Nevin Manimala

Diabetologia. 2025 Nov 21. doi: 10.1007/s00125-025-06593-2. Online ahead of print.

ABSTRACT

AIMS/HYPOTHESIS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become an important option in clinical use for type 2 diabetes due to their dual benefits of glycaemic management and metabolic improvements. Efsubaglutide alfa, a novel long-acting GLP-1RA, was developed for sustained glycaemic management. This study aimed to confirm its recommended clinical dose and evaluate its efficacy and safety in drug-naive individuals with type 2 diabetes that was inadequately managed through lifestyle interventions.

METHODS: This two-stage Phase IIb/III trial employed an operationally seamless adaptive design and enrolled adults who had been newly diagnosed with type 2 diabetes and whose diabetes was inadequately managed by diet and exercise. In the Phase IIb stage, participants were randomised in a 2:2:2:1 ratio to receive once-weekly subcutaneous injections of efsubaglutide alfa (1, 2 or 3 mg) or placebo for 12 weeks. Based on an interim analysis, two recommended Phase III doses (RP3Ds) were selected by an independent data monitoring committee. In the Phase III stage, participants were randomised in a 2:2:1 ratio to receive efsubaglutide alfa at one of the two RP3Ds or to receive placebo. Participants, investigators and sponsors were masked to drug/placebo allocation throughout the trial. The primary endpoint was the change in HbA_1c from baseline to week 24. Secondary endpoints included changes in body weight and metabolic parameters at weeks 24 and 52. Safety was monitored throughout.

RESULTS: In the Phase IIb stage, 140 participants were randomised to efsubaglutide alfa (1 mg, n=41; 2 mg, n=39; 3 mg, n=41) or placebo (n=19). Based on interim analysis, 1 and 3 mg were selected as the RP3Ds. In the Phase III stage, 297 participants were randomised to efsubaglutide alfa (1 mg, n=118; 3 mg, n=117) or placebo (n=62). At week 24, the HbA_1c reductions from baseline were -18.91 mmol/mol (1.73%) (95% CI -20.98, -16.83) with the 1 mg dose, and -23.50 mmol/mol (2.15%) (95% CI -25.68, -21.31) with 3 mg. The estimated treatment difference vs placebo was -13.71 mmol/mol (-1.26%) (95% CI -17.39, -10.06) for the 1 mg dose and -18.36 mmol/mol (-1.68%) (95% CI -22.08, -14.64) for 3 mg. Additionally, 56% of participants receiving the 1 mg dose (95% CI 47, 65; p<0.001) and 68% of participants receiving the 3 mg dose (95% CI 59, 76; p<0.001) achieved an HbA_1c <53.0 mmol/mol (7.0%). There were significant reductions of fasting plasma glucose from baseline: 2.04 mmol/l (95% CI -2.40, -1.68) for the 1 mg dose, and 2.49 mmol/l (95% CI -2.87, -2.11) for 3 mg (estimated treatment difference vs placebo: -1.71 mmol/l [95% CI-2.34, -1.07] for the 1 mg dose, and -2.16 mmol/l [95% CI -2.80, -1.52] for 3 mg). There were also significant reductions in 2 h postprandial plasma glucose compared with the baseline: 3.7 mmol/l (95% CI -4.42, -3.03] for the 1 mg dose, and 4.6 mmol/l (95% CI -5.36, -3.86) for 3 mg (estimated treatment difference vs placebo: -3.2 mmol/l [95% CI -4.41, -1.98] for the 1 mg dose, and -4.1 mmol/l [95% CI -5.28, -2.88] for 3 mg). Body weight decreased by 0.97% (95% CI -1.76, -0.18) with the 1 mg dose and by 3.14% (95% CI -3.98, -2.31) with 3 mg (estimated treatment difference vs placebo: 0.97% [95% CI -0.41, 2.35] for the 1 mg dose, and -2.18% [95% CI -3.30, -1.05] for 3 mg). Gastrointestinal symptoms, including nausea, vomiting, diarrhoea and decreased appetite, were the most common adverse events, and were mostly mild to moderate in severity.

CONCLUSIONS/INTERPRETATION: Efsubaglutide alfa significantly improved glycaemic management and promoted weight loss in drug-naive individuals with type 2 diabetes, with a favourable safety profile. These results establish efsubaglutide alfa as a promising therapeutic option for type 2 diabetes and related metabolic disorders.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04994288 FUNDING: This study was sponsored by Innogen Pharmaceutical Co. Ltd.

PMID:41272211 | DOI:10.1007/s00125-025-06593-2

Support Care Cancer. 2025 Nov 21;33(12):1110. doi: 10.1007/s00520-025-10144-1.

ABSTRACT

PURPOSE: Lymphoma survivors face long-term treatment-related side effects that impact their quality of life (QOL) and needs. Yet, evidence on their specific challenges in the five years following diagnosis remains limited. Existing research has often examined unmet needs and QOL separately or within broader cancer populations, lacking a comprehensive analysis of their interconnections. This study explored the link between lymphoma survivors’ unmet needs and quality of life.

METHODS: A cross-sectional survey study recruited lymphoma survivors from the outpatient haematology-oncology services of five hospitals. The questionnaire comprised validated instruments for unmet needs (Short-Form Survivor Unmet Needs) and QOL (FACT-LYM and EQ 5D-5L). Descriptive statistics, hierarchical multiple regression and canonical correlation analyses were performed to analyse the data.

RESULTS: A survey was completed by 205 lymphoma survivors one to five years post-diagnosis. An increase in QOL was significantly associated with decreased unmet needs. Female and younger survivors were more likely to report higher unmet needs. The top two most frequently unmet needs items were ‘dealing with feeling tired’ (72.5%, n = 145) and ‘coping with having a bad memory or lack of focus’ (67.2%, n = 135).

CONCLUSION: The relationship between unmet needs and QOL among lymphoma survivors is complex, highlighting the need to address specific unmet needs and well-being dimensions to improve longer-term outcomes. This study supports the use of instruments to measure unmet needs, which help to identify survivors who may benefit from clinical attention or enhanced supportive care. The study findings suggest that interventions targeting unmet needs could improve survivors’ QOL.

PMID:41272209 | DOI:10.1007/s00520-025-10144-1

Sci Rep. 2025 Nov 21;15(1):41398. doi: 10.1038/s41598-025-25371-z.

ABSTRACT

Hypomyelinating leukodystrophies (HLDs) are genetic disorders characterized by deficient myelination. While TMEM63A variants are associated with HLD19, the specific lipid alterations in affected brain regions remain to be fully characterized. This study aimed to investigate the spatial distribution of lipid changes in a Tmem63a mutant rat model of hypomyelination. A homozygous Tmem63a c.500G > A p.(G167E) knock-in rat model (Tmem63a^G167E/G167E) was established. Brain sections from Tmem63a^G167E/G167E and Tmem63a^WT rats (n = 3/group) were analyzed using MALDI-MSI for lipid profiling across nine distinct brain regions. Myelin structure was characterized by transmission electron microscopy (TEM) and g-ratio quantification. Statistical analyses included Mann-Whitney U tests for g-ratio distributions and ROC analysis for feature screening. Out of 702 analyzed features, 124 were differentially expressed. Lipids constituted the most altered class (43 features), including 22 glycerophospholipid, 9 fatty acid, 5 sphingolipid, 5 sterol lipid, and 2 prenol lipid species. These alterations were predominantly observed in white matter-rich regions and gray-white matter junctions. TEM revealed thinner and less dense myelin sheaths in Tmem63a^G167E/G167E rats, with a reduced proportion of optimal g-ratios. This study provides a comprehensive spatial lipidomic characterization in a Tmem63a mutant rat model, revealing significant lipid alterations associated with hypomyelination. These findings offer new insights into the pathology of hypomyelination and highlight specific lipid species for future investigation.

PMID:41272208 | DOI:10.1038/s41598-025-25371-z

Commun Chem. 2025 Nov 21. doi: 10.1038/s42004-025-01803-9. Online ahead of print.

ABSTRACT

Stereoselective synthesis of cis- and trans- configurations remain challenging in molecular systems. Here, asymmetric 90^o Pt(II) acceptors enable stereoselective coordination-driven self-assembly of configuration-specific [Pt₂L₂] metallacycles. The coordination of trimethylphosphine or triethylphosphine (PR₃) and phosphangulene (Phang) to the Pt(II) centers yielded two asymmetric cis-PtCl₂(PR₃)(Phang) complexes. Upon ligand exchange, these acceptors assemble with the bispyridyl ligands to form statistical mixtures of cis- and trans- metallacycles. Stereoselective self-assembly is achieved by modifying the bis-pyridyl ligand with N-ortho-bismethyl groups, leveraging intramolecular C-H···π interactions with Phang, steric effects, and 90^o Pt(II) heteroligation to selectively generate trans- or cis- isomers. The stereochemistry is confirmed by NMR spectrometry, investigation of the mass spectrometry, density functional theory calculations, and single-crystal X-ray diffraction. Notably, hierarchical self-assembly in the crystalline state revealed stark structural divergences between trans- and cis- metallacycles, offering key insights into stereo-controlled supramolecular design.

PMID:41272184 | DOI:10.1038/s42004-025-01803-9

Sci Rep. 2025 Nov 21;15(1):41353. doi: 10.1038/s41598-025-25329-1.

ABSTRACT

The objective of this study was to investigate symptoms after vaccination with different COVID-19 vaccines reported from employees in an Austrian University hospital. A paper-based survey was conducted among adult employees of an Austrian University Hospital after receiving a first, second or booster dose of a COVID-19 vaccine during January 2021 and January 2022 to identify any side effects reported by participants. The survey further inquired about the participants’ demographic information, sick leave or hospitalisation due to the symptoms. Out of the approximately 5000 persons who have been vaccinated, 1093 participants completed the survey. A total of 818 of 1029 employees (79%) reported symptoms after the first, 613 of 1007 employees (61%) reported symptoms after the second and a total of 814 of 974 employees (84%) reported symptoms after booster vaccination. There were differences in the type of vaccination in relation to and number of different symptoms, sick leave as well as anxiety. In conclusion, according to the COVID-19 vaccine type, different side effects might occur following the first, second and booster doses of vaccination. These findings assist in addressing problems of vaccination hesitancy.Trial registration: ClinicalTrials.gov: NCT06035926, 2023-08-28 (retroactively registered).

PMID:41272132 | DOI:10.1038/s41598-025-25329-1

Commun Biol. 2025 Nov 21. doi: 10.1038/s42003-025-09214-1. Online ahead of print.

ABSTRACT

Accurate genotype imputation is essential for large-scale genetic studies and precision medicine. While East Asian (EAS)-specific reference panels like ChinaMAP and CHN100k have been developed, most studies still rely on multi-ancestry panels like TOPMed due to the large sample size. However, their performance in underrepresented groups like Southeast Asians remains unclear. Using high-coverage whole-genome sequencing and SNP-array data from 8,316 Chinese and Thai individuals, we systematically evaluate six state-of-the-art reference panels for genotype imputation. Our results show that EAS-specific panels outperformed multi-ancestry panels for East and Southeast Asian populations. For example, ChinaMAP achieves a mean heterozygosity concordance rate above 0.90 without R² filtering, whereas TOPMed requires an R² threshold of 0.60-0.70 to achieve comparable results. Notably, we find that recent positive selection drives regional disparities in imputation accuracy, as illustrated by the olfactory receptor gene cluster. More importantly, our results indicate that the choice of reference panel and R² thresholds have a significant impact on polygenic risk score estimation for disease prediction. These findings provide valuable guidelines for improving genotype imputation in East and Southeast Asian populations and underscore the need for ancestrally diverse reference panels to support globally equitable genomic research.

PMID:41272119 | DOI:10.1038/s42003-025-09214-1

Sci Rep. 2025 Nov 21;15(1):41404. doi: 10.1038/s41598-025-25291-y.

ABSTRACT

This paper presents a control of adaptive regularization for a hybrid variational model and its application to the denoising of color images, which combines total variation (TV) and [Formula: see text] regularizers with normalized data fidelity. The designed adaptive control works locally and is performed by a control parameter that intelligently selects the appropriate diffusion operator for smoothing (quadratic) and edge preservation (nonquadratic). In addition to combined diffusion operators, data term was normalized to ensure good balance between diffusion and fidelity terms. The idea of complementary data normalization enhances performance under high noise levels and mitigates artifacts. The resulting optimization framework leads to a time-dependent partial differential equation that is discretized using standard finite differences. Simulation experiments on benchmark data sets demonstrated that the proposed method consistently outperformed over conventional denoising techniques in terms of edge preservation, noise reduction and computational efficiency. Quantitative evaluation was performed using the peak signal-to-noise ratio (PSNR), structural similarity index (SSIM), root mean square error (RMSE), and convergence time (CT). A comparative analysis with state-of-the-art variational denoising models further highlights good performance of proposed approach in preserving sharp structural details while achieving effective noise suppression.

PMID:41272118 | DOI:10.1038/s41598-025-25291-y

Commun Biol. 2025 Nov 21. doi: 10.1038/s42003-025-09118-0. Online ahead of print.

ABSTRACT

Congenital heart defects, particularly those affecting the outflow tract (OFT), represent a significant cause of neonatal morbidity and mortality. The genetic and cellular mechanisms underlying OFT abnormalities, especially the migration of second heart field (SHF) cells, remain poorly understood. In this study, we identify two distinct migratory pathways for Osr1-expressing posterior SHF cells directed toward the OFT and inflow tract (IFT). We show that Osr1 regulates two key ligand-receptor signaling axes, Hedgehog-Ptch1 and Cxcl12-Cxcr7, both of which are essential for the directed migration of Osr1⁺ cells toward the OFT. We establish that Smo and Ackr3 (encoding CXCR7) are direct transcriptional targets of Osr1. Functional studies demonstrate that Osr1-Hh signaling governs SHF cell migration and OFT development, while Osr1-Cxcl12 signaling likely acts in synergy to support this process. These findings underscore the pivotal role of Osr1+ pSHF cells in directing heart pole development and reveal crucial ligand-receptor interactions involved in cell migration, potentially guiding future therapeutic targets for congenital heart defects.

PMID:41272108 | DOI:10.1038/s42003-025-09118-0

Sci Rep. 2025 Nov 21;15(1):41167. doi: 10.1038/s41598-025-26626-5.

ABSTRACT

Mechanical methods are hypothesized to have postoperative pain and more seroma formation than non-mechanical methods due to tissue trauma. Therefore, the current prospective cohort study aimed to assess postoperative pain and quality-of-life (QoL) after fibrin glue versus tack mesh fixation. From July 2022 to December 2023, 80 patients sought TEP at the Suez Canal University Hospitals outpatient clinic. Participants were divided into two groups based on mesh fixation: the Fibrin glue group (FG) and the Tack group (TG). The purpose of this study was to compare the rate of post-operative complications, post-operative pain, length of hospital stays, and wound complications. In the meantime, the two groups QoL were compared using the SF-36 scoring questionnaire and the Caroline Comfort score (CCS). The patients in TG had higher operative time (84.5 ± 5.5 min) compared to patients in FG (78.3 ± 6.4); without statistical significance (p = 0.21). The FG had a statistically significant shorter length of hospital stay compared to TG (p = 0.02) although the duration till initiation of weight bearing did not have statistical difference between both groups (p = 0.09). With a 30-day postoperative follow-up period, overall, there was no difference between both groups regarding the development of postoperative urine retention, seroma or wound infection (p = 0.09, 0.32, 0.3; respectively). Furthermore, after 6 months, FG had a higher overall QoL score using both CCS and SF-36 questionnaire (P = 0.001 and 0.02; respectively). Glue fixation may have a better quality of life and less postoperative pain; however further clinical trials are still needed.

PMID:41271995 | DOI:10.1038/s41598-025-26626-5

Sci Rep. 2025 Nov 21;15(1):41255. doi: 10.1038/s41598-025-25143-9.

ABSTRACT

Traditional static design approaches struggle to address the dynamic environmental conditions and evolving user needs of contemporary urban open spaces. This research proposes a comprehensive AI-driven real-time responsive design methodology that integrates multi-modal sensing data to enable dynamic optimization of urban open spaces. The proposed framework employs a hierarchical data fusion architecture that processes heterogeneous sensor streams including visual, acoustic, and environmental data through advanced machine learning algorithms. Deep learning-based spatial optimization models combined with reinforcement learning mechanisms generate adaptive design solutions that respond to real-time conditions while maintaining design quality standards. The system achieves sub-100ms response times through optimized computational architectures and intelligent caching strategies. Experimental validation conducted across three representative urban sites demonstrates significant improvements including 34.2% increase in space utilization efficiency (measured as the ratio of actively used area to total available space), 28.7% enhancement in pedestrian flow optimization (quantified through movement speed and path directness metrics), and 22.3% reduction in operational costs compared to conventional static design approaches. The practical application case study at Metropolitan Central Plaza, a 2.4-hectare transit-oriented public space in Shanghai’s dense urban district, validates the methodology’s effectiveness in real-world deployment, showing substantial improvements in user satisfaction metrics and environmental quality indicators. This research establishes foundational principles for developing intelligent urban environments that can continuously adapt to changing conditions while optimizing resource utilization and enhancing user experience quality.

PMID:41271992 | DOI:10.1038/s41598-025-25143-9