Reviews & Analysis

Vigorous intermittent lifestyle physical activity (VILPA) refers to brief bouts of strenuous movement performed as part of daily living, such as walking uphill or running for a bus. We find that as little as 3–4 minutes of VILPA per day is associated with substantially reduced mortality risk compared to no VILPA.

Subgroup analysis of the EMPEROR-Preserved clinical trial of the glucose-lowering drug empagliflozin in chronic heart failure with left ventricular ejection fraction (LVEF) >40% found improved clinical outcomes in the cohort of patients with LVEF ≥50%. This is, to our knowledge, the first time a drug therapy has been unequivocally demonstrated to benefit this patient population.

Inhaled particulates from environmental pollutants accumulate in macrophages in lung-associated lymph nodes over years, compromising immune surveillance via direct effects on immune cell function and lymphoid architecture. These findings reveal the importance of improved air quality to preserve immune health against current and emerging pathogens.

To enable large-scale screening for left ventricular dysfunction — a serious and under-detected cardiac disease — we applied artificial intelligence to electrocardiograms recorded by patients using their own Apple watches in a prospective, digital, remote study. We found that patients engaged with the system and that the watch electrocardiograms effectively screened for the disease.

Impaired glucose tolerance (IGT) is a common condition that affects glucose control after sugar consumption. Isolated IGT is undetected by screening and diagnostic strategies, leaving affected individuals at high risk of developing diabetes. Here, a machine-learning framework identifies a three-protein signature for detecting isolated IGT from a single blood sample.

Evidence — provided by a combination of amyloid-β and tau PET examinations — of advanced Alzheimer’s disease pathological changes in the brain in cognitively unimpaired individuals is strongly associated with short-term (3–5 years) cognitive decline. Thus, amyloid-β and tau PET have high clinical relevance.

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.