more related studies. Stroke trials have struggled to show beneficial effects and meta-analysis should be used more widely throughout the research process to either speed up the development of useful interventions, or halt more quickly research with hazardous or ineffective interventions. Summary of review. This review summarises the clinical research process and illustrates how and when systematic reviews may be used throughout the development programme. Meta-analyses should be performed after observational studies, preclinical studies in experimental stroke, and after phase I, II, and III clinical trials and phase IV clinical surveillance studies. Although meta-analyses most commonly work with summary data, they may be performed to assess relationships between variables (meta-regression) and, ideally, should utilise individual patient data. Meta-analysis techniques may alsoworkwith ordered categorical outcome data (ordinal meta-analysis) and be used to perform indirect comparisons where original trial data do not exist. Conclusion Systematic review/meta-analyses are powerful tools in medical research and should be used throughout the development of all stroke and other interventions

Informed consent in clinical research: do patients understand what they have signed?

Informed consent is an essential element of research, and signing this document is required to conduct most clinical trials. Its aim is to inform patients what their participation in the study will involve. However, increasingly, their complexity and length are making them difficult to understand, which might lead patients to give their authorization without having read them previously or without having understood what is stated. In this sense, the Ethics Committees for Clinical Research, and Pharmacists specialized in Hospital Pharmacy and Primary Care in their capacity as members of said committees, play an important and difficult role in defending the rights of patients. These Committees will review thoroughly these documents to guarantee that all legal requirements have been met and, at the same time, that they are easy to understand by the potential participants in a clinical trial.

Chromium supplementation in patients with type 2 diabetes and high risk of type 2 diabetes: a meta-analysis of randomized controlled trials

Introduction: Chromium is an essential trace mineral for carbohydrate and lipid metabolism, which is currently prescribed to control diabetes mellitus. Results of previous systematic reviews and meta-analyses of chromium supplementation and metabolic profiles in diabetes have been inconsistent. Aim: The objective of this meta-analysis was to assess the effects on metabolic profiles and safety of chromium supplementation in type 2 diabetes mellitus and cholesterol. Methods: Literature searches in PubMed, Scopus and Web of Science were made by use of related terms-keywords and randomized clinical trials during the period of 2000-2014. Results: Thirteen trials fulfilled the inclusion criteria and were included in this systematic review. Total doses of Cr supplementation and brewer's yeast ranged from 42 to 1,000 µg/day, and duration of supplementation ranged from 30 to 120 days. The analysis indicated that there was a significant effect of chromium supplementation in diabetics on fasting plasma glucose with a weighted average effect size of -29.26 mg/dL, p = 0.01, CI 95% = -52.4 to -6.09; and on total cholesterol with a weighted average effect size of -6.7 mg/dL, p = 0.01, CI 95% = -11.88 to -1.53. Conclusions: The available evidence suggests favourable effects of chromium supplementation on glycaemic control in patients with diabetes. Chromium supplementation may additionally improve total cholesterol levels.