COVID-19 vaccination, from first dose to booster: New insights into the frequency of most common systemic adverse events and possible booster nocebo effects based on a systematic review

Background: Based on placebo data, it has been recently demonstrated that the frequencies of most common adverse events (AEs) of COVID-19 vaccination are overestimated due to negative expectation bias of vaccine recipients (nocebo effect). Since booster studies lack comparators, estimating the extent of the nocebo effect is difficult. We aimed to overcome this obstacle through a systematic comparison of most common AE frequencies across vaccine doses (first, second, booster), age groups, and vaccine vs. placebo arms. Methods: We systematically assessed systemic AEs in approved COVID-19 vaccines according to the PRISMA guidelines. All documents regarding COVID-19 vaccines with a booster dose authorized by the FDA (cutoff date 19 November 2021) were systematically searched on PubMed and the FDA website. Solicited systemic AEs from all documents supporting approval/authorization were collected. After standardization of doses and age groups, AE frequencies were compared between vaccine and placebo. Findings: Two trials were identified for BNT162b2 (n=21,785 participants), two for mRNA-1273 (n=22,324), and one for Ad26.COV2.S (n=4,085). Fever cases dropped to about half with the booster dose in all vaccines, whereas all other systemic AE frequencies were similar to the preceding dose. Almost no fever cases occurred with placebo (first/second dose); all other systemic AEs occurred at high frequencies. After subtracting placebo arm values from vaccine values, the frequencies for the various AEs were roughly comparable within each dose for each vaccine. Interpretation: Fever is the only solicited systemic AE that can be assessed objectively. It occurs about 50% less often with the booster than with the preceding dose. This may indirectly indicate a considerable overestimation of systemic AEs in the case of booster vaccinations and a pronounced nocebo effect. The nocebo effect appears to substantially contribute to the differences in the frequencies of the various systemic AEs.

Operating Cash Flows and Earnings Target Revision: Evidence from Annual Cash Bonus Plans for CEOs

We empirically examine the impact of operating cash flows on future earnings targets in CEOs' annual cash bonus plans. Using target and actual compensation earnings-per-share (EPS) disclosed in proxy statements of large U.S. public firms, we find that operating cash flows have no significant incremental effects on the revision of future earnings targets in the presence of current earnings. We also observe a positive association between future target achievability and current operating cash flows, indicating that firms with higher operating cash flows set significantly easier future earnings targets for their CEOs. These findings suggest that the higher persistence of operating cash flows in predicting future earnings is not fully incorporated into target setting. Further analyses reveal that the positive association between future target achievability and current operating cash flows is attributable to both expectation bias and contractual considerations to reward CEOs who deliver greater cash flows and to limit activities that sacrifice cash flows.

Impact of natalizumab on quality of life in a real-world cohort of patients with multiple sclerosis: Results from MS PATHS

Background Optimizing multiple sclerosis treatment warrants understanding of changes in physical, mental, and social health. Objective To assess the impact of natalizumab on Quality of Life in Neurological Disorders (Neuro-QoL) scores. Methods Annualized change in T-scores and likelihood of ≥5-point improvement over baseline were calculated for each Neuro-QoL domain after natalizumab initiation. Comparisons with ocrelizumab-treated patients were conducted after propensity score weighting and adjustment for relevant co-medications, year, and drug-year interaction. Results Among 164 natalizumab patients analyzed, 8 of 12 Neuro-QoL domains improved significantly, with greater improvement in patients with abnormal baseline Neuro-QoL. In the subgroup comparison of natalizumab-treated ( n = 145) and ocrelizumab-treated ( n = 520) patients, significant improvement occurred in 9 of 12 and 4 of 12 domains, respectively. The difference between groups was statistically significant for positive affect and well-being ( p = 0.02), sleep ( p = 0.003), and satisfaction with social roles and activities (SRA) ( p = 0.03) in the overall population and for emotional and behavioral dyscontrol ( p = 0.01), participation in SRA ( p = 0.0001), and satisfaction with SRA ( p = 0.02) in patients with abnormal baseline Neuro-QoL. Conclusions Natalizumab can produce clinically meaningful improvements in mental and social health. Such improvements are unlikely to be primarily driven by expectation bias, as their magnitude exceeded improvements with another high-efficacy therapy, ocrelizumab.

A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats

Ayahuasca is a plant concoction containing N,N-dimethyltryptamine (DMT) and certain β-carboline alkaloids from South America. Previous research in naturalistic settings has suggested that ingestion of ayahuasca can improve mental health and well-being; however, these studies were not placebo controlled and did not control for the possibility of expectation bias. This naturalistic observational study was designed to assess whether mental health changes were produced by ayahuasca or by set and setting. Assessments were made pre- and post-ayahuasca sessions in 30 experienced participants of ayahuasca retreats hosted in the Netherlands, Spain, and Germany. Participants consumed ayahuasca (N = 14) or placebo (N = 16). Analysis revealed a main effect of time on symptoms of depression, anxiety, and stress. Compared to baseline, symptoms reduced in both groups after the ceremony, independent of treatment. There was a main treatment × time interaction on implicit emotional empathy, indicating that ayahuasca increased emotional empathy to negative stimuli. The current findings suggest that improvements in mental health of participants of ayahuasca ceremonies can be driven by non-pharmacological factors that constitute a placebo response but also by pharmacological factors that are related to the use of ayahuasca. These findings stress the importance of placebo-controlled designs in psychedelic research and the need to further explore the contribution of non-pharmacological factors to the psychedelic experience.

Automatic classification and segmentation of single-molecule fluorescence time traces with deep learning

Traces from single-molecule fluorescence microscopy (SMFM) experiments exhibit photophysical artifacts that typically necessitate human expert screening, which is time-consuming and introduces potential for user-dependent expectation bias. Here, we use deep learning to develop a rapid, automatic SMFM trace selector, termed AutoSiM, that improves the sensitivity and specificity of an assay for a DNA point mutation based on single-molecule recognition through equilibrium Poisson sampling (SiMREPS). The improved performance of AutoSiM is based on accepting both more true positives and fewer false positives than the conventional approach of hidden Markov modeling (HMM) followed by hard thresholding. As a second application, the selector is used for automated screening of single-molecule Förster resonance energy transfer (smFRET) data to identify high-quality traces for further analysis, and achieves ~90% concordance with manual selection while requiring less processing time. Finally, we show that AutoSiM can be adapted readily to novel datasets, requiring only modest Transfer Learning.

Psychiatric Interventions in Virtual Reality: Why We Need an Ethical Framework

Recent improvements in virtual reality (VR) allow for the representation of authentic environments and multiple users in a shared complex virtual world in real time. These advances have fostered clinical applications including in psychiatry. However, although VR is already used in clinical settings to help people with mental disorders (e.g., exposure therapy), the related ethical issues require greater attention. Based on a thematic literature search the authors identified five themes that raise ethical concerns related to the clinical use of VR: (1) reality and its representation, (2) autonomy, (3) privacy, (4) self-diagnosis and self-treatment, and (5) expectation bias. Reality and its representation is a theme that lies at the heart of VR, but is also of specific significance in a clinical context when perceptions of reality are concerned, for example, during psychosis. Closely associated is the autonomy of VR users. Although autonomy is a much-considered topic in biomedical ethics, it has not been sufficiently discussed when it comes to applications of VR in psychiatry. In this review, the authors address the different themes and recommend the development of an ethical framework for the clinical use of VR.

Effect of heuristic anchoring and adjustment, and optimism bias, in stock market forecasts

Stock market forecasting is an important and challenging process that influences investment decisions. This paper presents an experimental design that aims to measure the influence of the anchoring and adjustment heuristic and optimism bias in these forecasts. The study was conducted using information from the S&P MILA Pacific Alliance Select financial index; this was presented to 670 students from the cities of Concepción (Chile), Cali (Colombia), and Lima (Peru). Data was collected and presented through an instrument that asked participants to make a forecast judgment of the said financial index, based on the presented graphics, representing a year, a month, a week, and the last closing value of the index. Thus, it was possible to measure the influence of the anchor and adjustment heuristic in order to establish whether the presence of an initial value affected the financial forecast. Similarly, the study sought to determine whether the judgment issued was biased toward an optimistic or pessimistic position, thereby proving the presence of an error or expectation bias, known as optimism bias. The results were analyzed using the least squares method, and the data panel confirmed that the anchoring and adjustment heuristic influences the forecast of the financial index used in the study. Similarly, the presence of optimism bias in the cognitive process of forecasting in finance was inferred.

Placebo Response in Rheumatoid Arthritis Clinical Trials

Objective.Understanding the placebo response is critical to interpreting treatment efficacy, particularly for agents with a ceiling to their therapeutic effect, where an increasing placebo response makes it harder to detect potential benefit. The objective of this study is to assess the change in placebo responses over time in rheumatoid arthritis (RA) randomized placebo-controlled trials (RCT) for drug licensing authorization.Methods.The Cochrane Controlled Trials Register database was searched to identify RCT of biological or targeted synthetic disease-modifying antirheumatic drugs (DMARD) in RA. Studies were excluded if patients were conventional synthetic DMARD (csDMARD)–naive, not receiving background csDMARD therapy, or were biologic experienced. Metaregression model was used to evaluate changes in American College of Rheumatology (ACR) 20, ACR50, and ACR70 treatment response over time.Results.There were 32 trials in total: anti–tumor necrosis factor therapy (n = 15), tocilizumab (n = 4), abatacept (n = 2), rituximab (n = 2), and Janus kinase inhibitors (n = 9). From 1999 to 2018, there was no significant trend in the age or sex of patients in the placebo arm. Disease duration, swollen joint count, and 28-joint count Disease Activity Score using erythrocyte sedimentation rate at baseline all significantly declined over time. There was a statistically significant increase in placebo ACR50 and ACR70 responses (ACR50 β = 0.41, 95% CI 0.09–0.74, p = 0.01; ACR70 β = 0.18, 95% CI 0.04–0.31, p = 0.01) that remained significant after controlling for potential confounders.Conclusion.There has been a rise in the placebo response in RA clinical trials over the last 2 decades. Shifting RA phenotype, changes in trial design, and expectation bias are possible explanations for this phenomenon. This observation has important implications when evaluating newer novel agents against established therapies.