By S. Faesul. Finch University of Health Sciences/The Chicago Medical School. 2018.
The false-positives were largely the patible with the existence of a single locus having a value consequence of a combination of multiple testing and the of (s greater than 3 purchase 100mcg ventolin with mastercard. Unless extreme epistasis (interaction use of statistical methodology and significance levels derived between loci) exists discount 100mcg ventolin mastercard, models with two or three loci having from work on single-gene disorders buy discount ventolin 100mcg. It should be Despite the failure to identify regions of unambiguous emphasized that these calculations are based on the assump- linkage in multiply affected families discount ventolin 100mcg with visa, modest evidence for tion that the effects of genes are distributed equally across several regions has been reported in more than one data set. It is quite possible that genes of larger Areas implicated for which supportive data have also been effect are operating in a subset of patients—for example, obtained from international collaborative studies include those from families with a high density of illness. A number of other promising evidence that genetic factors increase the risk for schizophre- areas of putative linkage are also currently under investiga- nia. However, although it is possible to state that, as a group, tion by international consortia. However, in each general population, it is not currently possible to translate case, both negative and positive findings have been ob- this figure to the level of risk for a particular sibling in a tained, and in only two cases, those of chromosomes particular family. Another These positive findings contrast with those from a large important point is that risk to related individuals does not systematic search for linkage in which a sample of 196 af- directly equate with genetic risk because some relatives carry fected sibling pairs, drawn typically from small nuclear fami- one or more susceptibility alleles for schizophrenia but re- lies rather than extended pedigrees, was used (101). In other words, the results of simulation studies suggest that the power of this accumulation of susceptibility alleles, environmental risk study is greater than 0. This study yielded evidence at the level of the definition of Lander and Kruglyak (102) of 'suggestive' linkage to chromosomes 4p, 18p, and Xcen. However, none MOLECULAR GENETICS: LINKAGE STUDIES of the findings approached a genome-wide significance of 0. This was done in the hope that such families, in the search for genes for complex traits (103–106). First, or at least a proportion of them, were segregating genes of no finding is replicated in all data sets. Second, levels of sufficiently large effect that they could be detected unequiv- statistical significance are unconvincing and estimated effect ocally in this way. This approach has been successful in sizes are usually modest. Third, chromosomal regions of other complex disorders—Alzheimer disease, for example, interest are typically broad [often 20 to 30 centimorgan in which mutations in three genes, APP, PS1, and PS2, are (cM)]. In such At the present time, therefore, the linkage literature sup- cases, the disease is of unusually early onset and is transmit- ports the predictions made by Risch (79); it is highly un- ted through multiplex pedigrees in an autosomal dominant likely that a commonly occurring locus of effect size [(s] fashion (80–82). Studies of such large families also initially gions suggest that rarer alleles of larger effect may be segre- produced positive findings in schizophrenia (83), but unfor- gating in some large, multiply affected families. The reasons for this Linkage methods in sample sizes that are realistically have become clear as data from systematic genome scans achievable can detect smaller genetic effects than those in have accumulated; highly penetrant mutations causing the studies to date. For example, it is possible to detect schizophrenia are at best extremely rare and quite possibly alleles with values of (s of 1. However, the purpose of experiment is to reject that priority should now be given to collecting such samples a null hypothesis, and in the face of uncertainty, the burden with a robust clinical methodology that is comparable across of proof remains with the proponents of a particular candi- all interested research groups. Overall, the results in this extensive literature CANDIDATE GENE ASSOCIATION STUDIES are disappointing, but it should be noted that the sample sizes in many of the older studies would now generally be Once genes of smaller effect than (s 1. For this reason, many research- represent functional variants and that few genes have been ers have tried to take advantage of the potential of candidate systematically screened even for common functional var- gene association studies to identify such loci (109,110). However, more promising reports of candidate gene though a potentially powerful means of identifying genes associations have recently appeared, three of which are con- of small effect, association studies are not without their sidered here. First, for a complex and poorly understood disor- der such as schizophrenia, the choice of candidate genes Serotonin 5-HT2A-Receptor Gene is limited largely by the imagination and resources of the researcher. This places a stringent burden of statistical proof Many novel antipsychotic drugs affect the serotoninergic on positive results because of low prior probability and mul- system. The first genetic evidence that serotoninergic recep- tiple testing (111).
Much of this somatosensory stimuli or to interoceptive input through the network appears to participate in the general process of asso- viscera and the endocrine and autonomic nervous systems discount ventolin 100 mcg fast delivery. Charney: Mood and Anxiety Disorder Research Program 100mcg ventolin, National Institute of Mental Health buy cheap ventolin 100 mcg on line, Bethesda buy 100 mcg ventolin otc, Maryland. Drevets: Section on Mood and Anxiety Disorders Imaging, Molec- ular Imaging Branch, National Institute of Mental Health, Bethesda, Mary- The anatomic systems supporting fear learning are organ- land. The projections from sensory thalamus to the LA are The former processes depend on monosynaptic projections thought to support rapid conditioning to simple visual and from the sensory thalamus to the amygdala, whereas the auditory features, presumably accounting for fear responses latter involve projections from sensory association cortices below the level of conscious awareness (31). Thus, lesioning and mesiotemporal cortical structures to the amygdala (1, the auditory cortex before conditioning does not prevent 12). These neural networks also respond to visceral input conditioning to single auditory tones. In contrast, projec- received both directly through the nucleus paragigantocellu- tions to the LA from the primary sensory and sensory associ- laris and the nucleus tractus solitarius (NTS) of the vagus ation cortices appear to be essential for some aspects of nerve and indirectly through the locus ceruleus (LC), the conditioned responding to more complex sensory stimuli (4, anterior insula, and the infralimbic and prelimbic cortices 32). Finally, neural activity within the amygdala is disruption of the projections from the auditory thalamus modulated by cortisol, norepinephrine (NE), and other and auditory cortex to the LA specifically prevents acquisi- neurotransmitters and by mnemonic input related to previ- tion of fear conditioning to auditory stimuli and fear-condi- ous conditioning and reinforcement experiences conveyed tioned responses to previous auditory CSs (33–35). The most extensive extranuclear projections of are responsive to auditory, visual, and somatic stimuli, thus the LA are composed of reciprocal projections to the basal enabling the LA to serve as a locus of convergence for infor- and accessory basal nuclei and the central nucleus of the mation about CS and US (19). Olfactory input, in contrast, amygdala (CE) (37,38). Lesions of either the LA or the directly projects to the periamygdaloid cortex from the ol- CE—but not of other amygdala nuclei—disrupt fear condi- factory bulb through the olfactory tract (20). The olfactory tioning to a tone CS, a finding suggesting that this direct tract also sends projections to the pyriform cortex and the projection from LA to CE is sufficient to mediate condition- entorhinal cortex, areas with reciprocal connections to the ing to simple sensory features (4). Although the periamygdaloid cortex neu- The projections from LA to the basal amygdaloid nuclei rons project to deeper amygdaloid nuclei, the specific path- also participate in forming long-lasting memory traces for ways conveying olfactory information through the amygdala fear conditioning (2,15,39). Functional inactivation of the have not been delineated. The basal nuclei have wide- tions from the hippocampal formation to the amygdala spread intranuclear connections and also project to other through the fornix have been specifically implicated in spa- amygdalar nuclei, including the CE and the LA (41). Thus, lesioning these also share extensive, reciprocal projections with the orbital projections specifically prevents fear conditioning to the and mPFC (43). The basal nuclei are thus anatomically chamber or the position within a maze in which aversive positioned to modulate neuronal responses in both the LA stimulation previously occurred (22–25). Lesions of the latter regions reduce long-term potentiation–like associative processes (6). Plas- fear reactivity to contextual stimuli, but they do not affect ticity related to fear learning also occurs in cortical areas, CS acquisition or response extinction (26). In contrast, le- presumably making possible the establishment of explicit sions placed in the rostral perirhinal cortex after fear condi- or declarative memories about the fear-related event through tioning interfere with the expression of conditioned fear interactions with the medial temporal lobe memory system responses elicited by visual and auditory stimuli when these (44,45). The influence of the amygdala on cortically based stimuli are presented in contexts that differ from the initial memories has been most clearly characterized with respect conditioning context (27). Notably, genetic studies in mice to late plastic components of the auditory cortex neuronal identified a quantitative trait locus for contextual condition- responses to a CS. Single-unit recordings during fear condi- ing (28,29) that was associated with mouse 'emotionality' tioning indicate that some auditory cortex neurons, which in another study (30), although the molecular genetic, neu- before conditioning did not respond to the CS tone, develop Chapter 63: Neurobiological Basis of Anxiety Disorders 903 late-conditioned responses (i. These late-conditioned audi- Human neuroimaging and electrophysiologic and lesion tory cortical neuronal responses take more trials to learn analysis studies have also demonstrated that the amygdala and respond more slowly than LA neurons within trials, is involved in the recall of emotional or arousing memories and their late development is prevented by amygdala lesions. In humans, bursts of electroencephalographic ac- Thus, whereas rapid conditioning of fear responses to po- tivity have been recorded in the amygdala during recollec- tentially dangerous stimuli depends on plasticity in the tion of specific emotional events (56). Moreover, electrical amygdala, learning involving higher cognitive (i. Other auditory cortex neurons show an early (less than Role of the Amygdala in Organizing Emotional 50 milliseconds of stimulus onset) plastic component dur- Expression ing fear conditioning, in which the preexisting electrophysi- ologic responses of auditory cortex neurons to the CS be- The amygdaloid output nuclei, especially the CE, receive come enhanced by conditioning (46). This short-latency convergent information from multiple amygdala regions plasticity within the auditory cortex appears to depend on and generate behavioral responses that are thought to reflect input from the auditory thalamus and is unaffected by the sum of neuronal activity produced by different amygda- amygdala lesions. Nevertheless, such short-latency responses loid nuclei (36).
An economic evaluation of home care for children with newly 111 diagnosed diabetes: results from a randomized controlled trial ventolin 100 mcg line. Med Care 1998;36:586–98 Dougherty G generic ventolin 100 mcg on-line, Schiffrin A generic 100mcg ventolin otc, White D purchase 100mcg ventolin with mastercard, Soderstrom L, Sufrategui M. Home-based management can achieve 112 intensification cost-effectively in type I diabetes. Pediatrics 1999;103:122–8 Eakin MN, Rand CS, Bilderback A, Bollinger ME, Butz A, Kandasamy V, et al. Asthma in Head Start children: 113 effects of the Breathmobile program and family communication on asthma outcomes. J Allergy Clin Immunol 2012;129:664–70 Edwards RT, Céilleachair A, Bywater T, Hughes DA, Hutchings J. Parenting programme for parents of children 114 at risk of developing conduct disorder: cost effectiveness analysis. Parenting intervention in Sure 115 Start services for children at risk of developing conduct disorder: pragmatic randomised controlled trial. BMJ 2007;334:678 Espinoza-Palma T, Zamorano A, Arancibia F, Bustos MF, Silva MJ, Cardenas C, et al. Effectiveness of asthma 116 education with and without a self-management plan in hospitalized children. J Asthma 2009;46:906–10 Esposito-Smythers C, Spirito A, Kahler CW, Hunt J, Monti P. Treatment of co-occurring substance abuse and 117 suicidality among adolescents: a randomized trial. J Consult Clin Psychol 2011;79:728–39 Farber HJ, Oliveria L. Trial of an asthma education program in an inner-city pediatric emergency department. Happiness to be gained in paediatric 119 asthma care. Eur Respir J 2008;32:1555–62 Flores G, Bridon C, Torres S, Perez R, Walter T, Brotanek J, et al. Improving asthma outcomes in minority 120 children: a randomized, controlled trial of parent mentors. Pediatrics 2009;124:1522–32 Foster EM, Jensen PS, Schlander M, Pelham WE Jr, Hechtman L, Arnold LE, et al. Treatment for ADHD: 121 Is more complex treatment cost-effective for more complex cases? Health Serv Res 2007;42:165–82 Swanson JM, Kraemer HC, Hinshaw SP, Arnold LE, Conners CK, Abikoff HB, et al. Clinical relevance of 122 the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment. J Am Acad Child Adolesc Psychiatry 2001;40:168–79 Wells KC, Pelham WE, Kotkin RA, Hoza B, Abikoff HB, Abramowitz A, et al. Psychosocial treatment 123 strategies in the MTA study: rationale, methods, and critical issues in design and implementation. J Abnorm Child Psychol 2000;28:483–505 Molina BS, Hinshaw SP, Swanson JM, Arnold LE, Vitiello B, Jensen PS, et al. The MTA at 8 years: 124 prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009;48:484–500 Jensen PS, Garcia JA, Glied S, Crowe M, Foster M, Schlander M, et al. Cost-effectiveness of ADHD 125 treatments: findings from the multimodal treatment study of children with ADHD. Am J Psychiatry 2005;162:1628–36 The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for 126 attention-deficit/hyperactivity disorder. Arch Gen Psychiat 1999;56:1073–86 Franklin VL, Waller A, Pagliari C, Greene SA. A randomized controlled trial of Sweet Talk, a text-messaging 127 system to support young people with diabetes.
This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed discount ventolin 100mcg without a prescription, the full report) may be included in professional journals 59 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising order ventolin 100mcg on line. Applications for commercial reproduction should be addressed to: NIHR Journals Library purchase 100 mcg ventolin amex, National Institute for Health Research order 100mcg ventolin overnight delivery, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. STUDY D: NURSE AND PATIENT PERCEPTIONS OF USING THE PATIENT CENTRED ASSESSMENT METHOD No participant in their feedback stated that they were opposed to using the PCAM in the future or made any comments indicating that they would be avoiding using the PCAM. Long-term adoption of the PCAM appears likely for some of the nurse participants in this research, beyond the research project itself. Conclusion The PCAM implementation did not have a negative or obstructive impact on the consultation. There was some indication that a small number of patients may have been aware of more discussion about their lives and their broader concerns. The PCAM training was acceptable, but required a multifaceted approach to training that integrated key information/knowledge, role playing and opportunities to apply the training to real consultations. Future training delivery will require the incorporation of these different aspects, and in a way that is flexible with nurse availability and workload. Overall, it appears that the PCAM was fairly easily integrated into consultation, although some participants reflected that the process of integration took some time and support, which will need to be taken into account in future training and support. The nurse participants perceived this to be beneficial for both the patient and the nurse, in relation to both the quality of the relationship and the quality of the care provided. Resource packs were seen as integral to using the PCAM, and practices engaged with these resources, often to the extent of taking ownership of their continuing development. However, for some practices, this could be seen as a future problem (how to keep these resources up to date) that could have an impact on their use of the PCAM. Long-term adoption of the PCAM was seen as feasible and possible by some nurses, which indicates overall potential for the acceptability and feasibility of the PCAM for use in primary care nurse-led consultations. The data used for the overall evaluation comprised: l contributions from study A focus groups with practices and patients on the acceptability and feasibility of the use of the PCAM, and any early reflections on barriers to using the PCAM in PN consultations l researcher field notes of meetings and discussions with staff l any comments to the research team or reported by practice staff from patients during implementation l data from study D, the final interviews with practice staff and patients l data from open-ended questions on staff and patient questionnaires collected as part of study B. The methods for studies A, B and D have been reported elsewhere. The collection of study field notes was seen as a fundamental part of the process evaluation and was ongoing throughout the study. Each study researcher kept their own logbook of visits and contacts with practices and any reported incidents/ problems, actions or comments associated with the study. The two researchers (EC and PA) had the most contact with practices, and each had more of a relationship with particular practices, thereby building rapport with practice staff and facilitating catch-up telephone or e-mail conversations between practice visits. However, this relationship was not exclusive to a single researcher and, therefore, all researchers, including Carina Hibberd, had some familiarity with all practices. The research team met regularly to discuss any incidents/problems, actions or comments from each site in order to compare notes and reflect on observations. This alerted each practice contact to possible similar problems or allowed reflection on possible solutions based on experiences within other practices. However, close contact was still required with CAU practices to ensure that data collection was still being achieved. This model was helpful in guiding the areas of knowledge needed for the process evaluation, but was also helpful in the analysis stage in pulling together knowledge from across the relevant data sets to articulate the context, implementation and mechanisms of impact within and across practices. Field note analysis The analysis of study A, B and D data sets has been described elsewhere in this report. The contributions of each of these data sets to the process analysis were initially discussed by several members of the research team (MM, CH, EC, PA, RP), and key relevant points for the implementation of both the PCAM and trial methods were agreed and summarised in accordance with the key components in the Moore et al. The field note data were extracted from researcher logbooks into summary tables for each practice, one table reflecting on the trial process (for all six practices) and one table reflecting on the PCAM implementation (for three practices). 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 61 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. STUDY E: PROCESS EVALUATION any further discussion was needed across the team.