Research Briefing

We used a global mathematical model simulating different scenarios to study the effects of increased COVID-19 vaccine equity during 2021. Our results indicate that vaccine nationalism leads to increased infections and mortality worldwide, and by favoring the emergence of new viral variants, in the long term it may adversely affect all countries.

Using electronic health records data from the All of Us Research Program, we show that higher daily step counts in data collected over several years of Fitbit fitness tracker use were associated with lower risk of common, chronic diseases, including diabetes, hypertension, gastroesophageal reflux disease, depression, obesity and sleep apnea.

The identification of KRAS^G12C inhibitors has reignited interest in targeting RAS proteins. This work describes the discovery of the KRAS^G12D-specific inhibitor MRTX1133 and demonstrates the feasibility of potently and selectively targeting this oncogenic variant. MRTX1133 treatment markedly inhibited KRAS-dependent signaling and induced tumor regression in xenograft models harboring the KRAS^G12D mutation.

We show that patients who survive the first 30 days of acute SARS-CoV-2 infection have an increased risk of various post-acute neurological disorders after 1 year compared with uninfected contemporaries. The burden of these sequelae (aspects of ‘long COVID’) has serious implications for patients as well as society.

CAR-mediated trogocytosis contributes to dysfunction of natural killer (NK) cells by promoting fratricide and is an important mechanism of relapse after CAR-NK cell therapy. This problem can be overcome using a dual-CAR strategy that incorporates a dominant-negative signal to prevent NK cell fratricide and exhaustion, while sparing the CAR-activating signal against tumor targets.

Serial heart MRI scans conducted in previously well people with mild initial COVID-19 illness suggest that lingering cardiac symptoms may be explained, at least in part, by ongoing mild cardiac inflammation.

Early identification of at-risk people is critical in disease prevention, but current screening approaches are resource intensive and are often restricted to one disease at a time. We show how nuclear magnetic resonance (NMR) spectroscopy–derived metabolomics profiles can be used to predict multi-disease risk for the onset of 24 common conditions.

Colorectal cancers expressing the mutant BRAF^V600E comprise 10% of all metastatic colorectal cancers, present with a poor prognosis, and are refractory to common therapies. We discovered that a subgroup of these tumors that carries loss-of-function RNF43 mutations is associated with significantly improved response to the current standard-of-care anti-BRAF–anti-EGFR combination therapy.

Using population data on genetics and diseases and estimates of disability-adjusted life years, we generated a framework for estimating the effects of genetic factors on healthy life years, similar to the risk assessment framework for traditional modifiable epidemiological risk factors. This framework will help to inform the development and implementation of genetic-based clinical applications.

An engineered fusion protein exploits the efferocytosis pathway to clear amyloid-β (Aβ) from the brain without eliciting the severe inflammatory adverse effects associated with Aβ-targeting antibody-based immunotherapies. In mouse models of Alzheimer’s disease, this approach induced robust clearance of Aβ without inflammation, improved synapse protection, and decreased brain microhemorrhage, which result in superior behavioral recovery.

We identified and mapped at high-resolution RNA structures in viral genomes that are essential for virus reproduction. We then rapidly designed potent antivirals with high barriers to resistance that prevent or treat severe infections of these viruses with pandemic potential — via development of what we term ‘programmable antivirals’.

A large cohort of non-hospitalized adults with confirmed SARS-CoV-2 infection and matched controls were studied to investigate the symptoms of long COVID. SARS-CoV-2 infection was associated with 62 symptoms (three clusters) that persisted beyond 12 weeks, and with a range of risk factors.

The commonly indolent chronic lymphocytic leukemia may evolve into Richter transformation (RT), a very aggressive large B cell lymphoma. We identified early seeding of RT cells decades before its final expansion, mapped the underlying (epi)genomic alterations driving this process, and validated in vitro potential actionable therapeutic pathways.

The largest and most genetically diverse genome-wide association study thus far for coronary artery disease, a leading cause of death worldwide, identifies many new susceptibility loci and characterizes the genetic architecture in Black and Hispanic populations for the first time.

Analysis of genomics data and medical records of over 40,000 patients with cancer identifies hundreds of mutations that are predictive of how well patients respond to specific cancer therapies. These predictive biomarkers could inform personalized treatment planning.

Historically, hypertension control has been neglected in global and national health policies. We demonstrate how achieving an ‘80-80-80’ target for hypertension worldwide could considerably improve population-wide cardiovascular health and lessen inequalities across countries, forming a pillar of a renewed global non-communicable diseases agenda in the post-COVID-19 era.

Findings from a nationwide cohort study in Sweden, polygenic risk score analyses in a general population-based cohort in the United Kingdom, Mendelian randomization analyses and genetic correlation (linkage disequilibrium) analyses suggest a link between parental diagnosis of and genetic liability to inflammatory bowel disease and autism in children.

Analysis of SARS-CoV-2 evolution during chronic infection reveals that in this setting, the virus evolves to bear mutations similar to those seen in variants of concern, and that many of these mutations are associated with antibody evasion. However, as mutations associated with high SARS-CoV-2 transmissibility are not observed, the emergence of variants of concern during chronic infection might be rare.

Climate change is projected to increase the frequency and intensity of extreme ambient temperatures, particularly in the Global South. By analyzing temperature and mortality data from over 300 cities in Latin America, we found that sub-optimal ambient temperatures are associated with increases in age- and cause-specific mortality.