Genetic determinants of micronucleus formation in vivo.

Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.

The effect of COVID-19 on the non-COVID health outcomes of crisis-affected peoples: a systematic review.

BACKGROUND: The COVID-19 pandemic posed considerable risks to populations affected by humanitarian crises in low- and middle-income countries (LMICs). However, there is limited understanding of how the pandemic may have affected non-COVID health outcomes among crisis-affected populations. Our aim was to examine the evidence on the impact of the COVID-19 pandemic on non-COVID-19 health outcomes for crisis-affected populations in LMICs. METHODS: A systematic review methodology was applied following PRISMA guidelines. Eligibility criteria were: crisis-affected populations in LMICS; COVID-19; and all health topics, except for sexual and reproductive health which was covered in a linked review. Five bibliographic databases and additional grey literature sources were searched. The search period was from 2019 to 31 July 2022. Eligible papers were extracted and analysed using a narrative synthesis approach based on the study objectives and relevant health access and systems frameworks. A quality appraisal was also conducted. FINDINGS: 4320 articles were screened, and 15 eligible studies were identified and included in this review. Ten studies collected health outcomes data. Eight related to mental health, which generally showed worse mental health outcomes because of the pandemic, and pandemic-related stressors were identified. Two studies assessed physical health outcomes in children, while none addressed physical health outcomes among adults. Nine studies reported on access to healthcare, revealing worse access levels due to the pandemic and noting key barriers to care. Seven studies reported on the impact on health systems, with key challenges including reduced and distorted health care funding, reduced staff capacity, interrupted medicines and supplies, weak information and mixed-messaging, and weak leadership. All fifteen studies on the social determinants of health, particularly highlighting the effect of increasing poverty, the role of gender, and food insecurity on health outcomes. The quality of papers was limited overall. CONCLUSION: This review found some limited evidence indicating negative mental health effects, increased barriers to accessing care, damage to health systems and magnified impacts on the social determinants of health for crisis-affected people during the COVID-19 pandemic. However, the small number and limited quality of the studies make the overall strength of evidence quite weak.