Explore the vast range of titles available.

Digital therapeutics (DTx) have attracted attention as the substitutes or add-ons to conventional pharmacotherapy. The number of clinical trials for DTx has increased recently, and one of the main targets for DTx is psychiatric disorders. Generalized anxiety disorder (GAD) is one of the most common and notable psychiatric disorders, and it's known that the magnitude of placebo effect in the pharmacotherapy is quite large. The randomized controlled trials (RCTs) with digital placebos are the most reliable clinical trials to evaluate the safety and efficacy of DTx. However, the magnitude of the digital placebo effect and its moderators on GAD have not been investigated, although they are critical to assess the true treatment effect of DTx. The objectives of this study were to identify RCTs with digital placebos as comparators that evaluated GAD assessment scores, to review the characteristics of the RCTs and of the digital placebos in the systematic review, and to investigate the magnitude and its moderators in the meta-analysis. The RCTs evaluating the GAD assessment scores by setting digital placebos as comparators were identified by searching the database of PubMed, Web of Science, and Scopus in July 2024. The characteristics of the RCTs and of the digital placebos were reviewed systematically. The meta-analysis, including subgroup analyses and meta-regressions, was conducted to investigate the magnitude and its moderators of the digital placebos. A total of 54 RCTs were included in the systematic review and 32 RCTs with 3 GAD assessment scores were included in the meta-analysis with a total of 5311 participants. The magnitude of digital placebos for all the included studies was small to moderate (Hedges g=0.28, 95% CI 0.18-0.38). The subgroup analyses showed the significant difference in the magnitude among target population (P=.03), placebo approach (P=.02), and baseline values (P=.02). The meta-regressions also indicated that the primary psychiatric patients in the target population (P=.01), \"Removed\" type in placebo approach (P=.04) and high baseline values (P =.02) were moderators for the magnitude of digital placebos. This study showed the small-to-moderate and statistically significant digital placebo effect on GAD assessment scores. Target population, placebo approach, and baseline values were also identified as the moderators of the placebo effect. It would be effective to create the study protocols for the DTx trials with digital placebos by considering the moderators identified in this study.

•Assessing vaccine effectiveness (VE) became challenging due to incidental infection.•A case-control study in 24 hospitals during Delta and Omicron with various outcomes.•Multiple outcomes with high protection of 2 doses for Delta and 3 doses for Omicron.•There was a trend towards higher VE for more severe and specific disease outcomes.•Importance of severe/specific outcomes to accurately show VE against severe disease. Since the SARS-CoV-2 Omicron variant became dominant, assessing COVID-19 vaccine effectiveness (VE) against severe disease using hospitalization as an outcome became more challenging due to incidental infections via admission screening and variable admission criteria, resulting in a wide range of estimates. To address this, the World Health Organization (WHO) guidance recommends the use of outcomes that are more specific to severe pneumonia such as oxygen use and mechanical ventilation. A case-control study was conducted in 24 hospitals in Japan for the Delta-dominant period (August-November 2021; “Delta”) and early Omicron (BA.1/BA.2)-dominant period (January-June 2022; “Omicron”). Detailed chart review/interviews were conducted in January-May 2023. VE was measured using various outcomes including disease requiring oxygen therapy, disease requiring invasive mechanical ventilation (IMV), death, outcome restricting to “true” severe COVID-19 (where oxygen requirement is due to COVID-19 rather than another condition(s)), and progression from oxygen use to IMV or death among COVID-19 patients. The analysis included 2125 individuals with respiratory failure (1608 cases [75.7%]; 99.2% of vaccinees received mRNA vaccines). During Delta, 2 doses provided high protection for up to 6 months (oxygen requirement: 95.2% [95% CI:88.7–98.0%] [restricted to “true” severe COVID-19: 95.5% {89.3–98.1%}]; IMV: 99.6% [97.3–99.9%]; fatal: 98.6% [92.3–99.7%]). During Omicron, 3 doses provided high protection for up to 6 months (oxygen requirement: 85.5% [68.8–93.3%] [“true” severe COVID-19: 88.1% {73.6–94.7%}]; IMV: 97.9% [85.9–99.7%]; fatal: 99.6% [95.2–99.97]). There was a trend towards higher VE for more severe and specific outcomes. Multiple outcomes pointed towards high protection of 2 doses during Delta and 3 doses during Omicron. These results demonstrate the importance of using severe and specific outcomes to accurately measure VE against severe COVID-19, as recommended in WHO guidance in settings of intense transmission as seen during Omicron.