Tartu University Hospital

Developmental language disorder is characterized by difficulties in auditory processing and prosody perception. Estonian word prosody features a unique three-way quantity distinction, characterized by changes in syllable duration and pitch contour, which differentiate word meaning and grammatical cases. We investigated auditory discrimination in 50 children (25 with developmental language disorder), aged 4-7 years, using the event-related potential Mismatch Response and behavioral tasks longitudinally at two assessment points. Here, we specifically focus on the results of the second assessment and compared these results with those reported previously (Themas et al., 2025a) In the duration change condition, we observed a shift from a positive at mean age of 5;8 years to a negative Mismatch Response at mean age of 6;8 years, which was less pronounced in the developmental language disorder group compared to their typically developing peers. Interestingly, we found a significant negative association between the change of the Mismatch Response amplitude and behavioral discrimination, suggesting a stronger change from positive to a more negative Mismatch Response to be associated with better behavioral discrimination performance for both groups. In the duration and pitch change condition, no Mismatch Response was observed in either group at the first or second assessment. This study sheds light on the maturation of auditory change detection processes and deepens our understanding of the interplay between neurophysiological and behavioral indicators in children with and without language impairments.

Abstract Sex differences in atherosclerotic plaque biology underlie clinically distinct manifestations of acute coronary syndromes, yet the molecular mechanisms driving these differences remain incompletely understood. Endothelial-to-mesenchymal transition (EndMT) is increasingly recognized as a contributor to plaque remodeling, but whether EndMT is regulated in a sex-specific and stage-dependent manner across atherosclerosis has not been systematically examined. Here, we integrated bulk RNA sequencing with single-cell transcriptomic analyses in endothelial cells and human atherosclerotic plaques to define sex-specific EndMT regulation across healthy and advanced-stage disease. Using trajectory analyses in endothelial cells undergoing EndMT, we observed pronounced sex-specific regulation in healthy endothelium, with females exhibiting stronger early EndMT activation, whereas endothelial cells derived from atherosclerotic plaques displayed markedly attenuated sex differences with disease progression. Consistent sex-divergent pseudotime trajectories were observed in human carotid plaque endothelial single-cell RNA-seq data, with females showing greater EndMT activation at earlier stages and males at later stages. Together, these findings support a stage-dependent model of sex-specific EndMT regulation, indicating that the functional consequences of EndMT are highly context dependent and may differ across early and late disease stages. Integration of these datasets prioritized high-confidence sex-specific EndMT regulators, including COL4A1, PECAM1, CD151, JAG1, FN1, NEDD9, PODXL, MAFB, PROCR , and CDH13 , providing a mechanistic framework to explain clinically observed sex differences in plaque biology and to guide targeted functional interrogation.

Asthma severity is influenced by complex immunologic and environmental factors. While allergic asthma is linked to increased susceptibility to respiratory infections, the combined role of allergy and antibiotic-treated infections in progression to severe asthma has not been fully evaluated. To evaluate whether allergic asthma and recurrent respiratory infections (RRI) requiring antibiotics are associated with increased risk of developing severe asthma. We conducted a registry-based cohort study using Swedish national registry data. Adults with mild-to-moderate asthma were identified in 2014 (baseline) based on prescription records and absence of severe disease indicators. During a two-year exposure window (2015-2016), RRI was defined as ≥ 2 antibiotic prescriptions for lower respiratory tract infections. The outcome was development of severe asthma during 2017-2019, based on ERS/ATS treatment criteria. Allergic asthma was defined by ≥ 2 prescriptions for anti-allergic medications at baseline. Among 113,393 patients, 24,692 (21.8%) had allergic asthma. RRI occurred more frequently in allergic versus non-allergic asthma (7.5% vs. 5.9%, p < 0.001). A total of 869 patients (0.77%) developed severe asthma. Incidence was higher in those with RRI and highest among patients with both allergic asthma and RRI (2.0%), corresponding to a relative risk of 3.47 (95% CI: 2.49-4.83) versus patients with neither exposure. Results were consistent after adjustment for age, sex and comorbidities. Allergic asthma and antibiotic-treated respiratory infections were independent and additive predictors of severe asthma progression. These findings support a clinically actionable risk profile and may inform targeted preventive strategies in asthma management.

The gut microbiome has been shown to be affected by the use of many human-targeted medications, and the interaction can be bidirectional. This has been clearly demonstrated for type 2 diabetes medications that have been in clinical use for several decades. However, the bidirectional effects of novel type 2 diabetes drugs semaglutide, empagliflozin, and the gut microbiome have yet to be clearly described. Considering this, we investigate the effect of semaglutide and empagliflozin initiation on the gut microbiome of type 2 diabetes patients. In addition, we analyze whether the pre-treatment gut microbiome can predict the treatment efficacy. In the study, patients with type 2 diabetes donated gut microbiome fecal samples at four timepoints (Baseline, Month 1, Month 3, Month 12) that were studied using 16S ribosomal RNA gene sequencing and analysis. Subjects additionally donated plasma and urine samples for quantitative measurement of clinical markers before treatment initiation and at Months 3 and 12. Repeated measures ANOVA paired with paired t-tests were used to analyze the effects of drug initiation on the gut microbiome. Pearson correlation was used to identify microbial features associated with the change in clinical parameters. First, semaglutide and empagliflozin use is associated with changes in the gut microbiome after treatment initiation, but changes in microbial diversity were not detected. Moreover, the baseline gut microbiome predicted changes in glycohemoglobin for semaglutide and empagliflozin users. Based on the results, our findings suggest that semaglutide and empagliflozin impact the gut microbial community during treatment. In addition, the baseline gut microbiome can predict semaglutide treatment effects.

BackgroundChronic pancreatitis (CP) can lead to pancreatic exocrine insufficiency (PEI), causing protein malabsorption and altered amino acid levels. Our aim is to investigate amino acid levels in patients with CP and to assess the associations with exocrine insufficiency, pancreatic elastography, and the severity of CP.MethodsTwenty-five patients with CP were prospectively enrolled in this study. A control group included 28 age- and gender-matched subjects without pancreatic disease. Amino acids were quantified using the Biocrates MxP Quant 500 kit. Differences in amino acid levels were calculated using the non-parametric Wilcoxon test. Pancreatic stiffness was evaluated by EUS-elastography, PEI was assessed using fecal elastase-1 levels. The severity of CP was determined using the M-ANNHEIM classification.ResultsThe ratio of nonessential amino acids to essential amino acids, glutamic acid and aspartic acid levels were significantly increased in the CP group, whereas tryptophan levels were significantly decreased in CP. A positive correlation between proteinogenic amino acids and the severity of pancreatitis was found. Proline levels showed a strong correlation with the CP severity index (r = 0.63), a significant correlation with elastase-1 values (r = −0.48, p = 0.02), and a moderate correlation with pancreatic stiffness (r = 0.47, p = 0.09).ConclusionPatients with CP have altered amino acid blood levels, an increased ratio of nonessential to essential amino acids. The severity of CP was found to increase the levels of nonessential amino acids, with proline showing the strongest associations with severity, elastase-1 levels, and pancreatic stiffness.

Background and purposeAs more interventional clinical trials in Precision Cancer Medicine (PCM) are introduced, molecular descriptions of tumours have led to multiple subtypes, even within common tumour types. Therefore, the main limitation of these trials is the small number of eligible patients to assess the clinical benefit. The PRIME-ROSE project addresses this limitation by pooling data from multiple European Drug Rediscovery Protocol (DRUP)-like clinical trials, such that slowly accruing cohorts are accelerated. To achieve this task, a well-documented commonly approved procedure for data merging needs to be established.Patient/material and methodsData sharing is achievable when there is an organisation that includes people from different disciplines who can navigate institutional and country-specific information and governance requirements. Furthermore, alignment of all the study procedures are needed before data are shared. Next, the process of merging data requires harmonisation and standardisation. Implementation of the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) facilitates future data aggregation.ResultsBy aggregating data from European DRUP-like clinical trials, cohorts are completed that were unable to do so in stand-alone studies. Since initiation, the PRIME-ROSE project monitors over 300 cohorts across more than 20 treatments encompassing over 1,000 patients. At least 20 cohorts have progressed after interim analysis.InterpretationData sharing across European trials is feasible and enhances the advancements of PCM studies. The methodologies developed in the PRIME-ROSE project provide a foundation for future data integration efforts in PCM clinical trials, underscoring the viability of conducting robust trials in a global context.

Diabetes might increase risk of bladder cancer (BCa) incidence and bladder cancer specific death. To assess the potential association between diabetes and prognosis of BCa. Register-based cohort study included 14,638 participants with BCa diagnosed in Finland during 1995-2012. Three databases were used to obtain information on BCa, diabetes and comorbidities. Hyperglycemia was determined by blood glucose or HbA1c. The role of antidiabetic medication use was also assessed. Associations between diabetes and BCa-specific and overall mortality were evaluated using multivariable Cox regression models. During median follow-up of 4.3 years after BCa diagnosis 3,582 (24.5%) participants died of BCa. Diabetic post-diagnostic blood glucose level was associated with worse BCa-specific HR 1.58 (1.10-2.28) and overall survival HR 1.50 (1.20-1.89). The risk increase was slightly lower among hyperglycemic DM medication users (HR 1.43 (0,68-3.02) than non-users HR 1.80 (1.13-2.85). The main limitation of this study was insufficient information on tobacco smoking. Diabetes and diabetic glycemic status were associated with increased risk of both overall and BCa-specific death. In a Finnish population-based cohort study, diabetic bladder cancer patients had worse prognosis compared to non-diabetics. This was observed in both genders.

Acute myeloid leukemia (AML) includes genetically defined subsets. In allogeneic hematopoietic cell transplantation (allo-HCT), the frequency and prognosis of gene-gene interactions may differ from those of patients treated with chemotherapy alone. In this study, adult patients (N = 952) with AML allografted between 2015 and 2023, with available next generation sequencing (NGS) at diagnosis were included. Most frequent mutations were DNMT3A (24%), FLT3-ITD (21%), NPM1 (21%), RUNX1 (16%), NRAS (16%), TET2 (14%), and IDH2 (12%). Multiple correspondence analysis identified distinct groups of co-occurring mutations. Outcome analysis was performed on 646 AML patients allografted in first complete remission (CR1). Six non-overlapping groups were constructed: 1) TP53 mutation (N = 47); 2) NPM1 mutation (N = 129); 3) FLT3-ITD and/or DNMT3A mutation (N = 128); 4) SRSF2 and/or ASXL1 and/or RUNX1 mutation (SAR group) (N = 132); 5) IDH1 and/or IDH2 and/or TET2 mutation (N = 43); and 6) all ten genes unmutated (N = 167). In multivariable analysis, TP53 mutation, adverse karyotype, and age negatively affected leukemia-free survival (LFS) and overall survival (OS). OS was additionally negatively affected when the ten genes were unmutated. Notably, outcomes were excellent for SAR mutations (2-year LFS 76%, OS 84%), indicating allo-HCT in CR1 can overcome their adverse risk at diagnosis.