The increasing availability of large healthcare databases is fueling an intense debate on whether real-world data should play a role in the assessment of the benefit-risk of medical treatments. In many observational studies, for example, statin users were found to have a substantially lower risk of cancer than in meta-analyses of randomized trials. While such discrepancies are often attributed to a lack of randomization in the observational studies, they may be explained by flaws that can be avoided by explicitly emulating a target trial. Using the electronic health records of 733,804 UK adults, we emulated a target trial of statins and cancer and compared our estimates with those obtained using previously applied analytic approaches. Over the 10-year follow-up, 28,408 individuals developed cancer. Under the target trial approach, estimated observational analogs of intention-to-treat and per-protocol 10-year cancer-free survival differences were-0.5% (95% CI-1.0%, 0.0%) and-0.3% (95% CI-1.5%, 0.5%), respectively. By contrast, previous analytic approaches yielded estimates that appeared strongly protective. Our findings highlight the importance of explicitly emulating a target trial to reduce bias in the effect estimates derived from observational analyses.

Background The messenger RNA (mRNA)–based vaccines BNT162b2 and mRNA-1273 are more than 90% effective against coronavirus disease 2019 (Covid-19). However, their comparative effectiveness for a range of outcomes across diverse populations is unknown. Methods We emulated a target trial using the electronic health records of U.S. veterans who received a first dose of the BNT162b2 or mRNA-1273 vaccine between January 4 and May 14, 2021, during a period marked by predominance of the SARS-CoV-2 B.1.1.7 (alpha) variant. We matched recipients of each vaccine in a 1:1 ratio according to their risk factors. Outcomes included documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, symptomatic Covid-19, hospitalization for Covid-19, admission to an intensive care unit (ICU) for Covid-19, and death from Covid-19. We estimated risks using the Kaplan–Meier estimator. To assess the influence of the B.1.617.2 (delta) variant, we emulated a second target trial that involved veterans vaccinated between July 1 and September 20, 2021. Results Each vaccine group included 219,842 persons. Over 24 weeks of follow-up in a period marked by alpha-variant predominance, the estimated risk of documented infection was 5.75 events per 1000 persons (95% confidence interval [CI], 5.39 to 6.23) in the BNT162b2 group and 4.52 events per 1000 persons (95% CI, 4.17 to 4.84) in the mRNA-1273 group. The excess number of events per 1000 persons for BNT162b2 as compared with mRNA-1273 was 1.23 (95% CI, 0.72 to 1.81) for documented infection, 0.44 (95% CI, 0.25 to 0.70) for symptomatic Covid-19, 0.55 (95% CI, 0.36 to 0.83) for hospitalization for Covid-19, 0.10 (95% CI, 0.00 to 0.26) for ICU admission for Covid-19, and 0.02 (95% CI, −0.06 to 0.12) for death from Covid-19. The corresponding excess risk (BNT162b2 vs. mRNA-1273) of documented infection over 12 weeks of follow-up in a period marked by delta-variant predominance was 6.54 events per 1000 persons (95% CI, −2.58 to 11.82). Conclusions The 24-week risk of Covid-19 outcomes was low after vaccination with mRNA-1273 or BNT162b2, although risks were lower with mRNA-1273 than with BNT162b2. This pattern was consistent across periods marked by alpha- and delta-variant predominance. (Funded by the Department of Veterans Affairs and others.)

Micronutrient deficiency and depression are major global health problems. Here, we first review recent empirical evidence of the association between several micronutrients—zinc, magnesium, selenium—and depression. We then present potential mechanisms of action and discuss the clinical implications for each micronutrient. Collectively, empirical evidence most strongly supports a positive association between zinc deficiency and the risk of depression and an inverse association between zinc supplementation and depressive symptoms. Less evidence is available regarding the relationship between magnesium and selenium deficiency and depression, and studies have been inconclusive. Potential mechanisms of action involve the HPA axis, glutamate homeostasis and inflammatory pathways. Findings support the importance of adequate consumption of micronutrients in the promotion of mental health, and the most common dietary sources for zinc and other micronutrients are provided. Future research is needed to prospectively investigate the association between micronutrient levels and depression as well as the safety and efficacy of micronutrient supplementation as an adjunct treatment for depression.