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In most cases 60mg mestinon amex, we talked to only one respondent from participating general practices buy mestinon 60mg with amex. This was usually the GP responsible for leading use of PRISM, and their knowledge and use of PRISM was not always shared by other staff. In a minority of practices, the PRISM lead GP changed between the three data collection points, because they retired or moved practice. We were unable to gather the views of community health staff after the tool was implemented, as most staff declined to attend a follow-up focus group because their roles had changed. Only one health services manager agreed to be interviewed at the end of the study. General practitioners taking part in the PRISMATIC trial volunteered for the study. In interviews, several identified themselves as interested in, or supportive of, research and wanted to contribute to knowledge generation by participating. They were therefore likely to be atypical of many GPs and their response to PRISM may not be that of other members of their profession. A summary of service user involvement can be found in Table 42. TABLE 42 Summary of service user involvement in the PRISMATIC trial Type of involvement activity Role Process Comments Supporting Service users were actively Information, guidance, honoraria, Named individual (BAE) supported service user involved across all activities expenses and briefing sessions the trial manager (MRK) to ensure involvement associated with delivering were provided to facilitate active active involvement. In addition, the PRISMATIC trial involvement provided single contact for service users Service users recruited through the SUCCESS group: membership of this group gave access to mutual support and a wider service user perspective Mid-study meeting held to review involvement and further support needed Long time scales enabled strong relationships across all research partners RMG Two service users were 24 meetings scheduled (2010–16) One individual remained involved meetings invited to be members of throughout the study; the second the RMG, and contributed Two service users were at almost place was taken by four different to all decisions about all meetings; just one meeting individuals managing and undertaking took place without a service user the study member present Individuals received induction before starting role and were offered pre-meeting briefings Service user perspectives were sought at all stages, especially when developing patient consent process, preparing patient information and questionnaires, holding a prize draw for questionnaire respondents, interpreting final results TSC meetings Two service users were Five meetings held (2013–15) Service users received training before invited to be members of joining the TSC which covered the the six-person TSC, and Three out of the five meetings role of a TSC and provided provided independent attended by at least one service background about the PRISMATIC study scrutiny and user trial oversight Opportunity provided for briefing before each TSC meeting Qualitative One service user was Two meetings held (2013–14) analysis and invited to the qualitative write-up of subcommittee to develop Both meetings were attended by results coding framework and one service user and three review drafts of qualitative researchers. 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 103 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. SERVICE USER INVOLVEMENT TABLE 42 Summary of service user involvement in the PRISMATIC trial (continued) Type of involvement activity Role Process Comments Writing events To contribute service user Six meetings held (2012–15) Workshop sessions held at two perspective to all meetings to consider potential study discussions about Two service users were invited to outputs for service user audience communications and each meeting: at least one dissemination attended each meeting Discussions held about how to describe the PRISMATIC trial service user involvement in final report Service users contributed to all discussions as equal team members and agreed publications plan Publicity and Service users contributed to Service users reviewed and One service user contributed to dissemination publicity and dissemination contributed to seven PRISMATIC edition 6, writing about her materials about PRISMATIC newsletters, aimed at participating experience of being involved in GP practices and health services research managers One service user contributed to edition 7, explaining how risk prediction tools can help patients, especially those with early-stage chronic illness who can expect their condition to deteriorate Two newsletters contained articles by GP champions linked to the research team The SUCCESS group members advised on, and reviewed, the patient information pages of the PRISMATIC trial website Service users involved in Service users suggested production publicising PRISMATIC to patients and distribution of a poster about the PRISMATIC trial, for display in GP practices, to inform patients about the study One service user and one GP champion were interviewed by a TV crew about the study. The package was screened on the BBC Wales evening news Service users were co-authors on Service users co-authored conference all study outputs presentations Service users co-authored journal publication reporting baseline qualitative findings (Porter et al. As people changed, five individuals were involved over 5 years. All were diagnosed with chronic conditions and some also cared for family members. One of these individuals was actively involved throughout the whole period of the PRISMATIC trial. Poor health meant three other individuals had to give up their role. To reduce the burden on individuals, we recruited a reserve service user so there were potentially three to attend meetings and less need for anyone with family responsibilities or feeling unwell. Despite receiving briefings and project information, the reserve person reported that it was difficult to retain continuity when not regularly involved and there were long periods between meetings. When his health limited his ability to drive, the study team agreed not to recruit another person and resumed working with two service users. Halfway through the trial (December 2013), we held a meeting for service users and core research staff (BAE, MRK and HH) to review their experience and identify ways to enable them to sustain and increase their involvement. Study meetings At least one, often two, service users attended almost all RMG meetings (23/24). We recruited two different service users to the TSC; they attended three of five meetings. We also involved service users in task-related meetings such as writing days, meetings to undertake qualitative analysis and research development groups discussing further research linked to the topic of risk prediction. Research activities Throughout the period of the PRISMATIC trial, service users were involved in a range of research activities including: l RMG meetings – all aspects in an equal role with other RMG members l reviewing research information ¢ format of patient questionnaires ¢ patient letters and information sheets ¢ interview schedules ¢ abstracts and posters presented at conferences l qualitative data analysis l commenting on strategies to increase questionnaire response rates (prize draw) l deciding to have a patient page on the PRISMATIC trial website (RMG decision) l developing and reviewing the patient page of the PRISMATIC trial website (at SUCCESS group meetings) l commenting on consent issues relating to the use of anonymised data l publicity (British Broadcasting Corporation, newsletters); focus of British Broadcasting Corporation publicity was on one of the service users l TSC – two members l developing and piloting service user terms of reference (at SUCCESS group meetings and RMG) l informal dissemination about the PRISMATIC trial to patient networks l co-applicant on further research bids, including a systematic review of risk prediction models and developing an intervention to communicate risk scores with patients. 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 105 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. SERVICE USER INVOLVEMENT Reflections from one service user member of the PRISMATIC study I considered the PRISMATIC research to be advantageous to service users and I was pleased to be part of its development. I was able to pose questions and ask for explanations as part of the PRISMATIC team but felt there were some aspects of the research which could have taken a wider view. As a service user with chronic conditions I am aware of the problems with access to health services especially primary services, for example, GP surgeries. The research did not address the initial presentation at a GP surgery. GP receptionists were not able to identify the patients on the top of the PRISM pyramid (this was a problem when these patients were requesting an appointment). The remit for PRISMATIC did not include this and was considered to be the responsibility of the surgeries and I accept this. I do not have any issues to raise about involving service users as it has got to be beneficial in a research study. Service users, to be an asset to research and researchers, need to have some training and understanding of working within this environment. They must also understand the remit but never be afraid to put forward issues that they consider will benefit patients. That should be why we are taking part in research and we must not lose sight of this. What could be done better is explaining the remit more. There have been times when I could not see how a particular research project can work without some other basic changes made to make the research work in practice. When I have posed these questions I can tell the information is not compatible with the research criteria. Being part of a research project like PRISMATIC works for me. But what really worked for me was when I asked [name] to explain in plain English where we were at a particular time and the newsletter he produced after the event.

The range of informants evolved with the emergent theory 60mg mestinon free shipping. First purchase mestinon 60 mg with amex, we conducted pre-entry documentary analysis drawing on a wide range of sources. Second, we conducted face-to-face semistructured interviews. Although interviews can be a highly efficient and effective research tool, it is recognised that they also present the challenge that bias may arise because of the efforts of image-conscious informants. This challenge was mitigated through the use of multiple interviews among diverse informants who were likely to view the issues and events from different standpoints. Some of the interviews were conducted with both researchers present, other interviews with just one researcher. In the main, interviews were recorded and transcribed. The researchers drew on a semistandard interview schedule comprising semistructured interview questions. These had to be adapted to the varying situations including, for example, the subject of the service redesign under scrutiny and the role and vantage point of the interviewee. The semistructured interview schedule was adapted accordingly. Appendix 4 shows a typical example of one such interview guideline. 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 15 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. PROJECT DESIGN AND METHODOLOGY Case study data analysis As mentioned, members of the research team worked in pairs for each main case study. These subteams undertook the first stage of each data analysis process. In this way a coherent narrative of the flow of events within each case could be constructed. This was combined with a descriptive account of the issues and challenges encountered by the actors involved. These first-level reports used a common framework: (1) context, (2) focus and narrative of the case, (3) clinical leadership themes emerging and (4) emerging ideas for cross-case comparisons. The first three sections of these initial draft reports were fed back to informants in the case studies concerned, as a way of validating the accuracy of the data collected and the descriptive interpretations made. Next, the first-level case reports were discussed, in turn, at a monthly series of research team meetings. From these discussions emerged ideas for explanatory concepts that could be applied to understand differences and similarities in the nature of clinical leadership across the cases. This process of discussion, conceptualisation and comparison between the cases led to the development of the conceptual framework for analysing the cases set out at the beginning of Chapter 4. This second-level analysis was carried out by two members of the research team, who were also the main authors of this report. That analysis brings together the descriptive summary of events with an explanatory analysis of the forms of clinical leadership and their relationship to the achievements and difficulties encountered in bringing about service innovation. The analyses are compared and discussed further in Chapter 5. TABLE 2 Interviews for the case studies Interviewee role Number of interviews GP chairpersons, clinical leads, other GPs 65 CCG accountable officers and other managers 36 Nurses 8 Lay members 7 Acute sector doctors and managers, mental health 25 Community health managers and nurses 10 NHSE, CQC, NHS Improvement, CSU and other agencies 10 LA representatives, councillors, chief executives and directors, public health 9 Voluntary sector 9 GP practice managers 7 Patient representatives 8 Ambulance service, paramedics 8 Total 202 16 NIHR Journals Library www. First, the responses to each of the questions were gathered together and the results presented as tables and charts. Second, a number of cross-tabulations were made in order to investigate whether or not occupants of different roles answered questions in particular ways. Third, comparisons were made between our data and the ratings of CCGs made separately by NHSE. These correlations produced some very interesting findings. A notable feature of the completed questionnaires were the free-form questions. As a result of the careful preparation of the questionnaires in conjunction with a range of informants from the scoping phase, respondents readily recognised the relevance of the issues being raised and were very keen to share their thoughts. In the next chapter, the statistical results stemming from the structured questions are presented and analysed along with the free-text responses. Public and patient involvement We sought to involve the public and patients as far as was feasible, relevant and practicable at all stages. In the first instance, a nationally renowned patient and public involvement (PPI) representative with very extensive experience of PPI was appointed as co-chairperson of the Project Steering Committee. This representative was involved in all aspects of the research from the initial design, the oversight of research instrument construction and the review of findings at all stages, to the discussions about the dissemination of findings. During the course of the project, PPI was used mainly in relation to the specific service redesign initiatives that were the focal component of this study. These initiatives often had PPI arrangements in place and we tapped into these rather than seek to set-up new arrangements. One extension of this approach was that a member of the project team sought permission to become an active participant member of a PPI group that was associated with one of the service redesign initiatives in the core case studies. Full ethics approval from the Research Ethics Committee overseeing the project was sought and full disclosure was made to members of the PPI group. Another dimension was that in the surveys and the case studies we took steps to find out how patients and the public had been involved in the redesign of services. 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 17 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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Only adenosine has been approved for use as a Science 1998;282:1844–1845 mestinon 60mg otc. Ecto-nucleotidases: molecular struc- ular tachycardia cheap 60 mg mestinon mastercard, acute systemic uses that avoid some of tures, catalytic properties, and functional roles in the nervous system. Stage specific expression of Similarly, the unexpected in vivo effects of AK inhibitors P2Y receptors, ecto-apyrase and ecto-5′-nucleotidase in myeloid suggest that this is not a viable approach to the discovery leukocytes. Tordorov LD, Mihaylova-Todorova S, Westfall TD, et al. Neu- line for the treatment of asthma and the widespread use of ronal release of soluble nucleotidases and their role in neurotrans- caffeine as a CNS stimulant represent other P1-targeted mitter inactivation. The evaluation of A2A antagonists as indirect as potential drug targets. Biochem Pharmacol 2000;59: dopamine agonists for use in PD (73–75) is an intriguing 1173–1185. Nucleotide and dinucleotide der, although the side effect liabilities are unknown at effects on rates or paroxysmal depolarising bursts in rat hippo- present. Ion channel genes and human neurological In contrast, the highly discrete localization of P2X3 re- disease: recent progress, prospects, and challenges. Proc Natl Acad ceptors to sensory nociceptive neurons (79) has led to an Sci USA 1999;96:4759–4766. Similarly, the discrete localization of other P2 Biophys Biomol Struct 2000;29–46. Role of purines and pyrimidines in the central nervous system. In: Abbracchio MP, Williams M, gest that selective agonists and antagonists for these receptor eds. Molecular, nervous subtypes may represent very novel therapeutic agents as well and urogenitary system function handbook of experimental pharma- as research tools to understand target function. San endeavors, is that the less that is known regarding the func- Diego: Academic, 1977. Ecto-protein kinases as mediators for the action of secreted ATP in the brain. In the area of purinergic medications, the 120:411–426. Uridine and its nucleotides: biological based evaluation of compound efficacy and side effect liabil- actions, therapeutic potential. Trends Pharmacol Sci 1999;20: ity will greatly assist in the prioritization of therapeutic tar- 218–226. Effects of chronic uridine on striatal dopamine release and dopamine related behaviours in (57). Finally, the renewed interest in mitochondria as cellu- the absence of presence of chronic treatment with haloperidol. Uridine activates fast trans- for P1- and P2-receptor ligands that may have benefit in membrane Ca2 ion fluxes in rat brain homogenates. Neuroreport treating human disease states, especially those involving 1999;10:1577–1582. Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Adenosine and the concept of a retaliatory metabo- I would like to thank Mike Jarvis for his contributions to lite. Adenosine kinase inhibi- the previous CD-ROM version of this chapter. The reader is referred to reference 1 of adenosine kinase inhibitors as analgesic agents. Mutual occlusion of P2X P2T receptor: a novel approach to antithrombotic therapy. J Med ATP receptors and nicotinic receptors on sympathetic neurons Chem 1999;42:213–220. P2Z receptor for extracellular ATP identified as a P2X receptor. Development of selective purino- the P2X7 receptor Neuropharmacology 1997;36:1277–1283. Allosteric enhancement of adenosine A1 re- gated cation channels change their ion selectivity in seconds. Nat ceptor binding and function by 2-amino-3-benzothophenes. Adenosine A3receptors: novel ligands and paradox- phosphates, extracellular function and catabolism. Cloned adenosine A3 receptors: pharmacological prop- 55. Mitochondrial disorders: clinical and ge- approaches in experimental therapeutics. P2 Purine and pyrimidine receptors: neuromodulation: a historical perspective. In: Jacobson KA, Jarvis emerging superfamilies of G-protein coupled and ligand gated MF, eds. Aggressiveness, zation of recombinant human and rat P2X receptor subtypes. Reduced vas defer- multiple ATP subtypes during the differentiation and inflamma- ens contraction and male infertility in mice lacking P2X1 recep- tory activation of myeloid leukocytes. Curr Opin Neuro- display urinary bladder hyporeflexia and reduced nocifensive be- biol 1997;7:346–357. Decreased platelet aggrega- and P2X5receptor subunits reveals a novel ATP-gated ion chan- tion, increased bleeding time and resistance to thromboembolism nel. Effect of loss of Annu Rev Pharmacol Toxicol 2000;40:563–580.

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An open trial of fluoxe- of meta-chlorophenylpiperazine on cerebral blood flow in obses- tine in patients with anorexia nervosa cheap mestinon 60 mg overnight delivery. J Clin Psychiatry 1991; sive-compulsive disorder and controls generic mestinon 60mg on line. Human brain between a dopamine-5 receptor polymorphism and attention- serotonin synthesis capacity measured in vivo with alpha-(C- deficit/hyperactivity disorder: genetic and brain morphometric 11) methyl-L-tryptophan. Specific brain synthesis in the dentatothalamocortical pathway in autistic boys. Obsessive-compulsive disorder: con- therapy for child and adolescent psychiatric disorder. Tardive dyskinesia (TD) is an iatrogenic human hyperkinetic GABAergic) in gray matter regions in the segregated, paral- movement disorder associated with chronic antipsychotic lel frontal-subcortical modulatory motor circuits (35). The cause of the syndrome, namely, chronic dopamine-receptor blockade, is specifically known and is straightforward to model. Thus, disease pathophysiol- ogy has been approached with surrogate preparations. Tra- CLINICAL FEATURES AND COURSE OF ditionally, factors mediating TD have been sought in striatal TARDIVE DYSKINESIA dopaminergic transmission. However, several incompatibil- ities have developed between the characteristics of the dopa- The presentation of TD is typical of a dyskinesia, with oro- minergic model and the presentation of the disorder (10). The -aminobutyric acid (GABA)–ergic transmission within the movements worsen with stress and concomitant physical basal ganglia has also been targeted as the putative patho- activity and diminish or disappear during sleep. Here, although biochemical char- defining, in that all dyskinesias with their first onset within 6 acteristics between the model and the disease have appeared months of ongoing antipsychotic treatment are diagnosed compatible, therapeutic implications have not been fully as TD (50). Consequently, it is expected that the diagnosis met, possibly because of inadequate pharmacologic tools will be confounded by other categories of dyskinesia, includ- (10). TD is Research has suggested that both these transmitter altera- distinguished from parkinsonism, the other major category tions, dopaminergic and GABAergic, may reflect an action of antipsychotic-induced movements, by being hyperki- of antipsychotic drugs on neuronal activity within the basal netic, with delayed onset and delayed resolution after medi- ganglia thalamocortical motor circuit. Clinically, antipsy- cation discontinuation, and by its contrasting pharma- chotic drug action overall tends to normalize mental status cology. On a cellular basis, gradual alterations produced by these Although TD has a characteristic pharmacology, none of drugs over time, within selected subcortical brain regions the drugs that suppress movements in probe studies are and at selected synapses of this circuit, likely result in TD. Treatment The mechanism of all these clinical actions is thought to approaches for TD are discussed later. Tamminga: Maryland Psychiatric Research Center, University pine, with which reduced risk is probable. Therefore, even of Maryland School of Medicine, Baltimore, Maryland. Woerner: Department of Psychiatry Research, Hillside Hos- though TD may be diminishing as a significant clinical risk pital, Long Island Jewish Health System, Glen Oaks, New York. CUMULATIVE INCIDENCE OF TARDIVE DYSKINESIA Tardive Dyskinesia Persistent Tardive Neuroleptic Cumulative Incidence, Dyskinesia, (85% CI) Tardive Dyskinesia Exposure (y) (95% CI) Cumulative Incidence Hazard Ratea 1. The number represents the average yearly hazard rate over the 5-year block of time. Data from a prospective study of 971 young adult psychiat- Preliminary data suggest that prognosis for TD remission ric patients followed for up to 20years indicated a increasing is better for patients who are treated for shorter times within cumulative incidence rate of TD over the 20-year interval the follow-up period after TD diagnosis and for those (Table 126. The cumulative incidence of persistent TD treated with lower doses of antipsychotic during follow-up was lower but increased proportionally (40). These facts about TD encourage future study in ani- consistent with a declining rate of TD over time, illustrated mals and humans on TD mechanisms and treatment and by the declining hazard rate (Table 126. A similar pattern facilitate the research by providing a firm baseline and a develops in the hazard rates over 20years for persistent TD. A decline in hazard rate over time was also reported by Morganstern and Glazer (46), although their data show a sharper decline after the first 5 years. FUNCTIONAL HUMAN NEUROANATOMY OF Rates of TD are significantly affected by the age and ANTIPSYCHOTIC DRUG ACTION other characteristics of the several samples studied. An in- creased vulnerability to TD associated with increasing age The human central nervous system (CNS) has been the is the most consistently reported finding in TD research. These antipsychotic data are 53% after, 1, 2, and 3 years of antipsychotic drug treatment relevant to TD mechanisms insofar as the localization of (74). In the younger adult sample (40), the can suggest the regions that likely contain the neurochemi- hazard rate for TD was lowest for patients in their twenties cal disorder underlying TD. The firm association between and thirties at study entry, increased for those in their for- striatal dopamine-receptor blockade and antipsychotic drug ties, and sharply increased for those aged 50to 60years. It has been suggested TD risk in the prospective study (Table 126. Alternatively, as argued here, antidopaminergic peaks in dosage of antipsychotic drug (more than 1,000 mg drugs could deliver their antipsychotic action by altering in chlorpromazine equivalents), and intermittent antipsy- activity in neuronal populations within the long-loop feed- chotic treatment. Treatment with lithium is associated with back neurons in the basal ganglia thalamocortical pathways, a lower risk of TD development. The mechanisms responsible for TD may well occur (Table 126. Of these persistent Early investigators observed an elevation of neuronal ac- cases, 68% remitted within the next 2 years. For the half tivity in the human caudate and putamen with antipsy- whose initial episode was transient, there was a high risk chotic drug treatment using functional in vivo imaging (33, (32%) of developing a persistent episode within 1 year of 69). To refine the localization of the signal, our laboratory Chapter 126: Tardive Dyskinesia 1833 FIGURE 126. The regions of color indicate quantitativelythe areas of regional cerebral blood flow (rCBF) activation (ON-30 day OFF) or inhibition (30 dayOFF-ON) with subchronic haloperidol treat- ment (0. In the top two figures, at 04 and 00 mm from the anterior commisure/poste- rior commissure line (ACPC) plane, the basal ganglia show significant rCBF activation with haloperidol. In the bottom two figures, at 04 and 04 mm from the ACPC plane, both the anterior cingulate cortex and the middle frontal cortex show sig- nificant diminished rCBF with halo- peridol. In an animal prepara- using [18F]fluorodeoxyglucose carried out at the end of each tion, Abercrombie and DeBoer demonstrated the principle treatment period (35). Regional cerebral metabolic rates of that a pharmacologic perturbation delivered to a restricted glucose, calculated using the usual analytic techniques, were region in the basal ganglia (e.

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