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By X. Jerek. Pacific Lutheran University.

Prime contractor arrangement and outcome-based commissioning Table 12 shows a brief overview of the answers with percentages rounded to the nearest 5% discount 50 mg solian with mastercard. The answers to this question suggested some fundamental differences in the beliefs and perspectives held by those who hold positions on CCGs purchase solian 100 mg mastercard. As Table 12 shows cheap 100mg solian fast delivery, the majority leaned towards a view that commissioning through the use of contracts with clearer specification of outcomes was the surest way to proceed. 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 121 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 committed to the general principle and logic. A surprisingly high number of CCG board members (10%) admitted that they did not know what the terms meant. Another significant group (around 15%) comprised persons opposed to these contracting approaches in principle and/or viewed them as too complicated, impractical and overhyped. A significant number of these sceptics were more attracted to what they saw as emerging models such as MCPs and the STPs, which gave hints that they leaned more towards planning and collaboration rather than completion and contracts. Other responses were: I think this will take longer than 2–3 years to have an impact. It is difficult to get good reliable outcome measures in a number of areas. I think the major issue will be that acute providers will have a disproportionate influence, and too much effort will be spent on managing this. Prime contractor arrangements could be hugely important due to the risk around sustainability of individual providers and the blurring of responsibilities for sector based activity (i. They will only work, however, if there is a strong and sustainable provider in the economy who can lead on them. Wait to see, the power still seems to be with providers, and will continue to be so while the reorganisations are targeted at commissioners for political expediency. Other respondents suggested the potential value of outcome-based commissioning: It is very important. Creative solutions will require a focus on the patient and their desired outcomes. The current PbR [payment by results] framework and mechanism is a significant limiting factor on real transformation of service delivery. Need to be realistic and flexible about commissioning for outcomes. The future of Clinical Commissioning Groups Finally, the survey asked an open-ended question inviting these CCG board members to share their expectations about the future of their CCGs and CCGs in general. The notable feature arising from answers to this telling question is that the vast majority of respondents (65%) judged that CCGs – the organisations on which they were serving and devoting considerable amounts of their time – will not survive. Others (30%) expressed huge uncertainty about the future. Only a small minority of respondents said that they expected CCGs to continue. This is a surprising finding given the roles of these respondents. This was not a survey of GPs in general or of nurses and others of the > 1. If only to help resolve tensions arising from cognitive dissonance, one might reasonably have expected a more optimistic and positive assessment of the future of the CCGs from this population group. Questions were also raised about the continuing rationale. These responses, and others shown in Table 13, suggest that the future for CCGs was felt to be uncertain among many of the senior players who are needed to make them work. 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 123 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. Our morale is very low Clinical leadership will become clinical responsibility/accountability not leadership Too small, too much duplication, too much money spent on paying clinicians to do pure management roles Clinical engagement will reduce further Availability of GPs to provide clinical leadership uncertain Unlikely to survive due to lack of clinical engagement I think rationalisation is positive but also a shame as clinician–managerial relationship teams have matured to a point where I expect our CCGs to be considerably more effective going forward 124 NIHR Journals Library www. Only relevant up to next election in May 2020 Unsure Who knows? 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 125 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. EME HS&DR H TA PGfAR PHR Part of the NIHR Journals Library www. 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 . Self-care support for children and adolescents with long-term conditions: the REfOCUS evidence synthesis. Health Services and Delivery Research ISSN 2050-4349 (Print) ISSN 2050-4357 (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. HS&DR programme The Health Services and Delivery Research (HS&DR) programme, part of the National Institute for Health Research (NIHR), was established to fund a broad range of research. It combines the strengths and contributions of two previous NIHR research programmes: the Health Services Research (HSR) programme and the Service Delivery and Organisation (SDO) programme, which were merged in January 2012. The HS&DR programme aims to produce rigorous and relevant evidence on the quality, access and organisation of health services including costs and outcomes, as well as research on implementation. The programme will enhance the strategic focus on research that matters to the NHS and is keen to support ambitious evaluative research to improve health services. For more information about the HS&DR programme please visit the website: http://www. The final report began editorial review in October 2016 and was accepted for publication in May 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 HS&DR programme or the Department of Health.

Nicotine generic solian 50 mg line, a tertiary amine struc- with lung or throat cancer or those suffering from chronic turally similar to acetylcholine order solian 100 mg visa, binds to nicotinic choliner- obstructive lung disease behave similarly order solian with a visa. During smoking Tobacco-taking behavior is made more likely to recur, nicotine, steam distilled from the burning tobacco is inhaled reinforced by the pharmacologic actions of nicotine (49). Initial arterial blood levels of nicotine are two to six otine. Associations between cues associated with smoking, times greater than venous levels (11). Within 10 to 20 sec- anticipated nicotine effects and the resulting urge to use onds after each puff, relatively high levels of nicotine reach tobacco (craving) become all important in maintaining the brain. Nicotine levels in plasma and in brain tissue then smoking. By midafternoon, relatively constant, steady- associated with pleasurable effects. Unpleasant or dysphoric state, venous plasma levels, 20 to 40 ng/mL, are reached, moods come to serve as conditioned cues for smoking. For but with transient 50-ng/mL increments in arterial and example, an adolescent smoker, usually within the first year brain levels after each cigarette. During sleep, plasma con- of smoking, learns that not having a cigarette available is centration of nicotine falls progressively but is still measur- associated with feelings of irritability and learns that just a able on awakening when the first cigarette of the next day few puffs from a cigarette diminish irritability and other is smoked, typically within 30 minutes of awakening. After hundreds smoking results in exposure of brain to nicotine 24 hours of repeated experiences, irritability from any source serves of each day but with regular brain level perturbations after as a cue for smoking. Left to nature, it is unlikely that many people would Smokers regulate smoked nicotine intake to maintain make or find a cigarette, light it, and smoke it (49). Condi- their preferred range of concentrations by varying puff and tioning and learning linking nicotine pharmacology and en- vironmental contingencies are facilitated by advertising en- inhalation timing, volume, and number (49). Nicotine in- couraging, often in subtle ways, the use of tobacco. Smokers can compen- beginning, teenage smokers teach each other. Quickly, links sate for differing machine-determined nicotine yields to ob- between the pharmacologic actions of nicotine and associ- tain a preferred dose of nicotine whether smoking a high- ated behaviors become powerful (7). Nicotine delivered by cigarettes power only gradually without nicotine delivered in the right offers smokers individualized control of nicotine dose unat- dose and context. Conditioning is a major factor in relapse tainable by other nicotine delivery systems (49). Dealing with it is important attributes of smoked nicotine dosimetry are relevant when in any therapeutics for nicotine addiction. Cigarette smoking or nicotine ad- placement therapies (NRTs). In contrast to smoking, chew- ministration improves attention, reaction time, and prob- ing tobacco and snuff deliver nicotine through oral or nasal lem-solving, particularly in recently abstinent smokers (55, mucosa. Plasma and brain nicotine concentrations rise more 74). Smokers typically report enhanced pleasure and re- gradually, reach plateau levels after about 30 minutes, and duced anger, tension, depression, and stress after a cigarette. Whether enhanced performance and improved mood after smoking are mostly or entirely the result of the relief of abstinence symptoms or rather are intrinsic effects of nico- NICOTINE RECEPTOR–BASED NEURAL tine on the brain remains unclear (49). Improvement in the MECHANISMS RELEVANT TO performance of nonsmokers after nicotine suggests at least THERAPEUTICS some direct enhancement (8). Nicotine binds stereoselectively to a diverse family of nico- NICOTINE PHARMACOKINETICS AND tinic cholinergic receptors widely distributed in brain, auto- METABOLISM nomic ganglia, adrenal medulla, and neuromuscular junc- tions (15,16). Nicotinic cholinergic multiple neuronal systems remains to be determined (49). Re- which nicotine is needed to maintain normal neurotrans- ceptor diversity probably accounts for the diverse effects mission. As nicotine levels decrease, diminished neurotrans- of nicotine experienced by smokers (19). The undoubtedly mitter release or altered modulation of neurotransmitter sys- complex relationships between specific nicotinic cholinergic tems (17) contributes to a relative deficiency state and in receptor subtypes and release of specific neurotransmitters humans, symptoms of lethargy, irritability, restlessness, in- are still to be fully characterized (92). Neurotransmitter re- ability to concentrate, depressed mood, and other symptoms lease is assumed to mediate nicotine effects such as arousal, making up the nicotine withdrawal syndrome. Plasma con- relaxation, cognitive enhancement, relief of stress, and centrations of nicotine in smokers are sufficient to desen- depression. Thus, self-adminis- ion channel, with five subunits. Most brain nicotinic cholin- tration of eight to ten nicotine bolus doses (puffs) during the ergic receptors are composed of and subunits. The smoking of each cigarette would cause gradually decreasing subunits are responsible for ligand binding. The subunits dopamine release in the nucleus accumbens. With each suc- mediate other aspects of receptor function (29). The nico- cessive cigarette and gradually rising levels of brain nicotine, tinic cholinergic receptor, consisting of -4 and -2 sub- desensitization would increase. If so, tobacco smokers con- units, accounts for 90% of high-affinity nicotine binding tinue to smoke during the latter half of each smoking day in rat brain and may play a critical role in stimulant and under conditions in which nicotine is less likely to stimulate rewarding effects (21). The -2 subunit is critical for dopa- neurotransmitter release than while smoking the first ciga- mine release, judging from studies of knockout mice lacking rettes of the day. Thus, other mechanisms likely contribute that subunit who have less nicotine-induced dopamine re- to the rewarding properties of nicotine in the latter portion lease and do not self-administer nicotine as do wild-type of the daily cycle of smoking (49). Nicotine increases or decreases brain serotonin levels, de- When nicotine binds to nicotine receptors, allosteric pending on concentration and pattern of exposure (16). A changes lead to different functional states including a resting possible role for serotonin release in reward mechanisms is state, an activated state (channel open), and two desensitized suggested by selective serotonin (5-HT3) antagonists that states (channel closed) (10). Receptor change to the desensi- reduce nicotine reinforcing effects. Chronic exposure to nic- tized state probably accounts for tolerance and for the obser- otine results in reduced capacity to synthesize 5-HT in sero- vation that tolerance to nicotine is associated with increased tonergic terminals. Postmortem human studies indicate that numbers of nicotinic cholinergic receptors in animals dur- tobacco smoking is associated with reductions in hippocam- ing chronic nicotine treatment and in brains of human pal 5-HT and 5-hydroxyindole acetic acid (16). The mesolimbic dopamine system is assumed to release could result in anxiety and related symptoms com- mediate pleasurable and other rewards from nicotine as with mon during the early stages of nicotine withdrawal (49). Nicotinic receptors are on the nerve Nicotine-mediated release of norepinephrine plays a role terminal membranes in the nucleus accumbens and on in the release of adrenocorticotropic hormone (ACTH) and membranes of the dopamine-secreting neurons innervating cortisol. Nicotine, acting on -7 cholinergic receptors, re- nucleus accumbens located in the midbrain. Unlike cocaine leases glutamate, enhances fast excitatory synaptic trans- and amphetamine, which exert effects by binding to pre- mission possibly contributing to improved learning and synaptic dopamine transporters on nerve terminal mem- memory (28,36), and regulates dopaminergic function.

In unilateral stimulation solian 50mg amex, one electrode is attached to one side of the forehead and the second is placed further back on the scalp on the same side of the head buy solian cheap. With unilateral stimulation the electricity remains predominantly on one side of the head buy solian 100 mg without prescription. Here, electrodes are placed on the forehead, above the eyes. Results have been very encouraging (Phutane et al, 2013). Theoretically, this could give the greater efficacy of bilateral ECT, and with a smaller region of the brain exposed to electricity, minimal cognitive side-effects. Two sets of electrodes are attached to the patient to monitor the activity of the brain before, during and after ECT administration. One set is placed on the scalp (EEG) and the other on a limb. The observations assist in decision making regarding the adequacy of the physiological response. An anaesthetist, psychiatrist and at least two nurses are present. The anaesthetist inserts a cannula, an anaesthetic nurse attaches ECG electrodes, and the psychiatrist and psychiatric nurse attach ECT, EEG and peripheral muscle electrodes. When muscle relaxation has occurred, the ECT stimulus is applied. Using one popular device (Thymatron), the stimulus is delivered at a maximum frequency of 70 pulses per second. The longest the stimulus can continue, using this device, is 8 seconds. Usually there is bending of the elbows and pointing of the toes. When the convulsion has stopped (generally less than 30 seconds) the patient is rolled onto the side and transported to the recovery room. The whole procedure from arrival to departure from the procedure room takes in the order of 10 minutes. Electrode placement As mentioned, there are two main electrode placements, bilateral and unilateral. Memory is not located in any one particular region of the brain - current wisdom is that memory depends on many regions of the brain being anatomically and functionally linked together. It is known that severe memory problems occur when structures on both sides of the brain are damaged, for example, when both left and right temporal lobes are destroyed. There is evidence to indicate that bilateral ECT has a stronger antidepressant effect than unilateral ECT (UK ECT Review Group, 2003). However, bilateral ECT is also believed to be associated with greater temporary memory disturbance than unilateral ECT. Evidence shows that delivering a substantially larger amount of electrical energy unilaterally than is required to simply trigger a convulsion (“seizure threshold”) can produce similar antidepressant effects as bilateral ECT, but with less memory disturbance (Sackheim et al, 1993). This “high dose unilateral ECT” is now the most often chosen form. However, when a maximum antidepressant effect is required, bilateral ECT may be necessary. Dose determination Current thinking is that optimum antidepressant effect is achieved with electrical doses well above the seizure threshold (Sackheim et al, 1993). One is by first determining the “seizure threshold”. In this method a number of stimuli are applied, starting at a low level, and increasing the electrical energy of subsequent stimuli until a seizure is triggered. Treatment is then provided with a stimulus 2-3 times higher Pridmore S. This is called the “stimulus titration method”, and is favoured by many experts (Tiller and Ingram, 2006). Alternatives include delivering a dose determined by age (“age-based dosing algorithm”; Abrams 2002a), or a fixed high dose (Abrams 2002b). The jury is still out on whether the “stimulus titration method” or the “age-based algorithm” is the better method of dose determination. The APA Taskforce on the Practice of ECT (2001) approves both. Peterchev et al (2010) have recently have criticized the use of a “summary metric” (charge) to describe the dose of ECT. They provide theoretical and empirical evidence that stimulus parameters (pulse amplitude, shape, and width and time frequency, directionality, polarity, and duration) exert unique neurophysiological effects. Recently electrode size has been shown to influence the physiological response (Deng et al, 2013). Thus, the optimal dosing paradigms remain to be determined, and will depend on more than the oversimplified “summary metric” of charge. ECT is safer than dental extraction under anaesthesia. The few deaths which have occurred, have been a result of anaesthetic rather than the ECT complications. Searching 50 years of records, one death was found in 46,770 treatments (Kendall, 1977). There are less deaths among people with depression who are treated with ECT than among people with depression who are treated by other means (Avery & Winokur, 1978) Permanent brain damage and ECT ECT does not cause brain damage. Every possible investigation has been conducted including blood enzyme studies, imaging of the structure and chemical composition of the brain, and post mortem histological studies. No abnormalities have been detected which can be attributed to ECT. Memory and ECT Loss of memory strikes at the sense of autonomy and is fundamentally threatening to the individual. Two recent developments have reduced the memory disturbance associated with ECT. First, the introduction of stimulation by brief (1 ms) square waves. Early ECT devices delivered sine waves, which have limited stimulation potential relative to the amount of energy they deliver, and the unnecessary energy greatly disturbed memory. Second, was the introduction of unilateral ECT, which is not usually associated with the subjective experience of memory difficulties (Squire and Slater, 1983). Major depression per se, perhaps through distractibility and perhaps through the slowing of thought processes, has a detrimental effect on memory.

Similarly cheap 50mg solian fast delivery, a low PaCO2 will cause SjvO2 desaturation order generic solian from india. Neurocritical Monitoring | 69 Problems with SjvO2 Monitoring: The major criticism of SjvO2 is that it is a measure of global oxygen delivery and does not reflect metabolic inadequacies in focal areas of injury and hence may miss regional areas of ischemia solian 50 mg generic. Inaccuracies can occur with catheter misplacement, contamination with extra cerebral blood, when the catheter abuts the vessel wall, or if thrombosis occurs around the catheter tip. Contraindications and complications are similar to those of an IJV central line. Interpretation of Changes in SjvO2: If cerebral oxygen delivery is impaired, oxygen extraction increases and SjvO2 decreases. If autoregulation is intact, CBF increases to meet metabolic demand and SjvO2 is restored. However, in the injured brain autoregulation is often impaired and cerebral ischemia ensues. Brain Tissue Oximetry Interest in measuring brain tissue oxygenation via implantable sensors has grown in recent years. The Licox sensor is an implantable polarographic electrode that measures tissue oxygen tensions. It is inserted through a compatible bolt and ideally should be placed into the penumbral area of the injury. Oxygen diffuses from the tissue through the catheter into an 70 | Critical Care in Neurology electrolyte chamber where an electrical current is generated. Brain tissue oxygen tension is normally lower than arterial oxygen tension (15-50 mmHg); whilst tissue CO2 is normally higher (range 40-70 mmHg). The sensors are useful in monitoring local changes and trends in tissue oxygenation that might be missed by SjvO2 measurements. At present it is primarily used in severe head injury and poor- grade subarachnoid hemorrhage, and in conjunction with other monitoring modalities. The technique allows a continuous method of monitoring of regional tissue oxygenation and in particular, monitoring areas of high ischemic risk, and is a promising and reliable clinical tool. Direct measures of CBF: Measurement of injectable tracers that reach the brain after peripheral injection using signal intensity changes. Xenon-Enhanced CT: In this technique xenon, a diffusible agent is used. The patient inhales a mixture of 28% xenon and 72% oxygen for approximately 4 minutes after baseline CT scans are obtained. Sequential scanning of the same slices occurs during the inhalation period. The arterial concentration is proportional to the expired xenon concentration. Advantages are the relatively low cost and high ease of use. The downside is a high sensitivity to motion artifact (Andrew 2010). SPECT (Single Photo Emission CT): In SPECT scanning, the radioisotope technetium-99m (Tc-99m) is combined with hexamethylpropyleneamine (HMPAO) or ethyl cysteinate dimer. SPECT scanning has the advantage of being easy to perform. However, there are limitations with regards to assembly of the compound. MR Perfusion: “Dynamic Susceptibility Contrast Imaging” also called “first-pass” or “bolus tracking” MR perfusion imaging is based on rapid acquisition of MR signal intensity data from the brain during the injection of a contrast agent. Signal intensity- Neurocritical Monitoring | 71 time curves are generated for each pixel in the image then CBF is calculated. Noninvasive Monitoring Continuous measures of CBF by Transcranial Doppler Transcranial Doppler (TCD) is a noninvasive technique that calculates blood flow velocity in the cerebral vasculature. An ultrasound beam is reflected back by the moving bloodstream at a different frequency than it was transmitted (Doppler shift), and from the Doppler equation, the velocity of blood flow (FV) can be calculated. Changes in FV correlate well with changes in CBF, as long as the orientation of the transducer and the vessel diameter remain constant. It is used clinically to diagnose vasospasm, to test cerebral autoregulation, and to detect emboli during cardiac surgery and carotid endarterectomy (Moppett 2004). From the FV waveform systolic, diastolic, and mean velocities can be calculated. The mean FV in the middle cerebral artery (MCA) is usually 35-90 cm/s and correlates well with CBF. The FV can be influenced by age, being lowest at birth (24 cm/s), highest at age 4-6 years (100 cm/s), and then declining until the seventh decade of life (40 cm/s). FV is also 3-5% higher in females and increases in hemodilutional states. Technique for Insonating the Middle Cerebral Artery (MCA): The M1 branch of the MCA is the commonest vessel to be insonated, and is visualized through a transtemporal window with a 2 MHz pulsed Doppler signal. The anterior and posterior cerebral arteries can also be accessed through this window, whilst a transorbital approach allows access to the carotid siphon and the suboccipital route to the basilar and vertebral arteries. This reflects distal cerebrovascular resistance and correlates with CPP. Uses of TCD in Intensive Care Head Injury: Three distinct phases have been shown in severe head injury with regard to CBF and MCA FV. The use of TCD allows interpretation of the dynamic physiological changes seen in severe head injury, and in combination with other modalities allows perfusion and oxygenation to be optimized for the individual patient. The highest MCA FV recorded at any stage is an independent predictor of outcome from head injury, and the loss of autoregulation (calculated by regression of CPP on MCA FV) has also been shown to be a predictor of poor outcome from head injury. Subarachnoid Hemorrhage: Vasospasm occurs in approximately 50% of people with subarachnoid hemorrhage between 2-17 days post-event, and is associated with significant morbidity and mortality. TCD may be used to detect vasospasm by the increase in MCA FV associated with vessel narrowing. Spasm is also assumed to be occurring when blood velocity is Neurocritical Monitoring | 73 >120 cm/s. High MCA FV is associated with worse-grade SAH, larger blood loads on CT (assessed by Fisher Grade) and hence worse outcome (Steiger 1994). Near Infrared Spectroscopy While the criticism of jugular venous oximetry is that it is representative of global oxygen delivery, near infrared spectroscopy (NIRS) is a noninvasive technique that measures regional cerebral oxygenation. Light in the near infrared wavelength (700-1,000 nm) can pass through bone, skin, and other tissues with minimal absorption, but is partly scattered and partly absorbed by brain tissue. The amount of light absorbed is proportional to the concentration of chromophobes (iron in hemoglobin, and copper in cytochromes), and measurement of absorption at a number of wavelengths provides an estimate of oxygenation (Owen-Reece 1999). The probes illuminate a volume of about 8-10 ml of tissue and are ideally suited for use in neonates because of their thin skull, but have been used with success in adults. Advantages of this technique are that it is non-invasive, and provides a regional indicator of cerebral oxygenation. Its major limitation is its inability to distinguish between intra- and extra- cranial changes in blood flow.

As a GP board member argued: Managers are in charge generic solian 50mg on-line, and everything is driven by [them] solian 50 mg discount. GP member of CCG governing body This problem of a depleted clinical leadership pipeline was frequently noted in this case best solian 100 mg, as indeed in others, but to a lesser extent than in this case. A CCG chairperson argued that a lot of time had been spent on aligning practices and getting them engaged. This chairperson then described priority actions by this CCG: So, we have a primary care strategy which is divided into six work streams. My thinking, as the director of primary care, is in a slightly different place from other managers within the organisation and some of the clinical leads. So, I think part of the challenge is to try and get some corporate thinking around this. Our local federation has worked with another provider and secured a very large fund bid. The challenge for us is sustainability and what this does in terms of our CCG operational plan and so on. This interview extract reveals starkly the tension between multiple logics and multiple agents. Thus, not all clinically led innovations – even those that brought in extra funding – were necessarily welcomed and celebrated. There has been talk by the local acute provider about moving into primary care services. There is a plan to put in a bid around urgent care which will be provider driven. Again we need to assess how all this fits within our own wider plan. CCG chairperson These observations from the chairperson of one of the more influential CCGs in the county raises questions about the difficulties in aligning the plurality of initiatives being encouraged and launched in different arenas. Hence, once again we see the complexities of leadership in practice when the context is given proper consideration. I suspect it will sort of be a natural move in one direction or the other. 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 61 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. FINDINGS FROM THE CASE STUDIES This quotation is very revealing. The admissions from the CCGs that they lack the wherewithal to tackle the fundamental redesign of health-care systems which the Vanguards are seeking to deliver was made apparent by the individual CCGs in this case. More than 3 years into the CCG experiment, it indicates the extent and nature of CCG ambitions. We can elaborate on this important point by providing an illustration of just such a bottom-up, GP-led service redesign that was initially supported and then unsupported. We were informed of a new dementia service which located more care in GP practices and which therefore allowed patients to be treated locally rather than having to travel to the mental health trust. The redesign involved employment of care facilitators. Funding came jointly from the CCG and the mental health trust. However, despite apparent success and positive feedback, the initiative was ended and dementia services were taken away from primary care and returned solely into the hands of the acute sector, the mental health trust. Some GPs claimed that this resulted from pressure from the mental health trust which the CCG was unable to resist given its parlous financial state and the power of the trust. As interviewees noted, the federation had, so far, remained on the periphery of the core GP business of the General Medical Services and Personal Medical Services contracts. However, he noted that the access to extended hours work could catalyse a change as it creates a new workforce which would share information and patients across practices. Activity and clinical leadership at a neighbouring CCG were even less developed. Practice in this particular CCG reflected that found in many others which we encountered at the scoping phase of the study where little advantage was being taken of the CCG institution as a platform for change. Instead, it was treated as just another administrative unit. Thus, even the accountable officer made the assessment that: The function of the CCG to date, by and large, has been to fulfil statutory duties. In the early days of the CCG there were a large number of high-level strategies written around a number of things. So everything for the last year has been driven by the financial position in the CCG. Accountable officer This CCG is now in the hands of a managerial team which also manages two other CCGs. CCG chairperson Thus, in these instances, the work of the agents – managers and clinical leaders – in these new bodies was focused primarily on institution building. This included appointing chairpersons, accountable officers and other key figures plus the wider representation for the governing body. A practice nurse representative on this CCG likewise confirmed that assessment. Lack of resources and continued assertive intervention from the national centre had, in these cases, crowded out the hoped-for local leadership. The prime arena of the CCG, despite its statutory backing, was not enough in these cases to prompt the emergence of effective clinical leadership. In response to this increasingly evident lacuna, the national-level authority, in the shape of NHSE, initially encouraged much more cross-CCG collaboration and then moved more radically to offer firmer guidance in the shape of the models of collaboration outlined in the Five Year Forward View12 and then even more forthrightly with the creation (indeed imposition) of the STPs. However, not all of the six CCGS in the county were quite so passive and reactive. Despite the financial and other challenges, some local leaders were able to use the new institutions as a means of devising local solutions. He said he wanted to re-engineer the use of their two community hospitals. However, one of the hybrid clinical managers working across three of the CCGs reported: There is a definite lack of clinical leadership and engagement in practices in [this CCG]. Hybrid manager across three CCGs Thus, overall, the picture that emerged from the CCG level (the apex of Figure 24) in case D was that, in a number of CCGs, the senior teams (managers, clinicians and hybrids) had failed to utilise the privileged statutory positon, resources and power of the CCG board-level arena as a means to bring about a redesign of local services in the way that had been hoped by the national policy-makers. However, other teams had used the same arena to make a difference both in reforming primary care and in reimagining the roles of acute and community services. Increasingly, these more innovative teams were given power by NHSE to take over the agenda-setting for the more passive CCGs. 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 63 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. FINDINGS FROM THE CASE STUDIES Sustainability and transformation plan level As momentum built behind STPs from mid-2016, all actors involved in any significant service redesign attempts had to consider how these would align with the emerging STP systems architecture.

Infusing NTs such as BDNF or GDNF into the VTA neurons and glia in prefrontal cortex are reduced in patients can restore most buy solian american express, or all purchase 50 mg solian with amex, of these features to normal (71 generic solian 100 mg visa,72). The expression of BDNF in hippo- Additional studies have also implicated endogenous NT-3 campus is decreased by exposure of animals to stress (64). Furthermore, the role of This effect could contribute to the atrophy and death of ERK signaling in this system has been established. ERK hippocampal neurons, although it is also likely that other activity is increased in the VTA by chronic morphine expo- pathways are involved in this effect (61,62). Infusion of a specific antisense oligonucleotide In contrast to the actions of stress, antidepressant treat- against ERK1 into the VTA again blocks the morphine- ment increases the expression of BDNF, as well as its recep- induced biochemical changes (75). Chapter 16: Neurotrophic Factors and Intracellular Signal Transduction Pathways 213 Dissecting the mechanisms of signaling protein regula- 2. Prog Growth Fact Res tion within specific brain nuclei in the intact animal poses 1990;2:237–248. Role of neurotrophins in synapse development special challenges. However, using tools from in vitro stud- and plasticity. Trophic factors: an evolutionary cul-de-sac or door mechanism of this ERK up-regulation is unclear, but it has into higher neuronal function? NT-3, BDNF, is up-regulated in VTA after chronic morphine exposure and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Although levels of the neurotrophic factors themselves 6. Transient and persistent have not been found to be significantly altered in VTA by expression of NT-3/HDNF mRNA in the rat brain during post- chronic drug exposure, they may be regulated indirectly by natal development. Widespread and devel- opmentally regulated expression of neurotrophin-4 mRNA x in rat brain and peripheral tissues. Long-lasting neurotrophin-induced en- CONCLUSIONS hancement of synaptic transmission in the adult hippocampus. The neurotrophic factors and their signal transduction cas- 9. Hippocampal long-term poten- cades represent a complex array of pathways that influence tiation is impaired in mice lacking brain-derived neurotrophic many aspects of neuronal function and survival during de- factor. Recombinant BDNF velopment as well as in the adult central nervous system. Acute intrahippocampal˚ could be used to treat a variety of neurologic and psychiatric infusion of BDNF induces lasting potentiation of synaptic trans- illnesses. There is currently a tremendous amount of interest mission in the rat dentate gyrus. Transient expression and transport of blockade of certain components of the Ras/ERK pathway. Proc Natl Acad Sci USA 1998; in the normal nervous system may lead to identification of 95:11429–11434. BDNF mediates the effects of testosterone on the survival of new neurons in an adult opening of the field of growth factor action into the neuro- brain. Estrogen-inducible, sex- ful, if not more, as those that have been presented with the specific expression of brain-derived neurotrophic factor mRNA more traditional neurotransmitter systems. We would like to acknowledge the support of United States 17. Neurotrophic factors and their recep- Public Health Service grants DA00302, MH45481, tors. MH53199, and 2 PO1 MH25642, the Veterans Affairs 18. Similarities and differences in National Center Grant for Posttraumatic Stress Disorder, the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells. Growth factor signaling by receptor ance for Research on Schizophrenia and Depression tyrosine kinases. The PTB domain: a new protein DISCLAIMER module implicated in signal transduction. Duman serves as a consultant to Pfizer, Psychogenics, Raf as a result of recruitment to the plasma membrane. Requirement for Ras in member of the scientific advisory board for Psychogenics. Raf activation is overcome by targeting Raf to the plasma mem- brane. Science cades mediated by Ras/Rho proteins in the mammalian cell: the 1987;237:1154–1162. The mitogen-activated protein PYK2 involved in Ca(2 )-induced regulation of ion channel kinase activator. The mitogen-activated protein kinase signal transduc- 51. Induction of neurite trophic factors and their clinical implications. J Mol Med 1997; outgrowth by MAP kinase in PC12 cells. Signal transduction by the receptor J Biol Chem 1997;272:19103–19106. The tripartite CNTF receptor com- of phospholipase C-gamma 1 activity: comparative properties plex: activation and signaling involves shared with other cyto- of control and activated enzymes. Phospholipase C-gamma as a signal-trans- STAT pathway in the developing brain. Insulin and insulin-like of the catalytic activity of phospholipase C-gamma 1 by tyrosine growth factor receptors in the nervous system. Insulin-like growth factor-I is a differen- Annu Rev Biochem 1998;67:481–507. Structure and function of phosphoinosi- precursors: distinct actions from those of brain-derived neuro- tide 3-kinases. The neurotrophic action dylinositol phosphate kinases, a multifaceted family of signaling and signalling of epidermal growth factor. Stress, glucocorticoids, and damage to the nervous inositol-3-OH kinase as a direct target of Ras. Nature 1994;370: system: the current state of confusion. Neural plasticity to stress and spinal motor neurons through activation of the phosphatidylino- antidepressant treatment. Insulin signal transduction and the expression of brain-derived neurotrophic factor and neurotro- IRS proteins. Chronic antidepressant ad- Shc have distinct but overlapping binding specificities.

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