By Q. Vibald. Millikin University. 2019.
They may also have felt that their GP has not been responsive in some way generic 20 mg levitra professional with visa erectile dysfunction treatment in thailand. The case for continuing the service after the pilot period was widely linked to increasing the number of suitable jobs each shift buy levitra professional visa erectile dysfunction pre diabetes. By the end of the pilot period discount levitra professional 20 mg on line erectile dysfunction causes and solutions, the service was attending an average of around five patients per 12-hour shift. The CCG wanted this to be six or seven; the typical attendance for other ambulances and first-response cars was around 12 per shift. Although it was recognised by both the CCG and the ambulance trust that the service attendances were likely to take longer than regular emergency calls involving conveyance to hospital because of the treatment and possible onward referrals involved, there was acceptance that the number of jobs per shift needed to be greater. As a result of shortages of paramedics, the ambulance service and CCG agreed to take forward a modified version of the service which consists of a GP accompanied by a driver. This now operates from the local ambulance garage so that links with paramedics and other ambulance crew are maintained. Clinical leadership across different arenas Two kinds of clinical leadership were found to be important in this case: 1. The CCG urgent care lead GP and corresponding programme director were able to carry the case for funding this initiative to the strategic commissioning arena of the CCG governing body. This institutional work of achieving the vesting of resources in a new initiative was vital. Characteristics of clinical leadership for service redesign with this Clinical Commissioning Group Together, these two cases illustrate the distinctive roles of clinical leadership in first articulating the conception of a new approach to service delivery and then defining the operational realities of the new service. They show that the former aspect of clinical leadership can take place effectively in an arena such as a CCG programme board with operational responsibility for commissioning. The operational realities then need to be worked out in more practical detail by lead front-line clinicians in provider organisations. This second mode of leadership is of an adaptive kind. There is a need to bring the learning from operational experience with the new arrangement back into the commissioning arena. This can be seen as a further integrative element of clinical leadership, spanning the commissioning and provider roles. Case B: redesigning general practice and primary care This CCG is located in a part of Birmingham where the health of the population is generally worse than the England average. The CCG, which formed the site of this case study, derived its GP practices from three different former PCTs. The associated variability in practice and expectation is an important element in the case narrative. The CCG inherited huge variation in standards and coverage of care across its patch. The potential for GP practices that were to become unhappy with attempts at reform to renounce membership and join another CCG is also a significant feature. 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 47 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 was a very large CCG with > 100 GP practices and, as such, it saw a need to allow the localities a greater degree of influence than was often the case in other CCGs. Focus and theme of the case: the primary care improvement programme The research in this CCG focused on a major attempt that was made to redesign primary care across the whole patch. The particular focus of that initiative were the services provided by GP surgeries. The programme is of special interest here because it represents a service redesign initiative driven at the CCG strategic level and it used the official channels of the CCG. The problems to be tackled included unacceptable variation in the range and quality of care offered in GP practices across the CCG. There was also a lack of uniformity in the pattern of payments: practices were paid at differential rates for the same kind of work. It was the chairperson of the CCG and the accountable officer (both GPs) acting in concert who took the lead in identifying these issues as a priority. It is noteworthy that at the time (2014–15) many other CCGs were not viewing GP services and primary care as a main concern. Conversely, those CCGs with established teams of people who had a long history of working together in, for example, the previous PCTs may have been less inclined to make such a new determined effort. The first step was a baseline which all the practices were required to meet. This was a mandatory requirement to remain a member of this CCG. The second step was to standardise the local enhanced services offer. This meant that practices (in cluster form if necessary) were asked to improve their range of services so as to meet an acceptable standard. This started out as a voluntary exercise but increasingly became a requirement. The third step was a higher level of innovation in services offered. The CCG used a budget provided from the centre, which was geared towards care for the elderly, to invite bids for new enhanced services in this area. We first describe the primary care improvement programme (a pseudonym of the title actually used by this CCG) as it was presented in official terms. We then present an analysis of how the programme was received and understood by multiple agents, including some of the designers of the programme and those who were the recipients. The official picture The main initiative driven by this CCG was a service improvement programme designed to make a step change in the quality of primary care. The key declared objective was to: Reduce the level of variation in general practice and bring all practices up to the same standards of primary care. Through [primary care improvement programme] we will ensure there is universal coverage of services across our member practices and that these services are available for all patients, regardless of where they live. Case B: CCG policy document Attention focused on holistic care, integrated care, long-term conditions management and better care for the elderly and vulnerable. The constituent elements of the new model of primary care included universal coverage of some basic service standards across the whole CCG population; an overarching framework that allowed the freedom to identify creative solutions for how patients receive their care while ensuring accountability for care remains with practices; delivery of a patient-centred and integrated approach to improving primary care management of long-term conditions; and an up-skilled general practice workforce to deliver services that had previously been provided by secondary/community providers. Integration, access to mental health services and a transformation of urgent care were all elements of the total package of reform. The new plan from the top leadership duo was for a more integrated system built around general practices. This included new models of care with GPs and others working in new ways with support from secondary care, while also bringing in associated community services, community nursing and district nursing. Supporting elements included data sharing and use of the BCF to integrate social care. The problems of pressures on general practice, fragmentation and lack of a universal and equitable service provision were further reasons justifying action. In exchange for extra funding and support, the GP practices in the CCG were expected to offer care closer to home, delivering a wider range of tests and investigations in primary care settings, such as electrocardiography, spirometry and insulin initiation.
Thus levitra professional 20mg mastercard erectile dysfunction treatment fort lauderdale, knockout A 2 mice possessed functional GABAA receptors that responded normally to GABA site ligands or barbiturates buy discount levitra professional 20 mg line erectile dysfunction quad mix, but did not GABA System Transgenic Mice respond to benzodiazepines; these findings led to the con- The synthesis of GABA is regulated by two isoforms of the clusion that the 2subunit is not necessary for the formation enzyme glutamate decarboxylase (GAD) order levitra professional 20mg mastercard erectile dysfunction in teenage, GAD67, and the of functional GABAA receptors, but is required to create 894 Neuropsychopharmacology: The Fifth Generation of Progress the benzodiazepine-responsive site of those receptors. Mice rated from the negative side effects of these compounds, that were homozygous for the mutation, however, did not and that the 1 subunit of the GABAA receptor is likely live past weaning in this study. In mice carrying only one to mediate some of these potentially harmful properties of copy of the functional 2 gene, a 20% reduction in benzodi- benzodiazepines. Interestingly, McKernan and colleagues azepine sites was observed, but these mice did not show (160) demonstrate that a novel benzodiazepine-site ligand overt developmental deficits. In a recent study, a detailed that binds to GABAA receptors containing 2, 3,or 5 characterization of the behavioral profile of these animals subunits but avoids receptors with the 1 subunit produces was carried out. Heterozygotes displayed a decrease in the a behavioral profile that is identical to that of the 1 subunit number of entries into and amount of time spent in the knockout mice; in normal mice, this compound decreases open arms of an elevated plus maze and the bright compart- murine anxiety-like behaviors without eliciting sedation or ment of a light-dark box. Finally, 2 heterozygotes Stress-Related Disorders were found to react to partially conditioned stimuli (only weakly paired with aversive consequences) as if they were As stated above, the most widely used GABA system-based full and potent predictors of threat; compared to wild-types, drugs for the treatment of anxiety are the benzodiazepines, which showed low levels of defensive behaviors to the par- which facilitate GABA transmission through the GABAA tially conditioned stimulus, heterozygotes displayed high receptor. As outlined in the previous section, the search for levels of conditioned freezing to the partial conditioned novel compounds that may act selectively at specific GABAA stimulus that were identical to those displayed by all animals subunits is ongoing, with the ultimate hope of discovering in response to the full conditioned stimulus. This profile ligands that produce anxiolysis but do not cause some of has been proposed to be a model for the tendency to inter- the serious side effects that are commonly associated with pret neutral situations as threatening that is seen in anxiety benzodiazepines. Taken together, the results from this extensive be- leagues (160), drugs that selectively target certain GABAA havioral profile indicate that / mice have increased receptor subunits may hold great promise for the treatment 2 neophobia and stress-like responses and may thus provide of anxiety without harmful side effects. This development a model for increased anxiety-like behaviors (154—156). The use of targeted genetic in 2 heterozygotes were blocked by the benzodiazepine alterations in identifying the roles of various GABAA sub- diazepam, suggesting that this animal model may also have units will undoubtedly aid in this effort to create 'designer good predictive validity for identifying clinically effective drugs' for the treatment of anxiety (158). It is also extremely important to mention the 1 subunit General Issues and Caveats of Transgenic transgenic mice, whose behavioral profiles have been thor- Animal Studies oughly and insightfully reviewed in recent articles (157, 158). In these mice, a single amino acid is altered (histidine As mentioned above, mice carrying certain mutations replaced by arginine at the 101 position of the peptide) in within either the CRH, the 5-HT, or the GABA system the 1 subunit of the GABAA receptor complex. It appears that these change does not produce any overt alterations in baseline genetically engineered mouse models also have some predic- responses to stress in the genetically altered mice; these ani- tive validity; the stress-like endophenotype observed in at mals behave similarly to wild-type controls in tests such least two of the aforementioned models is normalized by as the elevated plus maze and the fear-potentiated startle administration of a clinically effective antianxiety agent that paradigm, a measure of conditioned fear (159,160). Thus, acts within the system that was genetically targeted. It re- under drug-free, normal conditions, these animals do not mains to be determined, however, the extent to which these display a behavioral pattern that is consistent with an anxi- genetically altered models serve to identify potential anti- ety-like endophenotype. When these mice are treated with anxiety agents from different chemical classes. For example, conventional benzodiazepines, however, they react very dif- do benzodiazepines reduce stress-like effects of CRH over- ferently to the drug than their wild-type counterparts. The extent to which the stress-like endopheno- with the mutation in the 1 subunit display a normal reduc- type in these animals is altered by compounds that act on tion of stress-induced anxiety-like behaviors after benzodi- systems that were not directly targeted by the genetic muta- azepine treatment, but fail to display some of the more tion will aid in determining the generalizability and utility deleterious side effects associated with this class of drugs of these models as predictors of novel anxiolytic agents. These results indicate one assumes that these animals provide a model of inherent that the anxiolytic effects of benzodiazepines can be sepa- trait-like anxiety, they can serve as a powerful tool for Chapter 62: Animal Models and Endophenotypes of Anxiety and Stress Disorders 895 screening new potential anxiolytics. These models do pro- contributions to the development of stress and anxiety-like vide a sound approach to study the long-term effects of endophenotypes in animals, further information is needed congenital abnormalities in these neurotransmitter and neu- to understand the precise nature of gene–environment in- ropeptide systems. It is likely that a particular Several broad issues should be considered when inter- stressor results in alterations of gene expression in myriad preting studies utilizing genetically altered mice. Generally, systems and that the overall response to stress involves the the hypotheses regarding the behavioral profiles of coordination of gene activation and/or suppression within transgenic mice are based on earlier findings from psycho- these various systems. For example, within the CRH field, have recently been developed that enable the expression of the prediction that CRH overexpressers would display in- thousands of genes to be assayed at once. When the outcome of the particular environmental perturbation or disease state (163, transgenic studies agrees with the psychopharmacology- 164). This approach and its application to psychiatry re- based prediction, the findings are taken as a confirmation search have been discussed comprehensively in a recent re- of that hypothesized mechanism of action. Briefly, gene chip and DNA array tech- come of the transgenic studies disagrees with the predicted nology involve the hybridization of gene transcripts from a phenotype, however, concerns about possible develop- tissue sample onto a glass slide or filter that contains up mental confounds are raised. One of the most commonly to 10,000 different nucleotide sequences. The amount and cited drawbacks of the transgenic/knockout strategy is that pattern of the signal hybridized to the array are then as- the gene of interest is altered from the embryonic stage, sessed; this method thus permits a rapid analysis of changes therefore possibly influencing other genes involved in the in the expression of multiple genes. This technology can normal development of the animal. Thus, it is difficult to also be used to identify single nucleotide polymorphisms in tease apart the effects of under- or overexpression of that a particular gene by comparing the hybridization patterns gene on the endpoints under study from effects due to com- of samples from different candidate populations on chips pensatory or downstream developmental changes that may that contain multiple copies of the gene of interest, each have occurred as a result of the mutation (86,87,161). Theoretically, depending on the size of the excellent method for modeling a congenital abnormality that leads to a disease state, but this approach may be less gene, it would be possible to carry out a base-by-base exami- useful for identifying the discrete functions of a specific nation of the entire gene on a single gene chip. However, gene product because of the problems of interpretation that it is important to realize that although a broad approach arise from the developmental confound. Indeed, with regard can be taken with this technology, it may not be sensitive to all of the studies discussed in this section on genetically enough to detect small but functionally important changes altered mice, it will be important in future studies to deline- in gene expression. This technology can be applied to pre- ate the compensatory alterations that occur in response to clinial and clinical questions regarding the complex genetic the congenital mutation, and that may indirectly contribute control of stress and anxiety by examining event-related to the adult endophenotypes that are reported for these gene expression changes and also baseline differences in gene animals. Future studies utilizing novel inducible-knockout sequences (polymorphisms) that might contribute to differ- strategies will circumvent the developmental issue; inducible ential stress responsivity (165). This technique, along with knockouts may thus become a valuable tool for exploring the recent completion of the Human Genome Project, not the functions of discrete gene products for which no selec- only raises the potential to simultaneously profile multiple tive ligands are available (123). The antisense functional role of these new genes in processes related to oligonucleotide approach, however, has been plagued with stress and anxiety. Given this daunting task, methods for a number of issues regarding toxicity, and may therefore not more specific and long-term gene targeting will increasingly represent the optimal method for studying gene function in gain importance in neuroscience research aimed at uncover- vivo (162). One technique that is likely to be helpful is that of virally me- FUTURE DIRECTIONS diated gene transfer. In this method, a gene of interest is cloned into viral vector (with most of the viral genome Although the studies summarized in this chapter have con- removed to reduce toxicity and infection) and the modified tributed a great deal of knowledge about some of the genetic vector is then infused into a particular brain region using 896 Neuropsychopharmacology: The Fifth Generation of Progress standard stereotaxic procedures (see ref. Animal models in cognitive behav- Depending on the gene insertion and the selection of the ioural pharmacology: an overview. Acta to obtain either an increase or decrease in the amount of Psychiatr Scand Suppl 1998;393:74–80. Alternative phenotypes for allows for highly selective gene regulation and thus provides the complex genetics of schizophrenia. Biol Psychiatry 1999;45: a valuable new tool with which to study the effects of a 551–558. Cerebrospinal fluid corti- particular gene product on stress-related functioning. The cotropin-releasing hormone levels are elevated in monkeys with virally mediated gene transfer approach also has certain ad- patterns of brain activity associated with fearful temperament. Linkage of a any time or into any brain region, it results in a fairly robust neurophysiologic deficit in schizophrenia to a chromosome 15 locus. Chicago: University of Chicago it can be used to insert several genes at once in the same Press, 1972.
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