Real-time fMRI neurofeedback (rt-fMRI-nf) is an endogenous neuromodulation approach whereby individuals are taught to self-regulate their own neural activity in the moment. Cognitive control in emotional contexts is related to risk for or protection against mental health disorders, such as depression, anxiety, or posttraumatic stress disorder. The left dorsolateral prefrontal cortex (dlPFC) has been shown to be centrally important in facilitating emotional cognitive control (ECC). Using a double-blind randomized controlled trial design, the present study tested a novel rt-fMRI-nf protocol to increase left dlPFC activity during ECC and improve ECC measured by self-report and behavioral task performance. Seventy healthy adult participants were enrolled and randomized to either active (n = 37; left dlPFC) or sham [n = 33; left postcentral gyrus (PCG)] neurofeedback. Linear mixed effects models tested for effects of time (practice/run 1/run 2/run 3/transfer), feedback target (active/sham), and their interaction on left dlPFC activity, left PCG activity, and ECC measures (self-report and behavior). Results showed a significant time-by-feedback interaction on left dlPFC activity (p = .031). This interaction was such that active feedback led to greater left dlPFC activity in run 1 (p = .030; d = .66) and run 2 (p = .042; d = .62), but not for run 3 nor the transfer run (when no feedback was provided). There were no significant effects of feedback on ECC measures. These findings demonstrate that rt-fMRI-nf had an initial but not a sustained effect on left dlPFC activity, providing evidence of neural target engagement. However, the lack of a sustained effect on neural activity nor any observed effects on ECC highlight the complexity of identifying the optimal design and dosing for novel rt-fMRI-nf protocols.

The transdiagnostic approach provides an efficacious and efficient alternative to disorder-based psychological therapies. Emerging evidence suggests that a single main process may maintain psychological distress, but its identity is unclear, and some studies have found additional processes. We included a larger range of process and symptom measures to address these issues. In addition, we used a measure developed from Perceptual Control Theory to test its capacity to describe the findings.

A total of 806 participants completed process measures including worry, rumination, emotion regulation, and experiential avoidance, and symptom measures including anxiety, depression, stress, eating behaviour and body shape concerns, social anxiety, obsessions, compulsions, and alcohol use. Exploratory principal components analysis was used to extract common variance across the process measures.

A total of 660 participants were retained for analysis, 36.4% of whom reported a mental health diagnosis. Three components were extracted, with greater variance explained by the first component, which was comprised of items from measures of recurrent negative thinking, experiential avoidance, and inflexible responding, as well as being highly associated with greater scores on most symptom measures. Component 2 constituted items related to reorganisation, appraisal, action and acceptance, but did not relate to symptoms, while Component 3 constituted items describing ignoring and seeking distraction from problems, less worry, and was mildly associated with greater symptoms.

These three preliminary components set the stage for future, process-focused research.

To synthesize the evidence on the implementation of the World Health Organization's Package of Essential Noncommunicable Disease Interventions (WHO PEN).

This narrative overview of reviews draws on evidence from systematic reviews and other review articles.

The findings reveal substantial gaps and challenges in public primary health facilities across many low- and middle-income countries, particularly in workforce capacity and the availability of essential medicines, diagnostics, and equipment. Several delivery strategies-such as high-risk population screening, task-shifting to non-physician health workers, team-based care, integrated HIV-NCD services, and the use of community pharmacies-were shown to effectively support WHO PEN implementation and expand access to NCD services. Strengthening the organization and resourcing of healthcare teams across system levels is essential. Additional promising approaches include leveraging existing service platforms, reinforcing district hospitals, adopting more patient-centered and prevention-oriented models within traditionally hospital-centric systems, and improving quality of care.

WHO PEN and similar strategies can improve NCD service delivery and outcomes, but sustained investments, context-specific adaptations, and longer-term evaluations are needed to overcome persistent implementation barriers.

Aberrant p53 expression may have prognostic significance in colorectal cancer; however, its role in patients with colorectal liver metastases (CRLM) who receive neoadjuvant chemotherapy but do not achieve pathological complete response (pCR) remains unclear.

We evaluated whether aberrant p53 expression assessed by immunohistochemistry (IHC) predicts recurrence-free survival (RFS) in patients with CRLM receiving neoadjuvant FOLFOXIRI followed by resection without achieving pCR.

A prospective cohort study was conducted on 39 patients with CRLM who met the inclusion criteria. All patients received neoadjuvant chemotherapy with the FOLFOXIRI regimen. Following surgical resection of both primary colorectal tumors and liver metastases, none of the patients achieved pCR. Immunohistochemistry was performed to assess p53 expression in resected liver metastasis specimens using a pattern-based interpretation model. RFS was analyzed using univariate and multivariate Cox proportional hazards models. Aberrant p53 expression was observed in 20 patients (51.3%). In univariate analysis, aberrant p53 expression (HR = 2.20; 95% CI: 1.02-4.71; p = 0.043), total tumor size > 6 cm (HR = 5.62; 95% CI: 2.31-13.68; p < 0.001), number of liver metastases > 4 (HR = 4.41; 95% CI: 1.59-12.26; p = 0.004), and positive surgical margin (HR = 2.62; 95% CI: 1.16-5.91; p = 0.021) were significantly associated with recurrence. In multivariate analysis, aberrant p53 expression (HR = 3.78; 95% CI: 1.56-9.15; p = 0.003) and total tumor size > 6 cm (HR = 5.23; 95% CI: 1.56-17.55; p = 0.007) remained independent prognostic factors for shorter RFS.cnr270701_RedLinePDF.

Aberrant p53 expression, as assessed by immunohistochemistry on post-neoadjuvant chemotherapy specimens, is an independent prognostic factor for early recurrence in patients with CRLM who did not achieve pCR. Together with total tumor size, aberrant p53 expression may serve as a useful marker for risk stratification and personalized postoperative treatment strategies in this high-risk patient population.

Pulmonary fibrosis is a progressive and life-threatening lung disorder characterized by excessive fibrogenesis and impaired respiratory function. Nerandomilast, a preferential phosphodiesterase 4B inhibitor, is currently approved for the treatment of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis in several countries following its demonstrated clinical efficacy in Phase III trials. However, its cellular mechanisms of action remain incompletely understood. In this study, we investigated the effects of nerandomilast on a bleomycin-induced mouse model of lung fibrosis. Nerandomilast treatment attenuates fibrotic remodeling and preserves alveolar epithelial architecture. Single-cell transcriptomic analyses revealed altered alveolar epithelial cell state dynamics accompanied by increased cell cycle-associated pathways in alveolar type 2 cells and an increased relative abundance of alveolar type 2 cells. Consistent with the single-cell findings, nerandomilast was associated with an increased SFTPC-positive area and the preservation of alveolar epithelial architecture in vivo. Collectively, our findings suggest that nerandomilast attenuates fibrotic remodeling while modulating alveolar epithelial cell state dynamics, which may provide a possible cellular explanation for its clinical efficacy in patients with pulmonary fibrosis.

Sepsis-induced capillary leak is a major contributor to circulatory dysfunction and tissue edema, yet remains therapeutically unaddressed: numerous interventions showing promise in preclinical models have failed to demonstrate clinical efficacy. This systematic review aimed to characterise preclinical studies evaluating therapeutic interventions specifically targeting capillary leak and to identify candidates with the highest potential for clinical translation.

A systematic search of PubMed, Embase, and Web of Science identified in vivo studies in experimental sepsis and endotoxemia evaluating interventions targeting capillary leak. Data on animal models, sepsis induction methods, capillary leak assessment, therapeutic targets, and intervention timing were extracted. Risk of bias was assessed using the SYRCLE tool. As a complementary step, all retained interventions were cross-referenced against randomized or prospective clinical studies in sepsis published since January 2015 and appraised using a four-criterion translational quality score (reproducibility, quality of the model, clinically relevant timing, and multimodal read-out).

Three hundred and three preclinical studies were included, exhibiting substantial heterogeneity in both models and outcomes. Rodent models predominated (81.2%), and lipopolysaccharide-induced endotoxemia was the most common induction method (59.7%). Dye-based assays constituted the most frequent capillary leak read-out in rodents (81.7%), whereas fluid balance and lymph-to-plasma ratios predominated in large-animal studies. The lung was the most frequently evaluated organ. Endothelial activation (12.2%), intercellular junctions (11.2%), and the nitric oxide pathway (8.9%) were the most targeted pathways. A beneficial effect of the intervention on at least one capillary leak outcome results was reported in 93.1% of studies, raising substantial concerns regarding publication bias. Of 232 distinct interventions, only a minority had been evaluated in randomized clinical trials since 2015, and no capillary leak-specific therapy has yet reached high translational priority.

Preclinical research on sepsis-induced capillary leak is characterized by methodological heterogeneity, a disproportionately high rate of studies reporting capillary leak reduction, and an overreliance on endotoxemia models. Bridging the translational gap will require standardized assessment of capillary leak, broader use of live-pathogen large-animal models, post-treatment dosing paradigms, and clinical trials enriched for endothelial dysfunction.

International Prospective Register of Systematic Reviews (PROSPERO) number CRD42024522372.

Osteoporosis is a silent systemic skeletal disease characterized by microarchitectural deterioration and increased fracture risk; thus, early case-finding is essential. Although dual-energy X-ray absorptiometry (DEXA) is the reference standard for bone mineral density (BMD) assessment, limited accessibility and cost restrict its use for large-scale screening. Given that cone-beam computed tomography (CBCT) is routinely obtained in dental practice, image-derived parameters-gray value (GV) and fractal dimension (FD)-may provide insight into their association with systemic bone mineral density measured by DEXA in postmenopausal women, without additional radiation exposure.

This cross-sectional study included 63 postmenopausal women aged 50-70 years undergoing dental CBCT (NewTom 3G; standardized acquisition). Six trabecular regions of interest (ROIs) were evaluated: mandibular retromolar, mandibular premolar, mandibular anterior (central), maxillary premolar, maxillary anterior (central), and maxillary tuberosity. GV values were extracted using OnDemand3D-Dental from standardized 25 × 25-pixel ROIs positioned to exclude cortical bone and dental structures. FD was calculated in ImageJ using a box-counting method following Gaussian blur subtraction, binarization, and skeletonization. Lumbar spine and hip BMD were measured by DEXA and categorized according to WHO criteria. Statistical analyses included t-tests/ANOVA, Pearson correlation (α = 0.05). Intra-observer reliability was assessed with intraclass correlation coefficients (ICC).

DEXA classified 49.2% as normal, 34.9% as osteopenic, and 15.9% as osteoporotic. Lumbar assessment identified more non-normal cases than the hip evaluation. Reliability was good (ICC > 0.70). Although mean GV and FD did not differ significantly between groups, site-specific GV-FD correlations were observed. Notably, FD at the maxillary premolar correlated with lumbar T-scores in the non-normal group (p = 0.030).

While GV and FD did not discriminate BMD categories overall, region-dependent associations between CBCT-derived parameters and systemic BMD were observed, suggesting potential clinical relevance in dental imaging. These exploratory findings should not be interpreted as diagnostic or screening indicators and require confirmation in larger studies.

Diabetes Mellitus Type 2 prevalence is still increasing around the world, and there is growing evidence of the role of environmental co-exposures to heavy metals-cadmium, lead, arsenic, mercury, and chromium-in glycaemia impairment. Contrarily to studies on single metal toxicology, real-life situations consist in exposure to mixtures of heavy metals through environmental, occupational and dietary pathways, especially in places like the Indo-Gangetic plain of India, characterized by the presence of geological arsenic pollution in association with metals exposure. This paper provides a narrative review on the current state of art in the domain of three key issues connected to risk stratification in Type 2 Diabetes Mellitus: methods for biomonitoring metals, inflammatory and molecular pathways involved in diabetes onset and progression related to metal exposures and statistical approaches for modeling joint effects of mixtures. Firstly, discuss on the biomonitoring methods, with particular emphasis to blood, urine and hair and nail as classical matrices and new emerging matrices (saliva, buccal cells). The analytical technique (AAS vs ICP-MS) is considered as well. It will focus on the heterogeneity between different methodologies, including matrix-specific exposure window and inter-laboratory variability. Regarding mechanistic aspects, there is an agreement in scientific literature on several molecular pathways involved in glycaemia alterations, including oxidative stress, NF-κB inflammation pathway, mitochondria dysfunction, epigenetics alteration and insulin signaling impairment, with possible synergistic rather than additive action of heavy metals in the impairment of beta-cell function and insulin resistance. Finally, it discusses some recent advances in quantifying joint metal effects on diabetes through specific statistics as WQS regression and Bayesian Kernel Machine regression (BKMR) and quantile g-computation. Even though important methodological advances have been made, a translational gap remains: no validated procedure currently exists that integrates exposure metrics, inflammatory biomarkers and clinical variables for individual risk stratification. We therefore outline a research-stage framework that could guide future development of such tools.

3D in vitro cancer models provide a more physiologically relevant representation of tumor architecture and cell-matrix interactions than conventional monolayer cultures. This study evaluated bacterial nanocellulose (BNC) as a scaffold for the 3D culture of colorectal cancer cells. BNC scaffolds were produced using paraffin spheres as porogens and subsequently characterized in terms of morphology, chemical structure, thermal stability, and mechanical properties. Human colorectal cancer cell lines SW480 and SW620, along with CHO-K1 cells, were exposed to BNC leachates and cultured on 2D and 3D BNC matrices. Cells grown on 2D BNC exhibited typical monolayer proliferation, whereas 3D matrices allowed cell infiltration and volumetric distribution, supporting multicellular organization and the formation of spheroid-like aggregates. Cell viability remained in both leachate and direct scaffold cultures. Genotoxicity assays showed low levels of DNA damage, with most cells displaying no detectable genotoxic effects, and mutagenicity tests revealed no significant differences compared to controls (p > 0.05). Overall, the results demonstrate that 3D BNC supports cell viability, multicellular organization, and genomic safety, highlighting its suitability as a biocompatible scaffold for in vitro 3D colon cancer models.

Anthracycline cardiotoxicity is often silent at the subclinical stage. Left ventricular ejection fraction (LVEF) detects injury late, and global longitudinal strain (GLS) is sensitive but usually used alone. This study aimed to develop and internally validate a baseline model combining speckle-tracking GLS, conventional echocardiography, and clinical factors to identify women at high risk of subclinical myocardial dysfunction before doxorubicin (DOX) chemotherapy.

In a single-center prospective study, 200 breast cancer patients scheduled for DOX-based chemotherapy underwent baseline and 1-month assessment. The primary outcome was subclinical myocardial dysfunction, defined as > 15% relative GLS reduction with preserved LVEF. P < 0.10 variables in univariable analysis entered multivariable logistic regression for nomogram construction. Discrimination, calibration, and decision curve analysis used 1000-bootstrap validation.

Subclinical myocardial dysfunction occurred in 60 of 200 patients (30.0%). Independent predictors were baseline GLS, LDL-C, trastuzumab use, planned cumulative dose, LAVI, and hypertension. The model reached an AUC of 0.803, higher than baseline GLS, a clinical-only model, and baseline LVEF. The bootstrap-corrected C-index was 0.777.

A baseline nomogram combining GLS, conventional echocardiography, and clinical factors may help identify patients at high risk of early subclinical myocardial dysfunction before chemotherapy, outperforming single parameters and supporting risk-stratified monitoring.