Lila Sciences

The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philanthropy to explore advances and challenges in tauopathy research. The meeting highlighted progress across tau biology, including emerging models of tau regulation, degradation, and propagation; advances in biomarker development for the diagnosis and staging of tauopathies; and evolving therapeutic strategies targeting diverse aspects of tau pathophysiology. Discussions also emphasized the importance of cross-sector collaboration, and global initiatives to address disparities in tau research. This report synthesizes key insights from the conference and underscores the critical role of interdisciplinary, biomarker-driven, and globally inclusive approaches in accelerating the translation of tau research into effective clinical applications.

Endoscopic local triamcinolone injection is a standard therapy for esophageal stricture (ES) prevention after extensive endoscopic submucosal dissection (ESD); however, oral prednisolone administration is a promising alternative. This trial aimed to investigate the superiority of oral prednisolone administration to local triamcinolone injection for ES prevention after extensive ESD. This phase 3, open-label, multicenter, randomized controlled trial enrolled patients with extensive superficial esophageal squamous cell carcinoma. The primary endpoint was stricture-free survival (SFS). Secondary endpoints were the number of endoscopic balloon dilations (EBDs) for 12 weeks after ESD, dysphagia score ≤ 1 at 12 weeks after ESD, and adverse events (AEs). A total of 281 patients from 45 institutions were enrolled. The 12-week SFS rates were 88.5% (95% confidence interval [CI]: 81.6-92.9) and 94.8% (95% CI: 89.4-97.5) in the triamcinolone and prednisolone arms, respectively (hazard ratio 0.672, 90% CI [0.361-1.250], p = 0.14). Thirty-eight and 26 EBDs were performed for 14 and 10 patients, respectively, in the triamcinolone and prednisolone arms within 12 weeks after ESD. In the triamcinolone and prednisolone arms, 73.8% (95% CI: 65.7-80.8) and 80.7% (95% CI: 73.2-86.9) of patients, respectively, had dysphagia scores ≤ 1 at 12 weeks after ESD (p = 0.20). Grade 3/4 AEs occurred in 12 (8.7%) and 9 patients (6.7%) in the triamcinolone and prednisolone arms, respectively. While oral prednisolone administration and local triamcinolone injection demonstrated comparable outcomes, oral prednisolone did not demonstrate superiority for ES prevention after extensive esophageal ESD.

Gluten-free fermented products remain technologically challenging due to the absence of gluten, which plays a key role in stabilizing batter structure and gas retention. This study proposes a mixture design-driven approach to develop gluten-free Algerian pancakes based on rice and teff formulations enriched with legumes and seeds, aiming to restore techno-functional properties while improving nutritional quality. Two formulations, a teff-based (TBF) and a rice-based (RBF) system, were optimized using a simplex centroid mixture design and evaluated in comparison with durum wheat pancakes. The results demonstrated that formulation strongly influenced batter rheology and final structure. The TBF system exhibited superior technological performance, with higher specific volume (1.77 cm3/g), lower density (0.56 g/cm3), and enhanced porosity, associated with improved protein and fiber content. In contrast, the RBF formulation showed higher antioxidant activity. The findings highlight the critical role of component interactions in modulating batter viscosity and foam stability, which directly affected pore development and product airiness. Both optimized formulations successfully reproduced the characteristic "light and airy" structure of traditional pancakes, achieving good sensory acceptability. Overall, this study demonstrates that mixture design can effectively guide the development of gluten-free fermented systems by linking composition, rheology, and structural properties, providing a strategy for improving the quality of traditional gluten-free foods.

Lung cancer remains the leading cause of cancer mortality, yet blood-based biomarkers are not routinely used in diagnosis. This study evaluated four commercial blood protein assays, originally validated for other indications, in indeterminate pulmonary nodules (IPN). Using a prospective specimen collection, retrospective blinded evaluation design, samples were collected from patients with screening-detected, incidental, or symptomatic IPNs. Cytokeratin 19 fragment (CYFRA 21-1), carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125), and human epididymis protein 4 (HE-4) concentrations were quantified on commercial immunoassays. Logistic regression models were developed using internal training (Train), external testing (Test), and combined reestimation (Train + Test) cohorts and externally validated in an outcome-blinded multicenter cohort (Lung Team Project-2, LTP-2). This study included 816 patients: 371 in Train, 166 in Test, and 279 in LTP-2. Malignancy rates were 54%, 44%, and 64%, respectively. In Train + Test, the area under the receiver operating curve (AUC) for lung cancer was 0.60 (95% confidence interval, 0.56-0.65) for CYFRA 21-1, 0.62 (0.58-0.67) for CEA, 0.60 (0.55-0.65) for CA-125, and 0.65 (0.60-0.70) for HE-4. In LTP-2, AUCs were 0.63 (0.56-0.70), 0.64 (0.57-0.70), 0.48 (0.40-0.55), and 0.61 (0.54-0.68), respectively. Combining all four biomarkers yielded an AUC of 0.70 (0.65-0.74) in Train + Test and 0.61 (0.54-0.68) in LTP-2. In the first biomarker study reporting external validation in LTP-2, CYFRA 21-1, CEA, CA-125, and HE-4 demonstrated diagnostic value in IPNs. By leveraging commercial assays, this study highlights opportunities to enhance lung cancer risk stratification using widely available diagnostics that could be rapidly integrated into clinical workflows.

Enteric infectious diseases claim more than 1 million lives annually and are among the top ten causes of death in children younger than 5 years. Remarkable global investment has been dedicated to enteric infectious disease prevention and control; however, the shifting global health landscape is testing the continuance of progress. To evaluate the current status and guide future interventions, we present the latest epidemiological estimates of enteric infectious diseases from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 and assess progress towards the Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) mortality target of fewer than 20 deaths per 100 000 children younger than 5 years by 2025. We quantified the incidence, mortality, and disability-adjusted life-years (DALYs) of enteric infectious diseases by age, sex, and year across 204 countries and territories from 1990 to 2023. In GBD 2023, the following were considered under the category of enteric infectious diseases: diarrhoeal diseases, enteric fever (typhoid and paratyphoid), invasive non-typhoidal Salmonella spp (iNTS) infections, and other intestinal infectious diseases. We also examined 15 aetiologies contributing to diarrhoeal diseases. Incidence and prevalence were estimated with DisMod-MR (version 2.1), a Bayesian meta-regression tool, drawing on data from systematic reviews, population-based surveys, claims data, and hospital sources. Cause-specific mortality was modelled with Cause of Death Ensemble Modelling based on data from sources including vital registration, mortality surveillance, verbal autopsy, and minimally invasive tissue sampling. Years of life lost and years lived with disability were computed and combined to derive DALYs. For aetiology-specific estimation, population-attributable fractions (PAFs) for 15 pathogens were derived with a counterfactual framework. Point estimates and 95% uncertainty intervals (UIs) were generated from 250 draws from the posterior distribution. In 2023, enteric infectious diseases resulted in an estimated 1·27 million (95% UI 0·963-1·68) deaths globally, declining from 3·69 million (3·04-4·56) in 1990. The global age-standardised mortality rate (ASMR) decreased from 74·1 (62·0-92·9) per 100 000 population to 16·4 (12·6-21·3) per 100 000 population during the same period. Diarrhoeal diseases accounted for most deaths in 2023 (1·11 million [0·811-1·54]), followed by enteric fever and iNTS. South Asia and sub-Saharan Africa remained the most affected regions in 2023, with 599 000 (441 000-882 000) and 501 000 (373 000-648 000) deaths due to enteric infectious diseases, respectively, predominantly from diarrhoeal disease. Rotavirus was the leading cause of all-age diarrhoeal disease deaths (PAF 16·3% [12·0-21·5]), followed by norovirus (10·2% [2·4-17·0]) and Shigella spp (9·3% [5·4-15·2]). Among children younger than 5 years, PAFs of deaths due to diarrhoeal diseases were 40·2% (32·5-48·5) for rotavirus, 24·0% (15·1-36·7) for Shigella spp, and 23·4% (13·7-34·3) for adenovirus. Across 204 countries and territories, 141 met the GAPPD mortality target in 2023. The driving aetiologies among countries that did not meet the target in 2023 varied slightly by GBD super-region, but the highest or second-highest number of deaths in children younger than 5 years were consistently attributed to rotavirus. Astrovirus and sapovirus, newly included in GBD 2023, were responsible for 24 600 (6290-49 000) and 18 800 (4650-44 400) deaths, respectively, in 2023, mainly in children younger than 5 years. Our findings show that mortality and ASMRs of enteric infectious diseases declined substantially between 1990 and 2023. This decline is consistent with the expansion of public health measures and broader socioeconomic development. However, the burden in 2023 remains considerably high, with the highest mortality concentrated in sub-Saharan Africa and south Asia. Considering that more than a quarter of all countries had yet to meet the GAPPD mortality target in 2023, sustained efforts are needed to address the persistent burden in affected countries and to adapt to the changing global health landscape. Gates Foundation.

The genetic architecture of sporadic Early-Onset Alzheimer Disease (sEOAD, onset ≤65 years) remains largely unknown. To assess the de novo mutation (DNM) hypothesis, we performed a nationwide recruitment of 37 novel sEOAD patients-unaffected parents trios. After assessing known monogenic genes, we performed trio-based exome sequencing and jointly analyzed novel trios with 12 previously reported ones. Of these, we selected 16 trios for genome sequencing. We identified three patients with a pathogenic DNM in APP or PSEN1. Then, from the 46 remaining trios, we identified 38 non-synonymous coding DNM and 4 de novo copy number variants (CNVs) in exome data. Four DNM (2 novel, in SPHK2 and DDR1) and bi-allelic inherited variants in two genes affected Alzheimer disease-related genes. No significant burden of rare coding variants in exome/genome data from 5643 EOAD cases and 16097 controls was identified using nested windows centered on each DNM position, at the transcript level. From genome data, one non-coding DNM was predicted to affect splicing in an AD-associated gene, PINX1. Overall, 48% probands carried ≥1 inherited risk factor with odds ratio (OR) > 1.5 and GWAS-defined Genetic Risk Scores (GRS) distribution was more consistent with random distribution than enrichment in higher scores in probands. We confirm that DNMs in known monogenic genes explain sEOAD in a minority of cases, while candidate DNMs in other genes might account for a small proportion of additional cases. The majority of sEOAD patients may have a complex etiology including multiple inherited variants, however, GRS might not explain most of its genetic component.

Determining a gene's functional importance within a cellular context has long been a challenge, as absolute expression level is an unreliable indicator. Here we introduce SIGnature, a framework for scoring gene importance using attributions derived from single-cell RNA-sequencing (scRNA-seq) foundation models. Attribution scores reduce technical noise, emphasize regulatory genes and facilitate cross-dataset comparison-a core challenge for scRNA-seq analyses. We developed the SIGnature package as a tool for generating and querying attributions, enabling rapid gene set searches across large scRNA-seq atlases. We demonstrate its utility using the MS1 monocyte signature, a poorly understood gene program activated in severe COVID-19 and sepsis. Searching 400 studies identified associations between the MS1 signature and multiple hyperinflammatory conditions, including Kawasaki disease. Experimental validation confirmed that serum from persons with Kawasaki disease induces the MS1 phenotype. These findings highlight that SIGnature can uncover shared mechanisms across conditions, demonstrating its power for large-scale signature scoring and cross-disease analysis.