By Z. Olivier. College of Mount Saint Joseph. 2018.
The health systems chosen were those where there seemed to be some likely comparative resonance and thus the opportunity to generate further insights through the use of the perspective allowed by these comparisons discount 160mg super p-force mastercard erectile dysfunction natural herbs. The main comparative economies selected were Canada discount 160mg super p-force overnight delivery erectile dysfunction doctor orlando, Germany, the Netherlands, Sweden and the USA. Phase 1 As part of the initial scoping work, studies were made of a relatively large sample of 15 CCGs and their associated hinterlands of HWBs, LAs and health-care providers. In this phase of the project, the research team were looking both outwards from focal CCGs and inwards from the perspectives of relevant others. This included gathering views from relevant stakeholder bodies such as NHSE, CQC, the Faculty of Medical Leadership and Management, the National Association of Primary Care, commissioning support units (CSUs), the London Office of CCGs, NHS clinical commissioners, clinical senates and local medical committees, LAs, HealthWatch, community services and acute hospitals (managers and consultants). Simultaneous with the work in the first phase we undertook a major literature review. This review, uniquely, not only embraced the literature on clinical leadership and leadership studies more generally, but reached out into related relevant literatures on CCGs and other earlier forms of local commissioning, and the literatures on service redesign and change in health services. The scoping phase was used to allow insight into the varied types of CCGs and to gain a sense of the range of practice across the country. Interviews were conducted with accountable officers, chairpersons and a representative sample of CCG office holders, including various clinical leads, locality leads, GP governing board members, lay members, nurses, secondary care doctors and patient and public representatives. Interviews were also conducted with LAs and with members of HWBs. This phase of the study also included observational studies of CCG board meetings and of HWBs. These were used to gain a sense of the scope of ambition and insight into which agents were engaged in what kinds of 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 11 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. PROJECT DESIGN AND METHODOLOGY The aim at this scoping stage was to capture and catalogue the range of issues. It was also designed to gain exposure to varied contexts across the country – allowing access to issues as experienced in inner and outer London, in Northern and Midland towns and cities, and in rural areas. Research team members used a common semistructured interview guide. Interviews were recorded and transcribed in most instances, depending on the wishes of the interviewees. Phase 2 The findings from this pilot phase were used to help construct the questionnaire for the first national survey of all 210 CCGs (following a merger the total later became 209) across England. In turn, the responses from that survey helped inform the selection of six core cases that were targeted for in-depth research over the ensuing 2 years. The findings from these cases helped inform the design of the final national survey that was conducted in the third year of the project. Phase 3 Central to the research design were the core cases studies. Theory building from multiple cases has 74 75, many recognised benefits – as well as challenges. Case studies enable exposure to rich data in their real-world contexts. The main case study work phase was informed by the initial scoping work and also by the results of the national survey. In the main in-depth case studies, the focus was sharpened more directly onto explorations of specific examples of service redesign and an identification of who did what in conceiving, planning, resourcing and driving the changes. So, although our point of entry was into six CCGs, the case analyses focused on eight specific service redesign attempts. Once again we used a common semistructured interview guide (see Appendix 4). We worked in fieldwork teams of two, sometimes three, researchers and, again, interviews were recorded when feasible and helpful. Interviews were supplemented with relevant documentary analysis and with observations of board meetings, programme board meetings and other events relevant to the particular service redesign. This included many questions which had been part of the first survey and, hence, comparisons over the intervening time period (nearly 2 years) were enabled.
Contralateral disappearance Psychiatr Neurol Scand 1960;35:358–377 generic 160mg super p-force with amex impotence medications. Ventroposterolateral quency stimulation in MPTP-treated monkeys purchase super p-force 160mg on line erectile dysfunction risk factors. Eur J Neurosci pallidotomy can abolish all parkinsonian symptoms. Subthalamic nucleus lesion year results of a pilot study. Neural mechanisms underlying parkinsonian symptoms based upon regional uptake disease. Complications of movement disorder surgery and ence 1990;249:1436–1438. Combined (thalamot- pamine pathway by intracerebral nigral transplants. Brain Res omy and stimulation) stereotactic surgery of the VIM thalamic 1979;177:555–560. Bankiewicz KS, Plunkett RJ, Jacobowitz DM, et al The effect thalamic nucleus. J Neuro- eral thalamic stimulation in the treatment of essential and par- surg 1990;72:231–244. Pathophysiology and biochemistry of dyskinesia: clues 231. Transplantation in for the development of non-dopaminergic treatments. Lancet of autologous adrenal medullary transplantation to the corpus 1999;353:1764–1765. Unilateral transplan- nist: a novel antiparkinsonian agent that does not provoke dyski- tation of human fetal mesencephalic tissue into the caudate nesia in parkinsonian monkeys. Survival of implanted release by nicotine in rat nucleus accumbens. J Neurochem 1987; fetal dopamine cells and neurologic improvement 12 to 46 49:1449–1454. Dose response to intraven- fluorodopa uptake in five grafted parkinsonian patients. N Engl J Med 1995;332: nigro-striatal degeneration in non-human primate models of 1118–1124. Mutations in the parkin implants in a subset of transplanted patients with advanced gene cause autosomal recessive juvenile parkinsonism. Nat Med 1997;3:350– ease and dementia with lewy bodies. Familial parkinson disease 1816 Neuropsychopharmacology: The Fifth Generation of Progress gene product, parkin, is a ubiquitin-protein ligase. Mov Disord and rational neuroprotective therapy is close to reality. MARGOLIS Huntington disease (HD) is a progressive neurodegenera- The nature of the motor symptoms changes over time. Early complaints include toms that are referable to specific regions of brain disease. In addition to limb and truncal movements, pa- the pathogenesis of the disorder and are leading to ap- tients may have motor tics or chorea involving respiratory, proaches designed to develop rational treatments. Thus, laryngeal, pharyngeal, oral, or nasal musculature. Chorea HD serves as a model for the future study of those psychiat- often plateaus and even wanes in the later stages of the ric disorders in which abnormal brain function is thought disease, but disturbances in voluntary movement continue to arise from predominantly genetic factors. In late-stage HD, patients typically become akinetic and largely nonverbal, with severe rigidity and joint contractures. At this point, they may have few involuntary CLINICAL FEATURES movements except for occasional movements of the entire body, resembling myoclonic jerks, when disturbed.
The added costs and plausible effects of bioimpedance-guided fluid management (based on four tests per year) were added to the baseline model discount super p-force 160mg overnight delivery erectile dysfunction caused by vascular disease, and the cumulative costs and QALYs were simulated over the lifetime of the cohort in the alternative arms of the model discount 160mg super p-force free shipping erectile dysfunction for women. In the base-case clinical effectiveness scenarios, proportional reductions in all-cause mortality and CV event-related or all-cause hospitalisation were applied in the bioimpedance-guided arm of the model. Given the limited direct evidence from the clinical effectiveness review, these effects [incorporated as hazard ratios (HRs)] were primarily estimated by linking effects on surrogate end points [arterial stiffness (pulse wave velocity; PWV) and hydration status] to possible effects on the final outcomes using secondary published sources. Results Clinical effectiveness A total of five RCTs (published in six papers) analysing a total of 904 participants, and eight non-randomised studies (published in nine papers) analysing a total of 4915 participants were included in the review of clinical effectiveness. All included studies investigated the use of the BCM in the relevant population, all of which were adults. Of the RCTs, one trial was rated as having a high risk of bias, and four trials did not provide sufficient information to make a robust judgement. The results of the meta-analyses conducted for this assessment showed that both absolute overhydration and relative overhydration were significantly lower in the BCM group than in the standard clinical assessment group [weighted mean difference –0. The pooled effects of bioimpedance monitoring on blood pressure (mean difference –2. Cost-effectiveness Six main clinical effectiveness scenarios were explored in the cost-effectiveness modelling, with HRs of varying magnitude applied to all-cause mortality and CV event-related or all-cause hospitalisation rates. One of the scenarios also explored the impact of modelling a reduction in the use (cost) of blood pressure medication with bioimpedance-guided fluid management. There was insufficient evidence to justify the inclusion of effects on dialysis requirements (number and duration of sessions), residual renal function and the health-related quality of life of patients receiving dialysis (independent of effects on hospitalisation). When dialysis costs were included in the model, the incremental cost-effectiveness ratios (ICERs) for bioimpedance-guided fluid management ranged from £58,723 to £66,007 per QALY gained. These ICERs related to mean incremental costs that varied between £4518 and £35,676, and corresponding lifetime incremental QALY gains that varied from 0. The costs of dialysis in added years made up the vast majority of the incremental costs. When dialysis costs were excluded from the model, the base-case ICERs ranged from £15,215 to £21,201. Sensitivity analyses Beyond the inclusion/exclusion of dialysis costs, the cost-effectiveness results were found to be most sensitive to the effect of bioimpedance-guided fluid management on all-cause mortality. When dialysis costs were included in the model, the ICER was most favourable (≈ £40,300) when the HR for all-cause mortality was set equal to one, that is, no reduction in mortality leading to no extra dialysis costs, but retained benefits on non-fatal hospitalisation events. With dialysis costs and an effect on mortality included in the model, there would need to be an accompanying effect of bioimpedance monitoring on the cost of dialysis and/or health state utility over the lifetime of patients receiving dialysis. There is currently limited available evidence to justify such scenarios. When dialysis costs were excluded from the model, the ICER for bioimpedance-guided fluid management remained below £20,000 in most scenarios assessed. Given the relatively low cost of adding bioimpedance testing four times a year, the ICERs remained favourable with modest effects on mortality and hospitalisation rates. With dialysis costs excluded, probabilities of cost-effectiveness ranged from 61% to 67% at a willingness-to-pay threshold of £20,000 per QALY gained. Discussion Strengths, limitations of the analyses and uncertainties The methods used to conduct this assessment were detailed and thorough. The main limitation was the lack of evidence on any of the specified devices, with the exception of the BCM, and on children receiving dialysis. In light of the limited available clinical effectiveness evidence, the economic modelling relied on estimated effects on surrogate end points (hydration status, arterial stiffness and blood pressure) to model plausible reductions in all-cause mortality and CV event-related/all-cause hospitalisation. Critically, there were no ideal sources of evidence to link intervention-induced changes in the relevant surrogates to effects on mortality and hospitalisation rates. Therefore, the possible effects were informed by reference to cross-sectional prognostic studies, leading to great uncertainty in the robustness of the cost-effectiveness findings. 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 xix 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. SCIENTIFIC SUMMARY Generalisability of the findings The included trials involved only the BCM, and it is not known if the effects of this device generalise across the other multiple-frequency bioimpedance devices specified for this appraisal.
Angelman Syndrome In patients with fragile X syndrome best super p-force 160 mg erectile dysfunction at age 20, the expanded CGG In contrast to PWS buy cheap super p-force 160mg on-line new erectile dysfunction drugs 2013, investigators have shown that one gene triplet repeats are hypermethylated, and the expression of in the deleted region can lead to AS (34). AS is a neurologic the FMR1 gene is repressed, which leads to the absence of disorder with a heterogeneous genetic origin. It most fre- FMR1 protein (FMRP) and subsequent mental retardation. The remaining 20% to 30% of of selective messenger RNA transcripts. FMRP is an RNA- patients with AS exhibit biparental inheritance and a normal binding protein that shuttles between the nucleus and cyto- pattern of allelic methylation in the 15q11-q13 region. This protein has been implicated in protein transla- this biparental inheritance group, mutations in the UBE3A tion because it is found associated with polyribosomes and gene have been shown to be a cause of AS. A similar mecha- described the phenotypic expression in 14 patients with AS nism is proposed for FMR2, which encodes a large protein involving eight UBE3A mutations (34). These were made of 1,311 amino acids and is a member of a gene family up of 11 familial cases from five families and three sporadic encoding proline-serine–rich proteins that have properties cases. Some subtle differences from the typical phenotype of nuclear transcription factors (44). Consistent features were psychomotor The fragile X syndrome was one of the first examples of delay, a happy disposition, a hyperexcitable personality, a 'novel' class of disorders caused by a trinucleotide repeat EEG abnormalities, and mental retardation with severe expansion in the X chromosome. The other main features of AS—ataxia, population, the CGG repeat varies from six to 54 units. Moreover, my- 200) in the first exon of the FMR1 gene (the full mutation). Most of these patients were over- have a repeat in the 43 to 200 range (the premutation). The absence of FMR1 protein results in able to a deficiency in the maternally inherited UBE3A al- fragile X syndrome. Finally, analysis of mutation transmission showed an fragile site at Xq27. These clinical findings have important consequences FRAXF, which is not consistently associated with mental for genetic counseling in AS. These two mutations also have CGG repeat expansions and are distal to the FMR1 site. The transcrip- tional silencing of the FMR2 gene also has been implicated Fragile X Syndrome in FRAXE mental retardation. FRAXE individuals have been The fragile X syndrome is characterized by mental retarda- shown to exhibit learning deficits, including speech delay tion, behavioral characteristics, and the physical findings of and reading and writing problems. Fragile X syndrome is the most common known cause variable in different populations because of founder effects of inherited mental retardation, and it may also result in (42). Thus, the prevalence in an English study was 1 in learning disabilities and social deficits in those who do not 2,200, and in an Australian study it was 1 in 4,000, but it 632 Neuropsychopharmacology: The Fifth Generation of Progress was higher in Finland, where it is proposed that the initial Speech and Language settlers included one or more fragile X carriers. Speech and language in fragile X syndrome is generally de- layed, even thought the IQ may be in the normal range. The behavioral phenotype has been the subject of con- in speech pitch are common, and auditory processing and siderable study and includes mental retardation and learning memory deficits are present. These patients are The FMR1 protein is expressed most abundantly in neurons more interested in social interactions than those with autis- and testes with the localization primarily in the cytoplasm. The behavioral phenotype may synaptogenesis in the hippocampus, cerebral cortex, and be more helpful than the physical phenotype in diagnosis cerebellum (46). The expression of the FMR2 protein also commonly associated, and hyperactivity may be a presenting has been characterized. To characterize the expression of symptom in nonretarded boys with fragile X syndrome. Female immunofluorescence experiments on cryosections of mouse patients with fragile X syndrome may be unaffected, al- brain. The FMR2 protein is localized in neurons of the though abnormalities in social interaction, thought process, neocortex, Purkinje cells of the cerebellum, and the granule and affect regulation have been reported in carriers. FMR2 staining is shown to schizotypal features and depression have also been found in co-localize with the nuclear stain 4,6-diamidino-2-phen- carriers. The localization of FMR1 and FMR2 protein to the anxiety. In women with the full mutation, the social anxiety mammalian hippocampus and other brain structures in- is associated with social awkwardness and schizotypal fea- volved with cognitive function is consistent with the learn- tures.
Te drug is thus of reducing the risk of cardiovascular difcult to administer and constitutes a burden disease cheap super p-force 160mg with amex injections for erectile dysfunction forum, such as dietary changes discount 160 mg super p-force fast delivery erectile dysfunction relationship, the pre- both for the patient and for the health system. The efficacy of an alternative drug, paro- momycin sulfate (PM), has been demonstrated Case-study 7 in India (49). There is, however, limited infor- mation on the efficacy of PM for VL in the Combination treatment with African setting where response to treatment sodium stibogluconate (SSG) may be different. A large observational study of 4263 VL patients in South Sudan showed and paromomycin compared to that a combination of SSG and PM for a shorter SSG monotherapy for visceral period of time (17 days) yielded better results leishmaniasis: a randomized than SSG alone (50). For registration of PM and evaluation of the efficacy of combination treat- controlled trial in Ethiopia, ment with SSG and PM in East Africa, efficacy Kenya, Sudan and Uganda and safety data were required from a phase III randomized controlled trial. The need for research Human visceral leishmaniasis (VL), also known Study design as kala-azar, is a life-threatening parasitic dis- A multicentre randomized controlled trial ease caused by Leishmania donovani and trans- was conducted in four East African countries mitted by phlebotomine sandfies (Fig. Te VL is the second largest parasitic killer in the trial had three arms: (i) SSG monotherapy (a world afer malaria, with an annual worldwide dose of 20 mg/kg/day for 30 days) used as the incidence of approximately 500 000 cases (47). In East Africa, the SSG and PM given for a shorter period (SSG 20 incidence rate is 30 000 cases with 4000 deaths mg/kg/day; PM 15 mg/kg/day for 17 days). Te Leishmania parasite migrates aim was to compare the efcacy and safety of to internal organs such as the liver, spleen and PM monotherapy and the combination of SSG bone marrow (hence the term “visceral”) and, if and PM to the reference arm of SSG alone. Efective primary efcacy end point was defnitive cure measures to eradicate the sandfy are lacking, defned as parasite clearance from splenic, bone death rates are high, and there are few afordable marrow or lymph node aspirates six months and efective treatment options. In the comparison between PM monotherapy Treatment for VL in East Africa is primarily and SSG alone, 205 patients were enrolled in each limited to the antimonial sodium stibogluco- arm with primary efcacy data available for 198 nate (SSG), which is efcacious but requires four and 200 patients respectively. In the comparison weeks of hospitalization and daily intramuscular between the SSG/PM combination and the SSG 73 Research for universal health coverage Fig. Clinical examination of a 4-year-old girl with visceral leishmaniasis (kala-azar), in Sudan reference, 381 and 386 patients were enrolled in lowered the associated costs. Te cost of the each arm respectively with efcacy data available drugs also favoured the combination treatment for 359 patients per arm. Te efcacy of PM monotherapy was sig- Te potential risk of parasite resistance to SSG nifcantly lower than the efcacy observed in was also limited by combination therapy. Te efcacy SSG/PM combination therapy for treatment of of the SSG/PM combination given for a shorter VL in East Africa. A WHO Expert Committee duration of 17 days was similar to the efcacy of recommended its use as a frst-line treatment for SSG given alone for 30 days (91. Tere were no apparent diferences in the safety profle of Main conclusions the three treatment regimens. An observational multicountry study was con- ■ Te fndings supported the introduction of ducted in primary government health facilities SSG and PM combination therapy as a frst- in Bangladesh, Brazil, Uganda and the United line treatment for VL in East Africa. Te clinical perfor- mance of health workers with a longer duration of pre-service training (such as doctors and clin- Case-study 8 ical ofcers) was compared with those having a shorter duration of training (all other health Task shifting in the scale-up workers such as nurses, midwives and nurse of interventions to improve assistants providing clinical care). Te quality of care was evaluated using standardized indica- child survival: an observational tors and according to whether the assessment, multicountry study in Bangladesh, classifcation and management of sick children Brazil, Uganda and the United by IMCI guidelines had been fully carried out. Every child was assessed twice, frst by the IMCI- Republic of Tanzania trained health worker who was being assessed and second by a supervisor who was blinded to The need for research the original diagnosis and treatment made by WHO estimates that the global health workforce the health worker. Although this research has has a defcit of more than four million persons been classifed as a study of the management of (51). Countries with high child mortality rates diseases and conditions, it is also health policy also tend to have a lack of qualifed health work- and systems research. Te Integrated Management of Childhood Illness (IMCI) is a global strategy that has been Summary of fndings adopted by more than 100 countries with a view Te study included a total of 1262 children to reducing child mortality. IMCI clinical guide- from 265 government health facilities: 272 chil- lines describe how to assess, classify and manage dren from Bangladesh, 147 from Brazil, 231 children younger than fve years of age who have from the United Republic of Tanzania, and 612 common illnesses (52). In Brazil, 58% of health workers expanding IMCI coverage is the lack of qualifed with training of long duration provided cor- health workers. Task shifing, which is the term rect management, compared with 84% of those used to describe the process whereby specifc tasks with shorter duration of training. In Uganda are moved, where appropriate, to health workers the fgures were 23% and 33% respectively with fewer qualifcations and a shorter duration of (Table 3.
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