After 10 years of clinical trials with liraglutide, do we know whether it is beneficial in diabetes?

Type 2 diabetes remains an escalating world-wide problem, despite a range of treatments. The revelation that insulin secretion is under the control of a gut hormone, glucagon-like peptide 1 (GLP-1), led to a new paradigm in the management of type 2 diabetes. Liraglutide is a long acting GLP-1 receptor agonist used in the treatment of type 2 diabetes. The review considers the clinical trials with liraglutide. There are many comparator trials between liraglutide and other medicines for the treatment of type 2 diabetes, and these trials have shown that liraglutide lowers HbA1c and body weight, and is well tolerated. A large cardiovascular safety trial with liraglutide is presently being undertaken. After 10 years of clinical trials with liraglutide, we do not know whether liraglutide has cardiovascular safety in subjects with type 2 diabetes and high cardiovascular risk. Although this is not a requirement for registration by the Food and Drug Administration (FDA), in my opinion, they should reconsider this. We also do not presently know whether liraglutide has any beneficial effects on clinical cardiovascular outcomes.

Clinical pathways for chronic cough in children

Background Chronic cough (a cough lasting longer than four weeks) is a common problem internationally. Chronic cough has associated economic costs and is distressing to the child and to parents; ignoring cough may lead to delayed diagnosis and progression of serious underlying respiratory disease. Clinical guidelines have been shown to lead to efficient and effective patient care and can facilitate clinical decision making. Cough guidelines have been designed to facilitate the management of chronic cough. However, treatment recommendations vary, and specific clinical pathways for the treatment of chronic cough in children are important, as causes of and treatments for cough vary significantly from those in adults. Therefore, systematic evaluation of the use of evidence-based clinical pathways for the management of chronic cough in children would be beneficial for clinical practice and for patient care. Use of a management algorithm can improve clinical outcomes; such management guidelines can be found in the guidelines for cough provided by the American College of Chest Physicians (ACCP) and the British Thoracic Society (BTS). Objectives To evaluate the effectiveness of using a clinical pathway in the management of children with chronic cough. Search methods The Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE, review articles and reference lists of re levant articles were searched. The latest search was conducted in January 2014. Selection criteria All randomised controlled trials of parallel-group design comparing use versus non-use of a clinical pathway for treatment of chronic cough in children (< 18 years of age). Data collection and analysis Results of searches were reviewed against predetermined cr iteria for inclusion. Two review authors independently selected studies and performed data extraction in duplicate. Main results One study was included in the review. This multi-centre trial was based in five Australian hospitals and recruited 272 children with chronic cough. Children were randomly assigned to early (two weeks) or delayed (six weeks) referral to respiratory specialists who used a cough management pathway. When an intention-to-treat analysis was performed, clinical failure at six wee ks post randomisation (defined as < 75% improvement in cough score, or total resolution for fewer than three consecutive days) was significantly less in the early pathway arm compared with the control arm (odds ratio (OR) 0.35, 95% confidence interval (CI) 0.21 to 0.58). These results indicate that one additional child will be cured for e very five children treated via th e cough pathway (number needed to treat for an additional beneficial outcome (NNTB) = 5, 95% CI 3 to 9) at six weeks. Cough-specific parent-reported quality of life scores were significantly better in th e early-pathway group; the mean difference (MD) between groups was 0.60 (95% CI 0.19 to 1.01). Duration of cough post randomisation was significantly shorter in the intervention group (early-pathway arm) compared with the control group (delayed-pathway arm) (MD -2.70 weeks, 95% CI -4.26 to -1.14). Authors’ conclusions. Current evidence suggests that using a clinical algorithm for the management of children with ch r onic cough in h ospital outpatient settings is more effective than providing wait-list care. Futher high-quality randomised controlled trials are needed to perform ongoing evaluation of cough management pathways in general practitioner and other primary care settings.

A method for matching patients to advanced prostate cancer clinical trials

Objective: To illustrate a new method for simplifying patient recruitment for advanced prostate cancer clinical trials using natural language processing techniques. Background: The identification of eligible participants for clinical trials is a critical factor to increase patient recruitment rates and an important issue for discovery of new treatment interventions. The current practice of identifying eligible participants is highly constrained due to manual processing of disparate sources of unstructured patient data. Informatics-based approaches can simplify the complex task of evaluating patient’s eligibility for clinical trials. We show that an ontology-based approach can address the challenge of matching patients to suitable clinical trials. Methods: The free-text descriptions of clinical trial criteria as well as patient data were analysed. A set of common inclusion and exclusion criteria was identified through consultations with expert clinical trial coordinators. A research prototype was developed using Unstructured Information Management Architecture (UIMA) that identified SNOMED CT concepts in the patient data and clinical trial description. The SNOMED CT concepts model the standard clinical terminology that can be used to represent and evaluate patient’s inclusion/exclusion criteria for the clinical trial. Results: Our experimental research prototype describes a semi-automated method for filtering patient records using common clinical trial criteria. Our method simplified the patient recruitment process. The discussion with clinical trial coordinators showed that the efficiency in patient recruitment process measured in terms of information processing time could be improved by 25%. Conclusion: An UIMA-based approach can resolve complexities in patient recruitment for advanced prostate cancer clinical trials.

Document timespan normalisation and understanding temporality for clinical records search

Previous qualitative research has highlighted that temporality plays an important role in relevance for clinical records search. In this study, an investigation is undertaken to determine the effect that the timespan of events within a patient record has on relevance in a retrieval scenario. In addition, based on the standard practise of document length normalisation, a document timespan normalisation model that specifically accounts for timespans is proposed. Initial analysis revealed that in general relevant patient records tended to cover a longer timespan of events than non-relevant patient records. However, an empirical evaluation using the TREC Medical Records track supports the opposite view that shorter documents (in terms of timespan) are better for retrieval. These findings highlight that the role of temporality in relevance is complex and how to effectively deal with temporality within a retrieval scenario remains an open question.

A 2-hour diagnostic protocol for possible cardiac chest pain in the emergency department: A randomized clinical trial

IMPORTANCE Patients with chest pain represent a high health care burden, but it may be possible to identify a patient group with a low short-term risk of adverse cardiac events who are suitable for early discharge. OBJECTIVE To compare the effectiveness of a rapid diagnostic pathway with a standard-care diagnostic pathway for the assessment of patients with possible cardiac chest pain in a usual clinical practice setting. DESIGN, SETTING, AND PARTICIPANTS A single-center, randomized parallel-group trial with blinded outcome assessments was conducted in an academic general and tertiary hospital. Participants included adults with acute chest pain consistent with acute coronary syndrome for whom the attending physician planned further observation and troponin testing. Patient recruitment occurred from October 11, 2010, to July 4, 2012, with a 30-day follow-up. INTERVENTIONS An experimental pathway using an accelerated diagnostic protocol (Thrombolysis in Myocardial Infarction score, 0; electrocardiography; and 0- and 2-hour troponin tests) or a standard-care pathway (troponin test on arrival at hospital, prolonged observation, and a second troponin test 6-12 hours after onset of pain) serving as the control. MAIN OUTCOMES AND MEASURES Discharge from the hospital within 6 hours without a major adverse cardiac event occurring within 30 days. RESULTS Fifty-two of 270 patients in the experimental group were successfully discharged within 6 hours compared with 30 of 272 patients in the control group (19.3% vs 11.0%; odds ratio, 1.92; 95% CI, 1.18-3.13; P = .008). It required 20 hours to discharge the same proportion of patients from the control group as achieved in the experimental group within 6 hours. In the experimental group, 35 additional patients (12.9%) were classified as low risk but admitted to an inpatient ward for cardiac investigation. None of the 35 patients received a diagnosis of acute coronary syndrome after inpatient evaluation. CONCLUSIONS AND RELEVANCE Using the accelerated diagnostic protocol in the experimental pathway almost doubled the proportion of patients with chest pain discharged early. Clinicians could discharge approximately 1 of 5 patients with chest pain to outpatient follow-up monitoring in less than 6 hours. This diagnostic strategy could be easily replicated in other centers because no extra resources are required.

Manufacturing and use of human placenta-derived mesenchymal stromal cells for phase I clinical trials: Establishment and evaluation of a protocol

Background/Aim. Mesenchymal stromal cells (MSCs) have been utilised in many clinical trials as an experimental treatment in numerous clinical settings. Bone marrow remains the traditional source tissue for MSCs but is relatively hard to access in large volumes. Alternatively, MSCs may be derived from other tissues including the placenta and adipose tissue. In an initial study no obvious differences in parameters such as cell surface phenotype, chemokine receptor display, mesodermal differentiation capacity or immunosuppressive ability, were detected when we compared human marrow derived- MSCs to human placenta-derived MSCs. The aim of this study was to establish and evaluate a protocol and related processes for preparation placenta-derived MSCs for early phase clinical trials. Methods. A full-term placenta was taken after delivery of the baby as a source of MSCs. Isolation, seeding, incubation, cryopreservation of human placentaderived MSCs and used production release criteria were in accordance with the complex regulatory requirements applicable to Code of Good Manufacturing Practice manufacturing of ex vivo expanded cells. Results. We established and evaluated instructions for MSCs preparation protocol and gave an overview of the three clinical areas application. In the first trial, MSCs were co-transplanted iv to patient receiving an allogeneic cord blood transplant as therapy for treatmentrefractory acute myeloid leukemia. In the second trial, MSCs were administered iv in the treatment of idiopathic pulmonary fibrosis and without serious adverse effects. In the third trial, MSCs were injected directly into the site of tendon damage using ultrasound guidance in the treatment of chronic refractory tendinopathy. Conclusion. Clinical trials using both allogeneic and autologous cells demonstrated MSCs to be safe. A described protocol for human placenta-derived MSCs is appropriate for use in a clinical setting, relatively inexpensive and can be relatively easily adjusted to a different set of regulatory requirements, as applicable to early phase clinical trials.

Experiences of countertransference: Reports of clinical psychology students

While historically linked with psychoanalysis, countertransference is recognised as an important component of the experience of therapists, regardless of the therapeutic modality. This study considers the implications of this for the training of psychologists. Fifty-five clinical psychology trainees from four university training programmes completed an anonymous questionnaire that collected written reports of countertransference experiences, ratings of confidence in managing these responses, and supervision in this regard. The reports were analysed using a process of thematic analysis. Several themes emerged including a desire to protect or rescue clients, feeling criticised or controlled by clients, feeling helpless, and feeling disengaged. Trainees varied in their reports of awareness of countertransference and the regularity of supervision in this regard. The majority reported a lack of confidence in managing their responses, and all reported interest in learning about countertransference. The implications for reflective practice in postgraduate psychology training are discussed.

The Queensland high risk foot form (QHRFF): Is it a reliable and valid clinical research tool for foot disease?

Background Foot disease complications, such as foot ulcers and infection, contribute to considerable morbidity and mortality. These complications are typically precipitated by “high-risk factors”, such as peripheral neuropathy and peripheral arterial disease. High-risk factors are more prevalent in specific “at risk” populations such as diabetes, kidney disease and cardiovascular disease. To the best of the authors’ knowledge a tool capturing multiple high-risk factors and foot disease complications in multiple at risk populations has yet to be tested. This study aimed to develop and test the validity and reliability of a Queensland High Risk Foot Form (QHRFF) tool. Methods The study was conducted in two phases. Phase one developed a QHRFF using an existing diabetes foot disease tool, literature searches, stakeholder groups and expert panel. Phase two tested the QHRFF for validity and reliability. Four clinicians, representing different levels of expertise, were recruited to test validity and reliability. Three cohorts of patients were recruited; one tested criterion measure reliability (n = 32), another tested criterion validity and inter-rater reliability (n = 43), and another tested intra-rater reliability (n = 19). Validity was determined using sensitivity, specificity and positive predictive values (PPV). Reliability was determined using Kappa, weighted Kappa and intra-class correlation (ICC) statistics. Results A QHRFF tool containing 46 items across seven domains was developed. Criterion measure reliability of at least moderate categories of agreement (Kappa > 0.4; ICC > 0.75) was seen in 91% (29 of 32) tested items. Criterion validity of at least moderate categories (PPV > 0.7) was seen in 83% (60 of 72) tested items. Inter- and intra-rater reliability of at least moderate categories (Kappa > 0.4; ICC > 0.75) was seen in 88% (84 of 96) and 87% (20 of 23) tested items respectively. Conclusions The QHRFF had acceptable validity and reliability across the majority of items; particularly items identifying relevant co-morbidities, high-risk factors and foot disease complications. Recommendations have been made to improve or remove identified weaker items for future QHRFF versions. Overall, the QHRFF possesses suitable practicality, validity and reliability to assess and capture relevant foot disease items across multiple at risk populations.

Angular dependence of the response of the nanoDot OSLD system for measurements at depth in clinical megavoltage beams

Purpose The purpose of this investigation was to assess the angular dependence of a commercial optically stimulated luminescence dosimeter (OSLD) dosimetry system in MV x-ray beams at depths beyondd max and to find ways to mitigate this dependence for measurements in phantoms. Methods Two special holders were designed which allow a dosimeter to be rotated around the center of its sensitive volume. The dosimeter's sensitive volume is a disk, 5 mm in diameter and 0.2 mm thick. The first holder rotates the disk in the traditional way. It positions the disk perpendicular to the beam (gantry pointing to the floor) in the initial position (0°). When the holder is rotated the angle of the disk towards the beam increases until the disk is parallel with the beam (“edge on,” 90°). This is referred to as Setup 1. The second holder offers a new, alternative measurement position. It positions the disk parallel to the beam for all angles while rotating around its center (Setup 2). Measurements with five to ten dosimeters per point were carried out for 6 MV at 3 and 10 cm depth. Monte Carlo simulations using GEANT4 were performed to simulate the response of the active detector material for several angles. Detector and housing were simulated in detail based on microCT data and communications with the manufacturer. Various material compositions and an all-water geometry were considered. Results For the traditional Setup 1 the response of the OSLD dropped on average by 1.4% ± 0.7% (measurement) and 2.1% ± 0.3% (Monte Carlo simulation) for the 90° orientation compared to 0°. Monte Carlo simulations also showed a strong dependence of the effect on the composition of the sensitive layer. Assuming the layer to completely consist of the active material (Al2O3) results in a 7% drop in response for 90° compared to 0°. Assuming the layer to be completely water, results in a flat response within the simulation uncertainty of about 1%. For the new Setup 2, measurements and Monte Carlo simulations found the angular dependence of the dosimeter to be below 1% and within the measurement uncertainty. Conclusions The dosimeter system exhibits a small angular dependence of approximately 2% which needs to be considered for measurements involving other than normal incident beams angles. This applies in particular to clinicalin vivo measurements where the orientation of the dosimeter is dictated by clinical circumstances and cannot be optimized as otherwise suggested here. When measuring in a phantom, the proposed new setup should be considered. It changes the orientation of the dosimeter so that a coplanar beam arrangement always hits the disk shaped detector material from the thin side and thereby reduces the angular dependence of the response to within the measurement uncertainty of about 1%. This improvement makes the dosimeter more attractive for clinical measurements with multiple coplanar beams in phantoms, as the overall measurement uncertainty is reduced. Similarly, phantom based postal audits can transition from the traditional TLD to the more accurate and convenient OSLD.

A clinical audit to compare peritonitis rates between peritoneal dialysis delivery systems

Peritonitis is a major problem for patients with end-stage kidney disease undergoing peritoneal dialysis (PD). It is the main cause of failure of PD. Two different PD delivery systems are used across Australia although there is inconsistent evidence comparing the systems. The aim of this retrospective audit is to compare the rates and risk of peritonitis in a cohort of incident patients using two PD delivery systems. All consecutive patients starting PD between 1 August 2010 and 31 March 2012 were included and followed until 30 June 2013. Data relating to accepted risk factors for peritonitis were collected and analysed. There were 50 patients (26 men; 24 women) aged between 30 and 87 years. There were 29 episodes of peritonitis in 17 patients. Rates of peritonitis were 1 episode per 69.19 patient-months compared with 1 episode per 18.67 patient-months. Mean times to first episode of peritonitis were 13.11 months compared to 7.13 months. The relative risk of PD-related peritonitis was twice as high (RR = 2.04, 95% CI = 0.85 to 4.94) for patients using the one system (44.4%) compared to a second system (21.7%). Since this is not a randomised trial no firm conclusions can be drawn. Centres should also monitor peritonitis rates for each system.

Randomised clinical trial of a family-based lifestyle intervention for childhood obesity involving parents as the exclusive agents of change

Parent-centred interventions for childhood obesity aim to improve parents' skills and confidence in managing children's dietary and activity patterns, and in promoting a healthy lifestyle in their family. However, few studies assess changes in parenting over the course of treatment. This study describes the evaluation of a lifestyle-specific parenting program (Group Lifestyle Triple P) on multiple child and parent outcomes. One-hundred-and-one families with overweight and obese 4- to 11-year-old children participated in an intervention or waitlist control condition. The 12-week intervention was associated with significant reductions in child BMI z score and weight-related problem behaviour. At the end of the intervention, parents reported increased confidence in managing children's weight-related behaviour, and less frequent use of inconsistent or coercive parenting practices. All short-term intervention effects were maintained at one-year follow-up assessment, with additional improvements in child body size. The results support the efficacy of Group Lifestyle Triple P and suggest that parenting influences treatment outcomes. Further research is needed to evaluate the long-term effectiveness of the intervention and to elucidate the mechanisms of change. © 2010 Elsevier Ltd.

The lean paradox : How can healthcare facilities shrink while clinical spaces expand?

Lean principles create highly efficient healthcare facilities by maximising the clinical value of every part of a facility and by removing everything else. In order that clinical accommodation can be used for a diverse set of functions including unexpected tasks and processes that haven’t even been invented, they have to be big. But somewhat surprisingly, whole facilities tend to shrink in terms of gross floor areas by disposing of non-clinical spaces when designed using Lean principles. And with the whole unit – the building costs shrink too. Using examples from the UK and the USA, this talk explores the unexpected solutions and improved outcomes when designers use a Lean approach to design.

Convergence of regenerative medicine and synthetic biology to develop standardized and validated models of human diseases with clinical relevance

In order to progress beyond currently available medical devices and implants, the concept of tissue engineering has moved into the centre of biomedical research worldwide. The aim of this approach is not to replace damaged tissue with an implant or device but rather to prompt the patient's own tissue to enact a regenerative response by using a tissue-engineered construct to assemble new functional and healthy tissue. More recently, it has been suggested that the combination of Synthetic Biology and translational tissue-engineering techniques could enhance the field of personalized medicine, not only from a regenerative medicine perspective, but also to provide frontier technologies for building and transforming the research landscape in the field of in vitro and in vivo disease models.

'Sink or swim': An evaluation of the clinical characteristics of individuals with high bone mass

Summary High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. Introduction High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. Methods Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. Results Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m 2, p < 0.001). Conclusion Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.