BackgroundSpeech-based features extracted from telephone-based cognitive tasks show promise for detecting cognitive decline in prodromal and manifest dementia. Little is known about the cerebral underpinnings of these speech features.ObjectiveTo examine associations between speech features, brain atrophy, and longitudinal cognitive decline in individuals at risk for Alzheimer's disease (AD).MethodsHealthy volunteers, individuals with subjective cognitive decline, and those with mild cognitive impairment completed phonebot-guided semantic verbal fluency (SVF) and 15-word verbal learning task (VLT). Speech features were automatically extracted, and a global cognitive score (SB-C score) was computed. We analyzed data from 161 participants for cognitive trajectories, 141 for cross-sectional brain atrophy, and 102 for longitudinal brain changes. Analyses were conducted using multiple linear regressions, mixed-effects models, and voxel-based morphometry.ResultsThe SB-C score was associated with bilateral hippocampal volumes, SVF features were primarily associated with left hemisphere regions, including the inferior frontal, parahippocampal, and superior/middle temporal gyri (p_uncorr < 0.001). SB-C score, SVF correct counts, and VLT delayed recall were associated with atrophy rates in the hippocampal/parahippocampal gyrus and left middle/inferior temporal gyri (p_FDR < 0.05). These features were also associated with cognitive decline assessed via Preclinical Alzheimer's Cognitive Composite 5, SVF, and Wordlist learning delayed recall (p_FDR < 0.01). Word frequency and temporal cluster switches showed varying associations with cognitive trajectories. Other features did not show robust associations.ConclusionsIn this study, we highlight the potential of digital speech features for identifying brain atrophy and cognitive decline over time in at-risk AD populations.

Osteoporotic fractures are a major public concern as a serious, fatal condition. We aimed to investigate the differences in the incidence and types of osteoporotic fractures between people with and without disabilities, including both mental and physical disabilities.

This is a serial cross-sectional study using the National Disability Registration and National Health Insurance claims data. After excluding individual with Paget's disease and cancer that damages bone, we analyzed trends and associated factors of osteoporotic fractures between 2008 and 2017.

The age-standardized incidence rate (ASIR) of osteoporotic fractures was higher in the disabled than in the non-disabled for 10 years (41.3 and 24.0 per 10 000 persons, respectively, in 2017). Vertebral fractures were the most common. However, the incidence of non-vertebral fractures was about twice as high in the disabled as in the non-disabled. In multivariate analysis, the highest odds ratios were observed for epilepsy (OR = 3.80; 95% confidence intervals = 2.40-5.99), liver disease (OR = 2.38), and intellectual disability (OR = 1.95) in men and for epilepsy (OR = 3.19), liver (OR = 1.64), and respiratory (OR = 1.49) disease in women.

Given the preventability and high incidence of fracture in disabled people, health systems should be designed to ensure timely and appropriate prevention and intervention for disabled people.

Previous studies have indicated that adolescents are susceptible to emotional cues and can benefit from peers' interpersonal emotion regulation (IER). However, it remains unclear how an adolescent regulator's personal traits shape an effective IER. The present study examined the role of regulator's trait empathy and social distance between the regulator and the target on IER effectiveness among adolescents and explored the underlying behavioral mechanism. A total of 420 adolescent dyads with ages ranging from 12 to 18 years participated (212 dyads of friends; 208 dyads of strangers). After reporting their empathy levels, each regulator inferred the emotional intensity of the target based on the given negative events the target had experienced and then wrote down regulation strategies. Targets rated their own emotions before and after reading regulation strategies and evaluated the suitability of the strategies for them. The results showed that regulators with higher cognitive empathy were better at accurately perceiving targets' negative emotions, which, in turn, enhanced their regulation effectiveness. Similarly, regulators' behavioral empathy was positively related to regulation effectiveness through target-perceived strategy suitability. Additionally, close social distance enhanced the role of regulator's cognitive empathy in emotion perception accuracy and strengthened the impact of the regulator's behavioral empathy on regulation effectiveness. In contrast, closer social distance weakened the positive effect of regulator's behavioral empathy on target-perceived strategy suitability. These findings first highlight how and when different components of an adolescent regulator's trait empathy are linked to IER effectiveness, emphasizing the importance of adopting a dyadic design in the field of IER. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Myhre syndrome is a rare progressive genetic disorder characterized by hearing loss, cardiovascular and joint problems, neoplasia, and neuropsychologic disabilities. Parents of children with Myhre syndrome and adults themselves face unique challenges, stresses, and fears associated with this diagnosis. Reflective writing in the form of journaling can provide psychosocial support and help individuals cope with this diagnosis. Adult patients and parents whose children were evaluated at the Massachusetts General Hospital Myhre Syndrome Clinic were invited to participate in a three-month journaling intervention. Participation in the study required the completion of a series of surveys prior to starting and upon completion of the study. Data from these surveys were analyzed to assess for change in mental well-being. Eleven individuals participated, six of whom completed the three-month journaling intervention and post-journaling surveys. Three participants indicated that journaling had an impact on their mental well-being, and of these, two planned to continue journaling. However, there was no statistically significant difference in mental well-being scores pre- and post-journaling intervention. The very small size of the study limits interpretation, but we think it is reasonable to suggest that expressive writing through journaling may be a coping mechanism and means of improving well-being for some individuals in the Myhre syndrome community.

Asthma is characterised by variable airflow obstruction and is associated with symptoms of cough, wheeze, and dyspnoea, and with airway inflammation and hyperresponsiveness. There are approximately 300 million people with asthma worldwide. Despite a current plateau, the burden of this disease is likely to increase due to population growth, urbanisation, and ageing. Disease onset is associated with low birthweight, preterm birth, viral infections, in-utero passive smoke exposure, urbanisation, and occupational exposures. Obesity is associated with increased incidence and severity of asthma, whereas exposure to small allergen particles leads to severe disease. In adults and adolescents, inhaled corticosteroids in combination with formoterol (as anti-inflammatory reliever or as maintenance and anti-inflammatory reliever therapy) are widely recommended to control the symptoms of asthma. For children, low-dose inhaled corticosteroid is the preferred first-line treatment. Monotherapy with short-acting β-agonists is strongly discouraged. The WHO Global Action Plan for the Prevention and Control of Non-communicable Diseases includes availability of affordable combination inhalers for asthma. Co-ordinated national asthma policies, ensuring access to inhalers, have resulted in fewer hospitalisations and school and work absences. Future asthma prevalence could be reduced by good maternal and infant care, with reduction in premature births and reduction in infant respiratory infections, and by reduction in obesity at all ages.

Gestational diabetes mellitus is defined as any glucose intolerance that begins during pregnancy, and it is one of the most common metabolic disorders complicating pregnancies, affecting approximately 10-14% of all pregnancies. Maternal carbohydrate metabolism changes during pregnancy to ensure adequate nutrition for the fetus, with the human umbilical vein and the placenta being important regulators of this physiological state. This study aimed to evaluate fractalkine (FKN) immunoreactivity in GDM pregnancies and its association with maternal/fetal health outcomes.

In this case-control study, a total of 89 pregnant women (44 GDM and 45 non-GDM) underwent a 50 g glucose loading test (GCT) between 24 and 28 weeks of gestation. GCT cutoff value was chosen as <140 mg/dl. Women with high GCT values underwent rapid diagnostic testing with a 3-hour glucose tolerance test (GTT). Placenta samples were obtained after cesarean section. Immunohistochemistry for FKN was performed on formalin-fixed and paraffin-embedded sections. Finally, the relationship between FKN expression and clinical manifestations of GDM was evaluated.

FKN expression was significantly different between pregnant women with and without GDM. Specifically, FKN expression was increased in the capillary endothelium (p < 0.0001) and human umbilical vein endothelial cells (HUVECs) (p = 0.0011) in pregnant women with GDM compared to those without GDM. Furthermore, FKN expression in HUVECs was found to be associated with fetal macrosomia (p = 0.0099) and neonatal hypoglycemia (p = 0.0291). Additionally, FKN expression in the capillary endothelium was found to be associated with preeclampsia (p = 0.0250). Regarding the pathological changes of the placenta with FKN expression, significant correlations were identified with both capillary endothelial FKN expression and HUVEC FKN expression.

The observed differences suggest a potential association between the immunohistochemical expression of FKN and the presence of GDM, placental changes, and adverse outcomes of pregnancy.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are currently at the forefront of type 2 diabetes mellitus (T2DM) and obesity treatment development and usage. However, recent focus on multi-receptor agonism with glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) receptors has been investigated to assess for improved glycemic control, weight loss, and safety profile.

Several dual GLP-1/GIP RAs are currently in development, with the GIP receptor assisting GLP-1 in modulating central and peripheral pathways to prompt weight loss by increasing lipolysis and fat oxidation. Dual GLP-1/Gcg is another novel combination that utilizes the Gcg receptor which increases energy expenditure by stimulating glucose production, fat oxidation, and mobilization of energy stores to promote weight loss. Triple agonism of GLP-1/GIP/Gcg is still mainly being investigated in clinical trials, but preliminary results show similar if not improved glycemic control and weight loss. However, despite the multi-agonist approach, gastrointestinal adverse events do not seem to be mitigated compared to traditional GLP-1 RAs.

The current literature shows promising results for the efficacy of dual and triple agonism of GLP-1/GIP/Gcg receptors. Further research should focus on direct comparative studies between current GLP-1 RAs against these multi-receptor agonist agents.

Huanglian Zhimu decoction (HLZMD), a classical formulation in traditional Chinese medicine, has historically been utilized in the management of diabetes. However, its therapeutic efficacy and the underlying mechanisms in the context of T2DM, particularly in relation to hepatic lipid dysregulation, have yet to be systematically investigated.

To explore the potential therapeutic effects and molecular mechanisms of HLZMD on T2DM.

Initially, a T2DM model was established in spontaneously diabetic Goto-Kakizaki (GK) rats through high-fat diet induction. To elucidate the molecular mechanisms underlying the therapeutic effects of HLZMD, an integrative approach combining hepatic lipidomic profiling and transcriptomic sequencing was employed to identify HLZMD-responsive pathways. Furthermore, the expression levels of key proteins within the PDE4D/cAMP/PKA signaling pathway were quantified via western blotting in both rat liver tissues and palmitic acid-stimulated HepG2 cells. To validate the pathway specificity, pharmacological inhibition experiments were performed using roflumilast, a selective PDE4D antagonist. Lastly, the chemical composition of HLZMD was characterized through ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), and molecular docking analysis was conducted to predict potential active components interacting with PDE4D.

In vivo experiments demonstrated that HLZMD significantly ameliorated fasting blood glucose levels and hepatic steatosis in T2DM rats. Lipidomic analysis further revealed that HLZMD effectively restored the homeostasis of diacylglycerols (DG), triglycerides (TG), sterols (ST), sphingolipids (SP), and glycerophospholipids (GP) in the liver. Integrative analyses incorporating lipidomics, transcriptomics, and western blotting suggested that HLZMD-mediated hepatic lipid modulation may be attributed to the regulation of the PDE4D/cAMP/PKA signaling pathway. In vitro, HLZMD treatment resulted in a significant reduction in extracellular glucose concentrations as well as intracellular TC and TG levels. Concurrently, HLZMD markedly upregulated the expression of PDE4D, SIRT1, and PPARγ proteins while downregulating the expression of cAMP, phosphorylated PKA (p-PKA/PKA), and phosphorylated hormone-sensitive lipase (p-HSL/HSL). Notably, pharmacological inhibition with roflumilast, a selective PDE4D antagonist, partially reversed the HLZMD-induced reduction in lipid deposition, supporting the specificity of this pathway in mediating HLZMD's effects. Furthermore, UPLC-Q-TOF-MS identified 80 chemical constituents in HLZMD. Molecular docking analysis predicted that 21 of these compounds may exhibit direct binding affinity for PDE4D, potentially modulating the cAMP/PKA signaling cascade.

This study is the first to provide evidence that HLZMD exerts its pharmacological effects through multi-component interactions with PDE4D, thereby modulating the cAMP/PKA signaling pathway. This regulatory mechanism contributes to the reduction of hepatic lipid accumulation, attenuation of hepatic insulin resistance, and restoration of glucose and lipid metabolic homeostasis.

Cholangiocarcinoma (CCA), a devastating malignancy originating from the bile ducts, is of significant clinical importance due to its rising incidence and poor prognosis. Quinones as being naturally occurring compounds and their frequent utility in anticancer drug development studies seem to be potential sources for the discovery of new chemotherapeutics. In this study, a synthetic naphthoquinone derivative newly synthesized and previously published by our group, named as MK13, has been tested against intrahepatic-CCA (iCCA) cell lines (CCLP1 and HUCCT1). Cell viability was measured with the MTT assay at the doses of 1.56-50 µM for 48 h treatment. Cell death was showed both morphologically with fluorescent double staining and biochemically with flow cytometry analysis of phosphatidylserine translocation. Oxidative stress and DNA damage were also measured with flow cytometry and gene expressions were interpreted via qPCR analysis. MK13 resulted in a strong reduction (about 80%) in viability, especially against CCLP1 cells when compared with doxorubicin. Cell death resulted from apoptosis was shown to be triggered by severe DNA damage that is independent of oxidative stress. Apoptosis was confirmed at molecular level with the upregulation of BAX, a pro-apoptotic BH-3 only protein, and DR5, a cell surface death receptor. MK13 seems to be a promising anticancer compound against iCCA and deserves further attention for in vivo proof-of-concept studies.

Hepatocellular carcinoma (HCC) is a major global health concern due to its high prevalence and mortality rate. Although emodin, a natural anthraquinone derivative, has demonstrated in vitro anticancer activity against HCC cells, its specific molecular targets in HCC remain unclear.

This study used an integrated approach combining in silico network pharmacology, molecular docking, molecular dynamics simulations (MDS), and in vitro cytotoxicity assays to evaluate three emodin derivatives: emodin, 3-acetyl emodin (ACE), and 1,3,8-triacetyl emodin (TAEM). Target predictions were performed using the SwissTargetPrediction database, and HCC-related genes were retrieved from cBioPortal. Functional annotations (Gene Ontology and Reactome) identified EGFR and KIT as key targets. Docking simulations were conducted to assess binding affinities, followed by 100 ns MDS to evaluate stability. Cytotoxic effects on HepG2 cells were also assessed.

TAEM showed the strongest binding affinity to both EGFR and KIT and demonstrated the highest cytotoxicity against HepG2 cells (IC50 = 0.021 mM). MDS results indicated that the KIT-TAEM complex was the most stable among all tested combinations, supported by RMSD, RMSF, Rg, protein-ligand distance, and MM-GBSA binding energy analyses.

These findings highlight TAEM as a promising therapeutic candidate for HCC. The study demonstrates the value of integrating computational predictions with experimental validation in early-stage drug discovery.