Submitted by Diogo Misoguti (diogo.misoguti@gmail.com) on 2016-06-24T19:26:24Z No. of bitstreams: 1 2015-12-doutorado-vinicius-ynoe-de-moraes.pdf: 2457117 bytes, checksum: 50900933fb9f0800bd7ea8be752b28c9 (MD5) / Approved for entry into archive by Diogo Misoguti (diogo.misoguti@gmail.com) on 2016-06-24T19:26:51Z (GMT) No. of bitstreams: 1 2015-12-doutorado-vinicius-ynoe-de-moraes.pdf: 2457117 bytes, checksum: 50900933fb9f0800bd7ea8be752b28c9 (MD5) / Made available in DSpace on 2016-06-24T19:26:51Z (GMT). No. of bitstreams: 1 2015-12-doutorado-vinicius-ynoe-de-moraes.pdf: 2457117 bytes, checksum: 50900933fb9f0800bd7ea8be752b28c9 (MD5) Previous issue date: 2015 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução: as lesões musculotendíneas (LMTs) são frequentes na prática ortopédica e acometem indivíduos jovens e/ou ativos. Há grande intersecção entre as modalidades de tratamento (conservadoras e cirúrgicas) para este grupo de lesões. Neste cenário, as terapias ricas em plaquetas (TRP) são uma opção de tratamento emergente. Esta tese tem como objetivo avaliar a efetividade (benefícios e malefícios) das TRP em pacientes com LMTs. Métodos: através de estratégia de busca definida, realizou-se a identificação e seleção de ECRs que comparem TRP versus placebo ou não intervenção. Incluímos as bases de dados até maio de 2013. Não houve restrições quanto ao idioma de publicação. O critério de inclusão dos estudos consistia em estudos randomizados ou quasi randomizados, que compararam a TRP versus placebo ou intervenções equivalentes ao placebo. Foram desfechos primários: função e dor, através de instrumentos validados e efeitos adversos. A avaliação da qualidade dos estudos foi realizada por meio da Cochrane Risk of Bias Tool. A Análise estatística consistiu de abordagem meta-analítica. Houve verificação dos efeitos dos tratamentos, por meio da mensuração da diferença entre as médias dos grupos para variáveis contínuas ou razão entre os riscos, para variáveis categóricas. As medidas-resumo foram acompanhadas de intervalos de confiança de 95%. Os métodos de meta-análise variaram ao longo da revisão e houve julgamento individual. Avaliação da heterogeneidade se baseou na estatística I2 e análise visual. Os dados foram apresentados em gráficos floresta. Para os fins da análise inferencial, optou-se por alfa de 5%. Resultados: incluímos 17 ECRs e 2 ensaios quasi randomizados (1088 pacientes). Três estudos foram considerados como com baixo risco de viés e outros 16 como risco elevado ou incerto. Metaanálises gerais (sem estratificação de doença) da função no curto (DPM 0,26; 95% IC -0,19 a 0,71; valor de p= 0,26; I2 = 51%; 162 participantes); médio (DPM -0,09, 95% IC -0,56 a 0,39; valor de p= 0,72; I2 = 50%; 151 participantes) e longo prazos (DPM 0,25, 95% IC -0,07 a 0,57; valor de p= 0,12; I2 = 66%; 484 participantes), demonstraram não haver diferenças entre a TRP e o placebo. Para dor, houve redução no grupo TRP no curto prazo, entretanto, com benefício clínico limítrofe (DM -0.95, 95% IC -1.41 a -0.48; valor de p<0,001; I2 = 0%; 175 participantes). Os efeitos adversos foram semelhantes entre os grupos (7/241 versus 5/245; RR 1.31, 95% IC 0.48 a 3.59; valor de p=0,60; I2 = 0%; 486 participantes). Nas meta-análises agrupadas por condição clínica, não se detectou qualquer diferença relevante entre os grupos, exceto para função (longo prazo) e dor (curto prazo), no grupo com lesão do manguito rotador, ambos de relevância clínica questionável. Ademais, algumas análises sofreram por elevada heterogeneidade e não foram realizadas. Conclusões: Nas avaliações gerais, para função, a TRP não é mais efetiva que o placebo no curto e longo prazo. Há benefício limítrofe (clinicamente irrelevante) em favor da TRP, para dor, no curto prazo. A taxa de complicações foi semelhante ao placebo. Na avaliação envolvendo lesões do manguito rotador, há benefício em favor da TRP para função (longo prazo) e dor (curto prazo), entretanto, clinicamente irrelevantes. Para outras condições (epicondilite lateral e lesão do LCA), as TRPs não se demonstraram efetivas. Para outras condições, são necessários mais estudos. / Introduction: Platelet-rich therapies are being used increasingly in the treatment of musculoskeletal soft tissue injuries such as ligament, muscle and tendon tears and tendinopathies. These therapies can be used as the principal treatment or as an augmentation procedure (application after surgical repair or reconstruction). Platelet-rich therapies are produced by centrifuging a quantity of the patient’s own blood and extracting the active, platelet-rich, fraction. The platelet-rich fraction is applied to the injured tissue; for example, by injection. Platelets have the ability to produce several growth factors, so these therapies should enhance tissue healing. There is a need to assess whether this translates into clinical benefit. This thesis aims to assess the effects (benefits and harms) of platelet-rich therapies for treating musculoskeletal soft tissue injuries. Methods: Study selection derived from a dedicated search strategy (may 2013) We also searched trial registers and conference abstracts. No language or publication restrictions were applied. We included randomised and quasi-randomised controlled trials that compared platelet-rich therapy with either placebo, autologous whole blood, dry needling or no plateletrich therapy for people with acute or chronic musculoskeletal soft tissue injuries. Primary outcomes were functional status, pain and adverse effects. Treatment effects were assessed using risk ratios for dichotomous data and mean differences (MD) or standardised mean differences (SMD) for continuous data, together with 95% confidence intervals. Where appropriate, data were pooled using the fixed-effect model for RR and MD, and the random-effects model for SMD. The quality of the evidence for each outcome was assessed using Risk of Bias Tool. Results: We included data from 19 small single centre trials (17 randomised and two quasi-randomised; 1088 participants) that compared platelet-rich therapy with placebo, autologous whole blood, dry needling or no platelet-rich therapy. Three trials were judged as being at low risk of bias; the other 16 were at high or unclear risk of bias relating to selection, detection, attrition or selective reporting, or combinations of these. Data assessing function in the short term (up to three months) were pooled from four trials that assessed PRT in three clinical conditions and used four different measures. These showed no significant difference between PRT and control (SMD 0.26; 95% confidence interval (CI) -0.19 to 0.71; P value 0.26; I2 = 51%; 162 participants; positive values favour PRT). Medium-term function data (at six months) were pooled from five trials that assessed PRT in five clinical conditions and used five different measures. These also showed no difference between groups (SMD -0.09, 95% CI -0.56 to 0.39; P value 0.72; I2 = 50%; 151 participants). Long-term function data (at one year) were pooled from 10 trials that assessed PRT in five clinical conditions and used six different measures. These also showed no difference between groups (SMD 0.25, 95% CI -0.07 to 0.57; P value 0.12; I2 = 66%; 484 participants). Although the 95% confidence intervals indicate the possibility of a poorer outcome in the PRT group up to a moderate difference in favour of PRT at short- and long-term follow-up, these do not translate into clinically relevant differences. Data pooled from four trials that assessed PRT in three clinical conditions showed a small reduction in short-term pain in favour of PRT on a 10-point scale (MD -0.95, 95% CI - 1.41 to -0.48; I2 = 0%; 175 participants). The clinical significance of this result is marginal. Four trials reported adverse events; another seven trials reported an absence of adverse events. There was no difference between treatment groups in the numbers of participants with adverse effects (7/241 versus 5/245; RR 1.31, 95% CI 0.48 to 3.59; I2 = 0%; 486 participants. The available evidence is insufficient to indicate whether the effects of PRT will differ importantly in individual clinical conditions. Conclusions: TRP are not more effective than placebo in the functional assessment. There is a significant, clinical irrelevant benefit of PRT in pain improvement in the short term when compared to placebo. Adverse effects were similar between groups. Dedicated analysis did not show any clinically relevant benefits regarding to PRTs.

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Filosofia e Ciências Humanas, Programa de Pós-Graduação em Psicologia, Florianópolis, 2015. / Made available in DSpace on 2015-05-05T04:07:58Z (GMT). No. of bitstreams: 1 333191.pdf: 6111403 bytes, checksum: 7ed41b2f28f373d58efde4b64f1d85f4 (MD5) Previous issue date: 2015 / O biofeedback cardiorrespiratório é uma técnica que propõe influir na modulação autônoma por meio da aprendizagem do feedback e da respiração lenta. Esta tese objetivou investigar características psicofisiológicas da técnica do biofeedback cardiorrespiratório associado à manipulação de características placebo. Para investigar o biofeedback cardiorrespiratório com a manipulação placebo, esta tese envolveu 2 estudos que utilizaram a variabilidade da frequência cardíaca (VFC) e a coerência cardíaca como marcadores indiretos do sistema nervoso autônomo. Nos dois estudos o objetivo durante o treino de biofeedback cardiorrespiratório foi de aumentar a coerência cardíaca por meio da visualização do feedback e por meio do treino da respiração abdominal suave. O estudo 1 verificou o efeito do biofeedback cardiorrespiratório associado ao feedback real e ao feedback placebo na VFC e na coerência cardíaca para todos os sujeitos e para classificação de performance na coerência cardíaca (bons aprendizes e fracos aprendizes de coerência cardíaca). Foram incluídos 26 participantes que realizaram 2 sessões: uma sessão de biofeedback com feedback real e outra sessão com feedback placebo. Os resultados sugerem que ambas as sessões possibilitaram aumento da atividade do nervo vago mas a sessão com feedback real mostrou mais índices da VFC com aumento significativo. Quanto a classificação da performance na coerência cardíaca, os bons aprendizes mostraram maior aumento de índices da atividade parassimpática durante a sessão. O estudo 2 propôs investigar os efeitos do biofeedback cardiorrespiratório associado a manipulação de instruções positivas e instruções neutras na coerência cardíaca e índices da VFC antes e durante a sessão, e no ERPs (potenciais relacionados a eventos) pós sessão durante tarefa cognitiva com detecção de erro e detecção de conflito. Foram investigados 52 participantes, divididos em dois grupos: grupo que recebeu manipulação de instruções positivas e grupo que recebeu instruções neutras. Os resultados sugerem influência da manipulação de instruções para a coerência cardíaca e VFC, mas o efeito da manipulação diminuiu depois que os participantes se engajaram na tarefa de biofeedback. Para os ERPs, o grupo com instruções positivas induzidas mostrou menor amplitude de ERN (negatividade relacionada ao erro) na tarefa Go No/Go e maior amplitude do ERP (potencial relacionado ao evento)11positivo de 700-800ms na tarefa Emotional Stroop. O ERN foi relacionado com a detecção de erro na tarefa de Go No/Go e o ERP positivo de 700ms ? 800ms foi relacionado com o componente SP (slow potential conflict) para tarefa de stroop e se relacionou com o monitoramento e implementação de atenção em tarefa de conflito emocional. Não foi observada diferença entre grupos para a performance cognitiva. Isso sugere que os ERPs que mostraram diferenças entre grupos foram influenciados pelo estado emocional, independente da performance cognitiva na tarefa. Os dois estudos sugerem que o biofeedback cardiorrespiratório utilizado nesta tese foi eficiente para influir no aumento da atividade do nervo vago do sistema nervoso autônomo em uma única sessão. O efeito do aumento da modulação vagal com o biofeedback também ocorreu para a manipulação placebo de feedback (estudo1) e para os dois grupos de manipulação de instruções (estudo2), mas sugere-se a melhor eficácia da técnica de biofeedback cardiorrespiratório com o feedback real. É possível também sugerir que o biofeedback cardiorrespiratório com manipulação de instruções influiu no processamento de erro e de conflito no cérebro, mas não na performance cognitiva. Esta tese mostrou que acreditar no tipo do feedback e no tipo de instrução do biofeedback cardiorrespiratório influencia em estados psicofisiológicos e emocionais do indivíduo.<br> / Abstract : The cardiorespiratory biofeedback is a technique that proposes to influence the autonomic modulation by the feedback learning and the slow breathing. This thesis aimed to understand the psychophysiological characteristics of the cardiorespiratory biofeedback technique associated with placebo characteristics manipulation. To investigate the cardiorespiratory biofeedback with the placebo manipulation, this thesis involved 2 studies using the heart rate variability (HRV) and the cardiac coherence as indirect markers of the autonomic nervous system. In both studies the objective during the cardiorespiratory biofeedback training was to increase the cardiac coherence by the feedback visualization and with a slow abdominal breathing training. The study 1 assessed the cardiorespiratory biofeedback effects associated with real feedback and placebo feedback on the HRV index and cardiac coherence for all subjects and for the cardiac coherence performance classification (good learners and poor learners of cardiac coherence). We included 26 subjects that participated in two sessions: the biofeedback session with real feedback and the biofeedback session with placebo feedback. The results suggest that both sessions showed increased on the vagus nerve but the session with real feedback induced more effects. In addition, the good learners of cardiac coherence showed higher increase of HRV parasympathetic activity during the session. The study 2 proposed investigate the cardiorespiratory biofeedback effects associated with positive misattribution instructions and neutral instructions on the HRV index and cardiac coherence before and during the session, and on the ERPs (event-related potentials) post session, for an error detection task and a conflict detection task. We investigated 52 subjects, divided into two groups: positive misattribution instructions group and neutral instructions group. The results suggest effects of misattribution instructions on cardiac coherence and HRV index, but the effect of misattribution instructions decreased after participants engaged in the biofeedback task. For the ERPs, the positive misattribution group showed lower amplitude of the ERN during Go No/Go task and higher amplitude of the positive ERP around 700-800ms during Emotional Stroop task. The ERN was related to error detection for Go No/Go task and the positive ERP around 700ms - 800ms was related to the SP component (slow potential conflict) of Stroop task and may related to13the monitoring and implementation of attention for emotional conflict task. There were no differences between groups for cognitive performance. The difference between groups on the ERPs suggests that these components can be influenced by emotional state, even without the cognitive performance differences. The two studies may suggest that the single session of the cardiorespiratory biofeedback used in this thesis, was efficient to influence the increase on the vagus nerve activity of the autonomic nervous system. The biofeedback effect on the vagal modulation increased also occurred for the placebo feedback manipulation (study1) and for the two groups of the misattribution instructions (study2), but it may be suggested more effects of the cardiorespiratory biofeedback technique with the real feedback. We can also suggest that the cardiorespiratory biofeedback with the misattribution instructions influenced the error and the conflict processing, but not the cognitive performance. This thesis showed that believe in the kind of the feedback and in the type of the cardiorespiratory biofeedback instructions can be variables to influence on the psychophysiological and emotional states.

abstract: With the number of internationally-run clinical drug trials increasing, the double standards between those in developed nations and those in developing nations are being scrutinized under the ethical microscope. Many argue that several pharmaceutical companies and researchers are exploiting developing nation participants. Two issues of concern are the use of a placebo control when an effective alternative treatment exists and the lack of drug availability to the country that hosted the clinical trial should the experimental drug prove effective. Though intuitively this seems like an instance of exploitation, philosophically, exploitation theories cannot adequately account for the wrongdoing in these cases. My project has two parts. First, after explaining why the theories of Alan Wertheimer, John Lawrence Hill, and Ruth Sample fail to explain the exploitation in clinical drug research, I provide an alternative account of exploitation that can explain why the double standard in clinical research is harmful. Rather than craft a single theory encompassing all instances of exploitation, I offer an account of a type, or subset, of exploitation that I refer to as comparative exploitation. The double standards in clinical research fall under the category of comparative exploitation. Furthermore, while many critics maintain that cases of comparative exploitation, including clinical research, are mutually beneficial, they are actually harmful to its victims. I explain the harm of comparative exploitation using Ben Bradley's counterfactual account of harm and Larry May's theory of sharing responsibility. The second part of my project focuses on the "standard of care" argument, which most defenders use to justify the double standard in clinical research. I elaborate on Ruth Macklin's position that advocates of the "standard of care" position make three faulty assumptions: placebo-controlled trials are the gold standard, the only relevant question responsive to the host country's health needs is "Is the experimental product being studied better than the 'nothing' now available to the population?", and the only way of obtaining affordable products is to test cheap alternatives to replace the expensive ones. In the end, I advocate moving towards a universalizing of standards in order to avoid exploitation. / Dissertation/Thesis / Ph.D. Philosophy 2013

Placebo associeras ofta med de sockerpiller som bland annat används i vetenskapliga studier. De används för att, som verkningslös substans, jämföras med och på så sätt bedöma ett aktivt läkemedels effekt. Placebo kan dock innefatta mycket mer än så. Det bemötande patienten får spelar stor roll men även förväntan, betingning och sinnestillstånd påverkar en eventuell placeboeffekt. Placeboeffekten möts ofta med skepsis och i värsta fall avfärdas den som inbillning. Forskning har dock visat att placebo kan ge både psykologiska och fysiologiska effekter. Syftet med denna litteraturstudie var att undersöka på vilka olika sätt placebo kan ge psykologiska och fysiologiska effekter. Artikelsökningen till denna litteraturstudie är gjord i databasen PubMed. Fem vetenskapliga kliniska studier valdes ut för närmare analys i arbetet. Studierna visar att placeboeffekten är komplex. Flera typer av responsmekanismer finns, vilka aktiveras av olika typer av stimuli. Förväntan kan exempelvis trigga opioida system medan betingning kan trigga både opioida och cannabinoida system samt immunförsvaret. De olika systemen kan aktiveras samtidigt och verka både oberoende av varandra och i kombination. Studierna har visat att placeboeffekterna kan ge både psykologiska och fysiologiska effekter. Dessa effekter är viktiga att ta hänsyn till, både i mötet med patienten, och vid upplägg och tolkning av vetenskapliga studier.

E-cigarette use has been increasing in recent years, and its ultimate public health impact is still unknown. In order to assess the addictive liability of these products, research is needed to investigate the roles of nicotine and other factors on psychological and physical effects of “vaping.” The goal of the current study was to investigate the role of expectancies, nicotine delivery, and their interactions on the effects of e-cigarette use via a balanced-placebo experiment. In this design, drug dosage (contains nicotine or not) was crossed with instructions (told nicotine or non-nicotine) during ad-lib e-cigarette use sessions by 128 current e-cigarette users. This design allows for parsing of the causal role of expectancies and pharmacology, as well as their interaction. Dependent variables included both psychological outcomes (cravings for cigarettes and e-cigarettes, mood, satisfaction, reward) and physiological variables (hunger, attention, aversion, respiratory tract sensations). Among cigarette smokers (n=52), a significant main effect of instruction emerged on reductions in craving to smoke, although moderation analyses revealed that this effect was limited to males. Overall, significant drug X instruction interactions were found on craving to vape, psychological reward, and enjoyment of respiratory tract sensations, indicating synergistic causal influences of both expectancies and nicotine. Expectancies, smoking status, and gender moderated some of these effects. The results of this study identified effects of e-cigarettes that were driven by either nicotine, cognitive drug expectancies, or both. Results should be considered in the context of methodological and theoretical limitations. This study contributes to the understanding of motivational influences that may affect the initiation and maintenance of e-cigarette use, which may guide the development of public health and clinical interventions.

Class of 2008 Abstract / Objectives: 1) To determine if data on weight change in the placebo arm of RCT's for weight loss were available, and 2) to conduct a pilot meta-analysis to estimate the average weight change in the placebo arm. Methods: Four randomized placebo controlled trials of rimonabant for weight loss were retrieved. A draft data extraction form was developed to record weight loss and demographic data. Potential for bias was assessed on design issues related to withdrawals, blinding, allocation procedure, adherence, and manufacturer influence. Based on available data, a forest plot was constructed and heterogeneity was assessed. The a priori alpha level was 0.05. Results: The placebo groups from all studies were similar. The pooled data indicated that individuals in the placebo arm lost an average of 3.3 kg, p < 0.001. One study had a significantly greater completion rate than the other studies. Participants were prescribed a hypocaloric diet and were instructed to increase physical activity but no data were reported on calories consumed or amount of physical activity. Weight loss of 5% ranged from 15-20% of participants. There was potential for bias relating to reported adherence, allocation concealment process, and manufacturer funding. Conclusions: Participants in the placebo arm of rimonabant trials lost an average of 3.3 kg, which was statistically significant. Little can be learned about weight loss in the placebo arm because no data on calories consumed, amount of exercise, or hunger were reported. Information from other RCT's is needed to provide additional data and to confirm the findings.

Background Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19. Methods Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed. Results We included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95% CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed. Conclusions There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19. / Revisión por pares

Social anxiety disorder (SAD) is characterized by fear and avoidance of social interactions and situations in which an individual is being the focus of attention. This current thesis aims to examine the efficacy of pharmacological treatment, particularly selective serotonin reuptake inhibitors (SSRIs) in individuals with a generalized social anxiety disorder (gSAD) in comparison with placebo (no active medication). In this systematic review, Scopus and Web of Science were searched for relevant research regarding the efficacy of the SSRI medication (paroxetine, sertraline, fluvoxamine and escitalopram) in comparison with placebo. Sixteen articles were included in this analysis. Results demonstrated that SSRI medication has greater efficacy in comparison with placebo both in short- and long-term time, prevent relapse in the long-term treatment of SAD and had a beneficial effect on different areas of individuals life's such as work, performance, romantic relationships etc.

No description available.

The Social Life of Placebos is an interdisciplinary study of the evolution of placebogenic responses – beneficial ones activated by psychosocial triggers -- and their elicitation in Asante medical contexts. Based on an extensive literature review in social, cultural, and medical studies and over 26 months of intensive research in rural Ghana, West Africa, it examines the therapeutic efficacy of Asante medical encounters by analyzing rites of care-giving within an evolutionary framework. Section 1 investigates why evolutionary processes appear to have made human physiology susceptible to psychosocial manipulation, what the health consequences of that susceptibility are in modern environments, and how culturally specific expectations and healing rituals might dampen or amplify that susceptibility. Because of key transitions in human evolution, the fitness consequences of sociality have increased rapidly and created the conditions whereby endogenous mechanisms have become responsive to sociocultural conditions. This explanation helps us better understand why culturally specific rituals can elicit powerful beneficial (placebo) and adverse (nocebo) physiological responses. Using a mixed methodology of physiological data and ethnographic case studies collected from hundreds of Asante medical encounters, Section 2 illuminates evolutionary and proximate processes in Asante contexts of care-giving and healing rituals in detailed chapters on pain, emotion, and stress. It examines the social and cultural resources and techniques that Asante health practitioners rely on for pain management in contexts where no pain medication is available. It analyzes the biocultural interactions that can take place when healers modify patient perceptions, emotions, and expectations. The dissertation concludes with biometric evidence that Asante indigenous ritual healing ceremonies actually promote significant entrainment and relaxation effects.