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If present quality malegra fxt plus 160 mg, this bias would mean that smaller studies in the review had overestimated intervention effects order malegra fxt plus 160 mg. We conducted targeted author searches for additional publications and/or unpublished data identified in conference abstracts generic 160mg malegra fxt plus otc, but did not extend our searches to grey literature or ongoing trial registries generic 160 mg malegra fxt plus. Our focus on quantitative evidence meant that we gained insights into intervention effect. We categorised our ESs according to magnitude, using a commonly accepted, yet somewhat arbitrary, classification system. ED visits were identified by our PPI panel as a particularly important aspect of health service utilisation for children, young people and their parents, and it is conceivable that very small reductions in ED use may be important and potentially more meaningful than equivalent effects on QoL. We did not conduct a mixed-methods or qualitative review, which may offer additional insights into the acceptability of self-care support to children, young people and their families, their preferred content and delivery formats and the meaning that they attribute to these very different outcomes. Pooled ESs suggest that self-care support has a positive but minimal effect on QoL (ES of 0. Evidence is most robust for children and young people with asthma (ES of 0. Lack of evidence for other conditions (or condition clusters) prohibits meaningful assessments of effect. A prior review of the clinical effectiveness of self-care support interventions for children and young people with physical health conditions31 reported positive impacts on QoL, but synthesised data narratively and did not present standardised ESs derived from a meta-analysis of intervention effects. The effect of self-care support on the health status of children and young people with mental health conditions has been studied separately; in this instance pooled ESs of 0. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that 41 suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. DISCUSSION AND CONCLUSIONS The size and the scope of the evidence base differ between different reviews. These differences are not 3132, unusual and reflect both practical and methodological variances. Earlier reviews adopted different search dates and applied different eligibility criteria, stemming from their need to address different research aims. In line with our protocol, we legitimately excluded studies that failed to report both clinical and economic outcomes. This was because our review was designed to identify those models of self-care support that could reduce health services utilisation and costs, without compromising outcomes for children and young people. Only studies reporting both forms of data could answer this brief. We acknowledge that some evidence with broader relevance to our population may have been excluded by these studies failing to meet our inclusion criteria. Our up-to-date and comprehensive review makes an important and meaningful contribution to service development and commissioning debates. When QoL was plotted against health service utilisation data, relatively fewer studies reported reductions in both outcomes. In drawing this conclusion, it is important to remember that study effects are conventionally reported at the level of the group. The available data apply only to those participants consenting to take part in the included research studies. Where reported, study participation rates appeared typical of behavioural intervention trials, but explorations of sample representativeness were limited by inconsistent data and ambiguous reporting. Thus, it may be prudent for health professionals to monitor the individual impact of self-care support, including any potential effects on these broader contexts, during routine consultations with their patients. On the basis of the current evidence, we cannot reliably conclude that self-care support significantly reduces overall health-care costs. Analysis of the impact of self-care support on total costs (our primary analysis) was limited by a lack of available data. Lack of a statistically significant effect on hospital admissions endured across different intervention intensities, evidence quality levels and LTCs. Small reductions in the number of ED visits may well confer multiple advantages on children, young people and their families, not least because accessing emergency care can be associated with acute emotional and logistical stressors. However, at a population level, uncertainty remains regarding the extent to which minimal reductions in emergency use can offset the costs of delivering self-care support and ameliorate the fiscal burdens facing contemporary health-care systems. Our exploratory subgroup analyses suggest that effects may be more pronounced in UK than in non-UK settings and that more intensively facilitated self-care support interventions may be necessary to secure minimal benefits for ED use. In the absence of meta-regression, these subgroup analyses are limited by the fact that many other factors may also differ between study groups. Any analysis focused on a single aspect of health-care utilisation is vulnerable to error. Arguably, cost shifting may have been a greater risk had substantial reductions in health service utilisation been revealed. In this instance, it would have become crucial to ascertain whether the observed effects reflected genuine reductions in health service use or whether costs had simply been transferred to other health-care sectors or on to patients. With the exception of ED visits and hospital admissions, health service utilisation data were inconsistently reported by the primary studies in our review. Total cost outcome data are necessary to provide policy-makers and service providers with clear evidence of the efficiency (or otherwise) of self-care support. By definition, these data sum costs across all service sectors and include the costs of delivering the intervention that is intended to generate these cost changes. Few primary studies reported total cost data in the current review, prohibiting this more robust analysis. Some of the studies in our review distinguished between scheduled and non-scheduled health service use, but did not report care appropriateness per se. We did not distinguish between elective and unplanned admissions in our analysis, nor did we distinguish between legitimate and inappropriate ED use. The effects of self-care support interventions on these different forms of health service utilisation may conceivably be very different. The optimal assessment of the hypothesis underlying this review would have been to restrict our analysis to the most comprehensive assessment of costs, including those related to NHS service use, social care and other services (e. From an operational perspective, it is difficult to foresee how self-care support interventions justified from a societal perspective will be implemented. Although any necessary reallocation of resources can be identified, transfers between sectors are not always considered desirable or feasible. Our review included 97 studies, of which only 35 reported formal economic analyses. The broader evidence base included in our review is reflective of a larger number of studies that report useful data on health service utilisation. Systematic assessment of this wider literature makes an important and much-needed contribution to policy and service development. A global economic crisis means that substantial effort continues to be invested in improving the efficiency of health-care systems. Yet, despite self-care being advocated as a key method of increasing service efficiency, there remains uncertainty regarding the scale of the contribution that can be made. Although a previous review has suggested that self-care support interventions may reduce hospital use and total costs in adults, our study has demonstrated potentially smaller effects in children and young people. Understanding the reason for these differences may be an important focus for future research efforts. Self-care support resonates with multiple policy strategies, including philosophical shifts towards partnership working and the delivery of personalised care. Consideration must thus be given to both its processes and outcomes, and the potential breadth of benefits that it will confer. Specific attention should be given to different stakeholder perspectives and whose views – population, policy, professional or patient – are the most important when minimal effects on QoL and health service utilisation are observed. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that 43 suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. DISCUSSION AND CONCLUSIONS The impact of self-care support interventions may depend less on intervention intensity and more on its delivery mechanisms Rigorous evaluation of the efficiency of self-care support interventions for children and young people with LTCs demands concurrent evaluation of patient well-being and health utilisation effects. The suggestion that self-care support may minimally benefit QoL, but not translate into marked benefits for health service use held, across different age groups, intervention intensities and settings. Constraints on the number of data underpinning these results demand some caution in their interpretation. In line with our protocol and previous review,26 we categorised intervention intensity according to a broad typology and compared pure or facilitated self-care support with more intensively facilitated or case-managed care. The threshold for intensive facilitation took account of both amount of self-care support (> 2hoursor four sessions), as well as the nature of the support provided. This threshold was an arbitrary empirical threshold that provided a reasonable distribution of studies among the different categories. Reductions in ED use were not consistent across LTCs or intervention type. Preliminary analyses suggest a significant reduction in emergency use for children aged < 13 years, children and young people with asthma and children and young people receiving more intensively facilitated self-care support interventions. However, the existing evidence base is of only moderate size and these different findings will, in part, reflect differences in the number of studies available and the precision of the pooled effects. Pooled effects suggest a significant benefit for self-care support interventions for asthma that is not confirmed in mental health.

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Adult brain neurogenesis term potentiation ion the hippocampus cheap malegra fxt plus 160mg visa. Nature 1993;361: and psychiatry: a novel theory of depression buy discount malegra fxt plus 160 mg. Bronzino JD effective malegra fxt plus 160mg, Abu-Hasaballah K generic 160mg malegra fxt plus with mastercard, Austin-LaFrance RJ, et al. Maturation of long-term potentiation in the hippocampal den- Acta Physiol Scand 1989;137:1–13. Development of a water maze procedure for 2000;47:1043–1049. GRACE Studies into the regulation of the dopamine (DA) system DA NEURON ANATOMY AND PHYSIOLOGY and its postsynaptic actions are often stymied by the myriad of actions that this neurotransmitter can produce. Thus, Both in vivo and in vitro studies have demonstrated that DA has been found to exert actions on the neurons it inner- DA-containing neurons in the midbrain exhibit sponta- vates both directly and via G-protein–coupled receptors. One of the prominent regulators of DA munication via its actions on gap junctions. It has been known for some time that DA neurons are very sensitive to DA can potently modulate its own dynamics, acting via autore- agonists, which inhibit spike firing as well as cause a pre- ceptors on DA nerve terminals and on DA neuron somata. Studies in- In fact, the DA system is under potent dynamic regulation dicate that DA neuron somatodendritic autoreceptors are in the short term by a multitude of feedback systems, and stimulated by an extracellular pool of DA released from the in response to prolonged alterations is subject to powerful dendrites of neighboring DA neurons rather than exclu- homeostatic mechanisms that can compensate for dramatic sively by autoinhibition back onto the releasing neuron. Such homeostatic altera- This is supported by data showing that partial lesions of tions can be compensatory in nature, such as those that the DA system result in DA autoreceptor supersensitivity occur in response to a partial DA system lesion, or patho- in the remaining neurons, which would only occur if the logic, such as the sensitization that can occur with repeated remaining neurons were responding to the decrease in DA psychostimulant administration. Nonetheless, the impor- caused by the loss of neighboring neurons (4). These autoreceptors appear to be ented toward increasing our understanding of this complex primarily of the D2 type, because D2-deficient mice do system in normal conditions as well as disease states. This not show autoreceptor-mediated inhibition of firing (6). This is not meant to be transferase does not alter this response (9). Exogenous transmitters also potently regulate dopamine inclusive: A search of Medline indicated that there were neurons. Thus, GABA afferents both from striatonigral neu- over 16,000 papers published on DA during the past 5 rons as well as from local circuit neurons in the midbrain years! Because of the exceedingly broad range that this topic cause inhibition of DA neuron activity (10) by both a encompasses, the focus is primarily on a subset of the nu- GABA-A– and GABA-B–mediated action (11–13). Gluta- merous improvements that are most related to advancing mate has also been shown to exert multiple actions on DA our understanding of psychiatric disorders in particular. Glutamate applied in vivo increases burst Topics related to specific disorders, such as drug abuse, firing (14). N-methyl-D-aspartate (NMDA) receptor acti- schizophrenia, and so on, are deferred to the appropriate vation mediates a slow excitatory postsynaptic potential chapters in this volume. This latter effect is apparently shared by muscarinic receptors, which Anthony A. Grace: Departments of Neuroscienceand Psychiatry, Univer- also depress both excitatory and inhibitory afferents, pre- sity of Pittsburgh, Pittsburgh, Pennsylvania. Thus, studies have shown that burst Afferent Input firing in DA neurons is associated with induction of c-fos The feedback systems between DA neurons and their post- and NG1-A in postsynaptic sites (19,20), and this response demonstrates a spatial and temporal specificity with respect synaptic targets appear to be quite complex, particularly in to brain region, genes activated, and cell phenotype. By analyzing a large number of retrograde and factor that is thought to regulate burst firing is the gluta- anterograde tracings, Haber and associates (32) found that matergic system. Several studies have shown that ionto- different striatal subdivisions are linked by overlapping feed- phoresis of glutamate onto DA neurons in vivo lead to burst back to DA neurons, in a manner that suggests an ascending firing (14), as do stimulation of glutamatergic afferents to spiral of regulation extending from the shell to the core to DA neurons (21,22); however, the evidence for glutamate the central striatum and finally to the dorsolateral striatum acting alone to induce burst firing in vitro is equivocal (23). As pointed out by Haber, such an anatomic ar- In contrast, evidence shows that burst firing can be induced rangement could account for the parallel psychomotor, af- in vitro by blockade of apamin-sensitive potassium channels fective, and cognitive disturbances seen in a variety of psy- that modulate a nifedipine-sensitive calcium conductance chiatric disorders. One source of glutamatergic input to ventral tegmen- The striatum provides a powerful feedback regulation tal area (VTA) DA neurons is proposed to arise from the of DA neuron firing. Thus, alterations in striatal activity prefrontal cortex (PFC) (25); however, recent studies (26, potently affect DA cell activity states. Striatal neuron activa- 27) show that the PFC input to the VTA innervates only tion is known to cause an activation of DA neuron firing the small proportion of VTA DA neurons that project to the (10,33). Moreover, single-pulse stimulation of the striatum PFC, providing a direct feedback loop, whereas the VTA- directly, or indirectly via activation of the PFC in rats, causes accumbens neurons innervated from the PFC are exclusively an inhibition/excitation response pattern (10,25). This rela- GABAergic neurons; therefore, it is unlikely that activation tionship can be altered by manipulation of second messen- of the PFC can induce increased DA levels in the accumbens ger systems in the striatum. One system in particular that by a direct projection to these neurons (28). On the other seems to affect striatal activation, leading to an alteration FIGURE 9. Studies using retrograde and anterograde tracers reveal that the feedback system between the mid- brain DA neurons and their striatal targets contains both reciprocal and feed-forward components. The shell of the accumbens (left) receives inputs from hippocampus, amyg- dala, and limbic cortex, and projects to both the ventral tegmental area (VTA) and dorsomedial substantia nigra DA neurons. The core receives afferent input from the orbital and medial prefrontal cor- tex (OMPFC); the afferent projection to the core from the medial substantia nigra (SN) then forms the first part of the spiral. The core in turn projects to more ventrodorsal SN regions; therefore, ventral striatal regions can modu- late the dopaminergic influence over more dorsal striatal regions via the spiraling midbrain-striatal-midbrain con- nections. The magnified insert shows a model of the recip- rocal versus feed-forward loops. The reciprocal compo- nent is proposed to (a) directly inhibit the DA neuron, whereas the feed-forward, nonreciprocal component ter- minates on a GABAergic interneuron; or (b) indirectly ex- cite the DA neuron by disinhibition. DL-PFC, dorsolateral prefrontal cortex; IC, internal capsule; S, shell; Snc, sub- stantia nigra, zona compacta; Snr, substantia nigra, zona reticulata; VTA, ventral tegmental area. Therefore, unlike acute exposure to stressful or noxious Increasing NO in the striatum by infusion of the substrate stimuli, chronic stress actually attenuates DA neuron base- for the synthetic enzyme nitric oxide synthetase (NOS), line activity. Such a decrease in baseline activity could enable coupled with striatal or cortical stimulation, was found to the system to show a magnified response to activating stim- increase the firing rate of striatal neuron DA neurons. This uli, thereby producing a sensitized DA response. In contrast, NOS inhibitors failed to affect REGULATION OF DA RELEASE baseline DA cell firing but did increase their response to stimulation (34); therefore, NO signaling in the striatum DA appears to be released by multiple factors within its facilitates DA neurotransmission by modulation of cortico- postsynaptic target; moreover, once it is released, there are striatal and striatonigral pathways. NO also appears to have several mechanisms that can modulate its site of action. In a role in regulating terminal DA release (see the following). Carbon fiber recordings, which plays a role both in acute behavioral responses and adapta- allow rapid measurement of DA overflow, show that stimu- tions to chronic stressful conditions. Although the nor- lation of DA axons causes rapid release of transmitter. More- adrenergic system has played a major role in these processes, over, the release varies with tissue content, with PFC show- recent evidence supports a role for the DA system as well. DA released by impulse differential increases in DA dynamics depending on the flow is then rapidly removed via the DA transporter, because brain regions involved. Thus, stressful stimuli tend to cause mice with knockouts of this transporter exhibit 300 times the largest increase in DA levels in the PFC region, with longer clearance half-life compared to controls (42). The markedly smaller changes in the limbic and dorsal striatal amount of DA released by impulses appears to depend on regions (35); however, this relationship is altered by lesions several factors. Previous volumes in the Generations of of different nuclei. Thus, stress causes release of DA in the Progress series have detailed how DA release can be modu- amygdala (36), and lesions of the amygdala tend to block lated by both synthesis- and release-modulating autorecep- stress-induced increases in PFC DA levels (37). It is becoming more evident that the PFC also affect this response. Studies in which the PFC heteroceptors also play a significant role in modulating DA DA innervation is lesioned show that subsequent stressors release (43). One is the DA that is released in a high-ampli- response (38). This suggests that PFC DA released in re- tude, brief pulsatile manner by means of action potentials, sponse to stress actually blunts the responsiveness of the and then is rapidly removed from the synaptic cleft via reup- subcortical limbic DA system. This has been termed the phasic component of DA of PFC DA levels were found to decrease the basal electro- release (44), and is believed to underlie most of the behav- physiologic activity of VTA DA neurons (39). The other is the level of basal DA levels in the accumbens are normal, one interpreta- DA present in the extrasynaptic space. This tonic DA exists tion is that the DA release system has adapted to the dimin- in very low concentrations; too low to stimulate intrasynap- ished DA neuron drive, allowing normal levels of DA trans- tic DA receptors, but of sufficient level to activate extrasy- mission to occur. However, if a stimulus then causes an naptic receptors, including DA terminal autoreceptors increase in DA neuron firing, the compensated release (thereby causing feedback-inhibition of phasic DA release) mechanism would produce an augmented response. It is this tonic DA the magnitude of increase in action potential-dependent DA compartment that is sampled by slower measures of DA release into the accumbens that occurs in response to a chal- dynamics, such as microdialysis. Recently, evidence has lenge may be augmented when the PFC DA response is been advanced to define what factors may contribute to the attenuated (39). Repeated stress also has important clinical implications Although studies suggest that neuronal impulse flow is with regard to the DA system and exacerbation of schizo- necessary for DA overflow in the striatum, there is substan- phrenia. A recent study examined how chronic stress in the tial evidence that the released DA can be controlled locally form of cold exposure affects the discharge of VTA DA by a number of factors. Thus, after exposing rats to cold, there was a 64% inputs increases DA release within the striatum, and evi- decrease in the number of spontaneously active DA neurons, dence suggests that this can occur via afferents to DA cell with no significant alteration in their average firing rate.

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This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed cheap malegra fxt plus 160 mg without prescription, the full report) may be included in professional journals 139 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising order malegra fxt plus 160mg mastercard. Applications for commercial reproduction should be addressed to: NIHR Journals Library discount malegra fxt plus 160mg with visa, National Institute for Health Research malegra fxt plus 160 mg lowest price, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 141 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. APPENDIX 5 • • o • o o • • o • • • • 142 NIHR Journals Library www. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 143 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 145 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. APPENDIX 5 • • o o o o • o o • • • • • • o • o • 146 NIHR Journals Library www. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 147 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Stretching (including positional constraint-induced movement therapy) Eye-gaze skills stretching, splints) l Sensory/sensory integration l Adaptive/problem-solving skills Language development Endurance training (specific approaches mentioned: l Occupational performance coaching; Narrative/storytelling skills Cardiovascular fitness training Cognitive Orientation to daily Occupational Performance Reciprocal communication (e. Specific techniques: l Self-care/life skills baby-signing; intensive interaction) Constraint-induced movement Adjusting/changing a task to support a Aided Language Simulation therapy child to manage it independently Articulation therapy Bimanual training Providing equipment to enable child to engage in activities Breath support skills Proprioceptive neuromuscular facilitation l Seating Facial oral tract therapy l Postural management Hip and spine surveillance l Mobility (including powered) Dysphagia (swallowing, saliva control) l Small items (e. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 149 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. APPENDIX 6 Physiotherapy Occupational therapy Speech and language therapy Hydrotherapy Changing the environment to support Augmentive and alternative engagement in activities or address communication systems Functional electrical stimulation care needs Feeding/drinking equipment Botulinum (botox) l Housing adaptations l Hoists Sports (e. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health Published by the NIHR Journals Library . He also reports a grant from the NIHR Public Health Research programme during the conduct of the study. Colin Green served as a member of the funding panel for the NIHR Programme Grants for Applied Research programme from 2009 to 2013. Colin Green (2007–13) and Siobhan Creanor (2013–present) served as members of the NIHR Research Funding Committee for the South West Region of the Research for Patient Benefit Programme. Intervention costs for this study were paid for by the Peninsula College of Medicine and Dentistry. Stuart Logan (NF-SI-0515–10062) and Rod Taylor (NF-SI-0514–10155) are NIHR senior investigators. This study was undertaken in collaboration with the Peninsula Clinical Trials Unit (CTU), a UK Clinical Research Collaboration-registered CTU in receipt of NIHR CTU support funding. None of the funders had any involvement in the Trial Steering Committee, data analysis, data interpretation, data collection or writing of the report. Cluster randomised controlled trial and economic and process evaluation to determine the effectiveness and cost-effectiveness of a novel intervention [Healthy Lifestyles Programme (HeLP)] to prevent obesity in school children. Public Health Research ISSN 2050-4381 (Print) ISSN 2050-439X (Online) This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (www. Print-on-demand copies can be purchased from the report pages of the NIHR Journals Library website: www. PHR programme The Public Health Research (PHR) programme, part of the National Institute for Health Research (NIHR), evaluates public health interventions, providing new knowledge on the benefits, costs, acceptability and wider impacts of non-NHS interventions intended to improve the health of the public and reduce inequalities in health. The scope of the programme is multi-disciplinary and broad, covering a range of interventions that improve public health. The Public Health Research programme also complements the NIHR Health Technology Assessment programme which has a growing portfolio evaluating NHS public health interventions. For more information about the PHR programme please visit the website: http://www. The final report began editorial review in November 2016 and was accepted for publication in February 2017. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. However, they do not accept liability for damages or losses arising from material published in this report. This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the PHR programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the PHR programme or the Department of Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Public Health Research Editor-in-Chief Professor Martin White Director of Research and Programme Leader, UKCRC Centre for Diet and Activity Research (CEDAR), MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge; Visiting Professor, Newcastle University; and Director, NIHR Public Health Research Programme NIHR Journals Library Editor-in-Chief Professor Tom Walley Director, NIHR Evaluation, Trials and Studies and Director of the EME Programme, UK NIHR Journals Library Editors Professor Ken Stein Chair of HTA and EME Editorial Board and Professor of Public Health, University of Exeter Medical School, UK Professor Andrée Le May Chair of NIHR Journals Library Editorial Group (HS&DR, PGfAR, PHR journals) Dr Martin Ashton-Key Consultant in Public Health Medicine/Consultant Advisor, NETSCC, UK Professor Matthias Beck Professor of Management, Cork University Business School, Department of Management and Marketing, University College Cork, Ireland Dr Tessa Crilly Director, Crystal Blue Consulting Ltd, UK Dr Eugenia Cronin Senior Scientific Advisor, Wessex Institute, UK Dr Peter Davidson Director of the NIHR Dissemination Centre, University of Southampton, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Dr Catriona McDaid Senior Research Fellow, York Trials Unit, Department of Health Sciences, University of York, UK Professor William McGuire Professor of Child Health, Hull York Medical School, University of York, UK Professor Geoffrey Meads Professor of Wellbeing Research, University of Winchester, UK Professor John Norrie Chair in Medical Statistics, University of Edinburgh, UK Professor John Powell Consultant Clinical Adviser, National Institute for Health and Care Excellence (NICE), UK Professor James Raftery Professor of Health Technology Assessment, Wessex Institute, Faculty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Kleijnen Systematic Reviews Ltd, UK Professor Helen Roberts Professor of Child Health Research, UCL Institute of Child Health, UK Professor Jonathan Ross Professor of Sexual Health and HIV, University Hospital Birmingham, UK Professor Helen Snooks Professor of Health Services Research, Institute of Life Science, College of Medicine, Swansea University, UK Professor Jim Thornton Professor of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, University of Nottingham, UK Professor Martin Underwood Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, UK Please visit the website for a list of members of the NIHR Journals Library Board: www. There is little evidence of effective obesity prevention programmes for children in this age group. Objective: To determine the effectiveness and cost-effectiveness of a school-based healthy lifestyles programme in preventing obesity in children aged 9–10 years. Design: A cluster randomised controlled trial with an economic and process evaluation. Setting: Thirty-two primary schools in south-west England. Intervention: The Healthy Lifestyles Programme (HeLP) ran during the spring and summer terms of Year 5 into the autumn term of Year 6 and included four phases: (1) building a receptive environment, (2) a drama-based healthy lifestyles week, (3) one-to-one goal setting and (4) reinforcement activities. Main outcome measures: The primary outcome measure was body mass index (BMI) standard deviation score (SDS) at 24 months post baseline measures (12 months post intervention). The secondary outcomes comprised waist circumference SDS, percentage body fat SDS, proportion of children overweight and obese at 18 and 24 months, accelerometer-assessed physical activity and food intake at 18 months, and cost-effectiveness. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals vii provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ABSTRACT Results: We recruited 32 schools and 1324 children. We had a rate of 94% follow-up for the primary outcome. No difference in BMI SDS was found at 24 months [mean difference –0. No difference was found between the intervention and control groups in waist circumference SDS, percentage body fat SDS or physical activity levels. Self-reported dietary behaviours showed that, at 18 months, children in the intervention schools consumed fewer energy-dense snacks and had fewer negative food markers than children in the control schools. The cost of implementing the intervention was approximately £210 per child. The intervention was not cost-effective compared with control. The programme was delivered with high fidelity, and it engaged children, schools and families across the socioeconomic spectrum. Limitations: The rate of response to the parent questionnaire in the process evaluation was low. Although the schools in the HeLP study included a range of levels of socioeconomic deprivation, class sizes and rural and urban settings, the number of children for whom English was an additional language was considerably lower than the national average. Conclusions: HeLP is not effective or cost-effective in preventing overweight or obesity in children aged 9–10 years. Future work: Our very high levels of follow-up and fidelity of intervention delivery lead us to conclude that it is unlikely that school-based programmes targeting a single age group can ever be sufficiently intense to affect weight status. New approaches are needed that affect the school, the family and the wider environment to prevent childhood obesity. Trial registration: Current Controlled Trials ISRCTN15811706. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. See the NIHR Journals Library website for further project information. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals ix provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. CONTENTS Primary intention-to-treat analysis of body mass index standard deviation score at 24 months 28 Model diagnostics for the primary analysis of body mass index standard deviation score at 24 months 29 Secondary analysis of body mass index standard deviation score at 24 months 29 Subgroup analyses of body mass index standard deviation score at 24 months 30 Longitudinal analysis of body mass index standard deviation score 31 Primary analyses of secondary outcomes at 24 months (anthropometric measures only) 32 Primary analyses of outcomes at 18 months 32 Model diagnostics for the primary analysis of the secondary outcomes 37 Intraclass correlation coefficients 39 Complier average causal effect analysis 39 Chapter 4 Economic evaluation 41 Introduction 41 Methods 41 Estimating resource use and costs for delivery of the HeLP intervention 41 Development of modelling framework (Exeter Obesity Model) to estimate the cost-effectiveness of the HeLP intervention versus usual practice 44 Results 44 Estimating the resource use and cost of the HeLP intervention 44 A framework for the economic evaluation of HeLP 49 Discussion 68 Chapter 5 Process evaluation 71 Introduction 71 Aims 71 Research questions 71 Logic model 71 General methods 73 Section 1: process data collected from the intervention arm of the trial 73 Methods 73 Results 77 Summary 90 Section 2: mediation analyses 91 Background 91 Methods 91 Results 94 Summary 99 Conclusions from the process evaluation 100 Chapter 6 Discussion and conclusions 101 Summary of findings 101 Comparison with other studies 101 Understanding the lack of effectiveness 102 Trial strengths and limitations 103 Research recommendations 104 Conclusions 105 Acknowledgements 107 References 111 Appendix 1 Trial Steering Committee 121 x NIHR Journals Library www. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals xi provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

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Two reports from the cross-sectional US NHANES III study (N=14 purchase malegra fxt plus 160mg with visa,679) examined changes in serum calcium and phosphate324 and 25-hydroxyvitamin D325 by level of renal function order 160 mg malegra fxt plus with mastercard. A cross-sectional study compared levels of serum calcium cheap 160mg malegra fxt plus with mastercard, phosphate generic malegra fxt plus 160 mg amex, iPTH, and vitamin D amongst stage 3, 4, and 5 CKD. The prevalence of vitamin D deficiency, hyperphosphataemia, and hypocalcaemia was examined in people with stages 3 and 4 CKD. This study also reported the prevalence of abnormal calcium, phosphate, iPTH, and vitamin D with decreasing eGFR. All of these studies were limited by the use of one serum creatinine measurement to estimate renal function. Two of these studies reported the prevalence of hypocalcaemia in a CKD population. Of people with GFR <20 ml/min, 15% had abnormal Ca levels (Ca <2. Three of these studies showed that abnormal phosphate levels were highly prevalent when eGFR was <20 ml/min. Of people with eGFR 20–29 ml/min, 15% had abnormal phosphorus levels (P >1. Of people with GFR <20 ml/min, 40% had abnormal phosphorus levels. One of these studies reported the prevalence of hyperparathyroidism in the CKD population. The prevalence of 1,25-dihydroxyvitamin D deficiency was approximately 15%, 15%, 20%, 30%, 45%, 50%, and 65% in people with eGFR 70–79, 60–69, 50–59, 40–49, 30–39, 20–29, and <20 ml/min/1. The prevalence of deficiency in serum 25-hydroxyvitamin D (<15 ng/ml) 151 Chronic kidney disease remained stable until GFR <30 ml/min/1. The prevalence of serum 25-hydroxyvitamin D deficiency was approximately 15%, 20%, and 25% in people with eGFR 39–30, 29–20, and <20 ml/min/1. CrCl >80 ml/min, N=4347 328 1,814 % Abnormal Ca <10%, GFR 15%, GFR (Ca <2. Although there were statistically significant differences in mean calcium concentrations at different levels of GFR these were unlikely to be clinically significant differences. On the basis of the evidence the GDG agreed that there was no need to routinely measure serum calcium concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD. The GDG noted that although there were statistically significant differences in mean phosphate concentrations at different levels of GFR these values were all within the normal range. Serum phosphate concentrations generally fell within the normal range unless the GFR level was below 20 ml/min/1. On the basis of the evidence the GDG agreed that there was no need to routinely measure serum phosphate concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD. The prevalence of hyperparathyroidism in people with a reduced GFR was higher than in healthy individuals; however, the significance of modestly elevated PTH concentrations was thought unclear and there was no consensus on whether people with concentrations elevated to this extent 154 13 Specific complications of CKD – renal bone disease benefit from treatment. On the basis of the evidence the GDG agreed that there was no requirement to routinely measure serum PTH concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD in the absence of specific indications. Specific indications to measure serum PTH would include unexplained hypercalcaemia and symptoms suggestive of hyperparathyroidism. The prevalence of abnormally low vitamin D concentrations increased once the GFR fell below 45 ml/min/1. Most laboratories do not measure 1,25 dihydroxyvitamin D concentrations. On the basis of the evidence the GDG agreed that there was no need to routinely measure serum vitamin D concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD except where there are specific indications such as unexplained hypocalcaemia or symptoms suggestive of vitamin D deficiency. Because of the increased prevalence of abnormal serum calcium, phosphate, PTH and vitamin D concentrations in people with stage 4 and 5 CKD and the fact that these people may require treatment for renal bone disease it was recommended that calcium, phosphate and PTH concentrations should be measured in people with stage 4 and 5 CKD. There was no evidence to guide a recommendation about how frequently the calcium, phosphate, PTH and vitamin D concentrations should be measured in people with stage 4 and 5 CKD and the GDG agreed that this would be determined by the clinical circumstances. R65 Measure serum calcium, phosphate and PTH concentrations in people with stage 4 or 5 CKD (glomerular filtration rate (GFR) <30 ml/min/1. Determine the subsequent frequency of testing by the measured values and the clinical circumstances. Bisphosphonates inhibit bone resorption with relatively few side effects and are widely used for the prevention and treatment of osteoporosis. Osteoporosis can also develop in people with CKD and ESRD for many reasons beyond age-related bone loss and postmenopausal bone loss. People with CKD are far more likely than the general population to have conditions putting them at risk of osteoporosis and are much more likely to be prescribed medication promoting development of osteoporosis. The diagnosis of osteoporosis in people with advanced CKD is 155 Chronic kidney disease not as straightforward as it is in people with postmenopausal osteoporosis. The diagnosis of osteoporosis in people with CKD must be done by first excluding the other forms of renal osteodystrophy. Approximately 80% of the absorbed bisphosphonate is usually cleared by the kidney, the remaining 20% being taken up by bone. Relative bone uptake is increased in conditions of high bone turnover, with less of the drug being excreted by the kidneys. The plasma half-life is approximately one hour, while the bisphosphonate may persist in bone for the lifetime of the patient. Product data sheets do not recommend bisphosphonates for people with stage 4 or 5 CKD. What is the evidence for this and what is the evidence for the routine use of bisphosphonates in the prevention and treatment of osteoporosis in people with CKD? One open-label RCT was excluded due to limitations in randomisation. Limitations of this study include the small sample size, although there was no loss to follow-up. A meta-analysis of data from nine phase III trials (N=9883, 2 years follow-up, mean age 75 years) investigated the effects of risedronate in osteoporotic women with varying levels of renal function. A post-hoc analysis of the Fracture Intervention Trial (FIT, N=6458, 3 year follow-up, mean age 68 years)334 investigated the effects of alendronate on BMD and fracture in osteoporotic women with moderate/normal renal function (eGFR ≥45 ml/min, N=5877) or severe renal dysfunction (eGFR <45 ml/min, N=581). The safety and efficacy of bisphosphonates in preventing osteoporosis in people with CKD are summarised in Table 13. There was a NS decline in BMD in the risedronate group. The difference between BMD changes in the risedronate and vitamin D combination therapy group and the vitamin D alone group were statistically significant. Within the placebo group, new vertebral fractures increased significantly with increasing severity of renal impairment (p<0. There was a significant interaction between renal function and the increase in total hip BMD (p=0. Among women with osteoporosis (N=3214), alendronate produced a greater increase in BMD at the hip and femoral neck in the group with eGFR <45 ml/min than women with eGFR ≥45 ml/min. However at the spine the increase in BMD was greater in women with eGFR ≥45 ml/min. There was no significant interaction between renal function and increase in BMD. The risk reduction was significant in women with eGFR ≥45 ml/min for both clinical and spine fractures, but NS in women with eGFR <45 ml/min. R+A alfacalcidol Risedronate + alfacalcidol: +2% from baseline (p<0. Bisphosphonates appeared to have benefits on bone mineral density in people with CKD. The studies did not include prevention of osteoporosis in people with a GFR <30 ml/min/1. Guidelines on the management of osteoporosis do not make recommendations that relate to people with CKD. It is then hydroxylated in the liver to form 25-hydroxyvitamin D (calcidiol) and then hydroxylated 160 13 Specific complications of CKD – renal bone disease in the kidney to 1,25-dihydroxyvitamin D (calcitriol), which is the most active form. Vitamin D deficiency can therefore occur as a result of decreased intake or absorption, reduced sun exposure, increased hepatic catabolism, or decreased endogenous synthesis (via 25-hydroxylation in the liver and subsequent 1-hydroxylation in the kidney). Active vitamin D has a variety of actions on calcium, phosphate, and bone metabolism. By increasing intestinal calcium and phosphate reabsorption and increasing the effect of parathyroid hormone (PTH) on bone, in health vitamin D has the net effect of increasing the serum calcium and phosphate concentrations. Vitamin D deficiency or resistance interferes with these processes, sometimes causing hypocalcaemia and hypophosphataemia. Since hypocalcaemia stimulates the release of PTH, however, the development of hypocalcaemia is often masked. The secondary hyperparathyroidism, via its actions on bone and the kidney, partially corrects the hypocalcaemia but enhances urinary phosphate excretion, thereby contributing to the development of hypophosphataemia. In people with CKD the kidney component of this loop is increasingly compromised as CKD advances. As renal function declines, the hydroxylating activity of renal 1α-hydroxylase on 25-hydroxy- vitamin D3 also decreases, resulting in decreased production of active vitamin D (1,25-dihydroxy- vitamin D3) and decreased intestinal absorption of calcium. The decrease in calcium and active vitamin D3 alleviates the repression of parathyroid hormone (PTH) production, resulting in hyperproliferation of parathyroid cells. High PTH levels cause an increase in bone remodelling, leading to high bone-turnover (osteitis fibrosa), loss of bone density and structure. This excess bone remodelling liberates calcium and phosphorus from bone, resulting in hypercalcaemia and hyperphosphataemia and increasing the risk for vascular calcification.

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