Fluids and Barriers of the CNS

Background: Cervical spinal cord (CSC) compression and myelopathy are frequent, severe complications in mucopolysaccharidosis (MPS) types I and VI. Early detection is critical to prevent irreversible neurological deficits and preserve quality of life. This prospective study aimed to identify quantitative neuroimaging biomarkers of structural CSC damage and myelopathy in MPS I and VI. Methods: Structural and diffusion magnetic resonance imaging (MRI) of the CSC was analyzed in 17 MPS I patients, 3 MPS VI patients (19{+/-}7 years), and 19 case-matched healthy controls (20{+/-}7 years). CSC macrostructure (cross-sectional area, diameters) and microstructure (fractional anisotropy [FA], radial [RD], mean, axial diffusivities) were evaluated within and beyond the maximal compression areas. Results: MPS patients demonstrated reduced CSC cross-sectional area and anterior-posterior diameter at upper cervical levels, alongside widespread microstructural alterations (lower FA, higher RD) throughout the CSC versus controls (pFDR<0.05). Restricted foramen magnum space was associated with microstructural damage at lower cervical levels without overt macrostructural compression. Morphological and microstructural metrics were sensitive to CSC compression and myelopathy severity (pFDR<0.05). Lower CSC integrity correlated with more advanced growth retardation (p<0.001). Among patients receiving hematopoietic stem cell transplantation, earlier treatment correlated with preserved upper CSC morphology (p<0.05). Distinct neuroimaging phenotypes were observed across MPS genotypes (pFDR<0.05). Conclusions: CSC MRI provides candidate neuroimaging biomarkers for early detection and characterization of myelopathy in MPS I and VI. Structural damage extends beyond primary maximal compression areas, highlighting these markers for clinical monitoring and future therapeutic trials.

Introduction and objectives Hydrocephalus is a common complication of aneurysmal subarachnoid haemorrhage. This is one of several standard indications for the insertion of an external ventricular drain, but there are no standard guidelines for timing of extraventricular drain discontinuation in this population. Therefore, the study aims were to examine the 1) factors associated with extraventricular drain duration in aneurysmal subarachnoid haemorrhage and 2) association between extraventricular drain duration and clinical and resource-based outcomes. Methods In this single centre retrospective cohort study, data for adult patients treated in the ICU between 2015-2023 with aneurysmal subarachnoid haemorrhage and requiring an extraventricular drain were analysed. Data were extracted from both a prospective patient registry and the electronic medical record. Linear regression modelling was used to identify the factors associated with extraventricular drain duration. Measures used to examine the association between extraventricular drain duration, and the outcomes of interest included hazard ratio, relative risk, and mean differences as appropriate for a specific outcome. Results Of the participants (n=205), 68% (n = 140) were female, mean age was 60.7 (SD 13.3) years and 71% (n = 145) had a modified Fisher score of 4. Mean extraventricular drain duration was 15.3 (SD 8.6) days. The number of days mechanically ventilated and extraventricular drain challenge by clamp trial were associated with an increased duration of extraventricular drain treatment. Increased extraventricular drain duration was associated with an increased incidence of ventriculoperitoneal shunt insertion, and an increase in ICU and hospital length of stay when extraventricular drain duration exceeded 20 days. Conclusion The factors associated with an increased duration of extraventricular drain treatment were a longer duration of mechanical ventilation. The outcomes associated with an increased duration of extraventricular drain treatment were an increased incidence of ventriculoperitoneal shunt insertion, an increased incidence of ventriculitis when extraventricular drain duration exceeded 20 days, and an increase in ICU length of stay. These study findings may inform the conduct of a larger multi-centre study to examine the factors associated with duration of treatment with extraventricular drain, and outcomes associated with extraventricular drain duration.

BACKGROUND: White matter hyperintensities (WMHs), the principal imaging manifestation of cerebral small vessel disease, lack an animal model that produces pathology of sufficient magnitude to validate potential therapeutics. We characterized white matter (WM) degeneration in a renovascular hypertension (RVH) rat model, interrogated its mechanism, and tested its relevance in patients. METHODS: RVH was induced by two-kidney, two-clip surgery and assessed by T2-weighted and diffusion MRI, myelin and axonal histology, and blood-brain barrier (BBB) leakage markers. The influence of angiotensin II (Ang II) on barrier function in brain endothelial cells was examined using transendothelial electrical resistance and reactive oxygen species (ROS) assays. Losartan was infused intracerebroventricularly to block brain AT1R (Ang II type 1 receptor) without systemic blood pressure reduction. WMH burden was compared between patients with and without renal artery stenosis, and WMH progression across antihypertensive classes was assessed in the CHALLENGE (Korea), MSS2 (UK), LBC1936 (UK), and SPRINT-MIND-MRI (US) cohorts. RESULTS: Approximately two-thirds of RVH rats developed WMHs that expanded between 7 and 9 weeks, accompanied by reduced fractional anisotropy, demyelination, axonal and mature oligodendrocyte loss, and glial activation. IgG, albumin, and fibrinogen leakage was confined to affected WM. Ang II impaired endothelial barrier function and generated ROS through AT1R. Intracerebroventricular losartan attenuated WM pathology and improved behavior while blood pressure remained comparably elevated. Patients with renal artery stenosis had higher WMH volumes (10.52 versus 6.52 mL; P = 0.035). Angiotensin receptor blocker use was associated with the slowest tertile of annual WMH progression in the Korean cohort (OR, 2.57 [95% CI, 1.20-5.61]) and among White participants in SPRINT-MIND-MRI (OR, 3.52 [95% CI, 1.05-12.29]). CONCLUSIONS: RVH produces prominent ischemic WM degeneration driven by AT1R signaling, identifying a blood pressure-independent therapeutic target with corroborating clinical evidence.

Importance. Plasma phosphorylated tau 217 (p-tau217) is entering clinical use with fixed diagnostic threshold that do not account for kidney function. Chronic kidney disease (defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2), raises plasma p-tau217 concentrations and can produce false positive results. It remains unclear whether milder reductions in kidney function, above the CKD threshold, have the same effect. Objective. To determine whether plasma p-tau217 is elevated with mildly reduced kidney function, above the chronic kidney disease threshold, in adults without neurological disease. Design. Cross-sectional analysis of a cohort enrolled between 2023 and 2025 and biomarker analysis blinded to clinical data. Setting. Two private psychiatric inpatient facilities in Australia. Participants. Adults admitted with psychiatric disorders and free of neurological disease. Exposures. eGFR calculated from serum creatinine using the CKD-EPI 2021 equation. Main Outcomes and Measures. Plasma p-tau217, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), measured on the Simoa platform. Multivariable linear regression compared eGFR groups (< 60, 60 to 90, and [&ge;] 90 mL/min/1.73 m2), adjusted for age, BMI, and sex. Results. Among 180 participants (median age, 50.5 years [IQR, 38.0-61.5]; 94 [52%] female), eGFR was [&ge;] 90 mL/min/1.73 m2 in 106 (59%), 60 to 90 in 61 (34%), and < 60 in 13 (7.2%). Compared with an eGFR [&ge;] 90, plasma p-tau217 was 36% higher in both the 60 to < 90 group ({beta} = 0.42 [95% CI: 0.11, 0.74]; P = .008) and 116% higher in the < 60 group ({beta} = 1.05 [95% CI: 0.43, 1.72]; P = .002). Plasma NfL and GFAP were elevated in the < 60 group but differences in the 60 to < 90 group did not reach significance. Modelled continuously, plasma p-tau217 was 9.5% lower per 10 mL/min/1.73 m2 higher eGFR (95% CI: 3.3%, 15.4%). Conclusions and Relevance. Plasma p-tau217 was elevated in adults with mildly reduced kidney function, above the CKD threshold, in a cohort free of neurological disease. Kidney function across its full range should be incorporated into plasma p-tau217 reference ranges and clinical interpretation to reduce false positive and false negative results.

Objectives: To determine how strongly clinical referral text, rather than image content, drives the decisions of multimodal large language models (LLMs) differentiating glioma from brain abscess on MRI. Materials and methods: This retrospective single-center study included 60 contrast-enhanced T1-weighted brain MRI examinations (30 gliomas, 30 abscesses; reference-standard diagnosis). One axial slice per case was paired with five referral texts (explicitly inflammatory to explicitly tumor-suggestive) under three prompt instructions and submitted 20 times each to GPT-4o, Claude Sonnet 5, Gemini 3.5 Flash, and Qwen 3.6 (72,000 answers). The primary outcome was the text-driven span (difference in tumor-call frequency between explicit inflammatory and explicit tumor text). Two blinded radiologists classified the images without text; sensitivity, specificity, and accuracy were compared descriptively. Results: Patients (29 women) had a mean age of 55.8 +/- 16.4 years. With neutral text, models answered tumor in 45-67% of queries (specificity, 0.38-0.78), versus 52% and 60% for radiologists (specificity, 0.77 and 0.63). The text-driven span was 0.79-1.00 (p < 0.001 for all models), whereas confirmed gliomas and abscesses differed by only 0.01-0.10 in three models and 0.25 in Gemini 3.5 Flash. Subtle wording produced at least 83% of the span in three models. An instruction to ignore the text reduced the span to 0.48-0.70 in three models and to 0.04 in Gemini 3.5 Flash, partly through reversion to a tumor default. Model accuracy was 0.52-0.73 versus 0.78 and 0.73 for radiologists. Conclusion: Multimodal LLMs deferred to referral text over imaging evidence in differentiating glioma from brain abscess, and prompt instructions did not reliably correct this.

Neuropsychiatric symptoms (NPS) are highly prevalent in Mild Cognitive Impairment (MCI), conceptualized as an intermediate clinical state between normal aging and dementia. Although neuroimaging studies have reported associations between NPS and brain alterations in MCI, longitudinal evidence on NPS and their relationship with multimodal MRI measures remains limited. We aimed to investigate (1) longitudinal changes in NPS, volumetric assessment and measurement of regional cerebral blood flow (CBF) within the medial temporal lobe (MTL); (2) associations between longitudinal changes in MRI measures and NPS; (3) whether baseline MRI measures predicted longitudinal changes in NPS. Thirty individuals with MCI aged over 65 years were recruited, of whom eighteen followed up for a mean period of 29 {+/-} 8.9 months. There were significant reductions in total grey matter and white matter volumes, together with volume loss in the bilateral hippocampus, bilateral parahippocampal gyrus and right entorhinal cortex (pFDR[&le;]0.05) over the follow up period. Volume loss in the right parahippocampal gyrus was associated with increase in aggression (pFDR<0.01), and CBF increase in the right hippocampus and parahippocampal gyrus was associated with worsening in agitation (pFDR<0.01). Furthermore, lower baseline volume of the right entorhinal cortex was associated with increase in aggression, and lower baseline CBF in the right hippocampus and parahippocampal gyrus was associated with worsening of agitation (pFDR<0.05). Our findings highlight the importance of identifying NPS in individuals with MCI and the role of structural and perfusion MRI measures as promising biomarkers for monitoring disease progression and improving risk prediction of conversion to dementia.

Introduction: Cognitive intraindividual variability (IIV), a measure of fluctuation in performance across time or tasks, is an emerging marker of cognitive decline. However, little is known about within-domain IIV in Latino adults. To address this gap, we examined memory IIV and hippocampal integrity in older Latino individuals. Methods: Sixty-seven participants from the Boston Latino Aging Study underwent cognitive testing and MRI. Linear regressions assessed whether memory IIV was associated with hippocampal volume and hippocampus-cingulum tract fractional anisotropy. Additional analyses evaluated associations using mean memory performance as the outcome. Results: Higher mean performance was associated with greater hippocampal volume (=0.24, p=.03), while memory IIV was not (=0.028, p=.84). Higher memory IIV was associated with lower fractional anisotropy in the hippocampus-cingulum tract (=-0.34, p<.01), while mean performance was not (=-0.07, p=.52). Discussion: Memory IIV may be more closely linked to hippocampal white matter, while mean memory performance may better reflect hippocampal volume.

Src family kinases (SFKs) constitute a major non-receptor tyrosine kinase class that regulate processes important for pregnancy. We profiled placental SFKs to assess cell-specific expression, tissue localization, and clinical associations in early-onset preeclampsia (PE). Placental SFK transcripts were analyzed using bulk RNA sequencing discovery (GSE203507; n=15 PE, n=15 controls) and external validation (GSE114691; n=40 PE, n=21 controls) cohorts. Single-cell and single-nucleus RNA sequencing atlases mapped cell-specific expression. Computational deconvolution and causal mediation analyses were applied to bulk datasets. Findings were cross-validated by real-time quantitative PCR (qPCR; n=9 early-onset PE, n=7 controls) and immunohistochemistry (IHC). Transcriptomic data showed that LYN was the sole SFK member consistently elevated in early-onset PE placentas across discovery (1.8-fold, FDR<0.01) and validation cohorts (2.2-fold, FDR<0.001). Elevation was verified by qPCR (p<0.0001) and remained significant after adjusting for clinical covariates. Placental LYN abundance correlated positively with maximum antepartum maternal systolic blood pressure (r=0.63, p<0.01). Single-cell transcriptome atlases demonstrated LYN enrichment in myeloid lineages, extravillous trophoblasts, and syncytiotrophoblast (SCT). Deconvolution and mediation analyses indicated that altered tissue composition and increased per-cell expression each accounted for approximately half of the PE-associated LYN increase. IHC localized Lyn protein to Hofbauer macrophages and the apical microvillar SCT membrane in PE placentas. We conclude that placental LYN expression is selectively elevated in early-onset PE and correlates with maternal blood pressure severity. Lyn localization to trophoblasts and placental immune cells suggests potential roles in mediating inflammation and hypoxia-associated signaling in PE pathogenesis.

Purpose: Posterior pharyngeal wall (PPW) thickening is a common structural manifestation of treatment-related internal lymphedema in patients with head and neck cancer and can be evaluated using lateral videofluoroscopic images acquired during modified barium swallow (MBS) studies. However, no standardized method currently exists for quantitative measurement. Methods: This two-phase methodological study first conducted a scoping review to characterize existing approaches to PPW thickness measurement and identify the principal factors contributing to variation in PPW thickness measurement. Eight studies were identified with variation observed across these measurement factors. An empirical reliability study was then performed using 107 MBS studies from 93 Head and Neck Cancer patients. Two independent raters annotated 10 anatomical landmarks on pre-swallow and post-swallow resting frames, and a computer-assisted algorithm quantitatively generated seven candidate PPW thickness measurements based on different vertebral reference points and measurement directions. Reliability was assessed intraclass correlation coefficients (ICCs). Results: Inter-rater reliability was highest for the measurement originating from the midpoint of C3 and extending perpendicular to the anterior C3 surface (ICC, 0.78; 95% CI, 0.72-0.83). Among the normalization references, C2-C4 vertebral length demonstrated greater reliability than C3 vertebral length, with an ICC of 0.88 (95% CI, 0.85-0.91). No significant differences were observed between pre-swallow and post-swallow PPW thickness measurements across the evaluated approaches. Conclusions: These findings provide a methodological foundation for more standardized and reliable quantification of PPW thickness, with potential to expand the role of MBS from the functional evaluation of swallowing to include quantitative characterization of pharyngeal structural abnormalities.

Rationale: Conventional CT-derived pulmonary vascular metrics quantify vascular pruning but do not assess the spatial heterogeneity of vascular architecture. In COPD, peripheral microvascular pruning coexists with compensatory central vessel dilation, paradoxically preserving total vessel volume while reducing effective vascular penetration into lung parenchyma. Objectives: To develop and evaluate Vascular Proximity Coverage (VPC), a distance-based CT biomarker quantifying the spatial efficiency of pulmonary vascular distribution. Methods: This retrospective analysis included 7,881 COPDGene participants [PHASE] with complete vascular segmentations. VPC was estimated by integrating the area under the cumulative lung tissue coverage curve at distances of 0-10 mm from segmented vessel voxels. Multivariable models assessed associations with lung function, six-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, mMRC dyspnea score, and all-cause mortality over a median follow-up of [10.8] years, adjusting for demographics, smoking, emphysema, scanner type, and BV5. The cohort was stratified at median BV5 and VPC into concordant (high/high, low/low) and discordant (high-BV5/low-VPC, low-BV5/high-VPC) vascular phenotypes. Results: VPC declined across disease severity (5.82 {+/-} 0.50 [UNITS] in non-smokers to 5.21 {+/-} 0.64 in GOLD 4; p < 0.001). Among spirometrically normal smokers, current smokers had lower VPC than former smokers (5.31 vs. 5.68; p < 0.001). Each standard deviation decrease in VPC was independently associated with reduced 6MWD ({beta} = -16.8 m, 95% CI: -19.5 to -14.0), worse SGRQ ({beta} = 1.9, 95% CI: 1.4 to 2.4), and greater dyspnea (RR = 1.05, 95% CI: 1.03 to 1.08; all p < 0.001). The lowest VPC quartile was associated with 38% higher mortality than the reference quartile (HR = 1.38, 95% CI: 1.18 to 1.62; p < 0.001). The high-BV5/low-VPC phenotype showed 24% higher mortality than high-BV5/high-VPC (HR = 1.24, 95% CI: 1.08 to 1.42; p = 0.002) despite preserved vessel volume. Conclusions: VPC captures spatial heterogeneity of vascular architecture independent of vessel volume, is reduced in smokers without airflow obstruction, and identifies excess mortality risk among individuals whose total vessel volume appears preserved.

Objectives To evaluate discrepancies between radiologists and referring physicians in the interpretation of diagnostic probabilities conveyed by common Japanese expressions used in radiology reports. Materials and Methods Fifteen expressions commonly used to convey diagnostic probabilities in radiology reports were selected by five attending radiologists. An anonymous online survey was distributed to 26 radiologists and 33 referring physicians at a single institution. Participants assigned a diagnostic probability (from 0% to 100% in 10% increments) to each expression. Differences in median probabilities between radiologists and referring physicians were analyzed using the Mann-Whitney U test. Variability in interpretation was assessed using interquartile range (IQR), with IQR [&ge;] 30% defined as substantial variability. Results All radiologists (26/26) and 97% of referring physicians (32/33) completed the survey. Seven of the 15 expressions showed statistically significant differences in interpretation between radiologists and referring physicians: "c/w" (80% vs. 60%; p = 0.031), the Japanese equivalents of "present" (100% vs. 100%; p = 0.024), "suspect of" (80% vs. 70%; p = 0.007), "possibly" (50% vs. 70%; p < 0.001), "unlikely" (10% vs. 10%; p = 0.022), "cannot be ruled out" (25% vs. 40%; p < 0.001), and "not inconsistent with" (80% vs. 90%; p = 0.008). Substantial variability in interpretation (IQR [&ge;] 30%) was observed for four expressions: "cannot be ruled out" (IQR, 10%-40%), "s/o" (IQR, 60%-90%), "c/w" (IQR, 50%-90%), and "not inconsistent with" (IQR, 70%-100%). Conclusion This study revealed that nearly half of the Japanese expressions commonly used to convey diagnostic probabilities were interpreted differently by radiologists and referring physicians. These discrepancies highlight the need for a standardized lexicon to improve clarity and consistency in radiology reporting.

Preterm birth is strongly linked to systemic inflammation and encephalopathy of prematurity, which underlies subsequent cognitive impairment. T-cell immunity contributes to brain-immune crosstalk across the life course but its role in the pathogenesis of encephalopathy of prematurity is unknown. Protein epigenetic scores are DNA methylation (DNAm)-based proxies of circulating proteins. We tested the hypothesis that T-cell dysregulation has a specific role in child neurodevelopment following preterm birth. Multimodal data were collected from 144 preterm infants (median gestational age at birth 29+5 weeks [range 23+3 to 32+6]) recruited to a prospective cohort study: saliva DNAm for protein epigenetic score derivation and brain MRI, both at term-equivalent age, and the Mullen Scales of Early Learning Composite score at 5 years from a subset. We investigated associations of the epigenetic scores for cytotoxic and regulatory T cell-associated molecule (DNAm CRTAM) and C-reactive protein (DNAm CRP; a non-specific marker of inflammation) with MRI metrics of encephalopathy of prematurity: global and regional brain volumes, and general factors of diffusion tensor imaging and neurite orientation dispersion and density imaging metrics averaged across 42 white matter tracts. We tested whether DNAm CRTAM explains more variance than DNAm CRP in MRI metrics of the encephalopathy of prematurity and cognitive scores in childhood. Higher neonatal DNAm CRTAM was associated with lower general factor of fractional anisotropy ({beta} = -0.252, q = 0.011) and higher general factors of radial diffusivity ({beta} = 0.215, q = 0.039), mean diffusivity ({beta} = 0.198, q = 0.047) and orientation dispersion index ({beta} = 0.201, q = 0.048), independent of inflammatory morbidities and other biological covariates after false discovery rate correction. DNAm CRTAM explained more variance than DNAm CRP (maximum incremental R2 = 4.2% vs 1.5%) in diffusion MRI metrics. Higher neonatal DNAm CRTAM was associated with lower cognitive scores at 5 years, independent of DNAm CRP and other covariates ({beta} = -0.332, P = 0.008), and explained more variance in cognitive scores than DNAm CRP (incremental R2 = 9.4% vs 1.2%). An epigenetic proxy of CRTAM in preterm infants is associated with both encephalopathy of prematurity in the neonatal period and lower cognitive performance at 5 years, explaining greater incremental variance than a non-specific marker of inflammation. The data implicate T-cell dysregulation in the pathophysiology of atypical neurodevelopment following preterm birth.

Stroke is a leading cause of mortality and disability in Uganda, with a prevalence of approximately 2.5% and a 25-30% 30-day mortality rate, exacerbated by limited access to predictive tools and advanced diagnostics. Machine learning (ML) offers potential for early stroke risk stratification, but its application in resource-constrained settings like Uganda requires tailored models and rigorous performance evaluation, as well as assessment of misclassification patterns. This study aimed to develop and internally validate an ML-based predictive model for stroke using clinical and socio-demographic characteristics among patients at Mulago National Referral Hospital (MNRH) and residents of Wakiso District, Uganda, identify key predictors and assess misclassification patterns to enhance targeted prevention. A retrospective case-control study utilized secondary data from 1,016 participants (254 stroke cases, 762 controls) across three prior studies conducted between 2006 and 2015. Eight ML algorithms were evaluated using 5-fold cross-validation, with performance metrics including accuracy, sensitivity, positive predictive value, F1-score, and area under receiver operator characteristics curve (AU-ROC). McNemars test compared model classification performance of the top 2 models. Feature importance identified key predictors, and misclassification patterns were analyzed using classification matrix and line graphs. The Random Forest (RF) model achieved the highest performance (95.18% accuracy, 90.10% F1-score, 97% AU-ROC). McNemars test confirmed RFs superior classification (p=0.01). Age, systolic blood pressure, total cholesterol, and waist-hip ratio were the top drivers of RF stroke predictions. RF misclassified 8.3% of stroke cases and 3.3% of non-stroke cases, due to overlaps in risk profiles (e.g., lower cholesterol, systolic blood pressure and age in false negatives). The RF model demonstrates strong potential for stroke risk prediction in Uganda, leveraging routine data to prioritize high-risk individuals. Misclassification analysis highlights areas for model refinement, supporting its potential for integration into clinical workflows for early intervention and stroke prevention in resource-limited settings. Future external validation across diverse populations is recommended.

Syntax processing impairment is a defining feature of primary progressive aphasia (PPA), particularly in the nonfluent/agrammatic variant. However, current models are derived largely from Indo-European languages, and it remains unclear whether the cognitive and neuroanatomical mechanisms of syntax processing generalize to Chinese, an analytic, pro-drop language that encodes grammatical relationships primarily through word order and function words rather than inflectional morphology. Participants were recruited from the international Chinese Language Assessment in PPA cohort and included 64 individuals with PPA (19 logopenic, 15 nonfluent/agrammatic, 15 semantic, and 15 unclassifiable/mixed) and 60 cognitively healthy controls. Participants completed sentence comprehension and production tasks with systematically manipulated syntactic features. Item-level linguistic determinants were examined using ridge regression, diagnostic performance using receiver operating characteristic analyses, and neuroanatomical correlates using voxel-based morphometry of structural MRI. Performance on sentence comprehension and production was influenced by grammatical and lexical features. Subject-relative clauses, passive constructions, a higher proportion of function words, longer character length, and greater lexical content were associated with poorer performance among participants with PPA. Sentence comprehension was impaired in the logopenic, nonfluent/agrammatic, and semantic variants, even when isolated to the syntactic component of the sentence comprehension task. Similarly, sentence production was impaired across all PPA variants (all P < 0.01 versus controls). No significant differences were observed among PPA variants. Adjusted receiver operating characteristic analyses demonstrated high discrimination between each PPA variant and controls, with areas under the curve ranging from 0.87 to 0.97 for sentence comprehension-syntax and from 0.91 to 0.97 for sentence production. However, pairwise comparisons showed no significant differences in discriminative performance among PPA variants after correction for multiple comparisons. Both sentence comprehension-syntax and sentence production showed associations with semantic and repetition measures in addition to motor speech measures. Voxel-based morphometry showed that higher sentence comprehension-syntax scores were associated with greater grey matter volume in left frontotemporal and cingulate regions, whereas higher sentence production scores were additionally associated with greater gray matter volume in frontostriatal structures, including the caudate, putamen, and thalamus. Syntactic processing impairment in Chinese-speaking individuals with PPA extends beyond the nonfluent/agrammatic variant and is associated with distributed frontotemporal and frontostriatal regions, as well as lexical-semantic and auditory verbal short term memory mechanisms. These findings suggest that the cognitive and neural manifestations of syntactic impairment may be shaped by language-specific typological properties, underscoring the need for linguistically informed approaches to the assessment and interpretation of PPA.

Computed tomography (CT) interpretation requires recognition of the anatomical level of each slice. Classification may facilitate preprocessing and AI-assisted fracture diagnosis. We developed deep learning models to classify craniofacial CT slices into six anatomical categories. A total of 11,769 images were collected from a multicenter database involving 10 Japanese university hospitals and the public Head-Neck-Radiomics-HN1 dataset. Patients were divided into training (70%) and evaluation (30%) sets. Five CNN architectures were trained from scratch, and hard- and soft-voting ensembles were evaluated. Individual-model accuracy ranged from 94.72% to 96.09%; the hard-voting ensemble achieved 96.46% accuracy (Cohen's k = 0.954). Although performance differed among individual models (Cochran's Q = 99.29, p < 0.001), the ensemble did not significantly outperform EfficientNetV2B1 (McNemar's p = 0.163). Errors occurred mainly between adjacent anatomical regions. Deep learning can classify craniofacial CT slices accurately and may support automated dataset organization and AI-assisted fracture diagnosis. External validation is needed.

Introduction: Kidney volume is associated with renal function, but conventional whole-organ measurements may miss regional changes in kidney substructures. We used magnetic resonance imaging (MRI) to test whether kidney substructure volumes and three-dimensional (3D) thickness phenotypes are associated with disease, adiposity, and incident outcomes. Methods: Automated abdominal MRI segmentations from 70,270 UK Biobank participants were used to quantify left and right kidney cortex, medulla, and parenchyma volumes and mesh-based thickness maps. Mass univariate regression generated statistical parametric maps linking regional thickness to anthropometric traits and disease (CKD, type-2 diabetes [T2D], hypertension). Bidirectional causal mediation analyses were performed using kidney substructure volumetric, thickness PCs and kidney adiposity. Longitudinal changes were assessed in 2,610 participants with repeat imaging. Cox proportional hazards models tested the associations between kidney volumes and principal component (PC) scores of thickness and incident CKD, T2D, hypertension, cardiovascular disease (CVD), and mortality. Results: CKD was associated with thinning of the parenchyma and most pronounced in the medulla (87.7% left, 72.8% right), whereas associations in the cortex were mixed. In contrast, T2D and hypertension were predominantly associated with increased thickness, most extensively in the cortex (T2D: 84.39% left, 96.35% right; hypertension: 94.8% left, 99.9% right). Age-disease interactions were associated with reduced thickness across all conditions. Smaller medulla volume and lower cortical thickness mediated the association between CKD and renal sinus fat. Kidney substructure volume was inversely associated with incident CKD across all substructures and both kidney sides (p<0.05), but positively associated with incident hypertension and mortality (p<0.05). Thickness PC scores also predicted outcomes independently of volume, with PC3 in the left cortex (HR 0.91 [0.84-0.98]), reflecting inferior pole/hilar thickness, associated with incident CKD. Conclusions: MRI-derived kidney substructure volumes and 3D thickness maps provide complementary, spatially-resolved markers of kidney morphology, that are mechanistically linked to renal adiposity and future disease risk.

Aims Rosuvastatin is commonly co-administered with ticagrelor in patients with acute coronary syndrome. Ticagrelor inhibits breast cancer resistance protein (BCRP/ABCG2), increasing rosuvastatin exposure and potentially the risk of rhabdomyolysis. This risk may be further influenced by age and the ABCG2 c.421C>A variant. We aimed to predict optimal rosuvastatin dosing with ticagrelor in elderly patients stratified by ABCG2 genotype using physiologically based pharmacokinetic (PBPK) modelling Methods PBPK models for rosuvastatin and ticagrelor were developed and validated in PK-Sim using clinical data from healthy adults, elderly patients, and individuals with wild-type or homozygous ABCG2 c.421C>A genotypes. Key parameters, including BCRP catalytic activity and age-dependent declines in CYP2C9 and CYP3A4 activity, were optimized. The drug-drug interaction model incorporated competitive BCRP inhibition by ticagrelor. Rosuvastatin steady-state exposure was simulated with half or quarter standard doses during ticagrelor co-administration, and exposure matching approach was used to identify optimal dosing. Results The PBPK models demonstrated good predictive performance across populations and genotypes. In young adults with the wild-type genotype, halving the rosuvastatin dose resulted in an AUC fold change of 1.44, supporting a half-dose strategy. In young homozygous variant carriers, half-dose co-administration produced comparable exposure (AUC fold change 0.78). In elderly wild-type individuals, a four-fold dose reduction achieved comparable exposure (AUC fold change 1.06), whereas elderly variant carriers required only a half-dose reduction (1.12). Conclusions PBPK modelling supported age- and ABCG2 genotype-specific rosuvastatin dosing with ticagrelor. Elderly wild-type patients may require a further dose reduction to minimise toxicity while maintaining therapeutic exposure.

The -Bonacci weighted sequence space {ell}(,) is introduced for [&ge;] 2, 1 [&le;] < {infty}, and > 0). It is proved to be a Banach space which is isometrically isomorphic to {ell}, with an unconditional Schauder basis. The space is also reflexive and uniformly convex. Its strict inclusion chain, continuous dual, and asymptotic truncation estimate of order - / are also established. Based on this framework, Scaled &#119898-BonacciNet is proposed as a lightweight CNN that rescales Fibonacci-Net channels using the dominant &#119898-Bonacci root and employs depth wise separable convolutions. Tribonacci-Net achieved 96.09% accuracy and a 0.9581 macro F1-score on the 15-class Brain MRI dataset using 0.85 million parameters and 0.366 GFLOPs. Pentanacci-Net attained 95.87% accuracy on the 44-class dataset while reducing parameters and FLOPs by 47.10% and 44.48%, respectively. On the CKD ultrasound dataset, Hexanacci-Net achieved 83.75% accuracy and a 0.7941 macro F1-score, with corresponding reductions of 50.37% and 45.10%. These findings support dominant-root scaling as a structured approach to lightweight CNN design.

Abstract Background: Placental insufficiency (PI), characterized by impaired placental function, is a leading cause of stillbirth. Although rare coding variants are known to cause a subset of stillbirths, their contribution to PI is poorly understood. Methods: We conducted a secondary analysis of stillbirth cases (N=292) of the Stillbirth Collaborative Research Network study with exome sequencing available on postmortem placental or fetal samples. PI was defined by standardized placental pathological lesions (e.g., maternal vascular malperfusion) and prespecified clinical criteria for placental dysfunction. Candidate gene-based rare-variant burden analysis was performed using the Sequence Kernel Association Test-Optimal framework, focusing on evolutionarily constrained developmental and placental-function genes. Primary analysis compared stillbirths with and without placental vascular malperfusion. Similar comparisons by clinical PI and other placental pathological lesions were conducted in secondary analysis. Results: Stillbirths with PI phenotypes demonstrated different patterns of genetic variation than stillbirths without PI. Specifically, we observed nominal differential enrichment of constrained variants in biologically prioritized placental-function genes, regulating extravillous trophoblast invasion and spiral artery remodeling (CTNND2, PHACTR1, SLIT1, VEGFA), placental angiogenesis (IGF2R, TEK), mitochondrial homeostasis (OPA1), and fetal growth (DLK1, GNAS). Secondary analyses on specific placental pathological lesions suggested recurrent enrichment of genes within similar placental developmental pathways. Conclusions: We observed nominal differential enrichment of constrained developmental and placental-function genes in stillbirths with PI compared to stillbirths without PI. The observed genetic signals across PI phenotypes suggest shared biological pathways underlie placental dysfunction. Our findings advance genotype-phenotype characterization and help prioritize candidate pathways for larger collaborative genomic and functional studies to improve stillbirth risk stratification and prevention.

Purpose To evaluate the external transportability of source-derived probability calibration for chest radiograph deep learning classifiers under distribution shift and determine its dependence on sample size and disease prevalence. Materials and Methods This retrospective secondary computational analysis of public, de-identified radiographic datasets involved no participant contact or new data collection. Cohort sizes were prespecified by availability without prospective power calculation: 106,686 NIH ChestX-ray14 images (29,323 patients; 1992-2015) for development and internal testing, 20,000 CheXpert images (20,000 patients; October 2002-July 2017), and 14,998 VinBigData images (2018-2020) for external testing. ResNet-18, DenseNet-121, and DeiT-Tiny classifiers for cardiomegaly and pleural effusion were trained across four patient fractions and three seeds (36 fits). Calibrators were fitted exclusively on NIH data. Twelve primary external Brier-score contrasts (temperature-scaled versus raw probabilities) were evaluated using paired cluster-bootstrapping with Holm adjustment. Results Temperature scaling reduced Brier scores in nine of 12 primary contrasts but worsened pleural effusion calibration on VinBigData across all architectures (Brier increases: ResNet-18, 0.001460 [95% CI: 0.001347, 0.001568]; DenseNet-121, 0.001193 [95% CI: 0.001109, 0.001274]; DeiT-Tiny, 0.000498 [95% CI: 0.000417, 0.000577]; all adjusted P=.006). Standardizing class weights to NIH prevalence reversed all CheXpert improvements. Although full versus 10% training improved external AUROC across all comparisons, DeiT-Tiny CheXpert pleural effusion Brier score worsened by 0.007039 despite a 0.032466 AUROC gain. At 80% selective image retention, calibrated ensembles retained only 12.3%-17.2% of VinBigData positive pleural effusion examinations. Conclusion Source-fitted calibration is not uniformly transportable across health systems, and discrimination gains do not guarantee calibrated probabilities. External evaluation must simultaneously assess probability reliability, prevalence shifts, and retained-case composition.