To test safety of two regimens at differing levels of radioactivity of PSMA-targeted alpha radionuclide 225Ac-J591. Patients with progressive, metastatic androgen pathway modulator resistant prostate cancer were enrolled in two parallel dose-escalation cohorts: (1) fractionated-dose regimen (single cycle of 45 - 65 KBq/kg of 225Ac-J591 on day 1 and day 15; main cohort agnostic to prior receipt of 177Lu-PSMA, additional cohort post 177Lu-PSMA) and (2) multiple cycles of 225Ac-J591 (45 - 65 KBq/kg administered every 6 weeks for up to 4 cycles). PSMA PET not utilized for eligibility. Primary end point was determination of dose-limiting toxicity (DLT) and recommended phase 2 dose (RP2D); the fractionated cohort was expanded. 42 patients were enrolled in fractionated (23 dose-escalation, 11 expansion, 8 post 177Lu-PSMA), 18 multiple dose. All received > 1 prior AR pathway inhibitor, 72% chemotherapy, 18% 177Lu-PSMA. Three patients had DLT in fractionated regimen with RP2D of 60 KBq/kg x2. Seven had DLT in multiple cycle regimen; this regimen is not recommended for further development. Amongst adverse events of special interest, temporary hematologic toxicity was most common [93% thrombocytopenia (32% grade >3), 65% neutropenia (13% grade >3), 63% anemia (20% grade >3)]; dry mouth occurred in 62% (2% grade 2). Across fractionated cohorts with or without prior 177Lu-PSMA, 60% with >50% PSA decline as best response; 28% with >50% PSA decline in multiple cycle. Fractionated dosing of 225Ac-J591 appears promising. Further investigation is underway.
We present a female pediatric patient with known neurofibromatosis type 1 (NF1) whose surveillance imaging began showing multifocal periventricular and juxtacortical lesions with transient enhancement, initially attributed to NF1-related focal areas of signal intensity. Over time, the radiographic pattern raised concern for demyelinating disease. CSF studies revealed 10 unique oligoclonal bands. Despite the absence of neurologic symptoms, treatment with dimethyl fumarate was initiated and later transitioned to rituximab in the setting of ongoing active radiographic disease. Although the patient never developed clinical manifestations of demyelinating disease, updated diagnostic criteria now permit a diagnosis of multiple sclerosis. Central vein sign on MRI aided in differentiating radiographic features. This case illustrates how NF1 and demyelinating processes can have evolving and overlapping clinical and MRI features.
Cytokine release syndrome (CRS) remains a major toxicity associated with bispecific antibody (BsAb) therapy in relapsed/refractory multiple myeloma (RRMM). Prophylactic IL-6 receptor blockade with tocilizumab has emerged as a potential strategy to mitigate CRS; however, its efficacy and safety have not been systematically evaluated. Databases were searched for studies evaluating prophylactic tocilizumab in patients with RRMM receiving BsAb therapy. Comparative and single-arm studies were included. The primary outcome was CRS incidence. Secondary outcomes included CRS severity, adverse events, hospitalization, and antimyeloma efficacy. Pooled risk ratios (RRs) were calculated using random-effects models due to heterogeneity across studies. Eight studies encompassing 704 patients were included, comprising five cohorts and three single-arm trials. Meta-analysis of three comparative studies demonstrated that prophylactic tocilizumab is associated with lower all-grade CRS incidence (RR 0.29, 95% CI 0.16-0.53; p < 0.0001), with moderate heterogeneity (I² = 59%). A pooled analysis of two studies evaluating grade ≥2 CRS showed a numerically lower risk with prophylaxis, although this did not reach statistical significance (RR 0.22, 95% CI 0.02-2.57; p = 0.23). CRS events were predominantly low grade, short-lived, and occurred during step-up dosing. ICANS was uncommon, and infection and hematologic toxicity rates were comparable between groups. No signal of reduced overall response rate was observed (RR 1.21, 95% CI 0.91-1.62; p = 0.19). Prophylactic tocilizumab is associated with lower CRS incidence without compromising efficacy in RRMM patients receiving BsAb therapy. Prospective randomized studies are warranted to confirm these findings and refine prophylactic strategies.
Therapy with anti-CD20 monoclonal antibodies is highly efficacious in various autoimmune diseases including multiple sclerosis (MS), a prototypic autoimmune inflammatory disease of the central nervous system (CNS). However, which B cell subsets and altered B cell-regulating factors mediate the clinical efficacy of anti-CD20 treatment is unclear. To address this gap in knowledge, we performed longitudinal high-dimensional single-cell transcriptomic and proteomic profiling of blood, cerebrospinal fluid (CSF), and intestinal samples from people with MS (pwMS), combined with immune profiling in a preclinical autoimmune encephalomyelitis model during anti-CD20 therapy. CSF analyses were performed using previously published datasets. Multisite intestinal profiling was conducted in one anti-CD20-treated patient with MS and one control participant. By applying algorithm-guided analyses of flow cytometry, single-cell transcriptomic, and immune receptor repertoire data, we found that anti-CD20 B cell depletion was associated with increased frequencies of regulatory mucosal-derived IgA-producing B cells in the periphery and CSF, together with increased B cell receptor clonal overlap between mucosal and systemic compartments, indicating enhanced trafficking of IgA B cells from gut mucosal tissues to the systemic circulation and the CNS. Moreover, we demonstrated that higher levels of B cell-activating factor and a proliferation-inducing ligand were related to favorable outcomes in pwMS during anti-CD20 treatment. Together, our findings suggest that mucosal immune regulatory mechanisms may be harnessed by anti-CD20 B cell depletion, opening previously unknown therapeutic avenues for MS.
MicroRNAs (miRNAs) are key regulators of plant development and stress adaptation. While conserved miRNAs have been extensively characterized, the agronomic roles of lineage-specific miRNAs in crops remain largely unexplored. Here, we demonstrate that tae-miR5048, a wheat-specific miRNA, functions as a master regulator concurrently modulating plant architecture and drought tolerance. Overexpression of tae-miR5048 enhanced early root growth, accelerated reproductive transition, and optimized plant architecture and grain morphology without compromising grain yield. Conversely, CRISPR/Cas9-mediated knockout of TaMIR5048 homoeologs impaired root development and delayed flowering, yet promoted vegetative growth and grain yield potential, revealing a bidirectional regulatory role. Cytological analysis showed that tae-miR5048 optimizes plant height, flag leaf size and grain dimension by fine-tuning cell proliferation and expansion in a tissue-specific manner. Moreover, tae-miR5048 confers drought resilience throughout the growth cycle by elevating osmolyte accumulation to maintain tissue water status and alleviating oxidative damage through suppression of ROS production and membrane lipid peroxidation. Mechanistically, degradome sequencing, RLM‑5' RACE, and transient co‑expression assays demonstrated that tae-miR5048 directly targets and downregulates multiple kinase genes, including receptor-like protein kinases and mitogen-activated protein kinases, thereby modulating key signalling hubs post-transcriptionally. Transcriptome profiling further revealed that tae-miR5048 fine-tunes architectural traits by regulating cellular growth-related genes and enhances drought tolerance through activation of stress-responsive and proline biosynthesis pathways. Collectively, our findings establish tae-miR5048 as a central integrator that balances plant architecture and drought adaptation, providing the first functional evidence for a lineage-specific miRNA as a promising target for breeding climate-resilient wheat varieties.
A 52-year-old male patient presented with coexisting electrocardiographic manifestations: 1: Alternation between wide and narrow QRS complexes of complete left bundle branch block (LBBB); 2: Alternation between wide and narrow QRS complexes of complete right bundle branch block (RBBB); 3: Paroxysmal third-degree atrioventricular block (PAVB).
Accurately predicting anticancer drug response is a central challenge in precision oncology. Existing computational methods, although valuable, often depend on pairwise molecular descriptors or limited graph-based encodings that cannot fully capture the complexity of molecular structures or their interactions with cellular states. These constraints hinder their robustness and generalization across diverse drugs and biological contexts, underscoring the need for more expressive frameworks. To address this gap, we propose MolDr, a topological deep learning framework that represents molecules as multiscale simplicial complexes and propagates information across higher-order structures. By integrating these molecular representations with cellular profiles, MolDr unifies chemical topology and biological context within a single predictive model. Comprehensive experiments show that MolDr consistently outperforms or matches state-of-the-art baselines across multiple benchmarks. It achieves stronger accuracy and robustness on continuous drug response tasks, while also generalizing effectively to discrete classification settings. Moreover, sensitivity analysis confirms the benefit of incorporating multiple topological scales, further supporting the importance of higher-order representations. Together, these results demonstrate that MolDr delivers reliable performance across heterogeneous pharmacogenomic scenarios and highlight the promise of topological modeling for advancing drug response prediction. Source code freely available at https://github.com/CS-BIO/MolDr. Supplementary data are available at Bioinformatics online.
Detecting abnormal events in physiological signals such as EEG and ECG is critical for early diagnosis of neurological and cardiovascular disorders. However, existing unsupervised anomaly detection methods often suffer from limited representation capacity and weak generalization across diverse signal domains. To address these challenges, we propose MAGE, a novel unsupervised anomaly detection framework that integrates multi head memory gating, self-supervised learning, and adversarial training within a unified convolutional autoencoder architecture. The proposed memory-augmented gating mechanism selectively preserves and adaptively integrates salient features, improving discriminability and robustness over prior memory-based approaches. To further enhance representation learning, a self-supervised auxiliary task based on multiple signal transformations is introduced to encourage structure-aware feature extraction. In addition, transformation-aware adversarial perturbations are incorporated during training to enhance robustness against distribution shifts. Extensive experiments on multiple benchmark EEG and ECG datasets demonstrate that MAGE consistently outperforms state-of-the-art baselines in standard within-dataset evaluation settings, achieving over 98% detection accuracy and superior F1-scores. These results highlight the effectiveness and clinical potential of MAGE for early anomaly detection and continuous health monitoring under realistic deployment conditions. Code available at https://github.com/wzxmodel/MAGE.
Word-finding difficulties (anomia) are common in poststroke aphasia. Although recent evidence suggests that written cues may benefit anomia, their optimal use remains unclear. This study investigates two parameters of orthographic cue use: the optimal unit for cueing and the durability of cueing effects on spoken word production across three outcomes (accuracies of initial and final naming responses, together with response time). Examining multiple dimensions of naming, for example, accuracies of both initial and final naming responses, provides a more rounded perspective on anomia treatment outcomes. Cueing interventions delivered over the internet and based on two different orthographic units, initial letters and whole words, were compared in five adults with chronic anomia using a crossover design. The three outcomes were measured 1 week and 4 weeks posttherapy to evaluate the durability of the cueing effects. After accounting for practice-related gains from repeated task exposure, four out of five participants showed significant improvement on at least two outcomes following whole-word written prompts at 1 and/or 4 weeks posttreatment. In contrast, initial letter cues yielded significant improvement in two participants. Gains from whole-word orthographic cues can persist up to 4 weeks posttherapy for three participants; effects from initial letter cues did not persist beyond 1 week posttreatment. This telepractice spoken naming aphasia therapy provides case series evidence that whole-word written cues produced superior therapeutic impacts compared to initial letter cues, with whole words benefiting a wider range of individuals and whose effects were more enduring. Clinicians are therefore encouraged to consider orthographic prompts, especially at the whole-word level, when designing spoken language treatments, including in telehealth. Researchers and clinicians are also encouraged to code and analyze naming responses across multiple outcomes to maximize our understanding, since individuals may show progress on one naming dimension but not on others. https://doi.org/10.23641/asha.32960696.
No recent study has examined whether method of abortion is associated with psychotropic medication use, an indicator of mild mental health problems. To examine whether medication or procedural abortions were associated with increased risk of psychotropic medication use. This population-based Danish registry cohort study followed the psychotropic medication redemptions of females aged 12 to 38 years having elective, first first-trimester abortions between January 1, 2000, and December 31, 2018, from 1 year before their medication or procedural abortion until their first psychotropic medication prescription claim (redemption), December 31, 2018, emigration from Denmark, or death, whichever came first. Analyses were conducted between June 2023 and June 2025. First abortion method (first medication abortion or first procedural abortion). Any first psychotropic medication prescription redemption, first antidepressant medication redemption, and first antianxiety medication redemption during the study period. Incidence rate ratios (IRRs) were calculated in adjusted regression models. Bonferroni-corrected P values were used to account for multiple tests. Of 67 390 females included in this study (mean [SD] age, 21.8 [4.6] years), 4575 (6.8%) had a prior psychiatric diagnosis; 33 793 had a record of a first medication abortion, 33 597 had a record of a first procedural abortion, and 19 979 (29.6%) had a first psychotropic medication redemption during the study period. In fully adjusted models, using the conventional P value level of .05, compared with the year before a medication or procedural abortion, there were small increased risks of any first psychotropic medication redemption in the first year after medication abortion (IRR, 1.10; 95% CI, 1.02-1.19; P = .01) and procedural abortion (IRR, 1.09; 95% CI, 1.01-1.16; P = .02). There were no statistically significant associations in 1 to 2 years and 2 to 5 years after abortion relative to the year before an abortion for each abortion method. There were decreased risks of any first psychotropic medication redemption more than 5 years after medication abortion (IRR, 0.85; 95% CI, 0.78-0.91; P < .001) and more than 5 years after procedural abortion (IRR, 0.83; 95% CI, 0.78-0.88; P < .001). Using the Bonferroni-corrected P value of .002, the small increased risks of psychotropic medication redemption observed in the first year after an abortion no longer met the criteria for statistical significance, while the lower risks for more than 5 years after abortion continued to meet the criteria for statistical significance. In this Danish population-based cohort study, compared with the year before a medication or procedural abortion, small increased risks of psychotropic medication prescription redemptions were observed during the first year after abortion, and decreases in risk of psychotropic medication prescription redemptions were observed more than 5 years after abortion when using conventional levels of statistical significance. The small increased risks observed in the first year after an abortion no longer met the criteria for statistical significance following Bonferroni adjustment for multiple statistical tests. Additional research may be needed to replicate and understand these results.
The aim of this study was to demonstrate the ability of a rosette readout trajectory to correct for three common sources of artifact in diffusion-weighted imaging (DWI): B0 inhomogeneities, diffusion gradient induced eddy currents, and shot-to-shot phase variations. Multi-shot rosette acquisitions were acquired in phantoms and an ex vivo ferret brain at 7T. Rosette and EPI DWI data were acquired from two mouse spinal cords in vivo at 15.2 T. Rosette DWI provided robust image quality in both ex vivo and in vivo samples at the two field strengths. Correction of shot-to-shot phase variations removed additional attenuation of diffusion-weighted signal caused by averaging of multiple shots with phase errors. Multi-shot rosette acquisitions produced high quality DWI, and demonstrated a robust ability to measure and correct for B0 inhomogeneities, diffusion eddy currents, and shot-to-shot phase variations.
This systematic review and meta-analysis assessed the efficacy and safety of ferric carboxymaltose (FCM) in treating iron-deficiency anemia secondary to gastrointestinal bleeding. A comprehensive search across multiple databases identified randomized controlled trials comparing FCM with other iron formulations. A total of 13 publications, reporting 16 trials and involving 1939 patients, were included. Pooled analyses demonstrated that FCM led to significantly greater improvements in key anemia parameters compared to alternative iron therapies, including a higher hemoglobin response rate [risk ratio = 1.24, 95% confidence interval (CI): 1.14-1.34], increased serum ferritin levels (mean difference = 293.52, 95% CI: 168.76-418.27), and greater transferrin saturation (mean difference = 9.71, 95% CI: 5.19-14.22). The overall incidence of drug-related adverse events was comparable between groups (risk ratio = 0.82, 95% CI: 0.51-1.34); however, FCM was associated with a substantially increased risk of hypophosphatemia (risk ratio = 21.00, 95% CI: 8.90-49.56). Notably, subgroup analysis confirmed that this therapeutic advantage remained consistent across both acute and chronic gastrointestinal bleeding settings. In conclusion, FCM is effective in correcting anemia in patients with gastrointestinal bleeding-related iron deficiency, despite a well documented risk of hypophosphatemia. Further research is warranted to optimize dosing strategies and identify patient subgroups most likely to benefit from FCM therapy.
There is increasing evidence that translation is not limited to annotated protein-coding genes. Ribosome profiling sequencing, mass spectrometry-based proteomics, and immunopeptidomics have identified the productive translation of non-canonical open reading frames (ORFs). This suggests that the functional proteome includes not only conserved proteins but also proteins hidden in non-coding RNAs and de novo proteins. Some of these translated products are functional peptides, while others may be non-functional, potentially arising from evolutionary events. Several non-canonical ORF-encoded peptides have been found to regulate multiple physiological and pathological functions, particularly in cancer, immunity, and inflammation, indicating that they have potential as biomarkers and novel therapeutic targets. To better understand the diversity of functional peptides and translated non-canonical ORFs based on existing data, we summarize their classification according to transcriptional features and supporting evidence, including non-canonical ORFs located in ncRNAs and canonical mRNAs. This review provides a concise summary of the origin, discovery methods, and classification of non-canonical ORFs. It offers insights into the origins and functions of non-canonical ORF-encoded peptides from an evolutionary perspective, while also exploring the biological functions and regulatory mechanisms of these non-canonical ORF-encoded hidden proteins in tumorigenesis and progression.
Childhood malnutrition remains a major public health concern in Nepal and other low-resource settings, while conventional case-finding approaches are labor-intensive and frequently unavailable in remote areas. This study provides one of the first applications of machine learning and deep learning to identify child malnutrition in Nepal. We systematically compared 16 algorithms spanning deep learning, gradient boosting, and traditional machine learning families, using data from the Nepal Multiple Indicator Cluster Survey (MICS) 2019. A composite malnutrition indicator was constructed by integrating stunting, wasting, and underweight status, and model performance was evaluated using ten metrics, with emphasis on F1-score and recall to account for substantial class imbalance and the high cost of failing to detect malnourished children. Among all models, TabNet achieved the highest scores among evaluated models, likely attributable to its attention-based architecture. A consensus feature importance analysis identified maternal education, household wealth index, and child age as the primary predictors of malnutrition, followed by geographic characteristics, vaccination status, and meal frequency. Collectively, these results demonstrate a scalable, survey-based screening framework for identifying children at elevated risk of malnutrition and for guiding targeted nutritional interventions. The proposed approach supports Nepal's progress toward the Sustainable Development Goals and offers a transferable methodological template for similar low-resource settings globally.
A Peptidase A1 domain-containing protein (SRP, 43.1 kDa, >95% purity) was isolated from the edible mushroom Stropharia rugosoannulata and characterized for its structural properties, and ACE inhibitory and vascular modulatory activities. This represents the first report of an intact Peptidase A1 family protein exhibiting bioactivities beyond its canonical proteolytic role. SRP inhibited ACE (IC50 = 108.84 ± 3.42 μg mL-1) through strong intermolecular interactions, with Glu264 contributing 45% (-20.76 kcal mol-1) of the total binding energy and additional contributions from conserved active-site residues. Isothermal titration calorimetry confirmed high-affinity binding to ACE (KD = 1.12 × 10-8 M), driven by both enthalpic and entropic contributions with entropy as the dominant thermodynamic force, suggesting a complex binding mode involving both primary and secondary interaction sites. In a zebrafish hypertension model, SRP at 62.5 μg mL-1 decreased cardiac output by 20-24% and increased vessel diameter by 17-18%, with effects comparable to those of captopril at the tested concentration. Integrative transcriptomic and proteomic analyses revealed that SRP reversed the downregulation of core genes and key proteins, modulating multiple vascular homeostasis pathways including calcium signaling, vascular smooth muscle contraction, Toll-like receptor signaling, and neuroactive ligand-receptor interaction. These findings expand the known functional repertoire of Peptidase A1 family proteins and highlight the multi-pathway modulatory potential of food-derived intact proteins.
Genetic profiles were successfully obtained from hair samples both directly plucked from the scalp and indirectly from personal items such as combs and hairbrushes. Additionally, 100 genetic profiles were generated from buccal swabs from all donors, allowing the calculation of population allele and genotype frequencies. Complete genetic profiles were recovered from samples containing less than 0.012 ng of total nuclear DNA. Nuclear DNA yield per hair root was highly variable, whereas hair shafts yielded up to 2 ng of total nuDNA and in some cases less than 0.1 ng. Multiple correspondence analysis (MCA) revealed that hair growth phase and the presence of a root were not significantly associated with successful profile recovery; instead, greater hair thickness and direct sampling correlated with higher success rates. In certain cases, the Insertion/Null (INNUL) markers system, InnoTyper 21, outperformed the Power Plex Fusion 6 C STR kit. For forensic purposes, using the entire hair shaft provided better profiling outcomes than using the root alone. All Insertion/Null (INNUL) markers were in Hardy-Weinberg equilibrium, except for a few loci showing minor linkage disequilibrium. These results highlight the analytical potential of INNUL markers for obtaining nuclear DNA profiles from hair, even in challenging forensic contexts.
Common bile duct (CBD) injury is a rare but devastating complication of laparoscopic cholecystectomy. Intraoperative indocyanine green (ICG) fluorescence cholangiography may improve biliary visualization, but its effect on CBD injury has not been well demonstrated. To evaluate the association between intraoperative ICG use and CBD injury after laparoscopic cholecystectomy. This cohort study included data from multiple hospitals in the Epic Cosmos dataset for adult patients (18 years and older) undergoing laparoscopic cholecystectomy between 2016 and 2024. Robotic cases, surgery for hepatobiliary malignancies, planned open procedures, and patients with inadequate follow-up were excluded from analysis. Data were analyzed from November 2025 to January 2026. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding by indication. Intraoperative ICG fluorescence cholangiography. The primary outcome was CBD injury within 1 year of surgery. Secondary outcomes included subsequent biliary intervention within 1 year, conversion to open surgery, and rates of any nonbiliary postoperative complications within 30 days. A total of 1 266 024 patients were included for analysis, of whom 164 695 (13%) underwent indocyanine green cholangiography. Among them, 118 626 (72.0) were female and 46 069 (28.0) were male; the mean (SD) age was 51 (17) years. ICG use increased from 1143 patients (1.6%) in 2016 to 47 816 (26%) in 2024. After IPTW adjustment, ICG was associated with lower rates of CBD injury (408 [0.25%] vs 659 [0.40%]; relative risk [RR], 0.62; 95% CI, 0.49-0.79; P < .001), need for any subsequent biliary intervention (7387 [4.49%] vs 8902 [5.39%]; RR, 0.83; 95% CI, 0.77-0.90; P < .001), conversion to open surgery (657 [0.40%] vs 1386 [0.84%]; RR, 0.48, 95% CI, 0.40-0.56; P < .001), and nonbiliary complications at 30 days (11 939 [7.25%] vs 14 275 [8.64%]; RR, 0.84; 95% CI, 0.78-0.91; P < .001). In this large national cohort, intraoperative ICG use was associated with lower rates of CBD injury, fewer postoperative biliary procedures and nonbiliary complications, and reduced conversion to open surgery. These findings support the use of ICG to enhance biliary safety in laparoscopic cholecystectomy and demonstrate its utility in reducing CBD injury.
Drought and salt stresses impose serious effects on plant proliferation and development, with multiple categories of transcription factors (TFs) playing important regulatory effects in modulation stress reaction. In this study, the apple R2R3 MYB TF, MdMYB73L, was cloned and characterized its role in conferring abiotic stress tolerance. Firstly, expression assays demonstrated that the transcript levels of MdMYB TFs changed substantially under salt and drought stresses. Subsequently, MdMYB73L-overexpressing transgenic Arabidopsis, apple calli and tomato plants all showed increased sensitivity to salt and drought treatments, manifesting as short roots and severe growth inhibition compared to controls. These results demonstrate that MdMYB73L functions as a key negative regulator in the response to drought and salt stresses. Overall, these research not only demonstrate the specific function of a MYB TF in stress responses but also provide a crucial framework for elucidating the broader effects of the apple MYB family in abiotic stress tolerance.
Resting-state functional MRI (rs-fMRI) was used to measure the differences in voxel-based indicators between patients with acute mild traumatic brain injury (mTBI) and healthy volunteers, and the correlation between the differences in these multimodal parameters and the cognitive performance of patients was analyzed. We collected rs-fMRI data from 35 mTBI patients within 7 days postinjury and 35 healthy volunteers. We employed amplitude of low-frequency fluctuations (ALFF), fractional ALFF, regional homogeneity, functional connectivity, and degree centrality to analyze the data and investigate the dysfunctional brain regions in acute mTBI. Neuropsychological assessments, including the Rivermead Post-Concussion Symptoms Questionnaire, Montreal Cognitive Assessment, Loewenstein Occupational Therapy Cognitive Assessment, and Trail Making Tests A and B, were administered to the 35 mTBI patients. Correlation analysis was performed between the graph theory parameters and the neuropsychological outcomes. The ALFF in the insula of the mTBI group was significantly lower than that in the control group, and the degree centrality in the angular gyrus was also significantly reduced. Increased functional connectivity was observed between the cuneus and the middle occipital gyrus, whereas functional connectivity in the dorsolateral superior frontal gyrus was significantly decreased. Correlation analysis between neuropsychological assessment scores and neural network function in the mTBI group suggested that multimodal rs-fMRI analysis may provide insights into dysfunctional brain regions in mTBI, though observed associations did not survive correction for multiple comparisons.
Clinical models are commonly applied in critical care for both descriptive and predictive purposes. However, methodological rigour is often lacking in their development and validation. This review examines the principles underlying the multiple domains of model validity. We argue that a clear model purpose and theoretical framework are essential preconditions for validity. Recently developed descriptive and predictive models illustrate different approaches to promoting validity. In developing SOFA-2, eCARTv5, Sepsis-3 and the PHOENIX paediatric sepsis criteria, authors used combinations of expert-driven consensus, data-driven derivation and iterative refinement. These examples demonstrate that validity requires a process of repeated evaluation across distinct populations, settings and time periods. The best approach to establishing validity combines a clear theoretical framework, structured expert consensus (including Delphi methodology), rigorous statistical evaluation (discrimination, calibration, net benefit) and prospective external validation. The distinction between models designed to predict outcomes and those designed to describe or quantify organ dysfunction is fundamental and should guide development and validation strategy from the outset.