The explanatory/pragmatic-trial distinction enjoys a burgeoning philosophical and medical literature and a significant contingent of support among philosophers and healthcare stakeholders as an important way to assess the design and results of randomized controlled trials. A major motivation has been the need to provide relevant, generalizable data to drive healthcare decisions. While talk of pragmatic and explanatory trials could be seen as convenient shorthand, the distinction can also be seen as harboring deeper issues related to inferential strategies used to evaluate (...) causal claims regarding medical treatments. A comprehensive, critical analysis of the distinction and underlying epistemological framework upon which the distinction is based, particularly with respect to treatment effectiveness, has yet to be forthcoming. I provide this, analyzing the distinction’s relationship to generalizability and cognate distinctions between ideal conditions and real-world practice, internal and external validity, and efficacy and effectiveness. I also analyze recent philosophical work that relies on the explanatory/pragmatic-trial distinction and that advocates for more pragmatic trials. I conclude that as an organizing principle for trial-design decisions and trial evaluation, the explanatory/pragmatic-trial distinction is conceptually problematic and not as useful as its proponents seem to think. Since some pragmatic-trial features can be inimical to establishing treatment effectiveness, pragmatic-trial features should not be conflated with pragmatic trials’ avowed goals. If the distinction is to be useful, it and some associated concepts, including generalizability, should be reformulated, lest they continue to underlie a medical epistemology that could contribute to methodologically flawed and potentially unethical advice for the design and interpretation of trials. (shrink)

Establishing the effectiveness of medical treatments is one of the most important aspects of medical practice. Bradford Hill's viewpoints play an important role in inferring causality in medicine,...

Applying causal methods to fields such as healthcare, marketing, and economics receives increasing interest. In particular, optimising the individual-treatment-effect – often referred to as uplift modelling – has peaked in areas such as precision medicine and targeted advertising. While existing techniques have proven useful in many settings, they suffer vividly in a dynamic environment. To address this issue, we propose a novel optimisation target that is easily incorporated in bandit algorithms. Incorporating this target creates a causal model which (...) we name an uplifted contextual multi-armed bandit. Experiments on real and simulated data show the proposed method to effectively improve upon the state-of-the-art. All our code is made available online at https://github.com/vub-dl/u-cmab. (shrink)

While issues of efficacy and specificity are crucial for the future of neurofeedback training, there may be alternative designs and control analyses to circumvent the methodological and ethical problems associated with double-blind placebo studies. Surprisingly, most NF studies do not report the most immediate result of their NF training, i.e. whether or not children with ADHD gain control over their brain activity during the training sessions. For the investigation of specificity, however, it seems essential to analyze the learning and adaptation (...) processes that take place in the course of the training and to relate improvements in self-regulated brain activity across training sessions to behavioral, neuropsychological and electrophysiological outcomes. To this aim, a review of studies on neurofeedback training with ADHD patients, which include the analysis of learning across training sessions or relate training performance to outcome, is presented. Methods on how to evaluate and quantify learning of EEG regulation over time are discussed. “Non-learning” has been reported in a small number of ADHD-studies, but has not been a focus of general methodological discussion so far. For this reason, selected results from the brain-computer interface (BCI) research on the so-called “brain-computer illiteracy”, the inability to gain control over one’s brain activity, are also included. It is concluded that in the discussion on specificity, more attention should be devoted to the analysis of EEG regulation performance in the course of the training and its impact on clinical outcome. It is necessary to improve the knowledge on characteristic cross-session and within-session learning trajectories in ADHD and to provide the best conditions for learning. (shrink)

The stratum-specific treatment effect function is a random variable giving the average treatment effect (ATE) for a randomly drawn stratum of potential confounders a clinician may use to assign treatment. In addition to the ATE, the variance of the stratum-specific treatment effect function is fundamental in determining the heterogeneity of treatment effect values. We offer a non-parametric plug-in estimator, the targeted maximum likelihood estimator (TMLE) and the cross-validated TMLE (CV-TMLE), to simultaneously (...) estimate both the average and variance of the stratum-specific treatment effect function. The CV-TMLE is preferable because it guarantees asymptotic efficiency under two conditions without needing entropy conditions on the initial fits of the outcome model and treatment mechanism, as required by TMLE. Particularly, in circumstances where data adaptive fitting methods are very important to eliminate bias but hold no guarantee of satisfying the entropy condition, we show that the CV-TMLE sampling distributions maintain normality with a lower mean squared error than TMLE. In addition to verifying the theoretical properties of TMLE and CV-TMLE through simulations, we highlight some of the challenges in estimating the variance of the treatment effect, which lack double robustness and might be biased if the true variance is small and sample size insufficient. (shrink)

This article studies the treatment effect models in which individuals are classified into unobserved groups based on heterogeneous treatment rules. By using a finite mixture approach, we propose a marginal treatment effect framework in which the treatment choice and outcome equations can be heterogeneous across groups. Under the availability of instrumental variables specific to each group, we show that the MTE for each group can be separately identified. On the basis of our identification result, (...) we propose a two-step semiparametric procedure for estimating the group-wise MTE. We illustrate the usefulness of the proposed method with an application to economic returns to college education. (shrink)

Randomized control trials (RCTs) are the gold standard for estimating causal effects, but often use samples that are non-representative of the actual population of interest. We propose a reweighting method for estimating population average treatment effects in settings with noncompliance. Simulations show the proposed compliance-adjusted population estimator outperforms its unadjusted counterpart when compliance is relatively low and can be predicted by observed covariates. We apply the method to evaluate the effect of Medicaid coverage on health care use for (...) a target population of adults who may benefit from expansions to the Medicaid program. We draw RCT data from the Oregon Health Insurance Experiment, where less than one-third of those randomly selected to receive Medicaid benefits actually enrolled. (shrink)

The problem of missingness in observational data is ubiquitous. When the confounders are missing at random, multiple imputation is commonly used; however, the method requires congeniality conditions for valid inferences, which may not be satisfied when estimating average causal treatment effects. Alternatively, fractional imputation, proposed by Kim 2011, has been implemented to handling missing values in regression context. In this article, we develop fractional imputation methods for estimating the average treatment effects with confounders missing at random. We show (...) that the fractional imputation estimator of the average treatment effect is asymptotically normal, which permits a consistent variance estimate. Via simulation study, we compare fractional imputation’s accuracy and precision with that of multiple imputation. (shrink)

This article reconsiders how to judge judicial independence by using the Japanese judicature, one of the allegedly-most dependent judiciary branches. In their influential work, Ramseyer and Rasmusen argue that judges who once belonged to a leftist group take longer to reach a under the long-term conservative rule of Japan. Their method does not, however, deal appropriately with the possibility of judges not reaching this position because the judge dies, retires early, or is still at the early stage of her career. (...) Ramseyer and Rasmusen also mistakenly assume that all judges will eventually obtain this position. This article develops a survival analysis model of judicial careers and attempts to solve the problems of censoring, left truncation, and split population. We also offer a way to utilize a matching procedure to estimate average treatment effects on censored time-to-event as well as event occurrence. We re-analyze a corrected version of Ramseyer and Rasmusen's data using their and our methods. One of the most important findings is that, contrary to what Ramseyer and Rasmusen argue, leftist judges are not discriminated against in terms of the timing of promotion. (shrink)

Comparative effectiveness research (CER) is one of the Patient Protection and Affordable Care Act's significant initiatives that aims to improve treatment outcomes and lower health care costs. This article takes CER a step further and suggests a novel clinical application for it. The article proposes the development of a national framework to enable physicians to rapidly perform, through a computerized service, medically sound personalized comparisons of the effectiveness of possible treatments for patients' conditions. A treatment comparison for a (...) given patient would be based on data from electronic health records of a cohort of clinically similar patients who received the treatments previously and whose outcomes were recorded. This framework has unique potential to simultaneously improve the quality of health care, reduce its cost, and alleviate public concerns about rationing and “one size fits all” medicine. (shrink)

In causal inference, a variety of causal effect estimands have been studied, including the sample, uncensored, target, conditional, optimal subpopulation, and optimal weighted average treatment effects. Ad hoc methods have been developed for each estimand based on inverse probability weighting and on outcome regression modeling, but these may be sensitive to model misspecification, practical violations of positivity, or both. The contribution of this article is twofold. First, we formulate the generalized average treatment effect to unify these (...) causal estimands as well as their IPW estimates. Second, we develop a method based on Kernel optimal matching to optimally estimate GATE and to find the GATE most easily estimable by KOM, which we term the Kernel optimal weighted average treatment effect. KOM provides uniform control on the conditional mean squared error of a weighted estimator over a class of models while simultaneously controlling for precision. We study its theoretical properties and evaluate its comparative performance in a simulation study. We illustrate the use of KOM for GATE estimation in two case studies: comparing spine surgical interventions and studying the effect of peer support on people living with HIV. (shrink)

Statistical power is often a concern for clustered randomized control trials (RCTs) due to variance inflation from design effects and the high cost of adding study clusters (such as hospitals, schools, or communities). While covariate pre-specification can improve power for estimating regression-adjusted average treatment effects (ATEs), further precision gains can be achieved through covariate selection once primary outcomes have been collected. This article uses design-based methods underlying clustered RCTs to develop Lasso methods for the post-hoc selection of covariates for (...) ATE estimation that avoids a lack of transparency and model overfitting. Our focus is on two-stage estimators: in the first stage, Lasso estimation is conducted using data on cluster-level averages or sums, and in the second stage, standard ATE estimators are adjusted for covariates using the first-stage Lasso results. We discuss l 1 {l}_{1} consistency of the estimated Lasso coefficients, asymptotic normality of the ATE estimators, and design-based variance estimation. The nonparametric approach applies to continuous, binary, and discrete outcomes. We present simulation results and demonstrate the method using data from a federally funded clustered RCT testing the effects of school-based programs promoting behavioral health. (shrink)

The unsustainable growth in U.S. health care costs is in large part attributable to the rising costs of pharmaceuticals and medical devices and to unnecessary medical procedures. This fact has led health reform advocates and policymakers to place considerable hope in the idea that increased government support for research on the comparative effectiveness of medical treatments will eventually help to reduce health care expenses by informing patients, health care providers, and payers about which treatments for common conditions are effective and (...) which are not. Comparative effectiveness research has shown in some cases that expensive but commonly used treatments are significantly less effective than relatively inexpensive alternatives. Critics warn, however, that CER will homogenize patient care, limit patient choices, and lead to improper health care rationing and even to the denial of lifesaving treatments. (shrink)

In the presence of heterogeneity between the randomized controlled trial (RCT) participants and the target population, evaluating the treatment effect solely based on the RCT often leads to biased quantification of the real-world treatment effect. To address the problem of lack of generalizability for the treatment effect estimated by the RCT sample, we leverage observational studies with large samples that are representative of the target population. This article concerns evaluating treatment effects on survival (...) outcomes for a target population and considers a broad class of estimands that are functionals of treatment-specific survival functions, including differences in survival probability and restricted mean survival times. Motivated by two intuitive but distinct approaches, i.e., imputation based on survival outcome regression and weighting based on inverse probability of sampling, censoring, and treatment assignment, we propose a semiparametric estimator through the guidance of the efficient influence function. The proposed estimator is doubly robust in the sense that it is consistent for the target population estimands if either the survival model or the weighting model is correctly specified and is locally efficient when both are correct. In addition, as an alternative to parametric estimation, we employ the nonparametric method of sieves for flexible and robust estimation of the nuisance functions and show that the resulting estimator retains the root- n n consistency and efficiency, the so-called rate-double robustness. Simulation studies confirm the theoretical properties of the proposed estimator and show that it outperforms competitors. We apply the proposed method to estimate the effect of adjuvant chemotherapy on survival in patients with early-stage resected non-small cell lung cancer. (shrink)

APPENDIX: The data emerging from the clinical and brain studies described above suggest that, in the case of OCD, there are two pertinent brain mechanisms that are distinguishable both in terms of neuro-dynamics and in terms of the conscious experiences that accompany them. These mechanisms can be characterized, on anatomical and perhaps evolutionary grounds, as a lower-level and a higher-level mechanism. The clinical treatment has, when successful, an activating effect on the higher-level mechanism, and a suppressive effect (...) on the lower-level one. (shrink)

Two essential components make up the semantic information that was used to pinpoint the video events. They consist of: (a) A spatial component of a video frame, such as the scenery, visible people, and visible objects. (b) A temporal component that is represented by a series of video frames across time, such as the actions of a character or the movements of an object. The video's audio, video, and text components are examined in order to provide the higher-level semantic data. (...) The semantic structure of the movie is discovered using a variety of cues from many modalities, such as auditory and visual elements, bridging the gap between high level semantic notions and low level qualities. A video contains three distinct modalities. The three are as follows: (1) Visual modality, which refers to the scene seen in the video; (2) Auditory modality, which refers to spoken words, background music, and other noises; and (3) Textual modality, which refers to written materials that describe the subject matter of the movie. There are numerous video databases and a sizable amount of video data in general. Even while there are tools for maintaining and exploring these collections, many decision-making applications increasingly require tools to extract the critical information hidden in the video data. (shrink)

Background: Depression is the largest cause of mental ill health worldwide. Although interventions such as Dance Movement Therapy (DMT) may offer interesting and acceptable treatment options, current clinical guidelines do not include these interventions in their recommendations mainly because of what is perceived as insufficient research evidence. The 2015 Cochrane review on DMT for depression includes only three RCTs leading to inconclusive results. It is therefore, necessary to also look beyond such designs in order to identify and assess the (...) range of current evidence. Methods: We therefore, conducted a systematic review of studies that aimed to explore the effectiveness in the use of DMT with people with depression. This led to a qualitative narrative synthesis followed by a subgroup analysis and a sensitivity analysis. In all meta-analyses a random effects model was used with Standardised Mean Differences (SMD) to accommodate for the heterogeneity of studies and outcome measures. Results: From the 817 studies reviewed, eight studies met our inclusion criteria. 351 people with depression (mild to severe) participated, 192 of whom attended DMT groups while receiving treatment as usual (TAU) and 159 received TAU only. Qualitative findings suggest there was a decrease in depression scores in favour of DMT groups in all studies. Subgroup analysis performed on depression scores before and three months after the completion of DMT groups suggested changes in favour of the DMT groups. When sensitivity analysis was performed, RCTs at high risk of bias were excluded, leaving only studies with adult clients up to the age of 65. In these studies, the highest effect size was found favouring DMT plus TAU for adults with depression, when compared to TAU only. Conclusions: Based on studies with moderate to high quality, we concluded that DMT is an effective intervention in the treatment of depression with adults. Furthermore, by drawing on a wide range of designs with diverse quality, we were able to compile a comprehensive picture of relevant trends. Despite the fact that there remains a paucity of high-quality studies, the results have relevance to both policy-making and clinical practice, and become a platform for further research. (shrink)

This article raises serious concerns regarding the widespread use of unproven interventions with juveniles who sexually offend and suggests innovative methods for addressing these concerns. Dominant interventions (i.e., cognitive-behavioral group treatments with an emphasis on relapse prevention) typically fail to address the multiple determinants of juvenile sexual offending and could result in iatrogenic outcomes. Methodologically sophisticated research studies (i.e., randomized clinical trials) are needed to examine the clinical and cost-effectiveness of cognitive-behavioral group interventions, especially those delivered in residential settings. The (...) moral and ethical mandate for such research is evident when considering the alternative, in which clinicians and society are willing to live in ignorance regarding the etiology and treatment of juvenile sexual offending and to consign offending youths to the potential harm of untested interventions. Encouraging signs of a changing ethical climate include recent federal funding of a randomized clinical trial examining treatment effectiveness with sexually offending youths and the introduction of separate (i.e., developmentally informed) clinical and legal interventions for juvenile versus adult sexual offenders. (shrink)

This multi-centre research investigates the effects of dance movement therapy (DMT) on participants diagnosed with depression. In total, 109 persons participated in the study in various locations in Finland. The participants were 39 years old, on average (range = 18–64 years), and most were female (96%). All participants received treatment as usual (TAU). They were randomised into DMT+TAU (n = 52) or TAU-only (n = 57). The participants in the DMT + TAU group were offered 20 DMT sessions twice (...) a week for 10 weeks in addition to standard care. The measurement points included pre-treatment measurement at the baseline, post-treatment measurement at the end of the intervention, and a follow-up measurement 3 months afterward. The observed effects of the intervention among participants in the DMT+TAU group were a greater reduction in depression (BDI-I) and in indicators of physical and psychological distress (CORE-OM and SCL-90) in comparison to the participants who received TAU-only. At the 3-month follow-up, the corrected between-group effect sizes (ES) were medium and in favour of the DMT+TAU group (d = 0.60–0.72). These results are in line with the increasing number of research studies showing the benefits of DMT intervention among participants with depression, and these results indicate that DMT may improve the effectiveness of standard care. (shrink)

Developmental Dyslexia significantly interferes with children’s academic, personal, social, and emotional functioning. Nevertheless, therapeutic options need to be further validated and tested in randomized controlled clinical trials. The use of transcranial direct current stimulation has been gaining ground in recent years as a new intervention option for DD. However, there are still open questions regarding the most suitable tDCS protocol for young people with DD. The current crossover study tested the effectiveness of a short and intensive tDCS protocol, including the (...) long-term effects, as well as the influence of age and neuropsychological processes at baseline on reading improvements. Twenty-four children and adolescents with DD were randomly assigned to receive active tDCS during the first slot and sham tDCS during the second slot or vice versa. Five consecutive daily sessions of left anodal/right cathodal tDCS set at 1 mA for 20 min were administered over the parieto-occipital regions. Reading measures and neuropsychological measures were collected before, immediately after, 1 week and 1 month later the treatment. Our results showed that only the active tDCS condition improved non-word reading speed immediately after and 1 month later the end of the treatment compared with baseline. In addition, the improvement in non-word reading speed was significantly correlated with age and with neuropsychological measures at baseline but only in the active tDCS condition. The current crossover study contributed to enforce previous effects of tDCS, including long-term effects, on non-word reading speed and to understand the effect of age and neuropsychological processes on reading outcomes. Our findings showed that tDCS could be a low-cost and easy-to-implement treatment option with long-term effects for children and adolescents with DD. (shrink)

In healthcare priority settings, early access to treatment before reimbursement decisions gives rise to problems of whether negative decisions for cost‐effectiveness reasons should result in withdrawing treatment, already accessed by patients. Among professionals there seems to be a strong attitude to distinguish between withdrawing and withholding treatment, viewing the former as ethically worse. In this article the distinction between withdrawing and withholding treatment for reasons of cost effectiveness is explored by analysing the doing/allowing distinction, different theories (...) of justice, consequentialist and virtue perspectives. The authors do not find any strong reasons for an intrinsic difference, but do find some reasons for a consequentialist difference, given present attitudes. However, overall, such a difference does not, all things considered, provide a convincing reason against withdrawal, given the greater consequentialist gain of using cost‐effective treatment. As a result, patients should be properly informed when given early access to treatment, that such treatment can be later withdrawn following a negative reimbursement decision. (shrink)

In the current study, we aimed at understanding the effect of exposure to complex input on speech sound development, by conducting a systematic meta-analysis review of the existing treatment-based studies employing complex input in children with speech sound disorders. In the meta-analysis review, using a list of inclusion criteria, we narrowed 280 studies down to 12 studies. Data from these studies were extracted to calculate effect sizes that were plotted as forest plots to determine the efficacy of (...) complexity-based treatment approaches. The outcome variables of interest were improvement on the treated and generalization to the untreated sounds. Meta-analysis revealed that the exposure to complex input not only promoted improvement in production of complex speech sounds but also facilitated the production of untreated simple speech sounds. Overall, the current findings revealed that the exposure to complex input promotes acquisition of both complex and simple speech sounds. The current findings are in line with the models of language learnability. The current findings have implications in the treatment of speech sound disorders. (shrink)

Electroacupuncture (EA) and electroconvulsive therapy (ECT) are often used in the management of schizophrenia. This study sought to determine whether additional EA and ECT could augment antipsychotic response and reduce related side effects. In this retrospective controlled study, 287 hospitalized schizophrenic patients who received antipsychotics (controls, n = 50) alone or combined with EA (n = 101), ECT (n = 55) or both (EA+ECT, n = 81) were identified. EA and ECT were conducted for 5 and 3 sessions per week, (...) respectively, with a maximum of 12 sessions for ECT during hospitalization. The Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) were used to assess the severity of psychotic symptoms. Clinical response on SAPS and SANS, weight gain, and adverse events were compared. Survival analysis revealed that the ECT and EA+ECT groups had markedly greater clinical response rate than controls on SAPS [72.7% and 90.1% vs. 64.0%; relative risk (RR), 1.974 and 2.628, respectively, P ≤ 0.004] and on SANS (67.3% and 70.4% vs. 42.0%; RR, 1.951 and 2.009, respectively, P ≤ 0.015). A significantly greater response rate on SANS than controls was also observed in the EA group (64.4% versus 42.0%; RR = 1.938, P = 0.008). EA-containing regimens remarkably reduced weight gain and incidences of headache, insomnia, dry mouth, and electrocardiographic abnormalities. These results suggest that EA and ECT can serve as additional treatment for enhancing antipsychotic response and reduce the side effects in hospitalized patients with schizophrenia. (shrink)

BackgroundMild cognitive impairment is a common neurological disorder. Moxibustion has been shown to be effective in treating MCI, but its therapeutic mechanisms still remain unclear. This study mainly aimed to investigate the modulation effect of moxibustion treatment for patients with MCI by functional magnetic resonance imaging.MethodsA total of 47 patients with MCI and 30 healthy controls participated in resting-state fMRI imaging scans. Patients with MCI were randomly divided into true moxibustion group and sham moxibustion group. The degree centrality (...) approach was applied to distinguish altered brain functions. Correlation analysis was then performed to examine the relationships between the neuroimaging findings and clinical symptoms.ResultsCompared with HCs, patients with MCI mainly showed decreased DC in the left middle frontal cortex and bilateral middle cingulate cortex. After moxibustion treatment, the SHAM group had no significant DC findings, while TRUE group mainly showed significant increased DC in the bilateral MFC and MCC, as well as decreased DC in the left middle occipital cortex. Repeated measures analysis of variance showed significant interactions between the two groups of patients with MCI. In addition, the higher Mini-Mental State Examination score was significantly positively correlated with increased DC in the right MFC and left MCC after moxibustion treatment.ConclusionOur findings demonstrate that the potential value of moxibustion treatment on MCI, which adds new insights into the popular view that moxibustion treatment may slow cognitive decline in patients with MCI. (shrink)

BackgroundThe prognosis of hypertensive intracerebral hemorrhage is poor at high altitudes. The objective of this study was to explore whether hyperbaric oxygen can improve the results of computed tomography perfusion imaging and the neurological function of patients with HICH, and influence the hemoglobin concentration.MethodThe patients with HICH were treated with puncture and drainage. Twenty-one patients were treated with HBO after the operation, and the other patients received conventional treatment. CTP was performed twice, and all indices were measured. Scatter plots (...) were used to determine the effect of hemoglobin concentration on CTP imaging. Receiver operating characteristic curves were plotted to analyze the effects of hemoglobin concentration and hematoma volume on recovery results. The patients were followed up for 6 months.ResultsForty-one patients with HICH were treated with puncture and drainage. In total, 21 were treated with HBO after the operation, and 20 received conventional treatment as the control group. No significant differences in the CBV and CBF values of the two groups were noted before treatment. After 10 days, the values of CBV and CBF in the HBO group were significantly higher than those in the control group. A scatter diagram showed there was no significant in the HBO group, but significant correlation for the CBV and CBF values in the control group’s hematoma center and margin. The ROC curves showed that hematoma volume had an influence on prognosis of the control group. The Glasgow Coma Scale scores of the HBO group were significantly higher than those of the control group.ConclusionsHBO therapy can improve the postoperative CBV and CBF values of patients with HICH and ameliorate their prognoses. There was no significant correlation between HBO group and hemoglobin concentration on admission. (shrink)

The placebo drug reactions from controlled trials were studied for the first time systematically for efficacy and the safety in drug data pooled from randomized, placebo-controlled, multicentre studies. Results: The efficacy of placebo on clinical symptoms and outcome varied between the therapeutic indications. However, no placebo effects on laboratory values, as e.g. blood glucose or Hb1c in diabetics, were noted. The frequency and type of placebo-induced adverse reactions also varied between indication groups. The placebo side effect profile was largely (...) similar to the side effect profile of the active treatment. The mechanisms of placebo effects are manyfold and varied (e.g. endorphin release, conditioning), much lacks explanation. Conclusion: Since the prescription of non-evidence based medicines (= pseudoplacebos) may clearly also result in serious adverse effects, such practice may not only be non-beneficial but may even be harmful. In clinical research, the judicious use of placebo remains essential to establish the efficacy and safety, safeguarding that patients receiving placebo will not be subject to harm and are fully informed. (shrink)

The placebo drug reactions from controlled trials were studied for the first time systematically for efficacy and the safety in drug data pooled from randomized, placebo-controlled, multicentre studies. Results: The efficacy of placebo on clinical symptoms and outcome varied between the therapeutic indications. However, no placebo effects on laboratory values, as e.g. blood glucose or Hb1c in diabetics, were noted. The frequency and type of placebo-induced adverse reactions also varied between indication groups. The placebo side effect profile was largely (...) similar to the side effect profile of the active treatment. The mechanisms of placebo effects are manyfold and varied (e.g. endorphin release, conditioning), much lacks explanation. Conclusion: Since the prescription of non-evidence based medicines (= pseudoplacebos) may clearly also result in serious adverse effects, such practice may not only be non-beneficial but may even be harmful. In clinical research, the judicious use of placebo remains essential to establish the efficacy and safety, safeguarding that patients receiving placebo will not be subject to harm and are fully informed. (shrink)

Obstructive sleep apnea (OSA) severely impacts sleep and has long-term health consequences. Treating sleep apnea with continuous positive airway pressure (CPAP) not only relieves obstructed breathing, but also improves sleep. CPAP improves sleep by reducing apnea-induced awakenings. CPAP may also improve sleep by enhancing features of sleep architecture assessed with electroencephalography (EEG) that maximize sleep depth and neuronal homeostasis, such as the slow oscillation and spindle EEG activity, and by reducing neurophysiological arousal during sleep (i.e., beta EEG activity). We examined (...) cross-sectional differences in quantitative EEG characteristics of sleep, assessed with power spectral analysis, in 29 adults with type 2 diabetes treated with CPAP and 24 adults undergoing SHAM CPAP treatment (total n = 53). We then examined changes in spectral characteristics of sleep as the SHAM group crossed over to active CPAP treatment (n = 19). Polysomnography (PSG) from the CPAP titration night was used for the current analyses. Analyses focused on EEG frequencies associated with sleep maintenance and arousal. These included the slow oscillation (0.5–1 Hz), sigma activity (12–16 Hz, spindle activity), and beta activity (16–20 Hz) in F3, F4, C3, and C4 EEG channels. Whole night non-rapid eye movement (NREM) sleep and the first period of NREM spectral activity were examined. Age and sex were included as covariates. There were no group differences between CPAP and SHAM in spectral characteristics of sleep architecture. However, SHAM cross-over to active CPAP was associated with an increase in relative 12–16 Hz sigma activity across the whole night and a decrease in average beta activity across the whole night. Relative slow oscillation power within the first NREM period decreased with CPAP, particularly for frontal channels. Sigma and beta activity effects did not differ by channel. These findings suggest that CPAP may preferentially enhance spindle activity and mitigate neurophysiological arousal. These findings inform the neurophysiological mechanisms of improved sleep with CPAP and the utility of quantitative EEG measures of sleep as a treatment probe of improvements in neurological and physical health with CPAP. (shrink)

The development of new effective but expensive medical treatments leads to discussions about whether and how such treatments should be funded in solidarity-based healthcare systems. Solidarity is often seen as an elusive concept; it appears to be used to refer to different sets of concerns, and its interrelations with the concept of justice are not well understood. This paper provides a conceptual analysis of the concept of solidarity as it is used in discussions on the allocation of healthcare resources and (...) the funding of expensive treatments. It contributes to the clarification of the concept of solidarity by identifying in the literature and discussing four uses of the concept: (1) assisting patients in need, (2) upholding the solidarity-based healthcare system, (3) willingness to contribute and (4) promoting equality. It distinguishes normative and descriptive uses of the concept and outlines the overlap and differences between solidarity and justice. Our analysis shows that the various uses of the concept of solidarity point to different, even conflicting, ethical stances on whether and how access to effective, expensive treatments should be provided. We conclude that the concept of solidarity has a role to play in discussions on the accessibility and funding of newly approved medical treatments. It requires, for instance, that healthcare policies promote and maintain both societal willingness to contribute to the care of others and the value of providing care to vulnerable patients through public funding. (shrink)

The development of new effective but expensive medical treatments leads to discussions about whether and how such treatments should be funded in solidarity-based healthcare systems. Solidarity is often seen as an elusive concept; it appears to be used to refer to different sets of concerns, and its interrelations with the concept of justice are not well understood. This paper provides a conceptual analysis of the concept of solidarity as it is used in discussions on the allocation of healthcare resources and (...) the funding of expensive treatments. It contributes to the clarification of the concept of solidarity by identifying in the literature and discussing four uses of the concept: (1) assisting patients in need, (2) upholding the solidarity-based healthcare system, (3) willingness to contribute and (4) promoting equality. It distinguishes normative and descriptive uses of the concept and outlines the overlap and differences between solidarity and justice. Our analysis shows that the various uses of the concept of solidarity point to different, even conflicting, ethical stances on whether and how access to effective, expensive treatments should be provided. We conclude that the concept of solidarity has a role to play in discussions on the accessibility and funding of newly approved medical treatments. It requires, for instance, that healthcare policies promote and maintain both societal willingness to contribute to the care of others and the value of providing care to vulnerable patients through public funding. (shrink)

The random]ized clinical trial is widely accepted as the optimal approach to evaluating the safety and efficacy of medical treatments. Resistance to randomized treatment assignment arises regularly, most commonly in situations where the disease is life-threatening and treatments are either unavailable or unsatisfactory. Historical control designs, in which all participants receive the experimental treatment with results compared to a prior cohort, are advocated by some as more ethical in such circumstances; however, such studies are often highly biased in (...) favor of the new treatment and frequently yield misleading results. Alternative controlled designs motivated by the desire to maximize the number of patients with the treatment ultimately determined to be superior have been proposed, but have been challenged on both methodological and ethical grounds. Debates about appropriate and ethical study designs recurred during the recent Ebola Virus Disease epidemic in West Africa. Despite its devastating nature, the EVD epidemic showed the ongoing necessity of conducting randomized trials to obtain convincing evidence of the safety and efficacy of therapeutic interventions. (shrink)

The case of Charlie Gard sparked an ongoing public and academic debate whether in court decisions about medical treatment for children in England & Wales the best interests test should be replaced by a harm threshold. However, the literature has scantly considered (1) what the impact of such a replacement would be on future litigation and (2) how a harm threshold should be introduced: for triage or as standard for decision-making. This article directly addresses these gaps, by first analysing (...) reported cases in England & Wales about medical treatment in the context of a S31 order, thus using a harm threshold for triage and second comparing court decisions about medical treatment for children in England & Wales based on the best interest test with Dutch and German case law using a harm threshold. The investigation found that whilst no substantial increase of parental discretion can be expected an introduction of a harm threshold for triage would change litigation. In particular, cases in which harm is limited, currently only heard when there are concerns about parental decision-making, may be denied a court hearing as might cases in which the child has lost their capacity to suffer. Applying a harm threshold for triage in decisions about withholding or withdrawing life-sustaining treatment might lead to a continuation of medical treatment that could be considered futile. (shrink)