Background Pancreatic ductal adenocarcinoma (PDAC) ranks among the deadliest malignancies, with limited survival benefits despite recent therapeutic advances. Few prognostic biomarkers are available for PDAC monitoring in clinical practice. We conducted a meta-analysis to evaluate and synthesise evidence on the prognostic significance of miRNA expression in PDAC. Methods The protocol was registered with PROSPERO (CRD42023463542). We conducted a systematic search in PubMed, CENTRAL, and Embase on January 27, 2026, to identify studies assessing miRNA expression levels in patients with PDAC with reported overall survival (OS) or progression-free survival (PFS) outcomes. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Prediction intervals (PI) were reported if feasible. Separate analyses were performed by miRNA functional categories: oncogenic, tumour suppressor, chemoresistance-related, metastasis-related, and dual-role miRNAs. Findings A total of 142 studies, including 13,824 patients, were included. High expression of oncogenic miRNAs was associated with worse univariate OS (HR 1.70, 95% CI 1.38–2.10; 95% PI 0.63–4.57) and PFS (HR 2.25, 95% CI 1.63–3.10; 95% PI 1.11–4.55). High expression of chemoresistance-related miRNAs was associated with worse multivariate OS (HR 2.11, 95% CI 1.68–2.66; 95% PI 0.96–4.68) and PFS (HR 2.51, 95% CI 1.89–3.33; 95% PI 1.58–3.97). Between-study heterogeneity varied substantially across pooled analyses (I2 range 0–94%). miRNA-21 was the most frequently studied individual biomarker and showed a consistent association with worse multivariate OS (HR 2.24, 95% CI 1.95–2.57; 95% PI 1.92–2.61). Interpretation Elevated expression of oncogenic and chemoresistance-related miRNAs is associated with worse survival outcomes in PDAC. However, substantial heterogeneity and wide prediction intervals observed in several pooled analyses indicate variability in effect sizes across studies. Among the investigated biomarkers, miRNA-21 has shown the most consistent prognostic association and may represent the strongest candidate for future clinical implementation. Further validation and standardisation are required before miRNA profiling can be integrated into routine clinical practice. Funding None to declare.
Background Early life is a critical window for co-development of the brain and gut microbiome (GM). Evidence supports a role for the GM in brain development, but longitudinal human data remain limited, particularly regarding the influence of social disadvantage (SD), a powerful determinant of child mental health and neurodevelopment. Here, we examine longitudinal relationships between the GM and neurodevelopmental outcomes over the first three years of life, and the impact of SD on them. Methods We sequenced and analysed stool samples of 187 children, collected at 5 timepoints over 4–36 months of life (MOL; 905 samples) using a whole-metagenome sequencing approach. Associations between GM-derived Gut-Brain Modules (GBM) and neuroactive potential were assessed using generalised linear mixed models, adjusting for covariates. Neurodevelopmental outcomes were evaluated by Bayley-III (cognitive, language, and motor), and neurobehavioural dysregulation and externalising/internalising-behaviour by the Infant-Toddler Social and Emotional Assessment (ITSEA) and Preschool Age Psychiatric Assessment (PAPA). Findings Temporal changes were observed in GBMs, including glutamate/GABA synthesis and degradation pathways, as well as short-chain fatty acids. GM community structure and GBMs were significantly associated with concurrent and later Bayley-III outcomes, most consistently for cognition and language (FDR < 0.10). Several GBMs were associated with both neurobehavioural outcomes and SD, including S-adenosylmethionine (SAM) synthesis, butyrate synthesis, and glutamate and GABA synthesis II (FDR < 0.10). A partial mediating effect between SD and 36 MOL language outcomes was observed using SAM synthesis at 4 MOL (β = −0.042, P = 0.048). Interpretation This longitudinal cohort study of GM neuroactive metabolic capacity across early transitional developmental windows reveals a dynamic pattern of GM-derived neuroactive metabolic pathways and identifies specific pathways associated with later neurodevelopmental (cognitive, language) and neurobehavioural outcomes, even after controlling for important covariates. These pathways are shaped by the socioeconomic status of mothers, starting with in-utero exposure, and GBMs partially mediated this effect. The study identifies microbial pathways associated with both SD and neurodevelopmental outcomes, highlighting potential biological processes that may contribute to neurodevelopmental risk and warrant further investigation. Funding This work was supported by the National Institute of Mental Health, March of Dimes, Children’s Discovery Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and National Center for Advancing Translational Sciences.
Background Early antiretroviral therapy (ART) after perinatal HIV infection can restrict reservoir size and diversity, offering potential for remission. We evaluated HIV-1 DNA dynamics up to four years of age and predictors of reservoir size in early-treated African children. Methods In this prospective, multicentre cohort study, infants with perinatal HIV from South Africa, Mozambique, and Mali who initiated ART before 6 months of age and within 3 months of diagnosis were enrolled. Children were followed at 2, 6, 12, and 24 weeks, then biannually for 4 years. Total HIV-1 DNA in PBMCs was quantified longitudinally by droplet digital PCR in 207 children. The main outcomes were HIV-1 DNA reservoir size at year 3 (log10 copies/million PBMC) and longitudinal HIV-1 DNA decay. Multivariable models were developed to identify predictors of reservoir size using generalised additive regression models, and decay dynamics were evaluated using mixed-effects Poisson models including random intercepts and viral load slopes. Findings Of 207 children, 155 (75%) had >12 months of follow-up. HIV was diagnosed at a median age of 31 days (IQR: 0, 47) and ART started at 33 days (IQR: 23.5, 69.5). Nineteen of 155 (12.3%) had undetectable HIV-1 DNA at year 4. Median decay rate was −0.020 log10 copies/million cells/month (−0.212/year). Smaller reservoirs at year 3 were associated with lower pre-ART viral load (β = 0.26, 95% CI: 0.09, 0.43) and faster first-year HIV-1 DNA decay rate (β = 1.09, 95% CI: 0.02, 2.19), with trends toward smaller reservoirs among females (β = −0.41, 95% CI: −0.87, 0.04) and larger reservoirs among children whose mothers reported social challenges (β = 0.42, 95% CI: −0.04, 0.87). Faster decay correlated with longer time on ART, lower serial viral loads, sustained viral suppression >12 months, earlier ART initiation, and region (Mali). Maternal health issues correlated with slower decay. Eleven “excellent controllers” maintained durable viral suppression, immunological control, and undetectable total HIV-1 DNA at last follow-up. Interpretation Early virological parameters may help identify children likely to develop smaller HIV reservoirs. Early ART is key to faster reservoir reduction. Maternal health issues influence reservoir decay, reflecting a parental legacy effect. Sex differences should be further explored to understand mechanisms of reservoir control. Children with sustained virological suppression, preserved immune status, and undetectable total HIV-1 DNA may represent candidates with favourable characteristics for HIV remission strategies, as these factors have been associated with a reduced burden of persistent HIV infection and have been observed in rare cases of post-treatment control. Funding EPIICAL consortium through ViiV Healthcare and Penta Foundation.
Background Tecovirimat was developed as an antiviral countermeasure against orthopoxviruses and approved by the US Food and Drug Administration Animal Rule based on efficacy in preclinical studies and clinical pharmacokinetic and safety trials. However, recent randomised clinical trials in patients with mpox who initiated tecovirimat an average of 6–9 days after onset of symptoms did not show improvement in time to resolution of skin lesions. Here, we evaluated whether timing of tecovirimat initiation influenced antiviral efficacy following mpox infection in nonhuman primates and defined the therapeutic window for treatment initiation. Methods In this randomised preclinical study, 32 cynomolgus macaques were challenged intravenously with 1 × 106 TCID50 mpox clade IIb virus. Oral tecovirimat (10 mg/kg, once daily for 14 days) treatment was initiated on Day 2 (post-exposure and pre-symptomatic), Day 5 (early symptomatic), or Day 9 (peak symptomatic) after mpox challenge, or no treatment was given as a control group. The primary study endpoint was area under the curve (AUC) and peak numbers of progressive skin lesions. The secondary endpoint was AUC and peak levels of plasma viral loads. Additional analyses included total skin lesions, adaptive immune responses, and transcriptomic signatures. Findings Treatment adherence was 100%. All tecovirimat-treated animals survived to study completion on Day 28, whereas two untreated control animals required early euthanisation on Days 16 and 17. Tecovirimat efficacy was time-dependent. Progressive skin lesion AUC was significantly lower when treatment was initiated on Day 2 (P < 0.0001) or Day 5 (P = 0.0359) compared with untreated controls, but treatment was largely ineffective when initiated on Day 9 (P > 0.99). Interpretation In this randomised preclinical study, tecovirimat demonstrated antiviral therapeutic efficacy but only when initiated early prior to peak viraemia. These findings emphasise the importance of early initiation of treatment and define the therapeutic window for optimal tecovirimat treatment in nonhuman primates. Funding This study was supported by SIGA Technologies.
