The clinical effectiveness and cost-effectiveness of exercise referral schemes: A systematic review and economic evaluation

- Background Exercise referral schemes (ERS) aim to identify inactive adults in the primary-care setting. The GP or health-care professional then refers the patient to a third-party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the individual. - Objective To assess the clinical effectiveness and cost-effectiveness of ERS for people with a diagnosed medical condition known to benefit from physical activity (PA). The scope of this report was broadened to consider individuals without a diagnosed condition who are sedentary. - Data sources MEDLINE; EMBASE; PsycINFO; The Cochrane Library, ISI Web of Science; SPORTDiscus and ongoing trial registries were searched (from 1990 to October 2009) and included study references were checked. - Methods Systematic reviews: the effectiveness of ERS, predictors of ERS uptake and adherence, and the cost-effectiveness of ERS; and the development of a decision-analytic economic model to assess cost-effectiveness of ERS. - Results Seven randomised controlled trials (UK, n = 5; non-UK, n = 2) met the effectiveness inclusion criteria, five comparing ERS with usual care, two compared ERS with an alternative PA intervention, and one to an ERS plus a self-determination theory (SDT) intervention. In intention-to-treat analysis, compared with usual care, there was weak evidence of an increase in the number of ERS participants who achieved a self-reported 90-150 minutes of at least moderate-intensity PA per week at 6-12 months' follow-up [pooled relative risk (RR) 1.11, 95% confidence interval 0.99 to 1.25]. There was no consistent evidence of a difference between ERS and usual care in the duration of moderate/vigorous intensity and total PA or other outcomes, for example physical fitness, serum lipids, health-related quality of life (HRQoL). There was no between-group difference in outcomes between ERS and alternative PA interventions or ERS plus a SDT intervention. None of the included trials separately reported outcomes in individuals with medical diagnoses. Fourteen observational studies and five randomised controlled trials provided a numerical assessment of ERS uptake and adherence (UK, n = 16; non-UK, n = 3). Women and older people were more likely to take up ERS but women, when compared with men, were less likely to adhere. The four previous economic evaluations identified suggest ERS to be a cost-effective intervention. Indicative incremental cost per quality-adjusted life-year (QALY) estimates for ERS for various scenarios were based on a de novo model-based economic evaluation. Compared with usual care, the mean incremental cost for ERS was £169 and the mean incremental QALY was 0.008, with the base-case incremental cost-effectiveness ratio at £20,876 per QALY in sedentary people without a medical condition and a cost per QALY of £14,618 in sedentary obese individuals, £12,834 in sedentary hypertensive patients, and £8414 for sedentary individuals with depression. Estimates of cost-effectiveness were highly sensitive to plausible variations in the RR for change in PA and cost of ERS. - Limitations We found very limited evidence of the effectiveness of ERS. The estimates of the cost-effectiveness of ERS are based on a simple analytical framework. The economic evaluation reports small differences in costs and effects, and findings highlight the wide range of uncertainty associated with the estimates of effectiveness and the impact of effectiveness on HRQoL. No data were identified as part of the effectiveness review to allow for adjustment of the effect of ERS in different populations. - Conclusions There remains considerable uncertainty as to the effectiveness of ERS for increasing activity, fitness or health indicators or whether they are an efficient use of resources in sedentary people without a medical diagnosis. We failed to identify any trial-based evidence of the effectiveness of ERS in those with a medical diagnosis. Future work should include randomised controlled trials assessing the cinical effectiveness and cost-effectivenesss of ERS in disease groups that may benefit from PA. - Funding The National Institute for Health Research Health Technology Assessment programme.

Nutrition during noninvasive ventilation: clinical determinants and key practical recommendations

Malnutrition and poor nutritional intake have been identified as key issues associated with poorer clinical outcomes in chronic obstructive pulmonary disease (COPD) patients. There is strong evidence showing nutritional support is effective in treating malnutrition in stable COPD, but there is only limited research regarding nutritional status in patients treated with noninvasive ventilation (NIV). The impact of NIV during acute exacerbations of respiratory disease on nutritional status requires further investigation.

A Bayesian approach for estimating detection times in horses : exploring the pharmacokinetics of a urinary acepromazine metabolite

We describe the population pharmacokinetics of an acepromazine (ACP) metabolite (2-(1-hydroxyethyl)promazine) (HEPS) in horses for the estimation of likely detection times in plasma and urine. Acepromazine (30 mg) was administered to 12 horses, and blood and urine samples were taken at frequent intervals for chemical analysis. A Bayesian hierarchical model was fitted to describe concentration-time data and cumulative urine amounts for HEPS. The metabolite HEPS was modelled separately from the parent ACP as the half-life of the parent was considerably less than that of the metabolite. The clearance ($Cl/F_{PM}$) and volume of distribution ($V/F_{PM}$), scaled by the fraction of parent converted to metabolite, were estimated as 769 L/h and 6874 L, respectively. For a typical horse in the study, after receiving 30 mg of ACP, the upper limit of the detection time was 35 hours in plasma and 100 hours in urine, assuming an arbitrary limit of detection of 1 $\mu$g/L, and a small ($\approx 0.01$) probability of detection. The model derived allowed the probability of detection to be estimated at the population level. This analysis was conducted on data collected from only 12 horses, but we assume that this is representative of the wider population.

Pharmacist review prevents evolving metformin-associated lactic acidosis

What is known There is controversy surrounding the risk of metformin and the development of lactic acidosis. There have been no reports of a pharmacist preventing a patient developing metformin-associated lactic acidosis. Objectives Our objective was to report on a pharmacist potentially preventing an evolving case of metformin-associated lactic acidosis (MALA). Case description A patient who had been having episodes of nausea and vomiting for a year was referred for a home medicines review (HMR) by his general practitioner. The pharmacist who conducted the HMR suspected that the patient's symptoms could have been due to metformin. It was recommended to measure the serum lactate level and suspend metformin. Our patient was found to have a high lactate level and was referred to the emergency department by his general practitioner. Recovery was prompt with symptomatic support and cessation of metformin. What is new This appears to be the first case reported in the literature of a pharmacist recognizing an evolving case of MALA. Conclusion Although the incidence of MALA is rare, health professionals should be aware of the initial symptoms of lactic acidosis, especially in elderly patients with risk factors, to prevent a fatal lactic acidosis event.

Good nutrition for good surgery: clinical and quality of life outcomes

Undernutrition is common in patients admitted for surgery and is often unrecognised, untreated and worsens in hospital. The complex synergistic relationship between nutritional status and the physiological responses to surgery puts patients at high nutritional risk. There are clear prospective associations between inadequate nutritional status and the risk of poorer outcomes for surgical patients, including infection, complications and length of stay. However, practically and ethically evidence that nutritional interventions can significantly reduce these poor outcomes is difficult to obtain. Nevertheless health professionals have a duty of care to ensure our patients are properly fed, by whatever means, to meet their physiological requirements.

The spermostatic and microbicidal actions of quinones and malemides : towards a dual-purpose contraceptive agent

There is an urgent need to develop safe, effective, dual-purpose contraceptive agents that combine the prevention of pregnancy with protection against sexually transmitted diseases. Here we report the identification of a group of compounds that on contact with human spermatozoa induce a state of “spermostasis,” characterized by the extremely rapid inhibition of sperm movement without compromising cell viability. These spermostatic agents were more active and significantly less toxic than the reagent in current clinical use, nonoxynol 9, giving therapeutic indices (ratio of spermostatic to cytotoxic activity) that were orders of magnitude greater than this traditional spermicide. Although certain compounds could trigger reactive oxygen species generation by spermatozoa, this activity was not correlated with spermostasis. Rather, the latter was associated with alkylation of two major sperm tail proteins that were identified as A Kinase-Anchoring Proteins (AKAP3 and AKAP4) by mass spectrometry. As a consequence of disrupted AKAP function, the abilities of cAMP to drive protein kinase A-dependent activities in the sperm tail, such as the activation of SRC and the consequent stimulation of tyrosine phosphorylation, were suppressed. Furthermore, analysis of microbicidal activity using Chlamydia muridarum revealed powerful inhibitory effects at the same low micromolar doses that suppressed sperm movement. In this case, the microbicidal action was associated with alkylation of Major Outer Membrane Protein (MOMP), a major chlamydial membrane protein. Taken together, these results have identified for the first time a novel set of cellular targets and chemical principles capable of providing simultaneous defense against both fertility and the spread of sexually transmitted disease.

Timeliness and Clinical Impact of Hospital-Initiated Medication Reviews

Background: Medication-related problems often occur in the immediate post-discharge period. To reduce medication misadventure the Commonwealth Government funds home medicines reviews (HMRs). HMRs are initiated when general practitioners refer consenting patients to their community pharmacists, who then engage accredited pharmacists to review patients' medicines in their homes. Aim: To determine if hospital-initiated medication reviews (HIMRs) can be implemented in a more timely manner than HMRs; and to assess the impact of a bespoke referral form with comorbidity-specific questions on the quality of reports. Method: Eligible medical inpatients at risk of medication misadventure were referred by the hospital liaison pharmacist to participating accredited pharmacists post-discharge from hospital. Social, demographic and laboratory data were collected from medical records and during interviews with consenting patients. Issues raised in the HIMR reports were categorised: intervention/action, information given or recommendation, and assigned a rank of clinical significance. Results: HIMRs were conducted within 11.6 6.6 days postdischarge. 36 HIMR reports were evaluated and 1442 issues identified - information given (n = 1204), recommendations made (n = 88) and actions taken (n = 150). The majority of issues raised (89%) had a minor clinical impact. The bespoke referral form prompted approximately half of the issues raised. Conclusion: HIMRs can be facilitated in a more timely manner than post-discharge HMRs. There was an associated positive clinical impact of issues raised in the HIMR reports.

Improved treatment of nicotine addiction and emerging pulmonary drug delivery

Nicotine addiction remains the leading cause of death and disease in developed and developing nations and a major cause of mortality around the world. Currently, nicotine replacement therapies (NRTs), bupropion, and varenicline are approved by the regulatory agencies as first-line treatments for nicotine addiction. Emerging evidence indicates that varenicline and bupropion have some therapeutic limitations for treating nicotine addiction with oral route of administration. Thus, continued investigation of innovative drug delivery for nicotine addiction remains a critical priority. This review will discuss some novel strategies and future directions for pulmonary drug delivery, an emerging route of administration for smoking cessation. It is anticipated that the advancement of knowledge on pulmonary drug delivery will provide better management for nicotine addiction and other addictive disorders.

Exenatide extended-release; clinical trials, patient preference, and economic considerations

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, medicines that directly stimulate, or that prolong the actions of the endogenous GLP-1, at its receptors. Exenatide is an agonist at the GLP-1 receptors, and was initially developed as a subcutaneous twice daily medication, ExBID. The clinical trials with ExBID established a role for exenatide in the treatment of type 2 diabetes. Subsequently, once weekly exenatide (ExQW) was shown to have advantages over ExBID, and there is now more emphasis on the development of ExQW. ExQW alone reduces glycosylated haemoglobin (HbA1c) and body weight, and is well tolerated. ExQW has been compared to sitagliptin, pioglitazone and metformin, and shown to have a greater ability to reduce HbA1c than these other medicines. The only preparation of insulin, which ExQW has been compared to, is insulin glargine, and the ExQW has some favourable properties in this comparison, notably causing weight loss, compared to the gain with insulin glargine. ExQW has been compared to another GLP-1 receptor agonist, liraglutide, and ExQW is non-inferior to liraglutide in reducing HbA1c. The small amount of evidence available, shows that subjects with type 2 diabetes, prefer ExQW to ExBID, and that adherence was high to these in the clinical trial setting. Healthcare and economic modelling suggests that ExQW will reduce diabetic complications and be cost-effective, compared to other medications, with long term use. Little is known about whether subjects with type 2 diabetes prefer ExQW to other medicines, and whether adherence is good to ExQW in practice, and these important topics require further study.

Attention and memory bias for body image and health related information using an Emotional Stroop task in a non-clinical sample

It has been proposed that body image disturbance is a form of cognitive bias wherein schemas for self-relevant information guide the selective processing of appearancerelated information in the environment. This threatening information receives disproportionately more attention and memory, as measured by an Emotional Stroop and incidental recall task. The aim of this thesis was to expand the literature on cognitive processing biases in non-clinical males and females by incorporating a number of significant methodological refinements. To achieve this aim, three phases of research were conducted. The initial two phases of research provided preliminary data to inform the development of the main study. Phase One was a qualitative exploration of body image concerns amongst males and females recruited through the general community and from a university. Seventeen participants (eight male; nine female) provided information on their body image and what factors they saw as positively and negatively impacting on their self evaluations. The importance of self esteem, mood, health and fitness, and recognition of the social ideal were identified as key themes. These themes were incorporated as psycho-social measures and Stroop word stimuli in subsequent phases of the research. Phase Two involved the selection and testing of stimuli to be used in the Emotional Stroop task. Six experimental categories of words were developed that reflected a broad range of health and body image concerns for males and females. These categories were high and low calorie food words, positive and negative appearance words, negative emotion words, and physical activity words. Phase Three addressed the central aim of the project by examining cognitive biases for body image information in empirically defined sub-groups. A National sample of males (N = 55) and females (N = 144), recruited from the general community and universities, completed an Emotional Stroop task, incidental memory test, and a collection of psycho-social questionnaires. Sub-groups of body image disturbance were sought using a cluster analysis, which identified three sub-groups in males (Normal, Dissatisfied, and Athletic) and four sub-groups in females (Normal, Health Conscious, Dissatisfied, and Symptomatic). No differences were noted between the groups in selective attention, although time taken to colour name the words was associated with some of the psycho-social variables. Memory biases found across the whole sample for negative emotion, low calorie food, and negative appearance words were interpreted as reflecting the current focus on health and stigma against being unattractive. Collectively these results have expanded our understanding of processing biases in the general community by demonstrating that the processing biases are found within non-clinical samples and that not all processing biases are associated with negative functionality

The PG500 series : novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy

Heparan sulfate mimetics, which we have called the PG500 series, have been developed to target the inhibition of both angiogenesis and heparanase activity. This series extends the technology underpinning PI-88, a mixture of highly sulfated oligosaccharides which reached Phase III clinical development for hepatocellular carcinoma. Advances in the chemistry of the PG500 series provide numerous advantages over PI-88. These new compounds are fully sulfated, single entity oligosaccharides attached to a lipophilic moiety, which have been optimized for drug development. The rational design of these compounds has led to vast improvements in potency compared to PI-88, based on in vitro angiogenesis assays and in vivo tumor models. Based on these and other data, PG545 has been selected as the lead clinical candidate for oncology and is currently undergoing formal preclinical development as a novel treatment for advanced cancer.

Ghrelin gene-related peptides : multifunctional endocrine/autocrine modulators in health and disease

Ghrelin is a multi-functional peptide hormone which affects various processes including growth hormone and insulin release, appetite regulation, gut motility, metabolism and cancer cell proliferation. Ghrelin is produced in the stomach and in other normal and pathological cell types. It may act as an endocrine or autocrine/paracrine factor. The ghrelin gene encodes a precursor protein, preproghrelin, from which ghrelin and other potentially active peptides are derived by alternative mRNA splicing and/or proteolytic processing. The metabolic role of the peptide obestatin, derived from the preproghrelin C-terminal region, is controversial. However, it has direct effects on cancer cell proliferation. The regulation of ghrelin expression and the mechanisms through which the peptide products arise are unclear. We have recently re-examined the organisation of the ghrelin gene and identified several novel exons and transcripts. One transcript, which lacks the ghrelin-coding region of preproghrelin, contains the coding sequence of obestatin. Furthermore, we have identified an overlapping gene on the antisense strand of ghrelin, GHRLOS, which generates transcripts that may function as non-coding regulatory RNAs or code for novel, short bioactive peptides. The identification of these novel ghrelin-gene related transcripts and peptides raises critical questions regarding their physiological function and their role in obesity, diabetes and cancer.

Public health and clinical dilemmas resulting from imprecise vitamin D tests

Objective: To determine whether there are clinical and public health dilemmas resulting from the reproducibility of routine vitamin D assays. Methods: Blinded agreement studies were conducted in eight clinical laboratories using two commonly used assays to measure serum 25-hydroxyvitamin D (25(OH)D) levels in Australasia and Canada (DiaSorin Radioimmunoassay (RIA) and DiaSorin LIAISON® one). Results: Only one laboratory measured 25(OH)D with excellent precision. Replicate 25(OH)D measurements varied by up to 97% and 15% of paired results differed by more than 50%. Thirteen percent of subjects received one result indicating insufficiency [25-50 nmol/l] and another suggesting adequacy [>50 nmol/l]). Agreement ranged from poor to excellent for laboratories using the manual RIA, while the precision of the semi-automated Liaison® system was consistently poor. Conclusions: Recent interest in the relevance of vitamin D to human health has increased demand for 25(OH)D testing and associated costs. Our results suggest clinicians and public health authorities are making decisions about treatment or changes to public health policy based on imprecise data. Clinicians, researchers and policy makers should be made aware of the imprecision of current 25(OH)D testing so that they exercise caution when using these assays for clinical practice, and when interpreting the findings of epidemiological studies based on vitamin D levels measured using these assays. Development of a rapid, reproducible, accurate and robust assay should be a priority due to interest in populationbased screening programs and research to inform public health policy about the amount of sun exposure required for human health. In the interim, 25(OH)D results should routinely include a statement of measurement uncertainty.