Accelerated filament disinhibition dementia: a frontotemporal dementia linked to formation from tau protein with specific FTDP-17 missense 17q21-22 purchase silagra 50mg mastercard. Somatodendritic locali-¨ and 5′-splice-site mutations in tau with the inherited dementia zation and hyperphosphorylation of tau protein in transgenic FTDP-17 discount 100 mg silagra amex. FTDP-17: an early- ing the shortest human tau isoform. Neuron 1999;24:751– onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation. Prominent axon- dementia with a novel missense mutation in the tau gene. Neu- opathy in the brain and spinal cord of transgenic mice overex- roreport 1999;10:497–501. Axonopathy and amy-¨ Natl Acad Sci USA 1999;96:55598—55603. Tau gene mutation Acta Neuropathol (Berl) 2000;99:469–481. G389R causes a tauopathy with abundant pick body-like inclu- 179. Characterization of pathol- sions and axonal deposits. J Neuropathol Exp Neurol 1999;58: ogy in transgenic mice over-expressing human genomic and 1207–1226. Alzheimer-type neu- loss in the human amyloid precursor protein V717F (PDAPP) ropathology in transgenic mice overexpressing V717F beta-am- transgenic mouse. Correlative memory defi- ease and transgenic models. Annu Rev Neurosci 1998;21: cits, Abeta elevation, and amyloid plaques in transgenic mice. Abeta deposition dence for the involvement of tau in progressive supranuclear is associated with neuropil changes, but not with overt neuronal palsy. Alois Alzheimer in suggest directions for future investigation or are the only 1907 (1) was remarkable for both her progressive cognitive studies available. Clinical interest in the noncognitive abnormali ties in Alzheimer disease (AD) has been substantial because DEPRESSION IN ALZHEIMER DISEASE of their high prevalence (2–4) and because noncognitive behavioral problems complicate patient management and Diagnostic Challenges often precipitate institutionalization (3,5–12). The real or The diagnosis and treatment of depression complicating the apparent resemblance of delusions, hallucinations, de- course of AD have received considerable attention. Because pressed mood, agitation, hostility, and other noncognitive depression per se can impair cognitive function (17), it is behavioral abnormalities of AD to the signs and symptoms reasonable to hypothesize that effective treatment of depres expressed in such classic psychiatric disorders as depression, sion in the patient with AD may maximize potential cogni schizophrenia, and mania has prompted the widespread use tive capacity. Furthermore, the consensus is that reduction of psychotropic drugs in the management of AD (13–16). Unfortunately, the apparently straightforward goal of cacy. In fact, data establishing the efficacy of psychotropic treating depression complicating AD becomes complex drugs for noncognitive behavioral problems in AD and when the problems involved in the diagnosis of depression other dementing disorders remain limited. Although reports in the context of AD or other dementing illnesses are consid of treatment outcome studies incorporating reliable and ered. A fundamental problem is the substantial overlap of valid outcome measures, well-defined patient samples, and signs and symptoms between depression and AD. Common randomization to an adequate trial of active medication or to both disorders are apathy and loss of interest, impaired placebo continue to appear, their number remains small. The macologic management of noncognitive behavioral prob- ability to diagnose depression in AD is further compromised lems in AD. Placebo-controlled studies are emphasized, but re- Even if investigators agreed on uniform diagnostic criteria sults of other studies and reports are discussed when they for syndromal depression in AD and used uniform assess ment instruments and interviews, discrepant prevalence rates would likely arise from the differential characteristics of the samples of AD patients studied. Raskind: Veterans Administration Northwest Network Men- AD with concurrent depression derived from clinical popu tal Illness Research Education and Clinical Center, Seattle, Washington. Barnes: Department of Psychiatry and Behavioral Sciences, lations are higher than those derived from research registries University of Washington School of Medicine, Seattle, Washington. For example, in an outpatient geriatric study carefully documented the presence of major depressive clinic, Reifler et al. Patients were treated for a mean duration contrast, Burke et al. HAM-D scores significantly and substantially de- included a longitudinally followed normal control group creased from a mean of 19 on admission to a mean of 5 matched for age, sex, race, and social position. This degree of improvement did not differ symptoms of depression occurred in both patients with AD significantly from that in an elderly, nondemented, de- and controls, but criterion-based major depression could pressed inpatient group treated in a similar naturalistic man not be diagnosed. However, the mean length of stay to achieve compara depression in a sample of subjects with AD screened to ble improvement in the elderly nondemented, depressed exclude those with a past history of major psychiatric disor group was substantially shorter than that in the demented, ders was reported by Kumar et al. Possible differential treatment responses mood was more frequent in the AD subjects than in age- between AD subjects with major depression and MID sub matched normal controls, depressed mood in the AD sub jects with major depression were not reported. Both Rey jects was unaccompanied by classic vegetative signs and nolds et al.
This reduced the prevalence of syphilis and the risk of HIV infection 100 mg silagra otc. Some benefits were immediately visible and led to rapid policy changes which were purchase silagra 100 mg, in some instances, implemented even before the research studies were completed. The research also helped to strengthen health services in some of the participating countries. In Brazil, for instance, it has provided a model for the provision of health services to indigenous populations, as well as a template for the introduction of new technologies. Tis section outlines analysis and communication; common standards the main responsibilities that fall on institu- for sharing information; mandatory publication tions and researchers in carrying out responsible of data in a reusable form to support fndings; research. Because these principles are laid out and the development of expertise and sofware clearly in international guidelines, the task is not for managing the enormous volume of digital necessarily to develop the principles further but data (93). In this Royal Society review, intelligent to see that they are applied everywhere. It is the basis for understanding and communi- Ethics and ethical review cating results that can be exploited for practical purposes, including the improvement of health. Te ethical principles that guide the behaviour Accompanying this general trend towards of researchers, overseen by ethical committees, openness is a proliferation of Internet-based are to ensure honesty, objectivity, integrity, jus- platforms for sharing information. Among these tice, accountability, intellectual property, pro- are the Health Research Web, Health Systems fessional courtesy and fairness, the protection of Evidence, and PDQ-Evidence (Box 4. As data participants in research studies, and good stew- exchange becomes commonplace, consistent ardship of research on behalf of others (83–88). Te be met in ethical reviews of health research with principles and practice for sharing genomic data human participants (Box 4. Tese standards are well advanced but those for sharing data on are designed to complement existing laws, regu- innovation, research and development are less lations and practices, and to serve as a basis on developed (94, 95). Te registration of clinical trials is a scientifc, ethical and moral responsi- Reporting and sharing research bility because decisions about health care must data, tools and materials be informed by all of the available evidence. From a practical standpoint, the International Clinical Te research community is responsible for ensur- Trials Registry Platform (ICTRP) helps research- ing the accuracy of methods, integrity of results, ers and funding agencies to avoid unnecessary production and sharing of data, adequacy of peer duplication, to identify gaps in clinical trials review, and protection of intellectual property research, and to fnd out about trials in which (81, 90, 91). Tis means openness of researchers with regulatory, legal, ethical and funding require- other scientists and with the public and media; ments for the oversight and conduct of clinical 110 Chapter 4 Building research systems for universal health coverage Box 4. Standards for the ethical review of research with human participants These standards (which are abbreviated here) are intended as guidance for research ethics committees and for the researchers who design and carry out health research studies (88). The task of ethical review involves more than standing committees and includes, for example, independent teams of trained external assessors that can investigate allegations of research misconduct (89). Responsibility for establishing the research ethics review system Ethical review must be supported by an adequate legal framework. Research ethics committees must be able to provide independent reviews of all health-related research at national, subnational and/or institutional (public or private) levels. Composition of research ethics committees Research ethics committees should have multidisciplinary and multisectoral membership, including individuals with relevant research expertise. Research ethics committee resources Research ethics committees should have adequate resources – staff, facilities and finance – to carry out their responsibilities. Independence of research ethics committees The independence of research ethics committee operations must be ensured in order to protect decision-making from influence by any individual or entity that sponsors, conducts or hosts the research it reviews. Training the research ethics committee Training should be provided on the ethical aspects of health-related research with human participants, on the application of ethical considerations to different types of research, and on the conduct of research reviews by the research ethics committee. Transparency, accountability and quality of the research ethics committee Mechanisms exist to make the operations of research ethics committees transparent, accountable, consistent and of high quality. The ethical basis for decision-making in research ethics committees The research ethics committee bases its decisions about the research that it reviews on a coherent and consistent application of the ethical principles that are articulated in international guidance documents and human rights instruments, as well as on any national laws or policies consistent with those principles. Decision-making procedures for research ethics committees Decisions on research protocols are based on a thorough and inclusive process of discussion and deliberation. Written policies and procedures Written policies and procedures include specification of the membership of the research ethics committee, commit- tee governance, review procedures, decision-making, communications, follow-up and monitoring, documentation and archiving, training, quality assurance, and procedures for coordination with other research ethics committees. Sharing information on current practice in health research: some examples Health Research Web (www. The platform uses an editable wiki-type format so that institutions and agencies can personalize entries to suit their own needs. The information presented includes research policies, priorities, projects, capacities and outputs, as illustrated in the following figure. The Health Research Web Governance and policies Information Research resources priorities Health Research Key projects Research institutions Web Civil society Research organizations ethics review Research nancing The number of users of the platform is growing at both regional and country levels. In the Americas, the Pan American Health Organization (PAHO) has developed Health Research Web – Americas (www. In Africa, the Tanzanian Commission for Science and Technology (COSTECH) uses the platform to issue public calls for research proposals. With this platform COSTECH can monitor which studies have been supported, see how these respond to national research priorities, check what public resources are allocated to the research, and consult the research findings.
Figure 6 shows that SBP was lower in participants who underwent bioimpedance measurements using the BCM device than in those assessed by standard clinical assessment buy 100 mg silagra, but the difference was not statistically significant (mean difference –2 100mg silagra for sale. Arterial stiffness Two trials (both rated as being at an unclear risk of bias) reported arterial stiffness results, which were 60 77, included in a meta-analysis. The measurement of pulse wave velocity (PWV) is generally accepted as the most simple, non-invasive, robust and reproducible method of determining arterial stiffness, with carotid–femoral PWV regarded as the gold standard. The PWV increases from 4–5 m/second in the ascending aorta to 5–6 m/s in the abdominal aorta and 8–9 m/s in the iliac and femoral arteries. Substantial statistical heterogeneity between trials was observed. Mortality 60 61 76, , Three of the included trials (all rated as being at an unclear risk of bias) reported mortality data. As mortality was reported with a HR, the log-HR and log-SE for the three trials were input manually (Table 3). Figure 8 shows that, compared with standard clinical assessment, the use of the BCM had no significant effects on mortality (HR 0. Moderate statistical heterogeneity was evident among trials. Absolute overhydration Four trials (one rated as being at a high risk of bias and three rated as being at an unclear risk of bias) 61 63 76 77, , , assessed absolute overhydration, which was defined as the difference between expected ECW and actual ECW. Figure 9 shows that absolute overhydration was significantly lower in the BCM assessment group than in the standard clinical assessment group [weighted mean difference (WMD) –0. Moderate statistical heterogeneity between trials was apparent. Figure 10 shows that ROH was significantly lower in the BCM assessment group than in the standard clinical assessment group (WMD –1. ROH was assessed by the BCM in both groups, therefore these results should be interpreted with caution. Randomised controlled trial evidence: subgroup and sensitivity analyses We had initially planned to perform subgroup analyses according to the type of dialysis (HD or PD), the type of population (children aged < 5 years) and ethnicity group, and according to certain characteristics of the patient population, that is, people for whom recommended configurations of electrodes could not be used, people who could not assume the required positions for measurements to be made or people at extremes of body composition measurements. However, because of a lack of available data, we were able to perform only subgroup analyses of SBP and absolute overhydration according to the type of dialysis utilised. Figure 11 presents the forest plot of the subgroup analysis of SBP according to the type of dialysis. As there was only one trial in the PD group, we considered that testing for subgroup effects would have been statistically unsound. We considered that the comparison of the overall effect with the HD group effect (similar to a sensitivity analysis) was a better, more reliable approach. In this case, the effect on blood pressure was still not significant (WMD –1. Figure 12 presents the subgroup analysis for absolute hydration according to the type of dialysis. As described above, we did not perform a test of subgroup effects. In the case of absolute overhydration, there is a difference between the overall effect compared with the HD subgroup effect (WMD –0. We were unable to perform the planned sensitivity analyses (i. Randomised controlled trial evidence: other outcomes Intermediate reported outcomes Hospitalisation 61 76 77, , 76 Three trials reported data on hospitalisation. In the standard clinical assessment group, there were 73 all-cause hospitalisation events, with an incidence of 0. E xp e rim e nt l ontrol M e a n d iffe re nce M e a n d iffe re nce St d y or b grou p M e n S ot l M e n S ot l W e ight V , ra nd om V , ra nd om H n- She ng – – to H r – – to – L o – – to – P once – – to T ot l – – to – H e te roge ne ity: d f T e tfor ov e ra lle ffe ct z – – F ou rs e xp e rim e nt l ou rs control F U R eta - a n a lys i fo a b o lute o ver hydr a tio n df degr ees o ff eedo m ; in ver e va r ia n c e; S D ta n da r d devia tio n E xp e rim e nt l ontrol M e a n d iffe re nce M e a n d iffe re nce St d y or b grou p M e n S ot l M e n S ot l W e ight V , ra nd om V , ra nd om H n- She ng – – to O nofrie cu – – to – P once – – to T ot l – – to – H e te roge ne ity: d f T e tfor ov e ra lle ffe ct z – – F ou rs e xp e rim e nt l ou rs control F U R eta - a n a lys i o fR df degr ees o ff eedo m ; in ver e va r ia n c e; S D ta n da r d devia tio n E xp e rim e nt l ontrol M e a n d iffe re nce M e a n d iffe re nce St d y or b grou p M e n S ot l M e n S ot l W e ight V , ra nd om V , ra nd om H H n- She ng – to H r – – to O nofrie s cu – – to P once – – to Sb tot l – – to H e te roge ne ity: d f T e tfor ov e ra lle ffe ct z P L o – – to Sb tot l – – to H e te roge ne ity: not p p lica b le T e tfor ov e ra lle ffe ct z T ot l – – to H e te roge ne ity: d f T e tfor ov e ra lle ffe ct z – – T e tfor b grou p d iffe re nce F ou rs e xp e rim e nt l ou rs control F U R S ub gr o up a n a lys i fo S B a c c o din g to the typ e o fdia lys i df degr ees o ff eedo m ; in ver e va r ia n c e; S D ta n da r d devia tio n E xp e rim e nt l ontrol M e a n d iffe re nce M e a n d iffe re nce St d y or b grou p M e n S ot l M e n S ot l W e ight V , ra nd om V , ra nd om H H n- She ng – – to H r – – to – P once – – to Sb tot l – – to – H e te roge ne ity: d f T e tfor ov e ra lle ffe ct z P L o – – to – Sb tot l – – to – H e te roge ne ity: not p p lica b le T e tfor ov e ra lle ffe ct z T ot l – – to – H e te roge ne ity: d f T e tfor ov e ra lle ffe ct z – – T e tfor b grou p d iffe re nce d f F ou rs e xp e rim e nt l ou rs control F U R S ub gr o up a n a lys i fo a b o lute o ver hydr a tio n a c c o din g to the typ e o fdia lys i df degr ees o ff eedo m ; in ver e va r ia n c e; S D ta n da r d devia tio n DOI: 10. Four participants were hospitalised in the standard clinical assessment group, with a hospitalisation rate/100 patient-years of 30. The difference between the groups was not statistically significant. The difference from baseline, although not statistically significant, decreased in both groups (from 67% and 53%, respectively). In contrast, there was no change in LVMI in the standard clinical assessment group [from 121 (SD 35) at baseline to 120 (SD 30) at 12 months; p = 0. Clinical outcomes Incidence of cardiovascular events One study reported a combination of acute fluid overload or CV-related events, which included hospitalisation related to CV or cerebrovascular events and episodes of acute fluid overload. Residual renal function No trials reported residual renal function, but two studies reported urinary volume, which could be considered a surrogate measure thereof. By contrast, there was no change in the proportion of anuric patients in the control group and the decrease in urine output in non-anuric patients was not significant at follow-up. Adverse effects associated with hypotensive episodes The top five intradialytic complications reported by Huan-Sheng et al. There were significant differences between the bioimpedance assessment group and the standard clinical assessment group for all of these complications, but not in the same direction. In the bioimpedance assessment group, there was significantly more cramping, chest tightness and headaches, but significantly less hypotension and skin itching.
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