A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA–lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran 1 (individualized neoantigen vaccine with backbone-optimized uridine mRNA–lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P  =  0.007). In responders, autogene cevumeran induces CD8+ T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8+ T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA–lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination.

To implement parallel transmit (pTx) 7T magnetic resonance imaging (MRI) in the pre‐surgical evaluation of 3T‐negative patients with drug‐resistant focal epilepsy, and to compare quality to conventional single transmit (specifically, circularly polarized [CP]) 7T MRI. We implemented a comparative protocol comprising both pTx and CP 7T MRI in consecutive adult candidates for epilepsy surgery who had negative or equivocal 3T MRI imaging. Here we report the outcomes from the first 31 patients. We acquired pTx and CP T 1 , T 2 , fluid‐attenuated inversion recovery (FLAIR) and edge‐enhancing gradient echo (EDGE) images, all in the same three‐dimensional (3D) 0.8 mm isotropic space. Two‐dimensional (2D) high‐resolution T 2 and T 2 *‐weighted sequences were acquired only in CP mode due to current technological limitations. Two neuroradiologists, a neurologist, and a neurosurgeon made independent, blinded quality and preference ratings of pTx vs CP images. Quantitative methods were used to assess signal dropout. 7T revealed previously‐unseen structural lesions in nine patients (29%), confirmed 3T‐equivocal lesions in four patients (13%), and disproved 3T‐equivocal lesions in four patients (13%). Lesions were better visualized on pTx than CP in 57% of cases, and never better visualized on CP. Clinical management was altered by 7T in 18 cases (58%). Nine cases were offered surgical resection and one laser interstitial thermal therapy (LITT). Three cases were removed from the surgical pathway because of bilateral or extensive lesions. Five cases were offered stereo‐electroencephalography (sEEG) with better targeting (in three because the 7T lesion was deemed equivocal by the multi‐disciplinary team (MDT), and in two because the lesion was extensive). Blinded comparison confirmed significantly better overall quality of pTx FLAIR images ( F (2, 184) = 13.7, p = 2.88 × 10 −6 ), whereas pTx MP2RAGE images were subjectively non‐inferior and had improved temporal lobe coverage with quantitatively less signal drop‐out. pTx‐7T is implementable in a clinical pathway, changed management in 58% of patients where 3T + FDG‐PET had not enabled resection, and is superior to single transmit 7T MRI.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly evolved over short timescales, leading to the emergence of more transmissible variants such as Alpha and Delta 1–3 . The arrival of the Omicron variant marked a major shift, introducing numerous extra mutations in the spike gene compared with earlier variants 1,2 . These evolutionary changes have raised concerns regarding their potential impact on immune evasion, disease severity and the effectiveness of vaccines and treatments 1,3 . In this epidemiological study, we identified two distinct patterns in the protective effect of natural infection against reinfection in the Omicron versus pre-Omicron eras. Before Omicron, natural infection provided strong and durable protection against reinfection, with minimal waning over time. However, during the Omicron era, protection was robust only for those recently infected, declining rapidly over time and diminishing within a year. These results demonstrate that SARS-CoV-2 immune protection is shaped by a dynamic interaction between host immunity and viral evolution, leading to contrasting reinfection patterns before and after Omicron’s first wave. This shift in patterns suggests a change in evolutionary pressures, with intrinsic transmissibility driving adaptation pre-Omicron and immune escape becoming dominant post-Omicron, underscoring the need for periodic vaccine updates to sustain immunity.

Abstract Introduction To estimate the effect of social media use in 14 year olds on risk of and inequalities in cigarette, e-cigarette, and dual use at 17 years, using the UK-representative Millennium Cohort Study (born 2000–2002). Aims and Methods The relationship of time spent on social media (using questionnaires [n = 8987] and time-use-diaries [n = 2520]) with cigarette, e-cigarette, and dual use was estimated using adjusted odds ratios (AORs) or relative risk ratios (ARRRs). Effect modification was examined (using parental education as an indicator for socioeconomic circumstances) by comparing adjusted risk differences within low and high-parental education groups. Analyses accounted for prespecified confounders (identified via directed acyclic graphs), baseline outcome measures (to address reverse causality), sample design, attrition, and item-missingness (through multiple imputation). Results Time spent on social media was associated with increased risk of cigarette, e-cigarette, and dual use in a dose–response manner. Social media use for ≥2 hours/day (vs. 1–<30 minutes) was associated with increased cigarette (AOR 2.76 [95% confidence interval 2.19 to 3.48]), e-cigarette (3.24 [2.59 to 4.05]), and dual use (ARRR 4.11 [2.77 to 6.08]). The risk of cigarette use among 30 minutes–<1 hour/day users (vs. non-users) were smaller in those with high versus low parental education (ARDs 1.4% vs. 12.4%). Similar findings were observed across the higher time categories. Analyses using time-use-diaries, in complete case samples, and with additional adjustment for baseline outcome measures generally revealed similar findings. Conclusions After accounting for observed confounders and potential reverse causality, findings suggest social media use increases the risk of cigarette, e-cigarette, and dual use in a dose–response manner. Guidance addressing adolescent online safety should be prioritized. Implications This study’s identification of a dose–response relationship and differential effects across socioeconomic groups, could assist in the development of guidance on time spent on social media. The adverse effects of social media use on adolescent cigarette, e-cigarette, and dual use supports legislation aimed at promoting adolescent online safety. Study findings strengthen calls to prohibit social media marketing of nicotine-related products and importantly highlight the need to increase awareness and understanding of the underlying algorithms which drive adolescent exposure to nicotine-related content on social media to ensure they are functioning in a way that best serves the adolescent population.

Healthy skeletal muscle can regenerate after ischaemic, mechanical, or toxin-induced injury, but ageing impairs that regeneration potential. This has been largely attributed to dysfunctional satellite cells and reduced myogenic capacity. Understanding which signalling pathways are associated with reduced myogenesis and impaired muscle regeneration can provide valuable information about the mechanisms driving muscle ageing and prompt the development of new therapies. To investigate this, we developed a high-throughput in vitro model to assess muscle regeneration in chemically injured C2C12 and human myotube-derived young and aged myoblast cultures. We observed a reduced regeneration capacity of aged cells, as indicated by an attenuated recovery towards preinjury myotube size and myogenic fusion index at the end of the regeneration period, in comparison with younger muscle cells that were fully recovered. RNA-sequencing data showed significant enrichment of KEGG signalling pathways, PI3K-Akt, and downregulation of GO processes associated with muscle development, differentiation, and contraction in aged but not in young muscle cells. Data presented here suggest that repair in response to in vitro injury is impaired in aged vs. young muscle cells. Our study establishes a framework that enables further understanding of the factors underlying impaired muscle regeneration in older age.

Organic molecules preserved in ancient Martian rocks provide a critical record of the past habitability of Mars and could be chemical biosignatures. Experiments conducted by the Sample Analysis at Mars instrument onboard the Curiosity rover have previously reported several classes of indigenous chlorinated and sulfur-containing organic compounds in Gale crater sedimentary rocks, with chemical structures of up to six carbons. Here, we report the detection of decane (C 10 H 22 ), undecane (C 11 H 24 ), and dodecane (C 12 H 26 ) at the tens of pmol level, released from the Cumberland drilled mudstone sample, using a modified SAM analytical procedure optimized for the detection of larger organic molecules. Laboratory experiments support the hypothesis that the alkanes detected were originally preserved in the mudstone as long-chain carboxylic acids. The origin of these molecules remains uncertain, as they could be derived from either abiotic or biological sources.