Nevin Manimala

Brief Bioinform. 2025 Nov 1;26(6):bbaf634. doi: 10.1093/bib/bbaf634.

ABSTRACT

Enhancer-enhancer interactions (EEIs) are critical regulatory components in transcriptional networks but remain computationally challenging to predict. While enhancer-promoter interactions have been extensively studied, EEIs remain comparatively underexplored. We developed ETNet (Enhancer-enhancer Interaction Explainable Transformer Network), a deep learning architecture integrating convolutional neural networks with Transformer modules to predict EEIs from DNA sequences. Evaluation across three cell lines (GM12878, K562, MCF-7) demonstrated superior performance compared to existing methods including EnContact, with statistical significance confirmed through DeLong tests across six cell lines. Rigorous validation through cross-validation and enhancer-level data partitioning confirmed robust generalization. ETNet exhibited effective cross-cell type transfer learning and showed transferability to enhancer-promoter interaction tasks, providing exploratory evidence for shared chromatin interaction principles. Feature attribution analysis recovered cell-type-specific regulatory motifs consistent with known transcription factors and revealed computational evidence for super-additive cooperative mechanisms, with cooperativity negatively correlating with sequence similarity-patterns representing hypothesis-generating observations requiring experimental validation. Proof-of-concept analysis demonstrated how single-nucleotide polymorphisms in JAK-STAT pathway genes may influence predicted interactions through motif alterations. ETNet advances computational approaches for studying enhancer interactions and provides a framework combining predictive capability with exploratory interpretability.

PMID:41319043 | DOI:10.1093/bib/bbaf634

Clin Transl Allergy. 2025 Dec;15(12):e70130. doi: 10.1002/clt2.70130.

ABSTRACT

BACKGROUND: Chat Generative Pre-Trained Transformer 4 (ChatGPT-4) represents an advancing large language model (LLM) with potential applications in medical education and patient care. While Allergen Immunotherapy (AIT) can change the course of allergic diseases, it can also bring uncertainty to patients, who turn to readily available resources such as ChatGPT-4 to address these doubts. This study aimed to use validated tools to evaluate the information provided by ChatGPT-4 regarding AIT in terms of quality, reliability, and readability.

METHODS: In accordance with EAACI clinical guidelines about AIT, 24 questions were selected and introduced in ChatGPT-4. Independent reviewers evaluated ChatGPT-4 responses using three validated tools: the DISCERN instrument (quality), JAMA Benchmark criteria (reliability), and Flesch-Kincaid Readability Tests (readability). Descriptive statistics summarized findings across categories.

RESULTS: ChatGPT-4 responses were generally rated as “fair quality” on DISCERN, with strengths in classification/formulations and special populations. Notably, the tool provided good-quality responses on the preventive effects of AIT in children and premedication to reduce adverse reactions. However, JAMA Benchmark scores consistently indicated “insufficient information” (median = 0-1), primarily due to absent authorship, attribution, disclosure, and currency. Readability analyses revealed a college graduate-level requirement, with most responses classified as “very difficult” to understand. Overall, ChatGPT-4 demonstrated fair quality, insufficient reliability, and difficult readability for patients.

CONCLUSIONS: ChatGPT-4 provides generally well-structured responses on AIT but lacks reliability and readability for clinical or patient-directed use. Until specialized, reference-based models are developed, healthcare professionals should supervise its use, particularly in sensitive areas such as dosing and safety.

PMID:41319041 | DOI:10.1002/clt2.70130

Hum Brain Mapp. 2025 Dec 1;46(17):e70422. doi: 10.1002/hbm.70422.

ABSTRACT

Human arousal is essential to survival and mediated by the ascending arousal network (AAN) and its connections. It spans from the brainstem to the diencephalon, basal forebrain, and cerebral cortex. Despite advances in mapping the AAN in adults, it is unexplored in fetal and early infant life, especially with high-resolution magnetic resonance imaging techniques. In this study, we conducted-for the first time-high-resolution ex vivo diffusion MRI-based analysis of the AAN in seven fetal, infant, and adult brains, incorporating probabilistic tractography and quantifying connectivity using graph theory. We observed that AAN structural connectivity becomes increasingly integrated during development, progressively reaching rostrally during the first postconceptional year. We quantitatively identified the dorsal raphe (DR) nucleus and ventral tegmental area (VTA) as AAN connectivity hubs already in the fetus persisting into adulthood. The DR appears to form a local hub of short-range connectivities, while the VTA evolves as a long-range global hub. The identified connectivity maps advance our understanding of AAN architecture changes due to normative human brain development, as well as disorders of arousal, such as coma and sudden infant death syndrome.

PMID:41319039 | DOI:10.1002/hbm.70422

Ann Afr Med. 2025 Nov 20. doi: 10.4103/aam.aam_335_25. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Ankylosing spondylitis (AS) poses considerable challenges for anesthesiologists due to its effect on spinal anatomy and potential airway difficulties. The characteristic ossification and vertebral fusion – commonly referred to as a “bamboo spine” – leads to rigidity and impaired spinal mobility, often complicating neuraxial anesthetic techniques. This study aimed to assess whether a preprocedural ultrasound-assisted approach improves the success rate of dural puncture with fewer needle attempts compared to the traditional landmark-guided technique in patients with altered spinal anatomy due to AS.

METHODOLOGY: Sixty American Society of Anesthesiologists physical status I and II patients aged 18-60 years with AS, scheduled for elective total hip arthroplasty, were enrolled and randomly divided into two equal groups. Group I received ultrasound-assisted subarachnoid blocks, whereas Group II underwent the conventional landmark-based approach. Hemodynamic parameters, total number of needle attempts, and the time required to administer the block were recorded. The primary outcome was the number of attempts for successful dural puncture. Secondary outcomes included time taken and postprocedural complications.

RESULTS: Group I (ultrasound-guided) demonstrated a significantly higher first-attempt success rate compared to Group II. Although the ultrasound method showed a slightly increased procedural duration, the difference was not statistically significant, and postprocedural complications were comparable.

CONCLUSION: Ultrasound guidance notably improves first-pass success rates for subarachnoid block in patients with AS, making it a valuable technique for spinal anesthesia in such cases.

PMID:41318896 | DOI:10.4103/aam.aam_335_25

Eur Spine J. 2025 Nov 30. doi: 10.1007/s00586-025-09646-7. Online ahead of print.

ABSTRACT

PURPOSE: Pedicle screw loosening (PSL) is a significant complication in transforaminal lumbar interbody fusion (TLIF), often associated with poor bone quality. This study evaluates the predictive value of MRI-based pedicle bone quality (PBQ) and vertebral body quality (VBQ) scores for PSL, hypothesizing that PBQ is a stronger predictor than VBQ.

METHODS: This retrospective cohort study analyzed 394 patients who underwent TLIF between January 2018 and January 2021. Preoperative PBQ and VBQ scores were derived from sagittal T1-weighted MRI images. The primary outcome measure was PSL, which was evaluated in accordance with established radiographic criteria. Secondary outcomes included fusion rates and patient-reported outcomes. Statistical analyses included receiver operating characteristic curves to determine predictive accuracy and multivariate logistic regression to identify other risk factors for PSL.

RESULTS: PBQ demonstrated superior predictive performance for PSL relative to VBQ, with higher sensitivity (75.93% vs. 50.00%) and specificity (92.31% vs. 87.06%). In addition, PBQ yielded higher positive predictive value (78.85% vs. 59.34%) and negative predictive value (91.03% vs. 82.18%). The discriminative ability of PBQ was further supported by a larger area under the ROC curve (0.894, 95% CI: 0.856-0.932) compared with VBQ (0.722, 95% CI: 0.664-0.781). Independent risk factors associated with PSL included advanced age, lower hip bone mineral density T-scores, longer fusion constructs, and reduced fusion rates. Furthermore, patients who developed PSL reported significantly higher postoperative back pain scores.

CONCLUSION: MRI-derived PBQ and VBQ scores independently predict PSL, with PBQ demonstrating superior performance. Incorporating PBQ into preoperative planning may improve surgical decision-making and potentially enhance outcomes in patients with reduced bone strength. Additionally, lower hip BMD T-scores, reduced fusion rates, longer fusion constructs, and advanced age were identified as significant risk factors for PSL.

PMID:41318873 | DOI:10.1007/s00586-025-09646-7

Eur Spine J. 2025 Nov 29. doi: 10.1007/s00586-025-09644-9. Online ahead of print.

ABSTRACT

PURPOSE: Upper lumbar disc herniations (L1-2, L2-3) present unique anatomical challenges due to narrow interlaminar windows and facet joint proximity. This pilot feasibility study aimed to evaluate the safety and short-term efficacy of a novel minimally invasive tubular trans-isthmus oblique approach for upper lumbar disc herniation, prior to a planned prospective trial.

METHODS: Twenty patients (13 males, 7 females; mean age 50.8 years) with imaging-confirmed L1-2 or L2-3 paracentral disc herniation and unilateral leg pain unresponsive to conservative management were enrolled between January 2022 and January 2024. All underwent decompression using the novel tubular trans-isthmus oblique approach designed to preserve the medial facet cortex. Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) for leg pain were assessed preoperatively and at 1, 3, 6, and 12 months. Modified Macnab criteria were recorded at 12 months. Dynamic radiographs and postoperative CT (in selected cases) assessed stability and facet preservation. Statistical analysis was performed using JASP v0.18 with Wilcoxon Signed Rank Test and Friedman test.

RESULTS: Median preoperative ODI was 83%, improving to 5% at 3 months (p < 0.001). VAS leg pain scores improved from a mean of 8.24 to 1, 0, and 0 at 1, 3, and 12 months respectively (p < 0.01). Seventeen patients had excellent outcomes, 2 good, and 1 fair per Macnab criteria. No recurrence or radiological instability was observed. One dural tear and one transient L2 dysesthesia resolved without sequelae.

CONCLUSION: To the best of our knowledge, this is the first clinical study to describe and evaluate a minimally invasive tubular trans-isthmus oblique approach for upper lumbar disc herniation. The technique appears technically feasible and safe. These encouraging results support the need for larger prospective trials to confirm long-term outcomes and reproducibility.

PMID:41318870 | DOI:10.1007/s00586-025-09644-9

Sci Rep. 2025 Nov 29. doi: 10.1038/s41598-025-30695-x. Online ahead of print.

ABSTRACT

The brown bear Ursus arctos, Eurasian lynx Lynx lynx, and gray wolf Canis lupus are Europe’s threatened large carnivores. The analyses were conducted using data on the abundance of these species in Poland, collected by the Polish Central Statistical Office (bear 1965-2023, wolf 1995-2023, and lynx 1996-2023). For the years 2000-2023, data were also available by region. We subjected these data to statistical analysis: chi-square tests, segmented regression, and principal component analysis. Biplots, charts of population dynamics, and distribution maps were created to visualize the results. In Poland in the analyzed time period, an increase in the population of all three studied carnivores was observed along with the westward expansion of the territorial range of lynx and wolf, while bear range remained unchanged. The most mean population increase was exhibited by the gray wolf (7.01%), followed by the brown bear (4.78%) and, finally, the Eurasian lynx (2.94%). The population dynamics of the carnivores showed trends over time, with a notable increase in the last decade. The use of multi-year data in modelling enables a better understanding of the mechanisms governing the abundance and distribution of populations of endangered species. This, in turn, facilitates the planning of more effective conservation measures.

PMID:41318866 | DOI:10.1038/s41598-025-30695-x

Inflammopharmacology. 2025 Nov 29. doi: 10.1007/s10787-025-02059-4. Online ahead of print.

ABSTRACT

BACKGROUND: Urarthritis is an inflammatory disorder triggered by monosodium urate (MSU) crystal deposition, and its pathogenesis involves interaction between oxidative stress (OS) and inflammation. Diacerein, an agent endowed with anti-inflammatory and antioxidant properties, has not yet been fully characterized in acute urarthritis. This study was designed to evaluate the therapeutic efficacy of diacerein in acute urarthritis and to elucidate its regulatory effects on the Nrf-2/HO-1 and NF-κB pathways.

METHODS: The Wistar rat model of acute urarthritis was established, and 50 rats were randomly divided into 5 groups (10 rats per group): normal control group (AG, gavage with 0.5% sodium carboxymethyl cellulose), model group (BG, gavage with 0.5% sodium carboxymethyl cellulose), low-dose diacerein group (CG, gavage with 50 mg/kg diacerein), medium-dose diacerein group (DG, gavage with 100 mg/kg diacerein), high-dose diacerein group (EG, gavage with 200 mg/kg diacerein), and positive control group (FG, gavage with 5 mg/kg indomethacin). After continuous administration for 7 days, the ankle joint swelling degree, mechanical pain threshold, serum inflammatory factors (IL-1β, TNF-α, IL-6) levels, renal function indicators (blood urea nitrogen BUN, creatinine Cr, uric acid UA, kidney index) of rats in each group were detected, and the expression of Nrf-2/HO-1 and NF-κB pathway-related proteins in ankle joint synovial tissue was analyzed by Western blot.

RESULTS: Compared with the BG, diacerein groups and the FG significantly reduced the percentage of ankle swelling (P < 0.001) and increased the mechanical pain threshold (P < 0.001): At 24 h after modeling, there was no statistical difference in the swelling percentage between the EG and the FG (P > 0.05); At 7 days after modeling, the mechanical pain threshold in the EG was similar to that in the FG (P > 0.05). The serum levels of IL-1β, TNF-α, and IL-6 in the intervention groups were reduced in a dose-dependent manner (P < 0.001), and the inhibition rate of IL-1β in the EG exceeded 73%, which was comparable to that in the FG (P > 0.05); Renal function indicators were significantly improved (P < 0.001), and there was no significant difference in the UA level between the EG and the FG (P > 0.05). Mechanistically, diacerein dose-dependently up-regulated the expression of Nrf-2 and HO-1 proteins (P < 0.001) and down-regulated the expression of NF-κB p65 and p-IκBα proteins (P < 0.001); The FG only significantly down-regulated the expression of NF-κB p65 and p-IκBα proteins (P < 0.001), with no significant effect on the expression of Nrf-2 and HO-1 proteins (P > 0.05). The ratios of Nrf-2/GAPDH and HO-1/GAPDH in the EG were significantly higher than those in the FG (P < 0.001).

CONCLUSION: The anti-inflammatory, analgesic, and renal protective effects of high-dose diacerein are comparable to those of indomethacin, and its oral administration is convenient, which provides experimental references for the subsequent clinical transformation research of diacerein in acute urarthritis and the development of multi-target anti-gout drugs.

PMID:41318857 | DOI:10.1007/s10787-025-02059-4

Clin Rheumatol. 2025 Nov 29. doi: 10.1007/s10067-025-07830-0. Online ahead of print.

ABSTRACT

OBJECTIVE: To prospectively compare the efficacy of glucocorticoid(GC)-free maintenance therapy versus low-dose GC regimens and evaluate short-term safety in complete or partial remission lupus nephritis patients.

METHOD: This study is a prospective, open-label, randomized controlled trial that enrolled lupus nephritis patients who achieved remission within one year prior to screening and maintained stable immunosuppressive therapy. Ninety-three subjects were randomized to a GC-free group (n = 47, tapering off GC over 3 months) and a low-dose GC group (n = 46, prednisone dosage 2.5-10 mg/day), with basic immunosuppressants continued in both groups. Primary endpoints were total flare rate and time to flare, while secondary endpoints included renal or extrarenal flare, immunological changes of parameters, and subgroup analyses stratified by remission status (complete vs. partial) and different maintenance regimen types.

RESULTS: There were 91 patients who were analyzed. The low-dose GC group demonstrated a numerically lower flare rate compared to the GC-free group(4.5%vs. 17.0%, p = 0.065). Among patients experiencing flares, the median time to flare was significantly shorter in the GC-free group (9.4 months) compared with the low-dose group (39.32 months; HR 0.37, 95% CI 0.14-0.99, p = 0.044). Kaplan-Meier analysis revealed significantly higher cumulative flare rates in the GC-free group (log-rank p = 0.031). Notably, the GC-free group exhibited a 14.9% extrarenal flare incidence versus 0% in the low-dose group (absolute risk difference 14.9%, 95% CI 3.2-26.6; p = 0.017).

CONCLUSION: In this pilot study, the flare rate was numerically lower, and the time to flare was significantly longer in the low-dose GC group compared to the GC-free group. These preliminary findings suggest a potential benefit of low-dose GC maintenance therapy but still need large sample size trials to confirm. Key Points • In patients with SLE in remission, glucocorticoid-free therapy significantly increases flare risk and shortens time to flare. • Future biomarker-driven decision-making criteria should be uncovered to replace empirical withdrawal of individual decisions.

PMID:41318847 | DOI:10.1007/s10067-025-07830-0

Odontology. 2025 Nov 29. doi: 10.1007/s10266-025-01263-6. Online ahead of print.

ABSTRACT

To investigate the fracture and apparent flexural strength at fracture of three-unit implant-supported bridge restorations at different connector cross-sectional areas according to material type, produced on ti-base abutments using the CAD-CAM system. A total of 42 three-unit implant-supported bridge restorations were designed digitally (maxillary canine and second premolar as abutment and 1st premolar as a pontic). Two main groups (N = 21) were created to be manufactured from monolithic zirconia and lithium disilicate. Then, each group was divided into three subgroups (n = 7) according to the connector cross-sectional area (9 mm², 12 mm², 15 mm² for monolithic zirconia; 12 mm², 16 mm², 20 mm² for lithium disilicate). The samples were subjected to a fracture test on a universal testing machine and the values obtained were formulated to calculate the apparent flexural strength at fracture. In terms of fracture strength, there were statistically significant differences for both monolithic zirconia and lithium disilicate (p < 0.001, p < 0.001, respectively). In terms of apparent flexural strength at fracture, there were statistically significant differences for both monolithic zirconia and lithium disilicate (p = 0.012, p = 0.007, respectively). When monolithic zirconia and lithium disilicate samples with a common connector cross-sectional area (12 mm²) were compared, it was found that monolithic zirconia was statistically significantly stronger (p = 0.002). Under the present static test conditions, monolithic zirconia can be used as three-unit bridges safely in the premolar region. Lithium disilicate can also be used as three-unit bridges in the premolar region; in cases where there is sufficient connector area and the patient does not have parafunctional habits. As a result, increasing the connector cross-sectional area increases the strength significantly (p < 0.05).

PMID:41318837 | DOI:10.1007/s10266-025-01263-6