Research Briefing

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  • Tumor mutation burden is an imperfect predictor of response to immunotherapies. Mutations in regions of the genome unlikely to undergo loss during tumor evolution constitute a persistent tumor mutation burden that may drive sustained immunological tumor control in the context of cancer immunotherapy.

    Research Briefing
  • We demonstrate the power of a data-informed medicines-based approach in discovering the indirect effect of the COVID-19 pandemic on cardiovascular events using 1.32 billion records of dispensed medications in England, Scotland and Wales. We estimate that interruption of preventive care could result in more than 13,000 extra cardiovascular events.

    Research Briefing
  • By performing a large-scale biobank-based genome-wide association study, we identified a strong link between the underlying risk of cardiometabolic disease and patterns of lifelong medication use in hyperlipidemia, hypertension and type 2 diabetes. We discover hundreds of genetic predictors of medication use behavior and show medication-use-enhanced applications for polygenic prediction in cardiometabolic diseases.

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  • The cause of pregnancy loss or perinatal death often remains unexplained, even following a standard autopsy. Comprehensive genomic investigation of pregnancy loss or perinatal death identifies a cause in over 50% of cases, particularly where congenital abnormalities are present. Causes of stillbirths without congenital abnormalities remain difficult to identify.

    Research Briefing
  • Clinical trials in neurological diseases often involve subjective, qualitative endpoints, such ‘by eye’ observations of movement. We developed an artificial intelligence–based method to analyze natural daily behavior data from people with Duchenne muscular dystrophy, using machine-learning algorithms to accurately predict their personal disease trajectories better than conventional clinical assessments.

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  • The large, ongoing CIRCULATE-Japan trial is investigating the role of circulating tumor DNA (ctDNA)-based molecular residual disease testing in patients with resectable colorectal cancer after radical surgery. An interim analysis of GALAXY, a prospective, observational arm of CIRCULATE-Japan, establishes ctDNA as a prognostic and predictive biomarker.

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  • A machine learning algorithm identifies four reproducible clinical subphenotypes of long COVID from the electronic health records of patients with post-acute sequelae of SARS-CoV-2 infection within 30–180 days of infection; these patterns have implications for the treatment and management of long COVID.

    Research Briefing
  • 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.

    Research Briefing
  • 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.

    Research Briefing
  • 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.

    Research Briefing
  • 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.

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  • 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.

    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.

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  • 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.

    Research Briefing
  • The identification of KRASG12C inhibitors has reignited interest in targeting RAS proteins. This work describes the discovery of the KRASG12D-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 KRASG12D mutation.

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  • 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.

    Research Briefing
  • 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.

    Research Briefing
  • 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.

    Research Briefing