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Early-onset colorectal cancer (EO-CRC) occurring in individuals under age 50 is rapidly increasing globally. In comparison, later-onset colorectal cancer (LO-CRC) incidence has decreased or remained stable over recent years. Despite these increases in EO-CRC incidence, the etiology of EO-CRC is largely unknown. This study aimed to compare the metabolomes of EO-CRC (N=53) and LO-CRC (N=314) patients from a cohort of 367 patients using patient matched samples of stages I-IV tumor and healthy colon tissue. Hydrophilic interaction liquid chromatography mass spectrometry (HILIC-MS) and reversed phase liquid chromatography mass spectrometry (RPLC-MS)-based untargeted metabolomics were applied to identify features present in the samples, and these were matched to an in-house library of metabolites. Pathway analyses were conducted using MetaboAnalyst software, and signaling networks were explored using Ingenuity Pathway Analysis (QIAGEN IPA). Between the two groups, 131 metabolites were similarly dysregulated. Two metabolites, fructose 1,6-bisphosphate and 4-hydroxy-3-methoxyphenylacetic acid, were unique to EO-CRC samples. There were similarities between EO- and LO-CRC in enrichment of pathways, including enrichment of purine metabolism and aminoacyl-tRNA biosynthesis. However, LO-CRC uniquely showed enrichment of arginine biosynthesis. In EO-CRC tumors, evidence of resilience to oxidative stress was observed through unique activation of glutathione peroxidase as a result of ERK1/2 and growth hormone activation. This appeared to reduce lipid hyperoxides and free hydrogen peroxide, allowing cells to survive, where, in a normal cellular environment, they should fail. For LO-CRC tumors, we observed coordinated networks of pro-carcinogenic molecules, including nitric oxide synthase, and immune responses, which are likely contributing to tumor cell proliferation that may be distinct from EO-CRC.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions ( n  = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world. Protocol registration The stage 1 protocol for this Registered Report was accepted in principle on 12 May 2020. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.c.4878591.v1 This Registered Report presents evidence from 87 countries and regions showing that brief emotion-regulation interventions consistently reduced negative emotions and increased positive emotions during the COVID-19 pandemic.