Cathy Jackson

Methods to improve recruitment to randomised controlled trials: Cochrane systematic review and meta-analysis

This review is an abridged version of a Cochrane Review previously published in the Cochrane Database of Systematic Reviews 2010, Issue 4, Art. No.: MR000013 DOI: 10.1002/14651858.MR000013.pub5 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and Cochrane Database of Systematic Reviews should be consulted for the most recent version of the review. Objective To identify interventions designed to improve recruitment to randomised controlled trials, and to quantify their effect on trial participation. Design Systematic review. Data sources The Cochrane Methodology Review Group Specialised Register in the Cochrane Library, MEDLINE, EMBASE, ERIC, Science Citation Index, Social Sciences Citation Index, C2-SPECTR, the National Research Register and PubMed. Most searches were undertaken up to 2010; no language restrictions were applied. Study selection Randomised and quasi-randomised controlled trials, including those recruiting to hypothetical studies. Studies on retention strategies, examining ways to increase questionnaire response or evaluating the use of incentives for clinicians were excluded. The study population included any potential trial participant (eg, patient, clinician and member of the public), or individual or group of individuals responsible for trial recruitment (eg, clinicians, researchers and recruitment sites). Two authors independently screened identified studies for eligibility. Results 45 trials with over 43 000 participants were included. Some interventions were effective in increasing recruitment: telephone reminders to non-respondents (risk ratio (RR) 1.66, 95% CI 1.03 to 2.46; two studies, 1058 participants), use of opt-out rather than opt-in procedures for contacting potential participants (RR 1.39, 95% CI 1.06 to 1.84; one study, 152 participants) and open designs where participants know which treatment they are receiving in the trial (RR 1.22, 95% CI 1.09 to 1.36; two studies, 4833 participants). However, the effect of many other strategies is less clear, including the use of video to provide trial information and interventions aimed at recruiters. Conclusions There are promising strategies for increasing recruitment to trials, but some methods, such as open-trial designs and opt-out strategies, must be considered carefully as their use may also present methodological or ethical challenges. Questions remain as to the applicability of results originating from hypothetical trials, including those relating to the use of monetary incentives, and there is a clear knowledge gap with regard to effective strategies aimed at recruiters.

Adverse Respiratory Effect of Acute β-Blocker Exposure in Asthma: A Systematic Review and Meta-analysis of Randomized Controlled Trials

BACKGROUND β-Blockers are avoided in asthma over concerns regarding acute bronchoconstriction. Risk is greatest following acute exposure, including the potential for antagonism of β2-agonist rescue therapy. METHODS A systematic review of databases was performed to identify all randomized, blinded, placebo-controlled clinical trials evaluating acute β-blocker exposure in asthma. Effect estimates for changes in respiratory function, symptoms, and β2-agonist response were pooled using random effects meta-analysis with heterogeneity investigated. RESULTS Acute selective β-blockers in the doses given caused a mean change in FEV1 of −6.9% (95% CI, −8.5 to −5.2), a fall in FEV1 of ≥20% in one in eight patients (P=.03), symptoms affecting one in 33 patients (P=.18), and attenuation of concomitant β2-agonist response of −10.2% (95% CI, −14.0 to −6.4). Corresponding values for acute nonselective β-blockers in the doses given were −10.2% (95% CI, −14.7 to −5.6), one in nine patients (P=.02), one in 13 patients (P=.14), and −20.0% (95% CI, −29.4 to −10.7). Following investigation of heterogeneity, clear differences were found for celiprolol and labetalol. A dose-response relationship was demonstrated for selective β-blockers. CONCLUSIONS Selective β-blockers are better tolerated but not completely risk-free. Risk from acute exposure may be mitigated using the smallest dose possible and β-blockers with greater β1-selectivity. β-Blocker-induced bronchospasm responded partially to β2-agonists in the doses given with response blunted more by nonselective β-blockers than selective β-blockers. Use of β-blockers in asthma could possibly be based upon a risk assessment on an individual patient basis.

Objective assessment of changes in nuclear morphology and cell distribution following induction of apoptosis

BackgroundTo objectively measure changes in nuclear morphology and cell distribution following induction of apoptosis.MethodsA spontaneously immortalized retinal pigment epithelial cell line (ARPE-19) was cultured for three days in DMEM/F12 with 10% fetal bovine serum followed by 24 hours incubation in staurosporine to induce apoptosis. Cells that were not incubated in staurosporine served as control. Caspase-3 expression in apoptotic cells was demonstrated by quantitative immunofluorescence. Nuclei were counterstained with DAPI. Assessments of nuclear morphology and cell distribution were performed using ImageJ software. Statistical analyses included Student’s t-test and Pearson’s correlation coefficient. Nearest neighbor analysis was used to assess cell nuclei distribution.ResultsCaspase-3 expression in staurosporine-incubated cells increased by 471% ± 182% compared to control (P = 0.014). Relative to the control, cells in the staurosporine-incubated cultures had smaller average nuclear area (68% ± 5%; P < 0.001) and nuclear circumference (78 ± 3%; P < 0.001), while nuclear form factor was larger (110% ± 1%; P < 0.001). Cell nuclei from the staurosporine-group (R = 1.12 ± 0.04; P < 0.01) and the control (R = 1.28 ± 0.03; P < 0.01) were evenly spaced throughout the cultures, thereby demonstrating a non-clustered and non-random cell distribution. However, the staurosporine-incubated group had a significantly lower R-value compared to the control (P = 0.002), which indicated a move towards cell clustering following induction of apoptosis. Caspase-3 expression of each individual cell correlated significantly with the following morphological indicators: circumference of the nucleus divided by form factor (r = -0.475; P < 0.001), nuclear area divided by form factor (r = -0.470; P < 0.001), nuclear circumference (r = -0.469; P < 0.001), nuclear area (r = -0.445; P < 0.001), nuclear form factor (r = 0.410; P < 0.001) and the nuclear area multiplied by form factor) (r = -0.377; P < 0.001).ConclusionsCaspase-3 positive apoptotic cells demonstrate morphological features that can be objectively quantified using freely available ImageJ software. A novel morphological indicator, defined as the nuclear circumference divided by form factor, demonstrated the strongest correlation with caspase-3 expression.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3271993311662947

How can student experience enhance the development of a model of interprofessional clinical skills education in the practice placement setting

The practice placement setting offers opportunities and challenges for engaging students in high-quality interprofessional learning. The Fife Interprofessional Clinical Skills Model for Education was established to develop structured interprofessional learning opportunities for students during their clinical attachments in NHS Fife. This short report describes the delivery and evaluation of the model, which was piloted with students from the nursing, medicine and allied health professions. Scheduled workshops were delivered within primary and secondary care locations. The learning activities involved exploring and comparing their professional identities, discussing roles and responsibilities within the healthcare team and practicing nontechnical clinical skills. Students who participated in the workshops reported that they developed a better understanding of each others roles and responsibilities and also identified that this would be transferable knowledge to their future practice. Exploring the student experience has assisted in developing relevant and accessible interprofessional learning opportunities within the practice placement setting.

Cultured epidermal stem cells in regenerative medicine

Transplantation of cultured epidermal cell sheets (CES) has long been used to treat patients with burns, chronic wounds, and stable vitiligo. In patients with large area burns this can be a life-saving procedure. The ultimate goal, however, is to restore all normal functions of the skin and prevent scar formation. Increased focus on the incorporation of epidermal stem cells (EpiSCs) within CES transplants may ultimately prove to be key to achieving this. Transplanted EpiSCs contribute to restoring the complete epidermis and provide long-term renewal.Maintenance of the regenerative potential of EpiSCs is anchorage-dependent. The extracellular matrix (ECM) provides physical cues that are interpreted by EpiSCs and reciprocal signaling between cells and ECM are integrated to determine cell fate. Thus, the carrier scaffold chosen for culture and transplant influences maintenance of EpiSC phenotype and may enhance or detract from regenerative healing following transfer.Long-term effectiveness and safety of genetically modified EpiSCs to correct the severe skin blistering disease epidermolysis bullosa has been shown clinically. Furthermore, skin is gaining interest as an easily accessible source of adult epithelial stem cells potentially useful for restoration of other types of epithelia. This review highlights the role of EpiSCs in the current treatment of skin injury and disease, as well as their potential in novel regenerative medicine applications involving other epithelia.

Prescribing of β-adrenoceptor antagonists in asthma: an observational study

Background β-Antagonists have recently been proposed for the treatment of chronic asthma; however, concerns regarding risk of acute bronchoconstriction in clinical trials remain. Objective To determine the frequency of oral β-blocker prescribing in patients with asthma and associations with severe asthma exacerbations requiring oral steroids in patients with active asthma defined by prior asthma-related medication use. Methods Patients with asthma registered on 31 March 2007 and all asthma-related medications from the preceding 2 years were identified from anonymised clinical data from one-third of Scottish general practices. The main outcome measure was the relative incidence of active asthma patients receiving oral steroids following a new oral β-antagonist prescription. Results Of the 53 994 adult patients identified with asthma 1527 (2.8%; 95% CI 2.69% to 2.97%) patients were prescribed an oral β-antagonist of which 441 (28.9%, 95% CI 26.7% to 31.2%) had active asthma and received a new β-blocker prescription. The average number of patients prescribed rescue steroids at baseline in 367 patients with sufficient follow-up was 3.4 (0.9%) patients every 2 weeks. Rescue steroids were prescribed to 3 (0.8%) patients in the first 2 weeks and to 3 (0.8%) patients in the second 2 weeks following the new oral β-antagonist (incidence rate ratio (IRR) 0.87, 95% CI 0.25 to 2.99 and IRR 0.89, 95% CI 0.26 to 2.97, respectively). No significant difference was found following stratification for β-antagonist selectivity. Conclusion These results suggest that prescribing new oral β-blockers for the purpose of investigating potentially beneficial effects of chronic treatment would not lead to large increases in patients treated with oral steroids acutely in general practice.

Patient, practice and organisational influences on asthma control: observational data from a national study on primary care in the United Kingdom.

BACKGROUND Achieving asthma control is central to optimising patient quality of life and clinical outcome. Contemporary models of chronic disease management across a variety of countries point to the importance of micro, meso and macro level influences on patient care and outcome. However, asthma outcomes research has almost invariably concentrated on identifying and addressing patient predictors. Little is known about higher level organisational influences. OBJECTIVE This paper explores the contribution of organisational factors on poor asthma control, allowing for patient factors, at three organisational levels: the individual patient, local service deliverers, and strategic regional providers. DESIGN, SETTING AND PARTICIPANTS Prospective cross-sectional observational cohort study of 64,929 people with asthma from 1205 primary care practices spread throughout the United Kingdom (UK). Patient clinical data were recorded during a routine asthma review. METHOD Data were analysed using simple descriptive, multiple regression and complex multi-level modelling techniques, accounting for practice clustering of patients. RESULTS Poor asthma control was associated with areas of higher deprivation [regression coefficient 0.026 (95% confidence intervals 0.006; 0.046)] and urban practice [-0.155 (-0.275; -0.035)] but not all local and regional variation was explained by the data. In contrast, patient level predictors of poor control were: short acting bronchodilator overuse [2.129 (2.091; 2.164)], days-off due to asthma [1.203 (1.148; 1.258)], PEFR<80 [0.76 (0.666; 0.854)], non-use of a self-management plan (SMP) [0.554 (0.515; 0.593)], poor inhaler technique [0.53 (0.475; 0.585)], poor medication compliance [0.385 (-0.007; 0.777)], and gender [0.314 (0.281; 0.347)]. Pattern of medication use, smoking history, age, body mass index (BMI), and health service resource use were also significant factors for predicting control. CONCLUSIONS Targeting of health service resource requires knowledge of the factors associated with poor control of asthma symptoms. In the UK the contribution of local and regional structures appears minimal in explaining variation in asthma outcomes. However, unexplained variation in the data suggests other unrecorded factors may play a part. While patient personal characteristics (including self-management plan use, inhaler technique, medication compliance) appear to be the predominant influence the complex nature of the disease means that some, perhaps more subtle, influences are affecting the variability at all levels and this variance needs to be explored. Further research in other international contexts is required to identify the likely applicability of these findings to other health care systems.

Effect of Storage Temperature on Cultured Epidermal Cell Sheets Stored in Xenobiotic-Free Medium

Cultured epidermal cell sheets (CECS) are used in regenerative medicine in patients with burns, and have potential to treat limbal stem cell deficiency (LSCD), as demonstrated in animal models. Despite widespread use, short-term storage options for CECS are limited. Advantages of storage include: flexibility in scheduling surgery, reserve sheets for repeat operations, more opportunity for quality control, and improved transportation to allow wider distribution. Studies on storage of CECS have thus far focused on cryopreservation, whereas refrigeration is a convenient method commonly used for whole skin graft storage in burns clinics. It has been shown that preservation of viable cells using these methods is variable. This study evaluated the effect of different temperatures spanning 4°C to 37°C, on the cell viability, morphology, proliferation and metabolic status of CECS stored over a two week period in a xenobiotic–free system. Compared to non-stored control, best cell viability was obtained at 24°C (95.2±9.9%); reduced cell viability, at approximately 60%, was demonstrated at several of the temperatures (12°C, 28°C, 32°C and 37°C). Metabolic activity was significantly higher between 24°C and 37°C, where glucose, lactate, lactate/glucose ratios, and oxygen tension indicated increased activation of the glycolytic pathway under aerobic conditions. Preservation of morphology as shown by phase contrast and scanning electron micrographs was best at 12°C and 16°C. PCNA immunocytochemistry indicated that only 12°C and 20°C allowed maintenance of proliferative function at a similar level to non-stored control. In conclusion, results indicate that 12°C and 24°C merit further investigation as the prospective optimum temperature for short-term storage of cultured epidermal cell sheets.

Long-acting β-agonist prescribing in people with asthma in primary care.

Long-acting β2-agonist (LABA) monotherapy is contraindicated in asthma following reports of serious adverse events. Anonymised Scottish health data were used to determine the prevalence of LABA prescribing and LABA monotherapy (sustained and episodic) in asthma during 2006. Of 73 486 asthma patients identified, 5592 (7.6%; 95% CI 7.4% to 7.8%) were prescribed LABAs as a separate inhaler of which 991 patients had LABA monotherapy (17.7% (95% CI 16.7% to 18.7%) of patients at risk). Asthma reviews were associated with reductions in sustained (OR 0.44; 95% CI 0.32 to 0.61) but not episodic monotherapy (OR 1.16; 95% CI 0.85 to 1.57). These findings support recent changes in UK asthma guidelines recommending LABAs in fixed-dose combination inhalers.

Effect of Storage Temperature on Structure and Function of Cultured Human Oral Keratinocytes

Purpose/Aims To assess the effect of storage temperature on the viability, phenotype, metabolism, and morphology of cultured human oral keratinocytes (HOK). Materials and Methods Cultured HOK cells were stored in HEPES- and sodium bicarbonate-buffered Minimum Essential Medium (MEM) at nine temperatures in approximately 4°C increments from 4°C to 37°C for seven days. Cells were characterized for viability by calcein fluorescence, phenotype retention by immunocytochemistry, metabolic parameters (pH, glucose, lactate, and O2) within the storage medium by blood gas analysis, and morphology by scanning electron microscopy and light microscopy. Results Relative to the cultured, but non-stored control cells, a high percentage of viable cells were retained only in the 12°C and 16°C storage groups (85%±13% and 68%±10%, respectively). Expression of ABCG2, Bmi1, C/EBPδ, PCNA, cytokeratin 18, and caspase-3 were preserved after storage in the 5 groups between 4°C and 20°C, compared to the non-stored control. Glucose, pH and pO2 in the storage medium declined, whereas lactate increased with increasing storage temperature. Morphology was best preserved following storage of the three groups between 12°C, 16°C, and 20°C. Conclusion We conclude that storage temperatures of 12°C and 16°C were optimal for maintenance of cell viability, phenotype, and morphology of cultured HOK. The storage method described in the present study may be applicable for other cell types and tissues; thus its significance may extend beyond HOK and the field of ophthalmology.