Primary brain tumor patients’ supportive care needs and multidisciplinary rehabilitation, community and psychosocial support services: Awareness, referral and utilization

Primary brain tumors are associated with significant physical, cognitive and psychosocial changes. Although treatment guidelines recommend offering multidisciplinary rehabilitation and support services to address patients’ residual deficits, the extent to which patients access such services is unclear. This study aimed to assess patients’ supportive care needs early after diagnosis, and quantify service awareness, referral and utilization. A population-based sample of 40 adults recently diagnosed with primary brain tumors was recruited through the Queensland Cancer Registry, representing 18.9% of the eligible population of 203 patients. Patients or carer proxies completed surveys of supportive care needs at baseline (approximately three months after diagnosis) and three months later. Descriptive statistics summarized needs and service utilization, and linear regression identified predictors of service use. Unmet supportive care needs were highest at baseline for all domains, and highest for the physical and psychological needs domains at each time point. At follow-up, participants reported awareness of, referral to, and use of 32 informational, support, health professional or practical services. All or almost all participants were aware of at least one informational (100%), health professional (100%), support (97%) or practical service (94%). Participants were most commonly aware of speech therapists (97%), physiotherapists (94%) and diagnostic information from the internet (88%). Clinician referrals were most commonly made to physiotherapists (53%), speech therapists (50%) and diagnostic information booklets (44%), and accordingly, participants most commonly used physiotherapists (56%), diagnostic information booklets (47%), diagnostic information from the internet (47%), and speech therapists (43%). Comparatively low referral to and use of psychosocial services may limit patients’ abilities to cope with their condition and the changes they experience.

Evaluation of an intervention for patients with alcohol-related injuries: results of a mixed methods study

Objective: To explore the effect of education and training on the delivery of alcohol screening and brief intervention and referral to high-risk patients in a hospital setting. Main outcome measures included; delivery of training; practice change in relation to staff performing alcohol screening, brief intervention and referrals. Methods: Observational study design using mixed methods set in a tertiary referral hospital. Pre-post assessment of medical records and semi-structured interviews with key informants. Results: Routine screening for substance misuse (9% pre / 71.4% post) and wellbeing concerns (6.6% pre / 15 % post) was more frequent following the introduction of resources and staff participation in educational workshops. There was no evidence of a concomitant increase in delivery of brief intervention or referrals to services. Implementation challenges, including time constraints and staff attitudes, and enablers such as collaboration and visible pathways, were identified. Conclusion: Rates of patient screening increased, however barriers to delivery of brief intervention and referrals remained. Implementation strategies targeting specific barriers and enablers to introducing interventions are both required to improve the application of secondary prevention for patients in acute settings. Implications: Educational training, formalised liaison between services, systematised early intervention protocols, and continuous quality improvement processes will progress service delivery in this area.

Neural stem cell characteristics affected by oncogenic pathways and in a human motoneuron disease

Neural stem cell characteristics affected by oncogenic pathways and in a human motoneuron disease Stem cells provide the self-renewing cell pool for developing or regenerating organs. The mechanisms underlying the decisions of a stem or progenitor cell to either self-renew and maintain multipotentiality or alternatively to differentiate are incompletely understood. In this thesis work, I have approached this question by investigating the role of the proto-oncogene Myc in the regulatory functions of neural progenitor cell (NPC) self-renewal, proliferation and differentiation. By using a retroviral transduction technique to create overexpression models in embryonic NPCs cultured as neurospheres, I show that activated levels of Myc increase NPC self-renewal. Furthermore, several mechanisms that regulate the activity of Myc were identified. Myc induced self-renewal is signalled through binding to the transcription factor Miz-1 as shown by the inhibited capacity of a Myc mutant (MycV394D), deficient in binding to Miz-1, to increase self-renewal in NPCs. Furthermore, overexpression of the newly identified proto-oncogene CIP2A recapitulates the effects of Myc overexpression in NPCs. Also the expression levels and in vivo expression patterns of Myc and CIP2A were linked together. CIP2A stabilizes Myc protein levels in several cancer types by inhibiting its degradation and our results suggest the same function for CIP2A in NPCs. Our results also support the conception of self-renewal and proliferation being two separately regulated cellular functions. Finally, I suggest that Myc regulates NPC self-renewal by influencing the way stem and progenitor cells react to the environmental cues that normally dictate the cellular identity of tissues containing self-renewing cells. Neurosphere cultures were also utilised in order to characterise functional defects in a human disease. Neural stem cell cultures obtained post-mortem from foetuses of lethal congenital contracture syndrome (LCCS) were used to reveal possible cell autonomous differentiation defects of patient NPCs. However, LCCS derived NPCs were able to differentiate normally in vitro although several transcriptional differences were identified by using microarray analysis. Proliferation rate of the patient NPCs was also increased as compared to NPCs of age-matched control foetuses.

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 x 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-kappaB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

VEGFR-3 and Tie pathways in vascular network formation

The blood and lymphatic vascular systems are essential for life, but they may become harnessed for sinister purposes in pathological conditions. For example, tumors learn to grow a network of blood vessels (angiogenesis), securing a source of oxygen and nutrients for sustained growth. On the other hand, damage to the lymph nodes and the collecting lymphatic vessels may lead to lymphedema, a debilitating condition characterized by peripheral edema and susceptibility to infections. Promoting the growth of new lymphatic vessels (lymphangiogenesis) is an attractive approach to treat lymphedema patients. Angiopoietin-1 (Ang1), a ligand for the endothelial receptor tyrosine kinases Tie1 and Tie2. The Ang1/Tie2 pathway has previously been implicated in promoting endothelial stability and integrity of EC monolayers. The studies presented here elucidate a novel function for Ang1 as a lymphangiogenic factor. Ang1 is known to decrease the permeability of blood vessels, and could thus act as a more global antagonist of plasma leakage and tissue edema by promoting growth of lymphatic vessels and thereby facilitating removal of excess fluid and other plasma components from the interstitium. These findings reinforce the idea that Ang1 may have therapeutic value in conditions of tissue edema. VEGFR-3 is present on all endothelia during development, but in the adult its expression becomes restricted to the lymphatic endothelium. VEGF-C and VEGF-D are ligands for VEGFR-3, and potently promote lymphangiogenesis in adult tissues, with direct and remarkably specific effects on the lymphatic endothelium in adult tissues. The data presented here show that VEGF-C and VEGF-D therapy can restore collecting lymphatic vessels in a novel orthotopic model of breast cancer-related lymphedema. Furthermore, the study introduces a novel approach to improve VEGF-C/VEGF-D therapy by using engineered heparin-binding forms of VEGF-C, which induced the rapid formation of organized lymphatic vessels. Importantly, VEGF-C therapy also greatly improved the survival and integration of lymph node transplants. The combination of lymph node transplantation and VEGF-C therapy provides a basis for future therapy of lymphedema. In adults, VEGFR-3 expression is restricted to the lymphatic endothelium and the fenestrated endothelia of certain endocrine organs. These results show that VEGFR-3 is induced at the onset of angiogenesis in the tip cells that lead the formation of new vessel sprouts, providing a tumor-specific vascular target. VEGFR-3 acts downstream of VEGF/VEGFR-2 signals, but, once induced, can sustain angiogenesis when VEGFR-2 signaling is inhibited. The data presented here implicate VEGFR-3 as a novel regulator of sprouting angiogenesis along with its role in regulating lymphatic vessel growth. Targeting VEGFR-3 may provide added efficacy to currently available anti-angiogenic therapeutics, which typically target the VEGF/VEGFR-2 pathway.

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

VEGF-C/VEGFR-3 and PDGF-B/PDGFR-b pathways in embryonic lymphangiogenesis

The circulatory system comprises the blood vascular system and the lymphatic vascular system. These two systems function in parallel. Blood vessels form a closed system that delivers oxygen and nutrients to the tissues and removes waste products from the tissues, while lymphatic vessels are blind-ended tubes that collect extravasated fluid and cells from the tissues and return them back to blood circulation. Development of blood and lymphatic vascular systems occurs in series. Blood vessels are formed via vasculogenesis and angiogenesis whereas lymphatic vessels develop via lymphangiogenesis, after the blood vascular system is already functional. Members of the vascular endothelial growth factor (VEGF) family are regulators of both angiogenesis and lymphangiogenesis, while members of the platelet-derived growth factor (PDGF) family are major mitogens for pericytes and smooth muscle cells and regulate formation of blood vessels. Vascular endothelial growth factor C (VEGF-C) is the major lymphatic growth factor and signaling through its receptor vascular endothelial growth factor receptor 3 (VEGFR-3) is sufficient for lymphangiogenesis in adults. We studied the role of VEGF-C in embryonic lymphangiogenesis and showed that VEGF-C is absolutely required for the formation of lymph sacs from embryonic veins. VEGFR-3 is also required for normal development of the blood vascular system during embryogenesis, as Vegfr3 knockout mice die at mid-gestation due to failure in remodeling of the blood vessels. We showed that sufficient VEGFR-3 signaling in the embryo proper is required for embryonic angiogenesis and in a dosage-sensitive manner for embryonic lymphangiogenesis. Importantly, mice deficient in both VEGFR-3 ligands, Vegfc and Vegfd, developed a normal blood vasculature, suggesting VEGF-C- and VEGF-D- independent functions for VEGFR-3 in the early embryo. Platelet-derived growth factor B (PDGF-B) signals via PDGFR-b and regulates formation of blood vessels by recruiting pericytes and smooth muscle cells around nascent endothelial tubes. We showed that PDGF-B fails to induce lymphangiogenesis when overexpressed in adult mouse skin using adenoviral vectors. However, mouse embryos lacking Pdgfb showed abnormal lymphatic vessels, suggesting that PDGF-B plays a role in lymphatic vessel maturation and separation from blood vessels during embryogenesis. Lymphatic vessels play a key role in immune surveillance, fat absorption and maintenance of fluid homeostasis in the body. However, lymphatic vessels are also involved in various diseases, such as lymphedema and tumor metastasis. These studies elucidate the basic mechanisms of embryonic lymphangiogenesis and add to the knowledge of lymphedema and tumor metastasis treatments by giving novel insights into how lymphatic vessel growth could be induced (in lymphedema) or inhibited (in tumor metastasis).

Molecular Pathways of Disturbed Sleep and Depression: Studies on Adenosine and Gene Expression Patterns

Background: Adenosine is a potent sleep-promoting substance, and one of its targets is the basal forebrain. Fairly little is known about its mechanism of action in the basal forebrain and about the receptor subtype mediating its regulating effects on sleep homeostasis. Homeostatic deficiency might be one of the causes of the profoundly disturbed sleep pattern in major depressive disorder, which could explain the reduced amounts of delta-activity-rich stages 3 and 4. Since major depression has a relatively high heritability, and on the other hand adenosine regulates sleep homeostasis and might also be involved in mood modulation, adenosine-related genes should be considered for their possible contribution to a predisposition for depression and disturbed sleep in humans. Depression is a complex disorder likely involving the abnormal functioning of several genes. Novel target genes which could serve as the possible common substrates for depression and comorbid disturbed sleep should be identified. In this way specific brain areas related to sleep regulation should be studied by using animal model of depression which represents more homogenous phenotype as compared to humans. It is also important to study these brain areas during the development of depressive-like features to understand how early changes could facilitate pathophysiological changes in depression. Aims and methods: We aimed to find out whether, in the basal forebrain, adenosine induces recovery non-rapid eye movement (NREM) sleep after prolonged waking through the A1 or/and A2A receptor subtype. A1 and A2A receptor antagonists were perfused into the rat basal forebrain during 3 h of sleep deprivation, and the amount of NREM sleep and delta power during recovery NREM sleep were analyzed. We then explored whether polymorphisms in genes related to the metabolism, transport and signaling of adenosine could predispose to depression accompanied by signs of disturbed sleep. DNA from 1423 individuals representative of the Finnish population and including controls and cases with depression, depression accompanied by early morning awakenings and depression accompanied by fatigue, was used in the study to investigate the possible association between polymorphisms from adenosine-related genes and cases. Finally to find common molecular substrates of depression and disturbed sleep, gene expression changes were investigated in specific brain areas in the rat clomipramine model of depression. We focused on the basal forebrain of 3-week old clomipramine-treated rats which develop depressive-like symptoms later in adulthood and on the hypothalamus of adult female clomipramine-treated rats. Results: Blocking of the A1 receptor during sleep deprivation resulted in a reduction of the recovery NREM sleep amount and delta power, whereas A2A receptor antagonism had no effect. Polymorphisms in adenosine-related genes SLC29A3 (equilibrative nucleoside transporter type 3) in women and SLC28A1 (concentrative nucleoside transporter type 1) in men associated with depression alone as well as when accompanied by early morning awakenings and fatigue. In Study III the basal forebrain of postnatal rats treated with clomipramine displayed disturbances in gamma-aminobutyric acid (GABA) receptor type A signaling, in synaptic transmission and possible epigenetic changes. CREB1 was identified as a common transcription denominator which also mediates epigenetic regulation. In the hypothalamus the major changes included the expression of genes in GABA-A receptor pathway, K+ channel-related, glutamatergic and mitochondrial genes, as well as an overexpression of genes related to RNA and mRNA processing. Conclusions: Adenosine plays an important role in sleep homeostasis by promoting recovery NREM sleep via the A1 receptor subtype in the basal forebrain. Also adenosine levels might contribute to the risk of depression with disturbed sleep, since the genes encoding nucleoside transporters showed the strongest associations with depression alone and when accompanied by signs of disturbed sleep in both women and men. Sleep and mood abnormalities in major depressive disorder could be a consequence of multiple changes at the transcriptional level, GABA-A receptor signaling and synaptic transmission in sleep-related basal forebrain and the hypothalamus.

Effect of exercise referral schemes in primary care on physical activity and improving health outcomes: Systematic review and meta-analysis

Objective To assess the impact of exercise referral schemes on physical activity and health outcomes. Design Systematic review and meta-analysis. Data sources Medline, Embase, PsycINFO, Cochrane Library, ISI Web of Science, SPORTDiscus, and ongoing trial registries up to October 2009. We also checked study references. Study selection - Design: randomised controlled trials or non-randomised controlled (cluster or individual) studies published in peer review journals. - Population: sedentary individuals with or without medical diagnosis. - Exercise referral schemes defined as: clear referrals by primary care professionals to third party service providers to increase physical activity or exercise, physical activity or exercise programmes tailored to individuals, and initial assessment and monitoring throughout programmes. - Comparators: usual care, no intervention, or alternative exercise referral schemes. Results Eight randomised controlled trials met the inclusion criteria, comparing exercise referral schemes with usual care (six trials), alternative physical activity intervention (two), and an exercise referral scheme plus a self determination theory intervention (one). Compared with usual care, follow-up data for exercise referral schemes showed an increased number of participants who achieved 90-150 minutes of physical activity of at least moderate intensity per week (pooled relative risk 1.16, 95% confidence intervals 1.03 to 1.30) and a reduced level of depression (pooled standardised mean difference −0.82, −1.28 to −0.35). Evidence of a between group difference in physical activity of moderate or vigorous intensity or in other health outcomes was inconsistent at follow-up. We did not find any difference in outcomes between exercise referral schemes and the other two comparator groups. None of the included trials separately reported outcomes in individuals with specific medical diagnoses. Substantial heterogeneity in the quality and nature of the exercise referral schemes across studies might have contributed to the inconsistency in outcome findings. Conclusions Considerable uncertainty remains as to the effectiveness of exercise referral schemes for increasing physical activity, fitness, or health indicators, or whether they are an efficient use of resources for sedentary people with or without a medical diagnosis.

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.

Levels and predictors of exercise referral scheme uptake and adherence: A systematic review

Background The effectiveness of exercise referral schemes (ERS) is influenced by uptake and adherence to the scheme. The identification of factors influencing low uptake and adherence could lead to the refinement of schemes to optimise investment. Objectives To quantify the levels of ERS uptake and adherence and to identify factors predictive of uptake and adherence. Methods A systematic review and meta-analysis was undertaken. MEDLINE, EMBASE, PsycINFO, Cochrane Library, ISI WOS, SPORTDiscus and ongoing trial registries were searched (to October 2009) and included study references were checked. Included studies were required to report at least one of the following: (1) a numerical measure of ERS uptake or adherence and (2) an estimate of the statistical association between participant demographic or psychosocial factors (eg, level of motivation, self-efficacy) or programme factors and uptake or adherence to ERS. Results Twenty studies met the inclusion criteria, six randomised controlled trials (RCTs) and 14 observational studies. The pooled level of uptake in ERS was 66% (95% CI 57% to 75%) across the observational studies and 81% (95% CI 68% to 94%) across the RCTs. The pooled level of ERS adherence was 49% (95% CI 40% to 59%) across the observational studies and 43% (95% CI 32% to 54%) across the RCTs. Few studies considered anything other than gender and age. Women were more likely to begin an ERS but were less likely to adhere to it than men. Older people were more likely to begin and adhere to an ERS. Limitations Substantial heterogeneity was evident across the ERS studies. Without standardised definitions, the heterogeneity may have been reflective of differences in methods of defining uptake and adherence across studies. Conclusions To enhance our understanding of the variation in uptake and adherence across ERS and how these variations might affect physical activity outcomes, future trials need to use quantitative and qualitative methods.

The cost-effectiveness of exercise referral schemes

Background Exercise referral schemes (ERS) aim to identify inactive adults in the primary care setting. The primary care professional 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 patient. This paper examines the cost-effectiveness of ERS in promoting physical activity compared with usual care in primary care setting. Methods A decision analytic model was developed to estimate the cost-effectiveness of ERS from a UK NHS perspective. The costs and outcomes of ERS were modelled over the patient's lifetime. Data were derived from a systematic review of the literature on the clinical and cost-effectiveness of ERS, and on parameter inputs in the modelling framework. Outcomes were expressed as incremental cost per quality-adjusted life-year (QALY). Deterministic and probabilistic sensitivity analyses investigated the impact of varying ERS cost and effectiveness assumptions. Sub-group analyses explored the cost-effectiveness of ERS in sedentary people with an underlying condition. Results Compared with usual care, the mean incremental lifetime cost per patient for ERS was £169 and the mean incremental QALY was 0.008, generating a base-case incremental cost-effectiveness ratio (ICER) for ERS at £20,876 per QALY in sedentary individuals without a diagnosed medical condition. There was a 51% probability that ERS was cost-effective at £20,000 per QALY and 88% probability that ERS was cost-effective at £30,000 per QALY. In sub-group analyses, cost per QALY for ERS in sedentary obese individuals was £14,618, and in sedentary hypertensives and sedentary individuals with depression the estimated cost per QALY was £12,834 and £8,414 respectively. Incremental lifetime costs and benefits associated with ERS were small, reflecting the preventative public health context of the intervention, with this resulting in estimates of cost-effectiveness that are sensitive to variations in the relative risk of becoming physically active and cost of ERS. Conclusions ERS is associated with modest increase in lifetime costs and benefits. The cost-effectiveness of ERS is highly sensitive to small changes in the effectiveness and cost of ERS and is subject to some significant uncertainty mainly due to limitations in the clinical effectiveness evidence base.

Republished research: Effect of exercise referral schemes in primary care on physical activity and improving health outcomes: systematic review and meta-analysis

Study question Can exercise referral schemes improve health outcomes in individuals with or without pre-existing conditions? Summary answer We found weak evidence of a short term increase in physical activity and reduction in levels of depression in sedentary individuals after participation in exercise referral schemes, compared with after usual care. What is known and what this paper adds Exercise referral schemes are commonly used in primary care to promote physical activity. Evidence indicating a health benefit of these schemes is limited, so their value in primary care remains to be ascertained.

Fluoroquinolone-resistant extraintestinal pathogenic Escherichia coli, including O25b-ST131, isolated from faeces of hospitalized dogs in an Australian veterinary referral centre

To determine rates of carriage of fluoroquinolone-resistant Escherichia coli and extraintestinal pathogenic E. coli (ExPEC) among dogs in a specialist referral hospital and to examine the population structure of the isolates. Fluoroquinolone-resistant faecal E. coli isolates (n232, from 23 of 123 dogs) recovered from hospitalized dogs in a veterinary referral centre in Sydney, Australia, over 140 days in 2009 were characterized by phylogenetic grouping, virulence genotyping and random amplified polymorphic DNA (RAPD) analysis. The RAPD dendrogram for representative isolates showed one group B2-associated cluster and three group D-associated clusters; each contained isolates with closely related ExPEC-associated virulence profiles. All group B2 faecal isolates represented the O25b-ST131 clonal group and were closely related to recent canine extraintestinal ST131 clinical isolates from the east coast of Australia by RAPD analysis. Hospitalized dogs may carry fluoroquinolone-resistant ExPEC in their faeces, including those representing O25b-ST131.