A generalist medical language model for disease diagnosis assistance.

The delivery of accurate diagnoses is crucial in healthcare and represents the gateway to appropriate and timely treatment. Although recent large language models (LLMs) have demonstrated impressive capabilities in few-shot or zero-shot learning, their effectiveness in clinical diagnosis remains unproven. Here we present MedFound, a generalist medical language model with 176 billion parameters, pre-trained on a large-scale corpus derived from diverse medical text and real-world clinical records.

High-efficiency base editing in the retina in primates and human tissues.

Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.

Remotely delivered weight management for people with long COVID and overweight: the randomized wait-list-controlled ReDIRECT trial.

Long COVID (LC) is a complex multisymptom condition with no known disease-modifying treatments. This wait-list-controlled open-label trial tested whether a remotely delivered structured weight management program could improve respective LC symptoms in people living with overweight. Adults with LC (symptoms >12 weeks) and body mass index >27 kg m (>25 kg m for South Asians) were randomized (n = 234, 1:1) to control (n = 116, usual care) or the remotely delivered structured weight management (n = 118, total diet replacement (850 kcal per day) for 12 weeks, followed by food reintroduction and weight loss maintenance support) via minimization and randomization (80:20) to balance dominant LC symptom, sex, age, ethnicity and postcode-based index of multiple deprivation between groups.

Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer's disease in humans.

Background: Alzheimer's disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear.

Method: In this post-hoc analysis of a randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome in the context of AD biomarkers, analyzing 784 lipid species across 47 classes using a targeted lipidomics platform.

A decade of advances in human gut microbiome-derived biotherapeutics.

Microbiome science has evolved rapidly in the past decade, with high-profile publications suggesting that the gut microbiome is a causal determinant of human health. This has led to the emergence of microbiome-focused biotechnology companies and pharmaceutical company investment in the research and development of gut-derived therapeutics. Despite the early promise of this field, the first generation of microbiome-derived therapeutics (faecal microbiota products) have only recently been approved for clinical use.

A hybrid machine learning approach for the personalized prognostication of aggressive skin cancers.

Accurate prognostication guides optimal clinical management in skin cancer. Merkel cell carcinoma (MCC) is the most aggressive form of skin cancer that often presents in advanced stages and is associated with poor survival rates. There are no personalized prognostic tools in use in MCC.

One-quarter of freshwater fauna threatened with extinction.

Freshwater ecosystems are highly biodiverse and important for livelihoods and economic development, but are under substantial stress. To date, comprehensive global assessments of extinction risk have not included any speciose groups primarily living in freshwaters. Consequently, data from predominantly terrestrial tetrapods are used to guide environmental policy and conservation prioritization, whereas recent proposals for target setting in freshwaters use abiotic factors.

Sulfide-rich continental roots at cratonic margins formed by carbonated melts.

The cratonic crust contains abundant mineral deposits of metals such as gold, copper and rare earths and is underlain by a thick mantle lithosphere rich in the volatiles carbon, sulfur and water. Although volatiles are known to be key components in metallogenesis, how and where they are distributed in the cratonic lithosphere mantle and their role in the initial enrichment of metals have not been sufficiently explored. Here we compile sulfur and copper contents of global cratonic peridotites, identifying sulfide-rich and copper-rich continental roots at depths of 160-190 km at cratonic margins.

A rare PRIMER cell state in plant immunity.

Plants lack specialized and mobile immune cells. Consequently, any cell type that encounters pathogens must mount immune responses and communicate with surrounding cells for successful defence. However, the diversity, spatial organization and function of cellular immune states in pathogen-infected plants are poorly understood.

Site-saturation mutagenesis of 500 human protein domains.

Missense variants that change the amino acid sequences of proteins cause one-third of human genetic diseases. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences. Here we present a large-scale experimental analysis of human missense variants across many different proteins.

New Silurian aculiferan fossils reveal complex early history of Mollusca.

Mollusca is the second most species-rich animal phylum, but the pathways of early molluscan evolution have long been controversial. Modern faunas retain only a fraction of the past forms in this hyperdiverse and long-lived group. Recent analyses have consistently recovered a fundamental split into two sister clades, Conchifera (including gastropods, bivalves and cephalopods) and Aculifera, comprising Polyplacophora ('chitons') and Aplacophora.

Heritable polygenic editing: the next frontier in genomic medicine?

Polygenic genome editing in human embryos and germ cells is predicted to become feasible in the next three decades. Several recent books and academic papers have outlined the ethical concerns raised by germline genome editing and the opportunities that it may present. To date, no attempts have been made to predict the consequences of altering specific variants associated with polygenic diseases.

A lifespan-generalizable skull-stripping model for magnetic resonance images that leverages prior knowledge from brain atlases.

In magnetic resonance imaging of the brain, an imaging-preprocessing step removes the skull and other non-brain tissue from the images. But methods for such a skull-stripping process often struggle with large data heterogeneity across medical sites and with dynamic changes in tissue contrast across lifespans. Here we report a skull-stripping model for magnetic resonance images that generalizes across lifespans by leveraging personalized priors from brain atlases.

Second harmonic generation imaging reveals entanglement of collagen fibers in the elephant trunk skin dermis.

Form-function relationships often have tradeoffs: if a material is tough, it is often inflexible, and vice versa. This is particularly relevant for the elephant trunk, where the skin should be protective yet elastic. To investigate how this is achieved, we used classical histochemical staining and second harmonic generation microscopy to describe the morphology and composition of elephant trunk skin.

Genetic associations of plasma metabolites with immune cells in hyperthyroidism revealed by Mendelian randomization and GWAS-sc-eQTLs xQTLbiolinks analysis.

Mendelian randomization (MR) was employed to investigate the causal relationships between immune cell phenotypes, hyperthyroidism (HD), and potential metabolic mediators. In this study, we acquired 731 immune cell phenotypes from genome-wide association studies (GWAS) (n = 18,622), HD data from the research by Handan Melike Dönertaş et al. (3,731 cases, 480,867 controls), and aggregated statistics of 1,400 blood metabolites from UK Biobank (n = 115,078).

Biochar filtration of drug-resistant bacteria and active pharmaceutical ingredients to combat antimicrobial resistance.

Antimicrobial resistance (AMR) is a major cause of death worldwide, with 1.27 M direct deaths from bacterial drug-resistant infections as of 2019. Dissemination of multidrug-resistant (MDR) bacteria in the environment, in conjunction with pharmapollution by active pharmaceutical ingredients (APIs), create and foster an environmental reservoir of AMR.

Higher spatial resolution is not always better: evaluating satellite-sensed sea surface temperature products for a west Pacific coral reef system.

As marine heatwaves and mass coral bleaching events rise in frequency and severity, there is an increasing need for high-resolution satellite products that accurately predict reef thermal environments over large spatio-temporal scales. Deciding which global sea surface temperature (SST) dataset to use for research or management depends in part on the desired spatial resolution. Here, we evaluate two SST datasets - the lower-resolution CoralTemp v3.

Enhanced antibody responses in CD19-Cre mice.

CD19-Cre is an important and widely used Cre-lox model for B cell-specific genetic manipulation in murine systems. Mice carrying one allele of CD19-Cre are, at the same time, rendered heterozygote for CD19, a crucial coreceptor of the B cell antigen receptor (BCR). As a result, CD19-Cre mice exhibit diminished expression levels of CD19, with potential, yet insufficiently examined, consequences in B cell activation.

Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals.

The analysis of circulating tumour DNA (ctDNA) through minimally invasive liquid biopsies is promising for early multi-cancer detection and monitoring minimal residual disease. Most existing methods focus on targeted deep sequencing, but few integrate multiple data modalities. Here, we develop a methodology for ctDNA detection using deep (80x) whole-genome TET-Assisted Pyridine Borane Sequencing (TAPS), a less destructive approach than bisulphite sequencing, which permits the simultaneous analysis of genomic and methylomic data.

Controllable synthesis of Pd and Pt shells on Au nanoparticles with electrodeposition.

Shells of Pd and Pt were synthesized on Au nanoparticles by electrodeposition, leading to controllable size and optical properties. This approach yielded core-shell structures with good homogeneity in size after the optimization of electrochemical parameters such as deposition current and charge transfer, as well as nanoparticle surface treatment. Dark field scattering microscopy and spectroscopy were used to track changes in the optical response of individual particles during deposition.

Foundation dentists' attitudes and experiences in providing dental care for dependant older adults resident in care home settings.

Introduction: There is a continued increase of older dependant adults in England. Foundation Dentists (FDs) are often the dental workforce being tasked with providing dental care to dependant older adults resident in care home settings. This study explores whether FDs have the experience and confidence to deliver this.