By Y. Zakosh. California State University, Hayward. 2018.

It is worth pointing out that clinical assessment does not directly measure fluid levels in the body to identify if a person is over- or underhydrated purchase 100 mg lamotrigine otc, but rather relies on the presence of symptoms and signs of overhydration and underhydration 100 mg lamotrigine with amex. This approach could 100 mg lamotrigine amex, therefore generic lamotrigine 100 mg line, miss individuals who are asymptomatic despite having an excess or deficit of body water. For example, symptoms such as oedema may not appear until individuals are substantially overhydrated and people with fluid overload do not always exhibit high blood pressure. Additionally, some clinical features are only surrogate markers for fluid overload and can, therefore, be the result of other unrelated causes. This could lead to fluid levels being inappropriately adjusted. For example, a response to high blood pressure assumed to be caused by fluid overload (but actually caused by other factors) may involve the removal of increasing volumes of fluid during dialysis, which, in turn, may lead to underhydration with potential loss of residual renal function. Management of Stage 5 Chronic Kidney Disease: NICE Pathway. 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 7 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. The evidence synthesis was conducted in accordance with the general principles of the Centre for Reviews and Dissemination guidance for conducting reviews in health care,69 the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions Version 5. Identification of studies Comprehensive electronic searches were conducted to identify relevant reports of published studies. Highly sensitive search strategies were designed, including appropriate subject headings and text-word terms, to retrieve studies that assessed the selected bioimpedance devices for CKD patients receiving dialysis. Three facets were combined using the Boolean operator AND: CKD, RRT and devices. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Science Citation Index and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for primary studies, while the Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment database were searched for reports of evidence syntheses. The searches were undertaken during the period of 27 June to 4 July 2016. The MEDLINE and EMBASE searches were rerun on 10 October 2016 to identify any recent reports. An additional search in MEDLINE and EMBASE was undertaken on 27 September 2016 to identify any published reports on validation of the devices that had not been identified by the main clinical effectiveness searches. Reference lists of all included studies were perused in order to identify additional potentially relevant reports. The expert panel provided details of any additional potentially relevant citations. Searches for recent conference abstracts (2014–16) were also undertaken and included the following annual conferences: European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), Kidney Week (American Society of Nephrology) and the Annual Dialysis Conference. Ongoing studies were identified through searching ClinicalTrials. Websites of professional organisations and health technology agencies were checked to identify additional reports. Full details of the search strategies used are presented in Appendix 1. Inclusion and exclusion criteria Studies fulfilling the following criteria were eligible for inclusion in this assessment. 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 9 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. ASSESSMENT OF CLINICAL EFFECTIVENESS l BioScan 920-II and BioScan touch i8 l InBody S10. Comparator The comparator considered in this assessment was standard clinical assessment, which takes account of the following parameters: l blood pressure l presence of oedema l changes in weight l residual renal function l pre-existing CV conditions l any patient-reported symptoms of overhydration or underhydration, for example cramps, fatigue, nausea, dizziness, breathlessness, decreased appetite or visual disturbances. Outcomes The following outcome measures were considered: l intermediate measures, including – ¢ number and length of HD sessions ¢ number of unplanned hospital visits/admissions as a result of fluid overload or dehydration ¢ use of antihypertensive medication ¢ incidence of anaemia ¢ blood pressure ¢ left ventricular hypertrophy ¢ left ventricular mass index (LVMI) ¢ arterial stiffness ¢ incidence of overhydration or underhydration ¢ changes of dialysis modality (from PD to HD) because of fluid overload ¢ adherence with recommended fluid intake. One further relevant outcome not specified in the scope or protocol was also considered because of its clinical importance: achievement of target weight. Study design Priority was given to RCTs assessing multiple-frequency bioimpedance devices versus standard clinical assessment and RCTs comparing the effectiveness of one device with that of another. As there was a large body of non-randomised evidence, which was not manageable in the time frame of this assessment, we decided to focus exclusively on non-randomised studies with a sample size of at least 100 participants, which assessed the hydration status of people with CKD receiving dialysis. Of the non-randomised studies, which were excluded based on these last criteria, three studies (published 24 72, –74 in four papers) with < 100 participants focused on paediatric populations. Appendix 2 presents the characteristics of these studies. In the list of non-randomised studies that were not deemed suitable for inclusion based on the above criteria, no UK-based studies, studies that included any of the specified devices (other than the BCM) or studies reporting relevant outcomes not otherwise described in the report were identified. The following types of studies were also excluded from this assessment: l narrative reviews, editorials and opinions l case reports l conference abstracts for which a full publication or further methodological information could not be found l non-English-language reports for which a translation could not be organised l studies reporting cross-sectional data only. Data extraction strategy One reviewer (MC) screened the titles and abstracts identified by the search strategies. A second reviewer (MB) independently screened a random sample of 10% of the titles and abstracts. Owing to time constraints, this strategy differed from that detailed in the protocol, which stated that two reviewers would independently screen all titles and abstracts. A data extraction form was designed and piloted specifically for this assessment (see Appendix 3). One reviewer (MC or MS) extracted information on characteristics of studies and participants, details of interventions and comparators (when applicable) and relevant outcome measures. All extracted data were cross-checked by a second reviewer (DC, MC, MB or MS). Any disagreements were resolved by discussion between reviewers. Assessment of risk of bias in included studies The standard Cochrane risk-of-bias tool was used to assess the risk of bias in randomised trials (see Appendix 4). Studies were not included or excluded based on the risk of bias rating. The Cochrane risk-of-bias tool incorporates the following domains: sequence generation, allocation concealment, blinding, incomplete outcome data and selective outcome reporting. Assessment of other sources of bias was based mainly upon the source of funding for the conduct of the study and potential links with the manufacturers of the devices under investigation. Individual risk-of-bias domains were rated as being at a high, low or unclear risk of bias.

The net effect of striatal dopamine release appears premotor cortex purchase 100mg lamotrigine overnight delivery, respectively (140) cheap lamotrigine 200mg on-line. As is the case with GPi buy lamotrigine 50mg without prescription, to be to reduce basal ganglia output to the thalamus and SNr also sends projections to the noncholinergic neurons other targets (see below) order lamotrigine 200mg online. This implies that a reduction of in the medial two-thirds of the PPN (117,243,271,277). The latter projection is far more prominent in Basal ganglia output arises from both GPi and SNr. The phylogenetically old animal species (amphibians) than in segregation of GPi into a caudoventral 'motor' portion and primates (189). The motor territory of GPi projects almost exclusively to the posterior ROLE OF THE BASAL part of the ventrolateral nucleus (VLo in macaques), which GANGLIA–THALAMOCORTICAL CIRCUITRY in turn sends projections toward the supplementary motor IN THE CONTROL OF MOVEMENT area (SMA) (143,249,280), the primary motor cortex (MI) (135,136,143,148,152,213,241), and premotor (PM) cor- At the most basic level, voluntary movements appear to be tical areas (135). The outflow from pallidal motor areas initiated at the cortical level of the motor circuit with output directed at cortical areas MI, PM, and SMA appears to arise to brainstem and spinal cord, and to multiple subcortical from separate populations of pallidothalamic neurons (135), targets, including the thalamus, putamen, and the STN. The focusing model, however, is difficult to rec- logic properties of corticostriatal projection neurons have oncile with the fact that basal ganglia neurons become active shown that these neurons are different from corticospinal after changes in cortex and thalamus are manifest (13,63, projection neurons (20,295) and tend to have slower con- 73,75,103,202,293,294,309). Both models are at odds with duction velocities and lower spontaneous rates, and are usu- the fact that although STN lesions (thus an interference ally not responding to somatosensory input. A multitude targeted neurons with subsequent disinhibition of related of other motor functions of the basal ganglia are strong thalamocortical neurons (142). The net effect is increased candidates, such as a role in self-initiated (internally gener- activity in appropriate cortical neurons, resulting in a facili- ated) movements, in motor (procedural) learning, and in tation of the movement. In contrast, activation of the striatal movement sequencing (115,250,318). These can only be neurons that give rise to the indirect pathway will lead to mentioned in passing here, but will probably gain greater increased basal ganglia output and, presumably, to suppres- prominence in future models of basal ganglia function. Because the majority of neurons in GPi increase their firing rate with movement (103,202), the pre- sumed increased suppression of unintended competing CHANGES IN BASAL GANGLIA CIRCUIT movements may be a particularly important role of the basal ACTIVITY IN PARKINSONISM ganglia. Depending on the precise timing and anatomic connectivity, this dual action on movement could result in Regardless of the precise causation of the disease, all of the limiting the spatial or temporal extent of movements. The combina- that result from loss of dopaminergic transmission in the tion of information traveling via the direct and the indirect basal ganglia has been greatly facilitated by the discovery pathways of the motor circuit has been proposed to serve that primates treated with MPTP develop behavioral and to either scale or focus movements (7,200,211). Scaling anatomic changes that closely mimic the features of PD in would be achieved by a temporal sequence of activity humans (17,47,100,170). Striatal output would first in- Changes in the activity over striatopallidal pathways were hibit specific neuronal populations in GPi/SNr via the di- first suggested by studies in MPTP-induced parkinsonism rect pathway, thus facilitating movement, followed by disin- in primates that indicated that the metabolic activity (as hibition of the same GPi/SNr neuron via inputs over the measured with the 2-deoxyglucose technique) is increased indirect pathway, leading to inhibition ('braking') of the in both pallidal segments (60,201,222,252). In the focusing model, by contrast, inhi- preted as evidence of increased activity of the striatum-GPe bition of relevant pallidal/nigral neurons via the direct path- connection and the STN-GPi pathway, or, alternatively, as way would allow intended movements to proceed, whereas evidence of increased activity via the projections from the unintended movements would be suppressed by concomi- STN to both pallidal segments. It was then shown directly tant increased excitatory input via the indirect pathway in with microelectrode recordings of neuronal activity that other GPi/SNr neurons (see discussions in refs. Overall, the effect exerted by the two pathways in reduced tonic neuronal discharge in GPe, and increased this case would be to further shape or sculpt the movement. Raster displays of spontaneous neuronal activity recorded in different basal gan- glia structures within the basal ganglia circuitry in normal and parkinsonian primates. Shown are ten consecutive 1000-msec segments of data from the external and internal segments of the globus pallidus (GPe, GPi, respectively), the subthalamic nucleus (STN), and the substantia nigra pars reticulata (SNr). The neuronal activity is reduced in GPe, and increased in STN, GPi, and SNr. In addition to the rate changes, there are also obvious changes in the firing patterns of neurons in all four structures, with a marked prominence of burstiness and oscillatory discharge patterns in the parkinsonian state. In parkinsonian patients undergoing pallidotomy it has also been shown that the discharge rates in GPe are significantly lower than those in GPi (83,182,284,302), as had previously been shown in the MPTP-primate model. Recently, we have shown that treatment with MPTP results also in changes of neuronal activity in the second output nucleus of the basal ganglia, the SNr (Fig. These changes in activity are qualitatively similar to those occur- ring in GPi (312). In addition, loss of dopamine in the striatum should also lead to reduced activity via the inhibi- tory direct pathway. To date, this has not been directly demonstrated, however. The changes in discharge rates in the subnuclei of the basal ganglia have been interpreted as indicating that striatal dopamine depletion leads to increased activity of striatal neurons of the indirect pathway, resulting in inhibition of GPe, and subsequent disinhibition of STN and GPi/SNr. The proposed pathophysiologic model of changes in the level of activity in the basal ganglia–thalamocortical motor circuit is summarized in Fig. The basal ganglia circuitry incorporates multiple negative and positive feedback loops that may play a prominent role in the development and maintenance of abnormal discharge FIGURE 122. Simplified schematic diagram of the basal gan- in the basal ganglia output structures. Some of the primary glia–thalamocorticalcircuitryunder normalconditions. Inhibitory connections are shown as filled arrows, excitatory connections as feedback loops that may directly affect GPi activity involve open arrows. The principal input nuclei of the basal ganglia, the intrinsic basal ganglia structures such as GPe and STN (the striatum, and the STN are connected to the output nuclei—GPi two pathways labeled 3 in Fig. Basalgangliaoutputis directedatseveralthalamicnuclei [ventral anterior/ventrolateral (VA/VL) and centromedian (CM)] of the basal ganglia, such as the thalamic nucleus CM (la- and at brainstem nuclei [pedunculopontine nucleus (PPN) and beled 1 in Fig. Some of the many important feedback connections are shown by the dashed lines. For further explanation of the model, (101,117,161,263), and the habenula (e. Positive feedback loops, such as the one involving PPN and the STN (labeled 2) and the pathway through CM and the putamen (labeled 1) will tend to aggravate or enhance the abnormali- ties of discharge in the basal ganglia output nuclei associated with movement disorders, such as PD, whereas negative feedback circuits, such as a feedback involving CM and STN (not shown) will act to normalize neuronal discharge in the basal ganglia output nuclei. It is worth noting that via the CM nucleus, activity changes in the indirect pathway may influence the activity along the direct pathway. Thus, increased STN output in parkinsonism, by an action via GPi and CM, may result in a reduction of activity along the direct pathway. The pathophysiology of early parkinsonism may differ FIGURE 122. Model of the proposed rate changes in the basal from that of late parkinsonism in several aspect. For in- ganglia–thalamocortical circuitry under normal (left) and parkin- stance, increased STN output in early parkinsonism may sonian conditions (right). In parkinsonism, dopaminergic neurons in the the substantia nigra pars compacta (SNc) degenerate, have a compensatory function by increasing glutamatergic which results, via a cascade of changes in the other basal ganglia drive on SNc neurons. Thus, it has been shown that local nuclei, in increased basal ganglia output from GPi and SNr. This, injections of glutamate receptor blockers into the SNc sig- in turn, is thought to lead to inhibition of related thalamic and cortical neurons. In addition to the changes shown here, there nificantly worsen motor signs in early stages of MPTP- are prominent alterations in discharge patterns (see text). MPTP-treated primates reverse all of the cardinal signs of At the same time, increased glutamatergic drive onto surviv- parkinsonism, presumably by reducing GPi activity (16,30, ing SNc neurons may also be (excito-) toxic (239).

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In addition buy 100mg lamotrigine free shipping, administration of the -adrenoreceptor antagonist generic 100mg lamotrigine with mastercard, yohimbine (which stimu- marker of central 2-adrenoreceptor function) is blunted 2 lates NE release by antagonizing presynaptic -adrenore- in social anxiety disorder (201) discount 50mg lamotrigine with visa, although the density of 2 ceptors) produces exaggerated anxiogenic and cardiovascu- lymphocyte -adrenoreceptors has not differed between so- lar responses and enhanced plasma MHPG and cortisol cial anxiety–disordered and control samples (202) (Table increases in PD relative to control subjects (133 generic lamotrigine 25 mg overnight delivery,172,173, 63. Finally, yohimbine administration resulted in Finally, Gerra et al. However, the Chapter 63: Neurobiological Basis of Anxiety Disorders 913 pretest baseline NE concentrations did not differ between Conversely, positive early-life experiences during critical the anxious and control subjects. For example, daily postnatal handling of Corticotropin-Releasing Hormone rat pups by human experimenters within the first few weeks of life has been shown to produce persistent (throughout Exposure to acute stress of various types results in release life) increases in the density of type II glucocorticoid recep- of CRH, ACTH, and cortisol. This increase was associated with enhanced feedback during acute stress can produce a transient elevation of the sensitivity to glucocorticoid exposure and reduced glucocor- plasma cortisol concentration and partial resistance to feed- ticoid-mediated hippocampal damage in later life (214, back inhibition of cortisol release that persists during and 215). These effects are hypothesized to comprise a type of shortly after the duration of the stressful stimulus. Taken ticoid receptors, because elevated glucocorticoid levels such together with the data reviewed in the preceding paragraph, as those elicited by acute stress decrease the number of hip- these data indicate that a high degree of plasticity exists in pocampal glucocorticoid receptors, with a resulting increase stress-responsive neural systems during the prenatal and in corticosterone secretion and feedback resistance (204). The During some types of chronic stress, adaptive changes feedback inhibition of CRH function by glucocorticoids (to in ACTH and corticosterone secretion occur such that the suppress HPA-axis activity) occurs at the level of the PVN plasma ACTH and corticosterone concentrations achieved of the hypothalamus, where systemically administered glu- are lower than those seen in response to acute stress (205). In contrast, other types of chronic stress are associated with cocorticoids reduce CRH expression, and the anterior pitui- enhanced corticosterone secretion in rats (206). Moreover, tary, where glucocorticoids decrease CRH receptor expres- Dallman and Jones showed that the experience of prior sion (217–220). The regulation of CRH receptor mRNA stress can result in augmented corticosterone responses to expression shows a regional specificity that becomes altered subsequent stress exposure (207). The factors that deter- when stress occurs concomitantly with elevated glucocorti- mine whether adaptation or sensitization of glucocorticoid coid concentrations. After both short-term and long-term activity occurs after chronic stress remain poorly under- corticosterone (CORT) administration, the CRH receptor stood. RNA expression decreases in the PVN and the anterior pi- Some stressors experienced within critical periods of neu- tuitary (219). However, after acute or repeated immobiliza- rodevelopment exert long-term effects on HPA-axis func- tion stress sufficient to produce a large increase in plasma tion. In rats exposed to either severe prenatal (in utero) stress CORT levels, the CRH mRNA expression decreases in the or early maternal deprivation stress (208,209), the plasma anterior pituitary, but increases in the PVN. In contrast, concentrations of corticosterone achieved in response to neither CORT administration nor restraint stress alters the subsequent stressors are increased, and this tendency to CRH receptor expression in the CE of the amygdala or the show exaggerated glucocorticoid responses to stress persists BNST. Furthermore, CRH secretion is not constrained by into adulthood. Early postnatal adverse experiences such as glucocorticoids in the CE or the lateral BNST, and CRH maternal separation are associated with long-lasting altera- mRNA expression increases in these areas during systemic tions in the basal concentrations of hypothalamic CRH CORT administration (217,218,220). It is thus conceivable mRNA, hippocampal glucocorticoid-receptor mRNA, me- that the positive feedback of glucocorticoids on extrahypo- dian eminence CRH, and in the magnitude of stress-in- thalamic CRH function in the amygdala or the BNST may duced CRH, corticosterone, and ACTH release (210–212). Adult monkeys who were raised in such involves functional differences between CRH-receptor a maternal environment are also hyperresponsive to yohim- subtypes. The CRH1 and CRH2 receptors appear to play bine and have elevated CRH concentrations and decreased reciprocal roles in mediating stress responsiveness and anxi- cortisol levels in the CSF, findings that parallel those in ety-like behaviors (221). Mice genetically deficient in humans with PTSD (213). CRH1-receptor expression exhibit diminished anxiety and 914 Neuropsychopharmacology: The Fifth Generation of Progress stress responses to threat or stress (222,223). In contrast, tion, cortisol suppression was found to be normal (234) or mice deficient in CRH2 receptors display heightened anxi- enhanced (228,235,236) in PTSD, with the latter result ety in response to stress (224,225). The affinity of CRH is particularly found in response to low-dose (0. This find- endogenously released in mice genetically altered to overex- ing, together with the observations that patients with PTSD press CRH (221). Also consistent with the hypothesis that show hypersensitivity to low-dose dexamethasone, led Ye- CRH1-receptor stimulation facilitates anxiety responses, huda et al. Preliminary data suggest that a reduced CSF CRH concentration and in the pituitary-adrenal and cortisol response after trauma exposure may predict PTSD adrenal-medullary activity) to acute social stress in monkeys development, a finding raising the possibility that enhanced (226). In monkeys, the CRH1-receptor two studies of CSF concentrations, both of which found density is high in most amygdaloid nuclei, the cingulate abnormally increased in chronic, combat-related PTSD cortex, the PFC, the insular cortex, the parietal cortex, the (239,240). Potentially consistent with this observation, dentate gyrus, and the entorhinal cortex, and it is moderate PTSD samples show a blunted ACTH response to CRH in the CE and the LC. The CRH2-receptor density is high relative to control samples (241,242). Although these obser- in the cingulate cortex, the mPFC, the CE, the CA-1 region vations would appear most consistent with findings that of the hippocampus, and the PVN and supraoptic nucleus basal cortisol secretion and excretion are abnormally in- of the hypothalamus. An important avenue of future re- creased in PTSD (190,192,232,233), they do not clearly search will involve assessments of the homeostatic balance contradict the findings of normal or reduced peripheral cor- between CRH1- and CRH2-receptor systems in anxiety dis- orders. Disorders Nevertheless, the studies that either identified reductions or were unable to identify elevations in peripheral cortisol The anxiety disorder for which abnormalities of CRH or concentrations in PTSD present a challenge to the hypothe- HPA-axis function has been most commonly reported is sis that the reduced hippocampal volume found in MRI PTSD. Nevertheless, the nature of such abnormalities has studies of PTSD (reviewed earlier) are accounted for by been inconsistent across studies, because basal plasma or cortisol hypersecretion (150). This hypothesis may still be 24-hour urine cortisol concentrations have been reported reconciled with the peripheral cortisol measures associated to be abnormally decreased (227–229), not different (230, with chronic PTSD if the cortisol secretion was elevated 231), or abnormally increased (190,192,232,233) in PTSD near the time of the stressor (191,243). Longitudinal studies samples relative to healthy or trauma-matched control sam- in male patients who developed PTSD after motor vehicle ples. Differences across these studies may reflect effects of accidents suggest that cortisol secretion is elevated 1 month gender, age of illness onset (i. During provoca- Hippocampal damage may thus conceivably occur in PTSD tion of PTSD symptoms by exposure to combat sounds, during a period of excessive cortisol secretion that follows the changes in plasma cortisol and ACTH concentrations the traumatic event and is prolonged enough so that hippo- did not differ between patients with combat-related PTSD campal neuronal atrophy becomes irreversible. An alterna- and either healthy or combat-matched, non-PTSD control tive hypothesis for the reduction of hippocampal volume subjects (232). In response to dexamethasone administra- in PTSD, however, is that this abnormality antedates the Chapter 63: Neurobiological Basis of Anxiety Disorders 915 TABLE 63. EVIDENCE OF ALTERATIONS IN Functional Interactions among CRF-HPA AXIS FUNCTION IN ANXIETY DISORDERSa Noradrenergic, HPA, and CRH Systems PTSD Panic Disorder Coordinated functional interactions between the HPA axis Alteration in urinary cortisol +/–a +/– and the noradrenergic systems play major roles in producing Altered plasma cortisol with + (dec. The secretion 24-hour sampling of CRH increases LC neuronal firing activity and results in Supersuppression with DST ++b – enhanced NE release in a variety of cortical and subcortical Blunted ACTH response to ++ +/– regions (252,253). Conversely, NE release stimulates CRH CRF Elevated CRF in CSF ++ – secretion in the PVN (the nucleus containing most of the Increased lymphocyte ++ NS CRH-synthesizing neurons in the hypothalamus). During glucocorticoid receptors chronic stress in particular, the LC is the brainstem nora- a drenergic nucleus that appears preferentially to mediate NE Findings of decreased urinary cortisol in older male combat veterans and holocaust survivors and increased cortisol in younger release in the PVN (254). Conversely, as CRH release in female abuse survivors may be explainable by differences in gender, the PVN stimulates ACTH secretion from the pituitary and age, trauma type, developmental epoch at the time of the trauma, thereby increases cortisol secretion from the adrenal glands, or timing within illness course. Glucocorticoid-mediated +/–, an equal number of studies support this finding and do not inhibition of NE-induced CRH stimulation may be evident support this finding; +, atleast one study supports this finding and primarily during stress, rather than under resting condi- no studies do not, or the majority of studies support the finding; ++, two or more studies support this finding, and no studies do not tions, as an adaptive response that restrains stress-induced support the finding; +++, three or more studies support this finding, neuroendocrine and cardiovascular effects mediated by the and no studies do not; ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor; CSF, cerebrospinal fluid; dec. NE, cortisol, and CRH thus appear tightly decrease; DST, dihydrostreptomycin; HPA, hypothalamic pituitary linked as a functional system that offers a homeostatic mech- adrenal axis; inc. A clinical phenomenon of anxiety disorders that may be specifically regulated by interactions between NE and glucocorticoid secretion involves the acquisition and consol- idation of traumatic memories.

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Imipramine in Disorders Association of America Abstract,Washington,DC, the treatment of social phobia. Low dose selegi- sertraline treatment of posttraumatic stress disorder: a random- line (L-Deprenyl) in social phobia. Randomized,double-blind phobia with the dopamine agonist pergolide.

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The bioimpedance technologies considered were the BCM lamotrigine 50 mg online, MultiScan 5000 buy cheap lamotrigine 50mg on-line, BioScan 920-II lamotrigine 25 mg with amex, BioScan touch i8 and the InBody S10 purchase lamotrigine 100 mg with mastercard. The specific objectives were to: l review existing economic evaluations of multiple-frequency bioimpedance devices for fluid management in people with CKD receiving dialysis l develop a de novo economic model to assess the cost-effectiveness of using the identified multiple-frequency bioimpedance devices compared with standard clinical assessment alone to guide fluid management in people with CKD receiving dialysis, from a UK NHS and personal social services perspective. Systematic review of existing cost-effectiveness evidence Electronic searches were undertaken to identify reports of economic evaluations. The following bibliographic databases were included: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, National Institute for Health Research Economic Evaluations Database (NEED), the Health Technology Assessment database and the Research Papers in Economics (RePEC) database. No date or language restrictions were imposed, and searches were undertaken on 5 July 2016. Details of the search strategies are reproduced in Appendix 1. In addition, recent conference proceedings (over the period of 2014–16), including those of the European Renal Association, American Society of Nephrology, the Annual Dialysis Conferences and the International Society for Pharmacoeconomics and Outcomes Research, were also screened. Relevant websites of key professional organisations, registries and device manufacturers were checked for additional data and information. The searches identified no full economic evaluations of relevance to the scope of this assessment. To help inform the design of the de novo economic model, broader searches were carried out to identify existing economic models in the area of CKD/ESRD, and NHS cost data applicable to relevant patient populations and health states were included in the model. A separate search was also developed for health state utility data relevant to the health states included in the economic model. Databases searched included MEDLINE, EMBASE, the Cost-effectiveness Analysis (CEA) Registry and ScHarrHUD (School of Health and Related Research Health Utilities Database). The searches were undertaken on 8 July 2016 and no date or language restrictions were imposed. Discussion of the potential data sources identified by these broader searches are provided under the relevant subheadings below. Independent economic assessment A de novo economic model was developed in TreeAge Pro (TreeAge Software, Williamstown, MA, USA). The model was designed to assess the cost-effectiveness using multiple-frequency bioimpedance testing to help guide fluid management decisions in people with CKD receiving dialysis. The model structure was informed by the hypothesised benefits of bioimpedance testing and review of published models in the area of ESRD, with particular emphasis on models previously used to inform NHS 17 95, –98 policy surrounding the provision of dialysis. 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 31 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. ASSESSMENT OF COST-EFFECTIVENESS The model was populated using data derived from focused reviews of the literature (to inform baseline mortality and hospitalisation risks in patients with ESRD), the systematic review of clinical effectiveness (to inform relative treatment effects) and other focused reviews to inform sources of cost and utility data. The model was built and analysed in accordance with the NICE reference case for the evaluation of 17 98, diagnostic tests and devices. It compares cumulative costs to the health service and quality-adjusted life-years (QALYs) gained for the alternative monitoring strategies. Methods Relevant patient population(s) The model compared the alternative fluid management strategies for a prevalent cohort of people with ESRD receiving either HD or PD. The base-case analysis was conducted using the weighted average of the median age and sex distribution for the respective prevalent dialysis cohorts, as reported in the UK Renal Registry report:99 aged 67. Thus, the base-case analysis was run for a mixed cohort at the average age of 66 years, 61% male, with 87% receiving HD and 13% receiving PD. Separate subgroup analyses were also conducted for the PD and HD cohorts, applying the median ages for the respective subgroups. In addition, comorbidity burden is also used in the model in the estimation of baseline hospitalisation risks, and this was estimated 99 100, from UK registry data. Based on these sources, 63% of patients aged ≥ 65 years and 36% of patients aged < 65 years are modelled to have at least one comorbidity at baseline. The estimated mean number of comorbidities in those with any comorbidity is 1. Monitoring strategies evaluated Bioimpedance monitoring strategies, to help adjust target weight and guide fluid management, were compared with standard clinical assessment, in which target weight is set based on clinical signs and symptoms, including blood pressure, presence of oedema, changes in weight, residual renal function, pre-existing CV conditions and patient-reported symptoms of overhydration or underhydration. For the bioimpedance strategies, it was assumed that all patients would have their hydration status assessed every 3 months (four times per year), and have their target weight modified in line with the results if necessary. The above monitoring strategy is in line with clinical opinion regarding the necessary frequency of bioimpedance testing in an adult dialysis population, and is also consistent with the approach used in two 60 81, of the trials included in the systematic review of clinical effectiveness. It is less intensive than the testing strategies applied in the other RCTs included in the clinical effectiveness review, which varied from once per week101 to once every 6 weeks. The impact of increased testing frequency is addressed in sensitivity analysis. The bioimpedance technologies included in the scope for this assessment were the BCM, MultiScan 5000, BioScan 920-II, BioScan touch i8 and the InBody S10. However, the review of existing literature only uncovered clinical effectiveness evidence relating to the BCM. Therefore, the economic modelling focused on assessing the cost-effectives of bioimpedance testing using the BCM device. For comparison, we include cost-per-test estimates using each of the other competitor devices, and assess the impact of applying these costs in a sensitivity analysis (assuming equivalent effects). Framework (method of synthesis) A discrete-time Markov cohort model was developed to assess the clinical effectiveness and cost-effectiveness of using multiple-frequency bioimpedance testing compared with standard clinical practice for guiding fluid management decisions in the dialysis cohort. This state-transition framework was chosen for its ability to capture the evolving disease process and recurrent event risks over time, while being relatively parsimonious in terms of data and computational requirements. This is to allow mortality and hospitalisation rates for the severely overhydrated portion of the prevalent cohort to be factored upwards, reflecting the observed adjusted association between 26306082, , , hydration status and these outcomes. Modelled transitions between the relative hydration states were then used to drive effects in an alternative scenario analysis (see Further adjustments to baseline risks for further details). States representing underhydration were not included in this alternative model structure because of a dearth of evidence on (1) the prevalence of underhydration, as measured by the BCM, in UK dialysis cohorts; (2) the impact of underhydration, as measured by the BCM, on the risk of adverse events and/or quality of life; and (3) the effectiveness of bioimpedance-guided fluid management on reducing the prevalence of underhydration. If underhydration (as measured by bioimpedance spectroscopy) is associated with adverse outcomes and quality of life, and bioimpedance-guided fluid management can reduce the prevalence of this, then this secondary model may fail to capture the associated benefits. The model simulates mortality, hospitalisation events and transition to transplant over the lifetime of the modelled cohorts on a constant 3-monthly cycle (in keeping with the BCM testing cycle). All-cause hospitalisation events are disaggregated across CV events and other causes. It is assumed in the model that hospitalisation for incident CV events results in an increased comorbidity burden, which increases the risk of subsequent hospitalisations. Costs of dialysis (by modality), background medication [blood pressure, erythropoiesis-stimulating agents (ESAs)], transplant, all-cause hospitalisation and outpatient attendances are included in the baseline model. Health state utility multipliers are applied to the dialysis states, and utility decrements are also incorporated for hospitalisations. These decrements are applied for an acute period for all hospitalisations. For hospitalisations caused by CV events, a long-term utility multiplier is also applied. This reflects the lasting impact that these events can have on health-related quality of life.

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