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By Q. Inog. University of Tennessee, Knoxville.

Some countries have much more than the foundations; they have thriving research communities with a growing number of “south–south” as well as “north– south” international links buy lady era 100mg with amex women's health clinic chico ca. By strengthening these systems purchase lady era 100mg on-line women's health center utexas, countries will be able to capitalize more efectively on the supply of ideas buy lady era amex menstrual smell, using formal research methods to turn them into useful products and strategies for better health best 100mg lady era menstrual medication. Te case for investing in research is made, in part, by demonstrating that scientifc investigations really do produce results that can be translated into accessible and afordable health services that provide benefts for health. Chapter 3 presents 12 examples of studies that show how research can address some of the major ques- tions about achieving universal health coverage, and can deliver results that have infuenced, or could infuence, policy and health outcomes. In one, a systematic review of survey data from 22 African countries showed how the use of insecticide-treated mosquito nets was associated with fewer malaria infections and lower mortality in young chil- dren. Tis evidence underlines the value of scaling up and maintaining coverage of insecticide-treated nets in malaria-endemic areas. In a second set of experimental trials in Ethiopia, Kenya, Sudan and Uganda, a combination of the drugs sodium stibogluconate and paromomycin was found to be an efective treatment for visceral leishmaniasis. Treatment with the drug combination is shorter than with sodium stibogluconate alone and is less likely to lead to drug resistance. On the basis of these fndings, WHO recommended the drug combination as a frst-line treatment for vis- ceral leishmaniasis in East Africa. A third systematic review of evidence from Brazil, Colombia, Honduras, Malawi, Mexico and Nicaragua showed how conditional cash transfers – cash payments made in return for using health services – encourage the use of these services and lead to better health outcomes. Te successes of these investigations, and the others described in Chapter 3, should be a stimulus to invest in further research. Not all investigations will fnd that ideas for improving health services are successful, or that the provision of new services actually improves health. In mapping the route to universal coverage, the negative results of research studies are just as valuable as the positive ones. Which research methods are used to answer questions about universal health coverage? Te examples described in Chapter 3 expose the diversity of questions about uni- versal health coverage, and also the variety of research methods used to investigate them. Methods include quantitative and qualitative evaluations, observational and case-control studies, intervention studies, randomized controlled trials, and sys- tematic reviews and meta-analyses. Te report shows the benefts of having evidence from multiple sources, explores the link between experimental design and strength of inference, and highlights the compromises in study design (better evidence is ofen more costly, but not always) that must be made by all investigators. Te survey xiv Executive summary of research methods reveals the nature of the research cycle, where questions lead to answers that lead to yet more questions. Te chapter illustrates some of the ways in which research is linked with health policy and practice. What can be done to strengthen national health research systems? Research is likely to be most productive when it is conducted within a supportive national research system. Chapter 4 is an introduction to the essential functions of national health research systems, namely: to set research priorities, to develop research capacity, to defne norms and standards for research, and to translate evidence into practice. Standard methods have been developed to set research priorities. Tese meth- ods should be used more widely by governments to set national priorities across all aspects of health and to determine how best to spend limited funds on research. With regard to strengthening capacity, efective research needs transparent and accountable methods for allocating funds, in addition to well-equipped research institutions and networks. However, it is the people who do research – with their curiosity, imagination, motivation, technical skills, experience and connections – that are most critical to the success of the research enterprise. Codes of practice, which are the cornerstone of any research system, are already in use in many countries. Te task ahead is to ensure that such codes of practice are comprehensive and apply in all countries, and to encourage adherence everywhere. Achieving universal health coverage depends on research ranging from studies of causation to studies of how health systems function. However, because many existing cost-efective interventions are not widely used, there is a particular need to close the gap between existing knowledge and action. Areas of research that need special attention concern the implementation of new and existing technologies, health service operations, and the design of efective health systems. To help bridge the gap between science and practice, research should be strengthened not only in academic centres but also in public health programmes, close to the supply of and demand for health services. How can research for universal health coverage be supported nationally and internationally? In the wake of many previous reports, Chapter 4 presents three mechanisms to stimulate and facilitate research for universal health coverage – monitoring, coor- dination and fnancing. Provided there is a commitment to share data, national and global observatories could be established to monitor research activities. Observatories could serve a variety of functions, acting as repositories of data on xv Research for universal health coverage the process of doing research and presenting and sharing the fndings of research studies. Such data would help in tracking progress towards universal health cover- age, country by country. Monitoring supports the second function, coordination, on various levels – by sharing information, by jointly setting research priorities, or by facilitating col- laboration on research projects. Regarding the third function, fnancing, health research is more efective and productive if there is a guaranteed, regular income. Sustained fnancing guarantees that research projects are not interrupted or otherwise compromised by a sudden lack of resources. Various mechanisms for raising and disbursing additional research funds have been proposed and are under discussion. Whatever mecha- nism is adopted, international donors and national governments should measure progress against their own commitments to investing in health research. How will WHO support research for universal health coverage? Chapter 5 draws out the dominant themes of the report, and proposes a set of actions by which the research community, national governments, donors, civil society and international organizations, including WHO, can support the research that is needed if we are to reach universal health coverage. Tis report is closely aligned with the aims of the WHO strategy, which encourages the highest-quality research in order to deliver the greatest health ben- efts to the maximum number of people. Key points ■ The goal of universal health coverage is to ensure that all people obtain the health services they need – prevention, promotion, treatment, rehabilitation and palliation – without risk of financial ruin or impoverishment, now and in the future. This is illustrated by progress towards the health- related Millennium Development Goals (MDGs), and in the widespread fall in cash payments made for using health services. Thus nearly half of all HIV-infected people eligible for antiretroviral therapy were still not receiving it in 2011; and an estimated 150 million people suffer financial catastrophe each year because they have to pay out-of-pocket for health services. Consequently, given limited resources, each nation must determine its own priorities for improving health, the services that are needed, and the appropriate mechanisms for financial risk protection. First, and most important, are questions about improving health and well-being – questions that help us to define the interventions and services that are needed, including financial risk protection, discover how to expand the coverage of these services, including the reduction of inequities in coverage, and investigate the effects of improved coverage on health. The second set of questions is about measurement – of the indicators and data needed to monitor service coverage, financial risk protection, and health impact. One task for research is to help define a set of common indicators for comparing progress towards universal coverage across all countries. Through the cycle of research – questions yield answers which provoke yet more questions – there will always be new opportunities to improve health. As a descendant of the “Health for All” movement (Box 1. Tese services range from clinical care for individual patients to the public services that protect the health of whole populations. Tey include services that come from both within and beyond the health sector. Financial risk protection is one element in the package of measures that provides overall social protection (7). And protection against severe fnancial difculties in the event of illness gives the peace of mind that is an integral part of well-being. Tese are personal and moral choices regarding the kind of society that people wish to live in, taking universal cov- erage beyond the technicalities of health fnancing, public health and clinical care. With a greater understanding of the scope of universal health coverage, many national governments now view progress towards that goal as a guiding principle for the development of health systems, and for human development generally. It is clear that healthier environments mean healthier people (9). Preventive and curative services protect health and protect incomes (10, 11). Healthy children are better able to learn, and healthy adults are better able to contribute socially and economically. Te path to universal health coverage has been dubbed “the third global health transition”, afer the demographic and epidemiological transitions (12). Universal coverage is now an ambition for all nations at all stages of develop- ment. Te timetable and priorities for action clearly difer between countries, but the higher aim of ensuring that all people can use the health services they need without risk of fnancial hardship is the same everywhere. The Alma Ata Declaration is best known for promoting primary health care as a means to address the main health problems in communities, fostering equitable access to promotive, preventive, curative, palliative and rehabilitative health services. The idea that everyone should have access to the health services they need underpinned a resolution of the 2005 World Health Assembly, which urged Member States “to plan the transition to universal coverage of their citizens so as to contribute to meeting the needs of the population for health care and improving its quality, to reducing poverty, and to attaining internationally agreed development goals” (3). The central role of primary care within health systems was reiterated in The world health report 2008 which was devoted to that topic (4).

Setting priorities for health interventions in developing countries: a review of empirical studies buy cheap lady era 100mg line menopause essential oils. Tropical Medicine & International Health buy discount lady era 100mg line women's health center shelton ct, 2009 buy 100 mg lady era with amex menopause problems,14:930-939 discount 100mg lady era with amex menstrual undergarments. Setting implementation research priorities to reduce preterm births and stillbirths at the community level. Setting research priorities to reduce almost one million deaths from birth asphyxia by 2015. Setting research priorities to reduce global mortality from childhood pneumonia by 2015. Setting research priorities to reduce global mortality from childhood diarrhoea by 2015. Setting priorities in child health research investments for South Africa. Mental health research priorities in low- and middle-income countries of Africa, Asia, Latin America and the Caribbean. 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A review of selected research priority setting processes at national level in low and middle income countries: towards fair and legitimate priority setting. Where there is no health research: what can be done to fll the global gaps in health research? The Paris Declaration on Aid Efectiveness and the Accra Agenda for Action. Paris, Organisation for Economic Co-operation and Development, 2005. Busan, Global Partnership for Efective Development Cooperation, 2011. The emergence and current performance of a health research system: lessons from Guinea Bissau. Building capacity in health research in the developing world. Bulletin of the World Health Organization, 2004,82:764-770. Building the feld of health policy and systems research: an agenda for action. A review of conceptual barriers and opportunities facing health systems research to inform a strategy from the World Health Organization. Strengthening capacity for health research in Africa. South African Medical Journal/Suid-Afrikaanse tydskrif vir geneeskunde, 2012, 102:228–233. What must be done to enhance capacity for health systems research? Improving implementation: building research capacity in maternal, neo- natal, and child health in Africa. Defning organizational capacity for public health services and systems research. Journal of Public Health Management and Practice, 2012,18:535-544. Developing ANDI: a novel approach to health product R&D in Africa. The world health report 2006 − working together for health. Guidelines for research in partnership with developing countries: 11 principles. Bern, Swiss Commission for Research Partnership with Developing Countries, (KFPE), 1998. Research and capacity building for control of neglected tropical diseases: the need for a diferent approach. Applying DOTS principles for operational research capacity building. How much longer will Africa have to depend on western nations for support of its capacity-building eforts for biomedical research? Tropical Medicine & International Health, 2011,16:258-262. UK investments in global infectious disease research 1997–2010: a case study. Mapping global health research investments, time for new thinking - a Babel Fish for research data. Transforming the fght towards elimination of tuberculosis. Tuberculosis Research and Development: 2011 report on tuberculosis research funding trends, 2005–2010. Tropical Medicine & International Health, 2012,17:1409-1411. Operational research for improved tuberculosis control: the scope, the needs and the way forward. The International Journal of Tuberculosis and Lung Disease, 2011,15:6-13. Five keys to improving research costing in low- and middle-income countries. Strategies for capacity building for health research in Bangladesh: Role of core funding and a common monitoring and evaluation framework. 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It is interesting to aversive region in paradigms such as the open field order lady era pills in toronto pregnancy glucose screening, elevated plus maze generic 100 mg lady era with mastercard 1st menstrual period after pregnancy, and the elevated zero maze; thus 5-HT knock- note cheap lady era 100mg with visa encyclopedia of women's health issues, however generic lady era 100 mg fast delivery women's health center munster indiana, that no changes in contextual or cue-induced 1A out mice avoid the center of an open field, the open arms conditioned freezing are observed in 5-HT1B mutant mice, of a plus maze, and the unenclosed regions of a zero maze suggesting that approach-avoidance conflicts and condi- (133–135). It is worth noting that this 'increased anxiety' tioned fear may be differentially modulated by the 5-HT pattern of results was found consistently across three differ- system. The other main behavioral effect of constitutive ent research labs, indicating its robustness and reproducibil- 5-HT1B receptor deletion is a marked increase in aggressive ity. Consistent with this profile is the finding that these behavior (89,140,141). This increase in 5-HT1B knockout mice may also provide valuable informa- stress-like responding is not accompanied by changes in tion on the neural and genetic factors associated with stress overall locomotor activity or motor and spatial coordina- and anxiety-related functioning (89,142). It should be noted that mice with null mutations of other Curiously, 5-HT1A knockout mice display increased mobil- 5-HT receptor subtypes have also been generated, but these ity in response to an acute stressor such as forced swimming animals have not been found to display as robust an anxiety- or tail suspension (133–135). Taken together, these find- related behavioral profile as the 5-HT or 5-HT knock- 1A 1B ings indicate that 5-HT1A knockout mice may represent out mice. It has been found that 5-HT receptor knockout 5A another animal endophenotype of increased anxiety. These knockout mice also do not respond ingly, a recent report indicates that this mutation alters differently from control subjects in tests of startle reactivity GABA system expression and function (136). It has been or in burying a probe that delivered a brief electric shock. Anal- ysis of brain tissue from these animals indicates that GABA profile from that of the 5-HT1A or 5-HT1B knockout mice. A receptor binding is reduced and that the expression of An initial report indicates that 5-HT6 receptor deficient 1 and subunits of the GABA receptor are decreased in the mice may exhibit increased avoidance of aversive environ- 2 A amygdala. The anxiolytic actions of benzodiazepines may in ments; although these preliminary findings are interesting, part be mediated by GABAA receptors within the amygdala; further work is needed to fully characterize the phenotype the profile of results in 5-HT1A knockout mice has led to of these mutant mice (144,145). Mice lacking either the the intriguing speculation that the anxiety-like endopheno- 5-HT2A or 5-HT2C receptors have also been created; to the type in these mice may actually in part derive from a de- best of our knowledge, the stress-related behavioral func- crease in the expression and function of the GABAA recep- tioning of these animals has yet to be reported (146,147). Chapter 62: Animal Models and Endophenotypes of Anxiety and Stress Disorders 893 Clinically Effective 5-HT System Drugs for Stress- shorter form GAD65 (149). Whereas GAD67 is thought Related Disorders to maintain basal GABA levels, GAD65 is thought to regu- late the synthesis of GABA at nerve terminals in response As mentioned above, one of the most commonly prescribed to high GABA demand (150). Given the important role and effective classes of drugs that is used in the treatment of GABA in inhibitory neurotransmission associated with of depression and anxiety is the SSRIs, which block the anxiolysis, several investigators have evaluated the behav- reuptake of 5-HT by its transporter and thereby increase ioral profile of genetically altered mice that lack the GAD65 serotoninergic transmission. Two separate groups have reported that GAD65 clinical studies including those obtained from 5-HT recep- mice display an increase in stress-like behaviors in numerous tor knockout mice, 5-HT1A agonists have been developed behavioral paradigms (151,152). The clinical utility of this class had fewer entries into and time spent in the center of an of compounds, however, remains to be determined. As these open field or the open areas of an elevated zero maze (similar transgenic approaches develop and become more refined, to an elevated plus maze), indicating that they were more they will undoubtedly aid in clarifying the roles of the many avoidant of inherently aversive areas. Similarly, these mice other 5-HT receptor subtypes in processes related to stress had lower levels of activity in the bright portion of a light- and anxiety and will aid in drug development. It should be mentioned that GAD65 / mice also displayed an elevation in the occur- The GABA System rence of spontaneous and stress-induced seizures, and that these mice had a dramatically increased mortality rate start- The primary inhibitory neurotransmitter in the CNS is ing at 4 to 5 weeks after birth (151). Thus, although the GABA; GABA-synthesizing cells are distributed throughout behavioral profile of GAD65 knockout mice is suggestive the brain (128). The actions of GABA are mediated by two of increased anxiety-like responses, it is possible that these major classes of receptors, GABAA and GABAB, both of effects are secondary to the occurrence of seizures and to which modulate the activity of ion channels. The principal the factors leading to early lethality. The usefulness of this mode of inactivation of GABA transmission is the presynap- knockout as a model for anxiety-related deficits may there- tic reuptake of GABA by its transporter protein. Given that benzodiazepines and barbiturates both types of GABA receptors are widely distributed act as positive modulators of GABA transmission at the through the CNS, several important differences exist be- GABA receptor by enhancing GABA-induced chloride A tween the two. Relevant to psychopharmacology is the find- channel opening, it is of interest to note that GAD65 / ing that traditional anxiolytics (benzodiazepines) do not mice were not sensitive to the effects of either benzodiaze- bind to GABAB receptors, but rather mediate their effects pines or barbiturates, but did respond to the direct GABA A through GABAA receptors. GABAA receptors consist of a agonist muscimol, which binds directly to the GABA site of chloride channel formed by the pentameric arrangement of the GABA receptor and increases opening of the chloride A at least 18 different protein subunits ( 1–6, 1–4, 1-3, , channel in the absence of GABA (152). This pharmacologic , , 1–3), thus allowing for considerable heterogeneity of profile is consistent with the finding that GABA synthesis the GABAA receptor isoforms (148). Typically, benzodiaze- is blocked by the GAD65 null mutation, but that GABA A pine-responsive GABAA receptors consist of , , and receptor binding is unaffected by this change. Furthermore, subunits; in addition to the benzodiazepine site, these recep- this mutation does not seem to alter the functioning of tors also contain distinct sites for the binding of GABA, GABA receptors because direct agonists stimulate the recep- barbiturates, and ethanol. These various regions act as allo- tor but indirect modulators of GABA do not. Although psychotherapeutic effects such as anxiolysis receptor subunits in the regulation of stress- and anxiety- are achieved through facilitation of GABA transmission at related behaviors, investigators have generated mutant mice this receptor, drugs that act as GABAA receptor agonists with alterations in the expression of specific GABA recep- A also produce several deleterious side effects. It was initially reported that deletion of the which differences in GABAA receptor subunit composition subunit led to a selective (94%) reduction in the expres- 2 might contribute to possible dissociations between the bene- sion of benzodiazepine sites in the CNS without alterations ficial and negative effects of these compounds is currently in the level of GABA sites or changes in the expression of being investigated. Thus, knockout A 2 mice possessed functional GABAA receptors that responded normally to GABA site ligands or barbiturates, 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), 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).

There is an alternative explanation: the low and high performers sensed the state of play and disowned or owned responsibility accordingly order lady era no prescription menopause research. Figure 5 shows comparative data for 2014/16 with regard to perceived influence on the design of services in the local health economy cheap lady era 100mg overnight delivery menstruation after c-section. There certainly seemed to be no sense of a growing influence purchase lady era 100mg with mastercard pregnancy 9 weeks. The largest group of respondents said that their own CCG was the major player (38% of influence in 2016) cheap lady era 100 mg line women's health vancouver. However, other bodies were also seen as important, and these included NHSE (14%) and local collaborations of CCGs (18%). There were significant differences in this assessment depending on the role of the respondent with regard to their views about NHSE and NHS Improvement. GP members of the governing bodies were most likely to perceive NHSE and NHS Improvement as influential. Next we looked at ratings of CCGs by perceived importance of collaboration among neighbouring CCGs. And perhaps they did not want to collaborate with others in case this affected their performance ratings. When asked to rate the influence exerted by hospitals and other providers, it tended to be respondents from CCGs rated as inadequate who were more likely to accord the highest influence to these bodies (Figure 7). This may reflect the reality of powerful local hospital trusts or it might reflect a lack of will or capability in tackling these providers. The next section shifts focus from the influence of CGGs to an analysis of relative influence within them. Most especially, there was the contentious issue of whether managers or clinicians were exercising power and, relatedly, what influence, if any, other role holders such as the lay members, the secondary care doctors and the nurses had. Influence within Clinical Commissioning Groups Given that the policy intent, as shown in Chapter 1, was to create commissioning organisations led by clinicians – and most especially by GPs – we wanted to know whether or not these institutions had lived up to that aspiration. We began with a question which asked about the relative influence of different groups on the redesign of services. The four groups were managers, GPs, other clinicians excluding GPs and lay members. 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. 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 27 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 5% Clinicians Managers 51% 43% Neither Both equally 1% FIGURE 17 Collaboration building. The results suggest that half the respondents saw managers and clinicians equally involved in this. However, a very significant proportion (43%) identified managers as leading on this, and only a very small proportion (5%) argued that clinicians led on this work. Qualitative, free-form answers added some depth and flavour to the question of the kind of contribution being made by clinical leaders. A central reason for much of the emphasis on clinical leadership, as we noted in the literature review, relates to the idea that clinicians have the potential to make a difference through a distinctive set of contributions. The answers clustered into eight main categories of types of response, as shown in the first column of Table 3. As these reservations stem from governing board members with a close-up view of proceedings in CCGs, it is especially interesting to note the scepticism about the impact of clinical leadership. 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 29 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. Obstacles to achieving clinical leadership This free-form question elicited many responses. The most commonly cited response was that GPs did not have the time to fulfil the role adequately. Respondents also took the opportunity to use this question to identify what they saw as the source of the failings and difficulties faced by CCGs. Hence, many GP respondents pointed to wider problems of the health service at large (such as fragmentation, complexity, political interference, bias towards the acute sector and the like). Some managerial respondents used the question to highlight shortcomings in the GP contribution (poor attendance, lack of system-wide understanding), whereas some GPs also pointed to managerial shortcomings. Some GP respondents argued that the sources of the problem were deeper – that they extend to intractable system problems, such as fundamental diversity of objectives and lack of autonomy for the CCGs to influence the system because of the power and influence of bodies (such as NHSE, NHS Improvement) and the power of the acute hospitals – all of which impeded the plans of the CCGs. In other words, there was evidence of a perceived vicious circle. Yes, many GPs were reluctant to step forward to commit significant time and energy to the work of the CCGs, but they contended that this was because there was little incentive to do so, and indeed little point in so doing because bigger forces are stacked against this being a rational action. These perceptions led to a paradox of disengagement.

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