Reviews & Analysis

A large meta-analysis of genome-wide association studies (N >40,000) on perivascular space (PVS) burden, an emerging brain imaging marker of cerebral small vessel disease, has revealed 24 genetic risk loci for extensive PVS burden. These findings provide novel insights into the biology and clinical significance of this trait.

Lung adenocarcinomas (LUADs) encompass a broad spectrum of histological appearances. We use multi-region, prospective and longitudinal sampling from the TRACERx dataset to show the relationship between LUAD morphologies and their underlying evolutionary genomic landscape, as well as clinical risk and the nature of metastatic dissemination.

Body mass index (BMI) is a clinically useful obesity measure that shows an association with healthspan and lifespan. We developed ‘biological BMI’ scores, calculated from multi-omics data (proteins and metabolites) and clinical laboratory tests from blood. We show that a biological BMI more accurately reflects metabolic health and is more responsive to lifestyle changes than a classically measured BMI.

We used deep neural networks trained on optical histology and open-source genomic data to predict the molecular genetics of brain tumors during surgery. Our results represent how AI-based diagnostics can provide a valuable adjunct to wet laboratory methods for molecular testing in patients with cancer.

The authors describe a localized toxicity syndrome that is associated with immunotherapy treatment for CNS tumors and propose a new grading scale—with the goal of promoting research and standardizing both reporting and management.

The composition of the intestinal microbiome may predict clinical outcomes of CAR-T cell therapy for lymphoma, which could inform microbiota-based intervention strategies.

Integrative approaches continue to improve diagnostic accuracy for pediatric brain cancers, but much more is needed from researchers, governments and regulators if precision medicine with curative treatments are to become a reality.

Using a systems-level, multi-omics approach, we reveal several genes associated with arachnoid cysts and identify four phenotypic subtypes of arachnoid cysts, the severity of which correlates with the presence of protein-damaging de novo variants. All candidate genes are expressed in the developing brain and encode molecules implicated in chromatin modification or transcriptional regulation.

Cardiometabolic health is tightly linked to diet and the gut microbiome. This Review explains how meta-omics technologies are revealing the intricate links between them and discusses the most promising paths to clinical translation.

Using observational data from over 200,000 participants with up to 32 years of follow-up, we compared the strengths of eight healthy dietary patterns for general health. We found that diets that lowered hyperinsulinemia, chronic inflammation and diabetes risk may offer the greatest protection against chronic diseases.

The NEOSTAR trial is a key step on route to better outcomes; but the best approach is likely to be an individualized one, reflecting the many factors that influence treatment response.

We developed a compact database, called a ‘Rareservoir’, that contains the rare variant genotypes and phenotypes of 34,523 patients with a rare disease and 43,016 unaffected relatives. We inferred 260 genetic associations with rare disease classes, of which 19 were previously unidentified, and validated etiological roles for ERG, PMEPA1 and GPR156.

To meet a current unmet medical need, we generated 15 genetically engineered mouse models that accurately reflect the key pathogenetic aspects of human multiple myeloma. By coupling mechanistic investigations and pre-clinical immunotherapy testing, these pre-clinical platforms provide knowledge that will aid the optimization of future immunotherapy clinical trial design.

This Review surveys the NASH clinical trial landscape and the main challenges to drug approval, and discusses new approaches to overcoming these, including innovative trial designs, non-invasive tests and biomarkers.

Epidural spinal cord stimulation improved upper limb function in two participants after stroke, revealing a potentially exciting new tool for stroke recovery.

The widely used artificial sweetener erythritol affects platelet function and is associated with major cardiovascular events — fuelling calls for a re-evaluation of the use and regulation of non-nutritive sweeteners.

We describe a 53-year-old man with HIV-1 who received allogeneic CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) in 2013 to treat acute myeloid leukemia. Four years after analytic treatment interruption (ATI), the absence of viral rebound and the lack of immunological correlates of HIV-1 antigen persistence provide convincing evidence for HIV-1 cure.

High-resolution meta-omics have enabled the discovery of the microbial enzymes that inactivate an ulcerative colitis drug and predict subsequent treatment failure, an approach that could enable more personalized treatment of inflammatory bowel disease.

Pre-symptomatic gene editing in preclinical models of hypertrophic cardiomyopathy shows therapeutic promise; clinical studies are now needed to assess safety and efficacy in humans.

This Review discusses the effect of comorbidities and multimorbidity on the three mechanistically distinct phases of COVID-19, evaluating the evidence in the context of confounding factors and our evolving understanding of the disease.