The 2022 report of the Lancet Countdown on health and climate change: health at the mercy of fossil fuels

The 2022 report of the Lancet Countdown is published as the world confronts profound and concurrent systemic shocks. Countries and health systems continue to contend with the health, social, and economic impacts of the COVID-19 pandemic, while Russia’s invasion of Ukraine and a persistent fossil fuel overdependence has pushed the world into global energy and cost-of-living crises. As these crises unfold, climate change escalates unabated. Its worsening impacts are increasingly affecting the foundations of human health and wellbeing, exacerbating the vulnerability of the world’s populations to concurrent health threats.  During 2021 and 2022, extreme weather events caused devastation across every continent, adding further pressure to health services already grappling with the impacts of the COVID-19 pandemic. Floods in Australia, Brazil, China, western Europe, Malaysia, Pakistan, South Africa, and South Sudan caused thousands of deaths, displaced hundreds of thousands of people, and caused billions of dollars in economic losses. Wildfires caused devastation in Canada, the USA, Greece, Algeria, Italy, Spain, and Türkiye, and record temperatures were recorded in many countries, including Australia, Canada, India, Italy, Oman, Türkiye, Pakistan, and the UK. With advancements in the science of detection and attribution studies, the influence of climate change over many events has now been quantified.</p

A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that lacks a predictive and broadly applicable biomarker. Continued focus on mutation-specific upstream mechanisms has yet to predict disease progression in the clinic. Utilising cellular pathology common to the majority of ALS patients, we implemented an objective transcriptome-driven approach to develop noninvasive prognostic biomarkers for disease progression. Genes expressed in laser captured motor neurons in direct correlation (Spearman rank correlation, p < 0.01) with counts of neuropathology were developed into co-expression network modules. Screening modules using three gene sets representing rate of disease progression and upstream genetic association with ALS led to the prioritisation of a single module enriched for immune response to motor neuron degeneration. Genes in the network module are important for microglial activation and predict disease progression in genetically heterogeneous ALS cohorts: Expression of three genes in peripheral lymphocytes - LILRA2, ITGB2 and CEBPD - differentiate patients with rapid and slowly progressive disease, suggesting promise as a blood-derived biomarker. TREM2 is a member of the network module and the level of soluble TREM2 protein in cerebrospinal fluid is shown to predict survival when measured in late stage disease (Spearman rank correlation, p = 0.01). Our data-driven systems approach has, for the first time, directly linked microglia to the development of motor neuron pathology. LILRA2, ITGB2 and CEBPD represent peripherally accessible candidate biomarkers and TREM2 provides a broadly applicable therapeutic target for ALS

BRAFV600E-mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism

BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis is poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of Braf V600E in the intestinal tissue of an inducible mouse model. We show that Braf V600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, Braf V600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in Braf V600E-mutant mice. Overall, our work unveils the long-term impact of Braf V600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins