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The four groups were managers sotalol 40mg on-line, GPs buy sotalol 40mg with amex, other clinicians excluding GPs and lay members discount 40mg sotalol free shipping. In broad terms, managers and GPs were seen to be the most influential by far. In 2014, of the two, GPs were marginally ahead; however, by 2016 the rankings had reversed and managers were marginally ahead in terms of ranked influence. This is especially notable given that the majority of respondents were GPs. Other members of the governing bodies (including the lay members, secondary care doctors and nurses) were rated as far less influential. 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 23 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 NATIONAL SURVEYS 45 40 35 30 Year 25 2014 20 2016 15 10 5 0 Managers GPs Other clinicians Lay members excluding GPs FIGURE 8 Influence of managers, GPs, other clinicians and lay members in the redesign of services. Some answers from 2016 were then broken down to show how different kinds of respondents answered this question. It was evident that finance officers tended to see managers as the most influential figures. GP members of governing boards and others (directors of public health and other managers) tended likewise to see managers as influential. Next, we delved deeper into the perceived influence of GPs, as broken down by role of respondent. As the results in Figure 10 show, GP members of the boards were, ironically, the least convinced that they had much influence. Accountable officers, for example, may have wished to reflect the idea that they were the servants of a membership organisation. We also wanted to know in what capacity GPs were acting when they influenced service redesign. Was it as official governing members, as clinical leads who did not have a seat on the governing body, as locality leads, or as leaders of GP federations? Perhaps not a surprise, given the role of many respondents, GPs sitting on the governing bodies were seen as the most influential of the GP categories. Of note also was that the perceived influence of locality-level commissioning GPs declined between 2014 and 2016. A related question concerned who sets the compelling vision. Were GPs and other clinicians making a leadership contribution through envisaging alternative service provision or was this vital leadership role filled by others? In 2014, the results for clinicians were the same (between 25% and 26% of respondents said that GPs set the compelling vision). The main difference between the two time periods was in the proportion of 25% Clinicians Managers Neither 54% Both equally 19% 2% FIGURE 12 Who sets the compelling vision for service redesign? 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 25 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. Figure 13 shows the breakdown by role of respondent to this same question. As shown in Figures 12 and 13, most respondents suggested that it was managers and clinicians equally who set out the compelling vision. These results suggest that the notion that GPs would be the visionaries and architects and that managers would play the role of delivery agents is not an accurate depiction of the reality in most cases. There is also more evidence here of dual leadership occurring – a particular type of distributed leadership. We asked about communication with patients and the public, and the results are shown in Figure 14. For these stakeholders, managers acting alone or acting equally with clinicians account for 87. Once again there was apparent progress between 2014 and 2016. In 2014, nearly one-quarter of respondents said that neither managers nor clinicians from the CCG were in communication with patients and the public, but in 2016 this fell to only 2%. In a related question, we asked who provided the insights into public and patient needs. The results (shown in Figure 15) suggest that the largest part of this is done jointly with managers and clinicians, although 21% of respondents said that managers were mainly responsible for this activity. An increasingly important theme since the formation of CCGs as independent statutory bodies has been the growth of the idea that more collaboration is required – with other CCGs and with other stakeholders, such as social services and voluntary bodies. Building collaborations The building of collaborations with providers and with other commissioners has increasingly become a vital activity for CCGs.

Other specific subgroups of interest were not explored within the included studies buy sotalol 40 mg fast delivery. Comparison of Drugs for Pharmacologic Cardioversion Overview Seventeen studies including 2 purchase 40 mg sotalol free shipping,455 patients compared 2 or more rate- or rhythm-control drugs 140 generic 40mg sotalol fast delivery,144,145,147,149,170,177,180,181,188-193,204,206 and assessed conversion of AF to sinus rhythm. Six studies 145,147,180,189,190,206 140,144,149,170,177,188,191-193 were multicenter, nine were single-center, and in two the 181,204 number of sites was not reported. Twelve studies were conducted in 140,144,145,147,170,177,188,191-193,204,206 149,190 181 Europe, two in Australia/New Zealand, one in the UK, 180,189 140,170,177,180,181 and two in the United States. Five studies were of good quality, 11 of fair 144,145,147,149,188-193,204 206 quality, and 1 of poor quality. Three studies were conducted in an 140,144,177 147,180,192 inpatient setting, three in an outpatient setting, four in the emergency 149,170,189,190 188 room, one in multiple settings, and in six the setting was not 145,181,191,193,204,206 145,180 reported. Two studies received industry funding, 1 received government 180 145,149,177,189 funding, 4 were funded by nongovernment, nonindustry sources, and 12 did not 140,144,147,170,181,188,190-193,204,206 report funding source. Nine studies included only patients with 144,145,147,170,177,192,193,204,206 189 persistent AF, and one included only patients with paroxysmal AF. Only seven of the studies included a comparison between two or more antiarrhythmic drugs 149,170,177,180,181,190,191 (Table 11). The most common comparison was between amiodarone and sotalol (four studies). Amiodarone was compared with ibutilide in one study and with flecainide and propafenone in one study, and ibutilide was compared with propafenone plus ibutilide in one 170,180 181 study. Three of the studies included placebo or control arms which were not included in our analyses. Two of these studies also included an additional intervention arm that evaluated the 149,190 use of digoxin. In four studies, electrical cardioversion was not part of the study protocol, while in the remaining three the effect of the drugs was evaluated before and after external electrical cardioversion. Restoration of sinus rhythm was assessed prior to electrical 149 cardioversion within 12 hours of drug administration in 1 of these 3 studies, within 28 days in 180 181 the second study, and within 6 weeks of drug initiation in the third. In the studies without use of electrical cardioversion, restoration of sinus rhythm was assessed at 48 hours in one study and within 24 hours in the other three studies. In addition, one study assessed recurrence of AF 177 within 24 hours. Two of the studies were conducted primarily in an emergency room 149,170 177,191 180,181,190 setting, two in an inpatient setting, and three in an outpatient setting. Studies including comparisons between antiarrhythmic drugs Study Sample Arm 1 Arm 2 Arm 3 Timing of Assessment Size (N) Outcome of Conversion Assessment Post-DCC? Prior to or Without DCC Thomas, 140 Amiodarone Sotalol (IV Digoxin (IV Within 12 Yes 149 2004 (IV then oral) then oral) then oral) hours a Vijayalakshmi, 94 Amiodarone Sotalol (oral) Control Within 6 weeks Yes 181 2006 (oral) 180 Singh, 2005 665 Amiodarone Sotalol (oral) - 28 days Yes (oral) 190 Joseph, 2000 115 Amiodarone Sotalol (IV Digoxin (IV 48 hours No (IV then oral) then oral) then oral) 170 Balla, 2011 160 Amiodarone Flecainide Propafenone Within 24 No (oral) (oral) (oral) hours 191 Kafkas, 2007 152 Amiodarone Ibutilide (IV) - Within 24 No (IV) hours Korantzopoulos, 100 Ibutilide (IV) Propafenone - Within 24 No 177 2006 (oral) + hours ibutilide (IV) Also assessed recurrence within 24 hours post- conversion aNot included in analyses. Abbreviations: DCC=direct current cardioversion In 8 studies (including 2 from Table 11), an antiarrhythmic drug (amiodarone, sotalol, or ibutilide) was compared with a rate-controlling drug (digoxin, diltiazem, carvedilol, or esmolol). Among these, restoration of sinus rhythm was assessed both before and after electrical 144,149,204 cardioversion in three studies. In the remaining five studies, external electrical 140,188,190,192,193 cardioversion was not part of the study protocol. In those studies, restoration of sinus rhythm was assessed from 30 minutes to 48 hours following drug initiation. In addition, 1 of the studies reported recurrence of AF within 24 hours of drug treatment and electrical 144 cardioversion. In four studies, rate-controlling drugs were used in both study arms, and the study assessed restoration of sinus rhythm. In three of these, restoration of sinus rhythm was assessed before 145,147,206 and after electrical cardioversion. In the remaining study, restoration of sinus rhythm 189 was assessed during the period of drug infusion (esmolol vs. In addition, one of the 206 studies also assessed recurrence of AF at 1 month following conversion. Restoration of Sinus Rhythm Results for comparisons between antiarrhythmic drugs are shown in Table 12. No statistically significant differences among the drugs were seen except between amiodarone versus ibutilide in one study and between ibutilide plus propafenone versus ibutilide alone in one study. Few adverse events were reported in any of the studies. Comparisons of antiarrhythmic drugs for restoration of sinus rhythm Study Sample Time Frame Restoration of SR pre-DCC P Value Restoration of SR Post-DCC P value Size (N) for (or Without DCC) Assessment Thomas, 140 12 hours Amiodarone: 27/52 (52%) NS Amiodarone: 22/25 (88%) NR 149 2004 Sotalol: 20/45 (44%) Sotalol: 23/25 (92%) Digoxin: 21/42 (50%) Digoxin: 20/21 (95%) Vijaya- 94 6 weeks Amiodarone: 7/27 (26%) 0. These studies represented 736 patients and estimated an OR of 1.

It is also input specific in that it is elicited at the ning to be explored (8) generic sotalol 40 mg without a prescription. One potential role of these short- synapses activated by afferent activity and not at adjacent term forms of synaptic plasticity is to transform incoming synapses on the same postsynaptic cell generic sotalol 40mg. This feature dramati- information in the temporal domain into a spatially distrib- cally increases the storage capacity of individual neurons Chapter 11: Synaptic Plasticity 149 TABLE 11 cheap sotalol 40 mg on line. AREAS OF BRAIN IN WHICH LTP HAS BEEN DEMONSTRATED Hippocampus Amygdala Dentate gyrus Cerebellum CA1 Thalamus CA3 Striatum Cerebral cortex Nucleus acumbens Visual Ventral tegmental area Somatosensory Motor Prefrontal FIGURE 11. Model for the induction of long-term potentiation (LTP). During normal synaptic transmission (left), synaptically re- that, because synapses can be modified independently, can leased glutamate acts on both NMDA and AMPA receptors. Na participate in the encoding of many different bits of infor- flows through the AMPA receptor channel but not through the NMDA receptor channel because of the Mg2 block of this chan- mation. Third, LTP is readily generated in in vitro prepara- nel. Depolarization of the postsynaptic cell (right) relieves the tions of the hippocampus, thus making it accessible to rigor- Mg2 block of the NMDA receptor channel and allows Na and Ca2 to flow into the cell. The resultant rise in Ca2 in the den- ous experimental analysis. Indeed, much of what we know dritic spine is a necessary trigger for the subsequent events lead- about the detailed mechanisms of LTP derives from studies ing to LTP. Fourth, LTP has been observed at vir- tually every excitatory synapse in the mammalian brain that has been studied. In con- in which LTP has been demonstrated, and it can be seen trast, as described in Chapter 6, the NMDA receptor ex- that regions thought to be particularly important for various hibits a strong voltage dependence because of the block of forms of learning and memory are prominent. Although its channel at negative membrane potentials by extracellular LTP is not a unitary phenomenon, most synapses appear magnesium. As a result, NMDA receptors contribute little to express a form of LTP that is identical or highly analogous to the postsynaptic response during basal synaptic activity. Thus, this form of LTP is the focus of the remainder ciates from its binding site within the NMDA receptor of this section. The resultant rise in intracellular calcium is a necessary and perhaps sufficient trigger for LTP. This local source of calcium within the dendritic spine ac- Triggering of LTP: A Critical Role for NMDA counts for the input specificity of LTP. Receptors and Calcium The evidence in support of this model for the initial It is well established that the triggering of LTP requires triggering of LTP is compelling. Specific NMDA receptor synaptic activation of postsynaptic N-methyl-d-aspartate antagonists have minimal effects on basal synaptic transmis- (NMDA) receptors, a subtype of ionotropic glutamate re- sion but block the generation of LTP (22,23). Preventing ceptor (see Chapter 6) and postsynaptic depolarization, the rise in calcium by loading cells with calcium chelators which is accomplished experimentally by repetitive tetanic blocks LTP (24,25), whereas directly raising intracellular stimulation of synapses or by directly depolarizing the cell calcium in the postsynaptic cell mimics LTP (25,26). How do these requirements ex- receptor activation causes a large increase in calcium level plain the properties of LTP? During basal low-frequency within dendritic spines (see 23 for references). The exact synaptic transmission, synaptically released glutamate binds properties of the calcium signal that is required to trigger to two different subtypes of ionotropic glutamate receptor, LTP are unknown, but a transient signal lasting only 1 to termed AMPA ( -amino-3-hydroxy-5-methyl-4-isoxazole 3 seconds appears to be sufficient (27). Whether additional propionic acid) and NMDA receptors, which are often, but sources of calcium, such as release from intracellular stores, not always (see later), co-localized on individual dendritic are required for the generation of LTP is unclear. The AMPA receptor has a channel that is permeable uncertain whether additional factors provide by synaptic to monovalent cations (Na and K ), and activation of activity are required. Various neurotransmitters found in AMPA receptors provides most of the inward current that the hippocampus such as acetylcholine and norepinephrine generates the excitatory synaptic response when the cell is can modulate the ability to trigger LTP, and such modula- 150 Neuropsychopharmacology: The Fifth Generation of Progress tion may be of great importance for the functional in vivo to CaMKII, whereas the tyrosine kinases Fyn and Src may roles of LTP. However, there is no compelling evidence to indirectly modulate LTP by affecting NMDA receptor suggest that any neurotransmitter other than glutamate is function (see 23 for references). Signal Transduction Mechanisms in LTP Expression Mechanisms and LTP A bewildering array of signal transduction molecules has been suggested to play a role in translating the calcium signal In the 1990s, tremendous confusion and controversy sur- that is required to trigger LTP into a long-lasting increase rounded the seemingly simple issue of whether LTP is in synaptic strength (28). However, for only a few of these caused primarily by presynaptic or postsynaptic modifica- has compelling evidence of a mandatory role in LTP been tions. The great challenge to answering this question largely presented. A major limitation of much of the work on this stemmed from the great technical difficulties inherent in topic is that investigators have not adequately distinguished examining the changes the occur at individual synapses that molecules that are key components of the signal transduc- are embedded in a complex network in which each cell tion machinery absolutely required for LTP from biochemi- receives 10,000 or more synapses. Most neurobiologists cal processes that modulate the ability to generate LTP or studying this question agree that the simplest postsynaptic play a permissive role. For example, any manipulation that change that could cause LTP would be a change in AMPA modifies the activity of NMDA receptors may affect LTP. First, it must be activated Most studies examining this issue have used electrophysi- or produced by stimuli that trigger LTP but not by stimuli ologic assays, and most of these are inconsistent with the that fail to do so. Second, inhibition of the pathway in hypothesis that the release of glutamate increases signifi- which the molecule participates should block the generation cantly during LTP (23,39). Third, activation of the pathway should lead to mitter release probability invariably influence various forms LTP.

In particular buy sotalol 40 mg without a prescription, four double-blind pla- on sleep and wakefulness may result from interaction with cebo-controlled studies have examined doses of 400 to 900 1940 Neuropsychopharmacology: The Fifth Generation of Progress mg of valerian extract over periods of time from 1 to 8 days buy discount sotalol 40 mg on-line, With regard to behavioral treatments sotalol 40mg cheap, one of the major and in diverse subject populations ranging from healthy challenges is designing well manualized and 'exportable' young adults to elderly insomniacs (126–129). Subjective treatments that can be applied more readily in a variety of effects include decreased sleep latency and improved sleep treatment settings, including primary care settings. One study also reported decreased studies have begun to examine the optimal combination of subjectively rated awakenings (126). Findings from these studies are hampered by small be developed. These studies do not demonstrate the effi- from basic neuroscience sources. For instance, recent evi- cacy of valerian extract in most groups of individuals with dence has accumulated regarding the role of adenosine as primary insomnia. Relative underacti- Clinical studies have suggested a generally favorable side vity of adenosinergic neurotransmission could potentially effect profile for valerian extract; however, the sedative ef- result in reduced sleep drive. Finally, done regarding its consequences for health and role func- recent findings regarding the role of orexin in sleep/wake tioning. Individuals with insomnia complain not only of regulation could have direct implications for the neurobi- sleep disturbance, but daytime consequences as well. In ad- ology and pharmacologic treatment of insomnia (133,134). This will help to define the underlying path- mal management of insomnia disorders. Finally, genetic studies have been very useful for identifying abnormalities associated 1. Prevalence and persistence of sleep complaints in a rural elderly community sample: the with narcolepsy and circadian rhythm sleep disorders. Arch Gen Psychiatry 1985; Several issues also remain with regard to treatment as- 42:225–232. Sleep complaints among elderly persons: an epidemiologic study of three communities. Epidemiologic study of sleep distur- issues are of considerable importance, given the potential bances and psychiatric disorders. The optimal duration of treatment and the conceptualiza- 6. Incidence and remis- tion of potential 'maintenance' treatments for insomnia is sion of insomnia among elderly adults: an epidemiologic study also an area open for further investigation. Chapter 133: Current and Experimental Therapeutics of Insomnia 1941 7. Clinical correlates of insomnia in of sleep may be attenuated in subjects with primary insomnia. The natural history of insomnia cortex abnormalities in mood disorders. Nature 1997;386: and its relationship to respiratory symptoms. Sleep prob- psychological and pharmacological therapies for insomnia. Sleep lems and their correlates in a working population. Prevalence, burden, and treatment ment of chronic insomnia. The effects of exercise upon sleep: a critical review. New epidemiologic findings about Biol Psychol 1981;12:241–290. Progress in behavior injurious falls among the home-dwelling elderly by functional modification, vol. The direct economic costs of insom- ceedings of the American Psychological Association 1972;395–396. Sleep problems and institutionalization interventions for insomnia: a meta-analysis of treatment effi- of the elderly. Dysfunctional beliefs ship between insomnia and mortality among community-dwell- and attitudes about sleep among older adults with and without ing older women. Acognitive-behavioral conceptualization of insom- dict depression in elderly people? Insomnia-psychological assessment and man- J Gen Pract 1993;43:445–448. Bright light induction epidemiologic data for primary prevention of disorders with of strong (type 0) resetting of the human circadian pacemaker. Alleviation of sleep psychiatric disorders: a longitudinal epidemiological study of maintenance insomnia with time exposure to bright light. The Johns Hopkins Precursors trials in psychophysiologic insomnia. Practice parameters bidity of insomnia uncomplicated by psychiatric disorders.