Research Briefing

A study of nearly one million people who underwent a CT scan before 22 years of age finds that the radiation from CT scans increased the risk of hematological malignancies in a dose-dependent manner. These findings highlight the continued need to justify CT scans and minimize radiation doses.

The prevalence of aneuploid cells in miscarried human embryos is higher than previously quoted. Genomic imbalances seem to be less tolerated in the embryoblast than the trophoblast, which indicates that allocation of aneuploid cells to the inner cell mass during blastocyst formation might have a detrimental effect on embryo development.

We find that people with non-suppressible human immunodeficiency virus (HIV) viremia despite antiretroviral therapy (ART) exhibit several distinguishing features. These include expanded CD4⁺ T cell clones containing HIV proviruses integrated into transcriptionally permissive regions, the presence of certain proviral defects or human leukocyte antigen (HLA)-escape mutations, enhanced survival signatures, and muted interferon and cytotoxic CD8⁺ T cell responses.

The induction of neutralizing antibodies is the main goal of an HIV-1 vaccine, although data on the longevity of such antibodies is lacking. By tracking neutralizing antibodies in a large cohort of individuals infected with HIV-1 who had varying viral loads, we show that the HIV-1 neutralization response can last for several years even at low antigen levels.

By analyzing human samples and multiple mouse models of Huntington’s disease, we found that complement proteins and microglia mediate early and selective loss of corticostriatal synapses. Strategies that block this process can reduce synaptic loss, increase excitatory input to the striatum and prevent the development of cognitive deficits in mice.

Aberrant immune responses to the intestinal microbiome have emerged as major contributors to chronic intestinal inflammation, but the microbial species involved in inflammatory bowel diseases remain unknown. Our study identified dietary and commensal yeasts of the gut that drive the expansion of some cross-reactive CD4⁺ type 1 helper T cells with cytotoxic effector functions, which potentially contributes to immunopathology in patients with Crohn’s disease.

A spatially coupled, individual-based simulation of malaria in Rwanda was used to evaluate changes in drug policy in response to artemisinin-resistant Plasmodium falciparum. Our findings suggest that the deployment of multiple first-line therapies has the potential to reduce treatment failures and slow the fixation of resistant alleles in populations.

Clinical and population-based cohorts revealed an interaction between the inherited PNPLA3 p.I148M variant and female sex in determining liver disease. Transcriptomic and functional studies showed that the mechanism encompasses ERα-dependent upregulation of PNPLA3 in hepatocytes, highlighting a target for precision medicine therapeutics in cisgender women.

Whole-genome sequencing of Clostridioides difficile from a densely sampled intensive care unit (ICU) population showed that many of these patients harbor toxigenic C. difficile. This carriage did not lead to high levels of cross-transmission but was associated with a greatly increased risk of developing clinically overt C. difficile infection.

By integrating genomic and in vitro functional analysis, this study uncovers tumor-intrinsic mechanisms of resistance to immunotherapies that target B cell maturation antigen (BCMA) or the orphan G-protein-coupled-receptor GPRC5D in multiple myeloma (MM), highlighting a pivotal role for mutations in the genes encoding BCMA and GPRC5D in driving clinical relapse. These insights provide crucial guidance for the selection of therapeutic strategies and the development of next-generation targeted immunotherapies in MM.

Our study exposes the determinants of healthy aging in Latin America, underscoring the importance of the effects of social and health disparities compared with traditional factors such as age and sex. Our findings highlight an urgent need for more targeted detection of health risks, interventions and policies, particularly in low-income regions.

We performed gene therapy to induce expression of GDNF in the ventral tegmental area of rhesus monkey brains. Our approach countered the hypodopaminergic state that is associated with chronic alcohol drinking and reduced alcohol intake to fewer than two drinks per day while other ingestive behaviors remained intact. These findings, along with results from our ongoing clinical trials of GDNF gene therapy in other diseases, support future application of this approach in humans with alcohol-use disorder.

OncoNPC, a machine learning classifier developed to predict the primary origin of tumors, made confident predictions for over 40% of cancers of unknown primary (CUP) cases analyzed. Patients with CUP who had received site-specific treatments that retrospectively matched the OncoNPC predictions had better outcomes than patients who had been treated with discordant site-specific therapies. OncoNPC predictions doubled the number of patients with CUP who would be eligible for genomically guided therapies.

We transplanted gene-edited porcine hearts into two brain-dead human recipients, then evaluated their cardiac function and immune response over the following 66 hours. Both hearts showed sustained cardiac function over the course of the study, without evidence of hyperacute rejection or zoonotic transmission.

Alzheimer’s disease is a complex and chronic disease that evolves over decades. Proteomic analysis of cerebrospinal fluid from people with dominantly inherited forms of the disease reveals the temporal progression of pathological changes in Alzheimer’s disease and identifies extracellular matrix proteins as some of the earliest biomarkers of the disease.

Cost-effective fluid biomarkers for tau aggregate pathology would improve the diagnostic and prognostic work-up of Alzheimer’s disease and facilitate the discovery of anti-tau therapies. We identified MTBR-tau243 as a specific marker for tau aggregate pathology that could be implemented in clinical practice and trials.

This study reveals that the production of cobalamin and succinyl-CoA is increased in the anal microbiome of patients with precancerous anal lesions. Testing for these two metabolites significantly improves diagnostic accuracy over standard cytology screening, which suggests potential for enhanced screening strategies for anal cancer.

Genome-wide polygenic scores quantify inherited risk by integrating information from many common DNA variants and hold considerable promise for enabling personalized medicine. By integrating information on coronary artery disease (CAD) and CAD-related risk traits from genetic datasets that were larger and more diverse than those used in the past, we developed an improved multi-ancestry polygenic predictor for CAD.

We show that integrating multi-omic approaches with ultra-rapid whole-genome sequencing improves diagnosis in critically ill infants and children with rare diseases and can be successfully delivered on a national scale.

We investigated the presence of genetic variants for 105 genes previously associated with premature ovarian insufficiency (POI) in over 100,000 women. We found that predicted damaging variants in these genes were commonly found in the heterozygous state in women that had menopause within the normal age range. This suggests that monogenic causes of POI are rare, and that POI is more likely to be a polygenic disorder.