Whole brain morphologic features improve the predictive accuracy of IDH status and VEGF expression levels in gliomas.

Glioma is a systemic disease that can induce micro and macro alternations of whole brain. Isocitrate dehydrogenase and vascular endothelial growth factor are proven prognostic markers and antiangiogenic therapy targets in glioma. The aim of this study was to determine the ability of whole brain morphologic features and radiomics to predict isocitrate dehydrogenase status and vascular endothelial growth factor expression levels. This study recruited 80 glioma patients with isocitrate dehydrogenase wildtype and high vascular endothelial growth factor expression levels, and 102 patients with isocitrate dehydrogenase mutation and low vascular endothelial growth factor expression levels. Virtual brain grafting, combined with Freesurfer, was used to compute morphologic features including cortical thickness, LGI, and subcortical volume in glioma patient. Radiomics features were extracted from multiregional tumor. Pycaret was used to construct the machine learning pipeline. Among the radiomics models, the whole tumor model achieved the best performance (accuracy 0.80, Area Under the Curve 0.86), while, after incorporating whole brain morphologic features, the model had a superior predictive performance (accuracy 0.82, Area Under the Curve 0.88). The features contributed most in predicting model including the right caudate volume, left middle temporal cortical thickness, first-order statistics, shape, and gray-level cooccurrence matrix. Pycaret, based on morphologic features, combined with radiomics, yielded highest accuracy in predicting isocitrate dehydrogenase mutation and vascular endothelial growth factor levels, indicating that morphologic abnormalities induced by glioma were associated with tumor biology.

Association of maternal weight gain in early pregnancy with congenital heart disease in offspring: a China birth cohort study.

OBJECTIVES: Little study has reported the association of maternal weight gain in early pregnancy with fetal congenital heart disease (CHD). We aimed to explore the potential relationship based on a China birth cohort while adjusting by multiple factors. DESIGN: Cohort study. SETTING: China birth cohort study conducted from 2017 to 2021. PARTICIPANTS: The study finally included 114 672 singleton pregnancies in the 6-14 weeks of gestation, without missing data or outliers, loss to follow-up or abnormal conditions other than CHD. The proportion of CHD was 0.65% (749 cases). PRIMARY AND SECONDARY OUTCOME MEASURES: Association between maternal pre-pregnancy weight gain and CHD in the offspring were analysed by multivariate logistic regression, with the unadjusted, minimally adjusted and maximally adjusted methods, respectively. RESULTS: The first-trimester weight gain showed similar discrimination of fetal CHD to that period of maternal body mass index (BMI) change (DeLong tests: p=0.091). Compared with weight gain in the lowest quartile (the weight gain less than 0.0 kg), the highest quartile (over 2.0 kg) was associated with a higher risk of fetal CHD in unadjusted (OR 1.36, 95% CI: 1.08 to 1.72), minimally adjusted (adjusted OR (aOR) 1.29, 95% CI: 1.02 to 1.62) and maximally adjusted (aOR 1.29, 95% CI: 1.02 to 1.63) models. The association remains robust in pregnant women with morning sickness, normal pre-pregnancy BMI, moderate physical activity, college/university level, natural conception or with folic acid (FA) and/or multivitamin supplementation. CONCLUSIONS AND RELEVANCE: Although the association of maternal pre-pregnancy weight gain on fetal CHD is weak, the excessive weight gain may be a potential predictor of CHD in the offspring, especially in those with morning sickness and other conditions that are routine in the cohort, such as normal pre-pregnancy BMI, moderate physical activity, college/university level, natural conception or with FA and/or multivitamin supplementation.

Regulation of 2-Acetyl-1-pyrroline Content in Fragrant Rice under Different Temperatures at the Grain-Filling Stage.

2-Acetyl-1-pyrroline (2-AP) is a key volatile organic compound in fragrant rice aroma. However, the effects of temperature on 2-AP biosynthesis in fragrant rice and its regulation mechanism have been rarely reported. In the present study, three fragrant rice varieties were used as plant materials, and four temperature treatments during the grain-filling stage, i.e., (T1) 22/17 °C, (T2) 27/22 °C, (T3) 32/27 °C, and (T4) 37/32 °C, were adopted. The results showed that grain contents of 2-AP, proline, and γ-aminobutyric acid (GABA) significantly (P < 0.05) increased with decreased temperature, while the lowest and highest 2-AP contents were recorded in the T4 and T1 treatments, respectively. Higher pyrroline-5-carboxylic acid (P5C) content was recorded in low-temperature treatments (T1 and T2) than in high-temperature treatments (T3 and T4). The transcript levels of genes BADH2, PRODH, and OAT significantly (P < 0.05) decreased with decreased temperature. Lower transcript levels of genes P5CR, P5CS2, DAO2, DAO4, and DAO5 were recorded in low-temperature treatments (T1 and T2) than in high-temperature treatments (T3 and T4). In conclusion, low temperature increased 2-AP content and high temperature decreased 2-AP content in fragrant rice. We deduced that temperature regulated 2-AP biosynthesis through the metabolism of proline and GABA.

A millimeter water-in-oil droplet as an alternative back exchange prevention strategy for hydrogen/deuterium exchange mass spectrometry of peptides/proteins.

Hydrogen/deuterium exchange mass spectrometry (HDX-MS) is a versatile bioanalytical technique for protein analysis. Since the reliability of HDX-MS analysis considerably depends on the retention of deuterium labels in the post-labeling workflow, deuterium/hydrogen (D/H) back exchange prevention strategies, including decreasing the pH, temperature, and exposure time to protic sources of the deuterated samples, are widely adopted in the conventional HDX-MS protocol. Herein, an alternative and effective back exchange prevention strategy based on the encapsulation of a millimeter droplet of a labeled peptide solution in a water-immiscible organic solvent (cyclohexane) is proposed. Cyclohexane was used to prevent the undesirable uptake of water by the droplet from the atmospheric vapor through the air-water interface. Using the pepsin digest of deuterated myoglobin, our results show that back exchange kinetics of deuterated peptides is retarded in a millimeter droplet as compared to that in the bulk solution. Performing pepsin digestion directly in a water-in-oil droplet at room temperature (18-21 °C) was found to preserve more deuterium labels than that in the bulk digestion with an ice-water bath. Based on the present findings, it is proposed that keeping deuterated peptides in the form of water-in-oil droplets during the post-labelling workflow will facilitate the preservation of deuterium labels on the peptide backbone and thereby enhance the reliability of the H/D exchange data.

Overburden of rare ALMS1 deleterious variants in Chinese early-onset type 2 diabetes with severe insulin resistance.

AIMS: Alström syndrome (AS) is a rare recessive disorder characterised by diabetes, obesity, insulin resistance (IR), and visual and hearing impairments. Mutations in the ALMS1 gene have been identified as the causative agents of AS. This study aimed to explore the relationship between rare ALMS1 variants and clinical features in Chinese patients with early-onset type 2 diabetes (age at diagnosis ≤40 years; EOD). MATERIALS AND METHODS: ALMS1 gene sequencing was performed in 611 Chinese individuals with EOD, 36 with postprandial hyperinsulinemia, and 47 with pre-diabetes and fasting IR. In-silico prediction algorithm and the American College of Medical Genetics Guidelines (ACMG) were used to evaluate the deleteriousness and pathogenicity of the variants. RESULTS: Sixty-two rare ALMS1 variants (frequency <0.005) were identified in 82 patients with EOD. Nineteen variants were predicted to be deleterious (pD). Patients with EOD carrying pD variants had higher fasting C-peptide, postprandial C-peptide, and HOMA2-IR levels than those without variants. The frequency of ALMS1 pD variants in the subgroup with more insulin-resistant EOD was higher than that in other EOD subgroups. Two patients with EOD, obesity, and IR who carried one heterozygous pathogenic/likely pathogenic rare variant of ALMS1 according to ACMG were identified. Moreover, rare heterozygous pD variants of ALMS1 were found in participants from cohorts of postprandial hyperinsulinemia as well as in pre-diabetes with fasting IR. CONCLUSIONS: ALMS1 rare pD variants are enriched in the populations with significant IR, which is a major hallmark of diabetes pathogenesis. Accordingly, our exploratory study provides insights and hypotheses for further studies of gene function.

Machine learning-based identification and characterization of mast cells in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is diagnosed and monitored using esophageal eosinophil levels; however, EoE also exhibits a marked, understudied esophageal mastocytosis. OBJECTIVES: Using machine learning, we localized and characterized esophageal mast cells (MCs) to decipher their potential role in disease pathology. METHODS: Esophageal biopsy samples (EoE, control) were stained for MCs by anti-tryptase and imaged using immunofluorescence; high-resolution whole tissue images were digitally assembled. Machine learning software was trained to identify, enumerate, and characterize MCs, designated Mast Cell-Artificial Intelligence (MC-AI). RESULTS: MC-AI enumerated cell counts with high accuracy. During active EoE, epithelial MCs increased and lamina propria (LP) MCs decreased. In controls and EoE remission patients, papillae had the highest MC density and negatively correlated with epithelial MC density. MC density in the epithelium and papillae correlated with the degree of epithelial eosinophilic inflammation, basal zone hyperplasia, and LP fibrosis. MC-AI detected greater MC degranulation in the epithelium, papillae, and LP in patients with EoE compared with control individuals. MCs were localized further from the basement membrane in active EoE than EoE remission and control individuals but were closer than eosinophils to the basement membrane in active EoE. CONCLUSIONS: Using MC-AI, we identified a distinct population of homeostatic esophageal papillae MCs; during active EoE, this population decreases, undergoes degranulation, negatively correlates with epithelial MC levels, and significantly correlates with distinct histologic features. Overall, MC-AI provides a means to understand the potential involvement of MCs in EoE and other disorders.

Inflammatory cytokines and oral lichen planus: a Mendelian randomization study.

Background: Inflammatory cytokines have long been considered closely related to the development of oral lichen planus (OLP), and we further explored the causal relationship between the two by Mendelian randomization (MR) method. Methods: We performed bidirectional MR analyses by large genome-wide association studies (GWAS). The data included a large-scale OLP dataset, as well as datasets of 41 inflammatory cytokines. All data were obtained from the University of Bristol database, which includes 41 inflammatory cytokines, and the GWAS Catalog database, which includes 91 inflammatory cytokines. OLP data were obtained from the Finngen database, which includes 6411 cases and 405770 healthy controls. We used the inverse variance weighted (IVW) method, MR-Egger method, weighted median method, simple mode method and weighted mode method to analyze the causal relationship between inflammatory cytokines and OLP, and we also combined with sensitivity analysis to further verify the robustness of the results. We performed a meta-analysis of positive or potentially positive results for the same genes to confirm the reliability of the final results. Results: We primarily used the IVW analysis method, corrected using the Benjamin Hochberg (BH) method. When p<0.00038 (0.05/132), the results are significantly causal; when 0.00038

Follow-up outcome analysis of 324 cases of early-onset and late-onset mild fetal ventriculomegaly: a retrospective cohort study.

BACKGROUND: Mild fetal ventriculomegaly (VM) is a nonspecific finding common to several pathologies with varying prognosis and is, therefore, a challenge in fetal consultation. We aimed to perform a constant, detailed analysis of prenatal findings and postnatal outcomes in fetuses with early-onset and late-onset mild ventriculomegaly, and provide a new evidence basis and new perspective for prenatal counseling. METHODS: This is a retrospective cohort study of women with a diagnosis of mild fetal VM between January 2018 and October 2020. The population was divided into two groups according to the gestational ages (GAs) at initial diagnosis: the early-onset group (diagnosed at/before 24+6 weeks) and the late-onset group (diagnosed after 24+6 weeks). Clinical data and pregnancy outcomes were obtained from hospital records. The children's neurodevelopment status was assessed using the Ages and Stages Questionnaire, Third Edition (ASQ-3) and telephone interviews. RESULTS: Our study cohort comprised 324 fetuses, out of which 94 (29%) were classified as early-onset group and 230 (71%) late-onset group. Early-onset group was more likely to have concurrent additional abnormalities, whereas in the late-onset group, isolated enlargement was more common (P = 0.01). Unilateral enlargement was more common in the late-onset group (P = 0.05), and symmetrical enlargement in the early-onset group (P < 0.01). In addition, early-onset mild VM cases were more likely to have intrauterine progression (P = 0.03), and many had a higher proportion of complex multisystem abnormalities. Compared with the late-onset group, the early-onset group was more often associated with congenital brain structure malformations. Approximately 11% of fetuses with mild VM had postnatal neurodevelopmental delay/disorders, and the risk was higher in the early-onset group (19.4% vs. 7.4%). Regression analysis showed that the GA at first diagnosis, non-isolated, and intrauterine progression significantly correlated with neurodevelopmental abnormalities. CONCLUSIONS: Early-onset and late-onset mild VM had significantly different ultrasound features and outcomes. Early-onset mild VM may have more complex potential abnormalities and are more likely to predict poor prognosis than the late-onset.

Effects of quercetin and l-ascorbic acid on heterocyclic amines and advanced glycation end products production in roasted eel and lipid-mediated inhibition mechanism analysis.

Eel is a commercially important marine fish, frequently featured as sushi or roasted preparations. This study determined the formation of heterocyclic amines (HAs) and advanced glycation end products (AGEs) in roasted eel and evaluated the inhibitory mechanism of quercetin and l-ascorbic acid on their formation. The results indicate a respective reduction of 75.07% and 84.72% in total HAs, alongside a decline of 23.03% and 39.14% in AGEs. Additionally, fundamental parameters of roasted eel, lipid oxidation indicators and precursors were measured to elucidate the mechanisms and impact of natural antioxidants on HAs and AGEs formation in roasted eel. Furthermore, endeavors were made to probe into the molecular mechanisms governing the influence of key differential lipids on the generation of HAs and AGEs through lipid-mics analysis. This research emphasizes the potential of natural antioxidants in preventing harmful substances formation during eel thermal processing, which is helpful to food manufacturers for healthier food production.

Melanoma Derived Exosomes Amplify Radiotherapy Induced Abscopal Effect via IRF7/I-IFN Axis in Macrophages.

Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor-bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single-cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor-derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I-IFN) secretion and M1 polarization via the miR-872-3p/IRF7 axis. Secreted I-IFN activated the JAK/STAT signaling pathway in CD8+ T cells, and promoted IFN-γ and GZMB secretion. Together, the study shows that tumor-derived exosomes promote I-IFN secretion via the circPIK3R3/miR-872-3p/IRF7 axis in macrophages and enhance the anti-tumor immune response of CD8+ T cells.

Characterization and drivers of water and carbon fluxes dynamics in dune ecosystems of the Horqin Sandy Land.

Sandy regions constitute pivotal components of terrestrial ecosystems, exerting significant influences on global ecological equilibrium and security. This study meticulously explored water and carbon fluxes dynamics within a dune ecosystem in the Horqin Sandy Land throughout the growing seasons from 2013 to 2022 by employing an advanced eddy covariance system. The dynamic characteristics of these fluxes and their underlying driving forces were extensively analyzed, with a particular focus on the impact of precipitation. The main results are as follows: (1) During the growing seasons of 2015 and 2016, the dune ecosystem acted as a modest carbon source, while in 2013, 2014, and 2017- 2022, it transformed into a net carbon sink. Notably, the annual mean values of water use efficiency (WUE) and evapotranspiration (ET) were 5.16 gC·kg-1H2O and 255.4 mm, respectively. (2) The intensity, frequency, and temporal distribution of precipitation were found to significantly influence the carbon and water fluxes dynamics. Isolated minor precipitation events did not trigger substantial fluctuations, but substantial and prolonged precipitation events spanning multiple days or consecutive minor precipitation events resulted in notable assimilation delays. (3) Air temperature, soil temperature, and fractional vegetation cover (FVC) were found to be key factors influencing the carbon and water fluxes. Specifically, FVC exhibited a negative logarithmic correlation with net ecosystem CO2 exchange (NEE) and a power function relationship with WUE. (4) The interaction between carbon and water fluxes is exhibited by exponential increases in ecosystem respiration (Reco) and gross primary productivity (GPP) with WUE, while NEE displayed an exponential decrease in relation to WUE. These findings are of high significance in predicting the potential ramifications of climate change on the intricate carbon and water cycles, and enhance our understanding of ecosystem dynamics in sandy environments.

Evaluation of Key Molecular Markers in Adult Diffuse Gliomas Based on a Novel Combination of Diffusion and Perfusion MRI and MR Spectroscopy.

BACKGROUND: Preoperative identification of isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion status could help clinicians select the optimal therapy in patients with diffuse glioma. Although, the value of multimodal intersection was underutilized. PURPOSE: To evaluate the value of quantitative MRI biomarkers for the identification of IDH mutation and 1p/19q codeletion in adult patients with diffuse glioma. STUDY TYPE: Retrospective. POPULATION: Two hundred sixteen adult diffuse gliomas with known genetic test results, divided into training (N = 130), test (N = 43), and validation (N = 43) groups. SEQUENCE/FIELD STRENGTH: Diffusion/perfusion-weighted-imaging sequences and multivoxel MR spectroscopy (MRS), all 3.0 T using three different scanners. ASSESSMENT: The apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) of the core tumor were calculated to identify IDH-mutant and 1p/19q-codeleted statuses and to determine cut-off values. ADC models were built based on the 30th percentile and lower, CBV models were built based on the 75th centile and higher (both in five centile steps). The optimal tumor region was defined and the metabolite concentrations of MRS voxels that overlapped with the ADC/CBV optimal region were calculated and added to the best-performing diagnostic models. STATISTICAL TESTS: DeLong's test, diagnostic test, and decision curve analysis were performed. A P value <0.05 was considered to be statistically significant. RESULTS: Almost all ADC models achieved good performance in identifying IDH mutation status, among which ADC_15th was the most valuable parameter (threshold = 1.186; Youden index = 0.734; AUC_train = 0.896). The differential power of CBV histogram metrics for predicting 1p/19q codeletion outperformed ADC histogram metrics, and the CBV_80th-related model performed best (threshold = 1.435; Youden index = 0.458; AUC_train = 0.724). The AUCs of ADC_15th and CBV_80th models in the validation set were 0.857 and 0.733. These models tended to improve after incorporation of N-acetylaspartate/total_creatine and glutamate-plus-glutamine/total_creatine, respectively. DATA CONCLUSION: The intersection of ADC-, CBV-based histogram and MRS provide a reliable paradigm for identifying the key molecular markers in adult diffuse gliomas. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Patterns of sleep quality and its influence factors: A latent class model among students of medical university in Hubei Province, China.

BACKGROUND: Sleep problem among undergraduate students has become one of the most pressing public health problems. This study aimed to explore the latent class of sleep patterns and the factors affecting sleep in Chinese students of medical university. METHODS: 3423 students participated in the cross-sectional study. The survey consisted of the reduced Morningness-Evening Questionnaire, the Pittsburgh Sleep Quality Index, and Health-Promoting Lifestyle Profile-II. Latent profile analysis and multinominal logistic regression analysis were performed. RESULTS: Three potential sleep categories were identified: "sleep disorder group" (1.87 %), "daytime dysfunction group" (24.42 %), and "good sleep group" (73.71 %). Compared with the "good sleep group," the "sleep disorder group" showed monthly living expenses (RMB) ≥ 3000 yuan (OR) = 13.04), interpersonal relationships as poor (OR = 3.71), health status as poor (OR = 45.09), circadian rhythm as eveningness (OR = 6.17), and poor health-promoting lifestyles (OR = 2.090) as its risk factors (all p < 0.05). Meanwhile, sophomore (OR = 1.75), junior (OR = 1.52), interpersonal relationships as poor (OR = 1.88), health status as poor (OR = 4.62), intermediate-chronotype (OR = 2.19), eveningness chronotype (OR = 5.66), and health-promoting lifestyles as poor (OR = 1.55) were identified as risk factors for the "daytime dysfunction group" (all p < 0.05). LIMITATIONS: Causal conclusions can not be drawn and recall bias in data collection. CONCLUSIONS: Significant population heterogeneity was found in the sleep quality. Implementing targeted interventions focusing on circadian rhythm and lifestyle is crucial to improve the sleep quality of students with different conditions.

Standardized Quantification of Mast Cells in the Gastrointestinal Tract in Adults.

BACKGROUND: Current data on the normal quantity of mast cells throughout the adult gastrointestinal tract are limited in several domains. These include microanatomic localization of mast cells, standardization of staining and counting methods, and reporting of microscope field of view. OBJECTIVE: To address this lack of reliable reference ranges to facilitate the study of and diagnosis of emerging mast cell-mediated diseases. METHODS: We examined biopsies obtained from the esophagus, stomach, duodenum, and colon from an unselected cohort. Mean and peak mast cell density were determined on slides stained for tryptase and CD117, and were expressed per high power field (hpf) and surface area (mm2), thus deriving reference ranges (average ± 2 SDs). RESULTS: For the most common hpf surface area (0.238 mm2), upper limits of the derived reference ranges for average/peak mast cells were 0.15/3.67 (esophagus, tryptase), 0.70/5.98 (esophagus, CD117), 22.56/35.30 (stomach, tryptase), 31.32/53.10 (stomach, CD117), 30.28/49.77 (duodenal crypts, tryptase), 41.96/65.26 (duodenal crypts, CD117), 4.98/11.56 (duodenal villi, tryptase), 8.38/14.17 (duodenal villi, CD117), 26.58/41.08 (colon, tryptase), and 35.57/57.92 (colon, CD117). Interobserver variability was moderate to good. There was significant correlation between average and peak mast cell counts. CONCLUSIONS: These data help standardize mast cell reference ranges throughout the gastrointestinal tract in adults, which can be used to determine whether abnormal levels of mast cells are present in patients with suspected mast cell-mediated disease. Our data show that the commonly used cutoff of 20 mast cells per hpf irrespective of the gastrointestinal tract segment is an underestimate of an appropriate cutoff in stomach, duodenum (crypt area), and colon.

Development and External Validation of an MRI-based Radiomics Nomogram to Distinguish Circumscribed Astrocytic Gliomas and Diffuse Gliomas: A Multicenter Study.

RATIONALE AND OBJECTIVES: The 5th edition of the World Health Organization classification of tumors of the Central Nervous System (WHO CNS) has introduced the term "diffuse" and its counterpart "circumscribed" to the category of gliomas. This study aimed to develop and validate models for distinguishing circumscribed astrocytic gliomas (CAGs) from diffuse gliomas (DGs). MATERIALS AND METHODS: We retrospectively analyzed magnetic resonance imaging (MRI) data from patients with CAGs and DGs across three institutions. After tumor segmentation, three volume of interest (VOI) types were obtained: VOItumor and peritumor, VOIwhole, and VOIinterface. Clinical and combined models (incorporating radiomics and clinical features) were also established. To address imbalances in training dataset, Synthetic Minority Oversampling Technique was employed. RESULTS: A total of 475 patients (DGs: n = 338, CAGs: n = 137) were analyzed. The VOIinterface model demonstrated the best performance for differentiating CAGs from DGs, achieving an area under the curve (AUC) of 0.806 and area under the precision-recall curve (PRAUC)of 0.894 in the cross-validation set. Using analysis of variance (ANOVA) feature selector and Support Vector Machine (SVM) classifier, seven features were selected. The model achieved an AUC and AUPRC of 0.912 and 0.972 in the internal validation dataset, and 0.897 and 0.930 in the external validation dataset. The combined model, incorporating interface radiomics and clinical features, showed improved performance in the external validation set, with an AUC of 0.94 and PRAUC of 0.959. CONCLUSION: Radiomics models incorporating the peritumoral area demonstrate greater potential for distinguishing CAGs from DGs compared to intratumoral models. These findings may hold promise for evaluating tumor nature before surgery and improving clinical management of glioma patients.

Clinical and genetic characteristics of CEL-MODY (MODY8): a literature review and screening in Chinese individuals diagnosed with early-onset type 2 diabetes.

OBJECTIVE: CEL-related maturity-onset diabetes of the young (CEL-MODY, MODY8) is a special type of monogenetic diabetes caused by mutations in the carboxyl-ester lipase (CEL) gene. This study aimed to summarize the genetic and clinical characteristics of CEL-MODY patients and to determine the prevalence of the disease among Chinese patients with early-onset type 2 diabetes (EOD). METHODS: We systematically reviewed the literature associated with CEL-MODY in PubMed, Embase, Web of Science, China National Knowledge Infrastructure and Wanfang Data to analyze the features of patients with CEL-MODY. We screened and evaluated rare variants of the CEL gene in a cohort of 679 Chinese patients with EOD to estimate the prevalence of CEL-MODY in China. RESULTS: In total, 21 individuals reported in previous studies were diagnosed with CEL-MODY based on the combination of diabetes and pancreatic exocrine dysfunction as well as frameshift mutations in exon 11 of the CEL gene. CEL-MODY patients were nonobese and presented with exocrine pancreatic affection (e.g., chronic pancreatitis, low fecal elastase levels, pancreas atrophy and lipomatosis) followed by insulin-dependent diabetes. No carriers of CEL missense mutations were reported with exocrine pancreatic dysfunction. Sequencing of CEL in Chinese EOD patients led to the identification of the variant p.Val736Cysfs*22 in two patients. However, these patients could not be diagnosed with CEL-MODY because there were no signs that the exocrine pancreas was afflicted. CONCLUSION: CEL-MODY is a very rare disease caused by frameshift mutations affecting the proximal VNTR segments of the CEL gene. Signs of exocrine pancreatic dysfunction provide diagnostic clues for CEL-MODY, and genetic testing is vital for proper diagnosis. Further research in larger cohorts is needed to investigate the characteristics and prevalence of CEL-MODY in the Chinese population.

MRI characteristics of H3 G34-mutant diffuse hemispheric gliomas and possible differentiation from IDH-wild-type glioblastomas in adolescents and young adults.

OBJECTIVE: H3 G34-mutant diffuse hemispheric gliomas (G34m-DHGs) are rare and constitute a new infiltrating brain tumor entity whose characteristics require elucidation, and their difference from isocitrate dehydrogenase-wild-type glioblastomas (IDH-WT-GBMs) needs to be clarified. In this study, the authors report the demographic, clinical, and neuroradiological features of G34m-DHG and investigate the capability of quantitative MRI features in differentiating them. METHODS: Twenty-three patients with G34m-DHG and 30 patients with IDH-WT-GBM were included in this retrospective study. The authors reviewed the clinical, radiological, and molecular data of G34m-DHGs and compared their neuroimaging features with those of IDH-WT-GBMs in adolescents and young adults. Visually Accessible Rembrandt Images (VASARI) features were extracted, and the Kruskal-Wallis test was performed. A logistic regression model was constructed to evaluate the diagnostic performance for differentiating between G34m-DHG and IDH-WT-GBM. Subsequently, FeAture Explorer (FAE) was used to generate the machine learning pipeline and select important radiomics features that had been extracted with PyRadiomics. Estimates of the performance were supplied by metrics such as sensitivity, specificity, accuracy, and area under the curve (AUC). RESULTS: The mean age of the 23 patients with G34m-DHG was 23.7 years (range 11-45 years), younger than the mean age of patients with IDH-WT-GBM (30.96 years, range 5-43 years). All tumors were hemispheric. Most cases were immunonegative for ATRX (95%) and Olig2 (100%), were immunopositive for p53 (95%), and exhibited MGMT promoter methylation (81%). The radiological presentations of G34m-DHG were different from those of IDH-WT-GBM. The majority of the G34m-DHGs were in the frontal, parietal, and temporal lobes and demonstrated no or only faint contrast enhancement (74%), while IDH-WT-GBMs were mostly seen in the frontal lobe and showed marked contrast enhancement in 83% of cases. The FAE-generated model, based on radiomics features (AUC 0.925) of conventional MR images, had better discriminatory performance between G34m-DHG and IDH-WT-GBM than VASARI feature analysis (AUC 0.843). CONCLUSIONS: G34m-DHGs most frequently occur in the frontal, parietal, and temporal lobes in adolescent and young adults and are associated with radiological characteristics distinct from those of IDH-WT-GBMs. Successful identification can be achieved by using either VASARI features or radiomics signatures, which may contribute to prognostic evaluation and assist in clinical settings.

Cortical myelin and thickness mapping provide insights into whole-brain tumor burden in diffuse midline glioma.

Systemic infiltration is a hallmark of diffuse midline glioma pathogenesis, which can trigger distant disturbances in cortical structure. However, the existence and effects of these changes have been underexamined. This study aimed to investigate whole-brain cortical myelin and thickness alternations induced by diffuse midline glioma. High-resolution T1- and T2-weighted images were acquired from 90 patients with diffuse midline glioma with H3 K27-altered and 64 patients with wild-type and 86 healthy controls. Cortical thickness and myelin content was calculated using Human Connectome Project pipeline. Significant differences in cortical thickness and myelin content were detected among groups. Short-term survival prediction model was constructed using automated machine learning. Compared with healthy controls, diffuse midline glioma with H3 K27-altered patients showed significantly reduced cortical myelin in bilateral precentral gyrus, postcentral gyrus, insular, parahippocampal gyrus, fusiform gyrus, and cingulate gyrus, whereas diffuse midline glioma with H3 K27 wild-type patients exhibited well-preserved myelin content. Furtherly, when comparing diffuse midline glioma with H3 K27-altered and diffuse midline glioma with H3 K27 wild-type, the decreased cortical thickness in parietal and occipital regions along with demyelination in medial orbitofrontal cortex was observed in diffuse midline glioma with H3 K27-altered. Notably, a combination of cortical features and tumor radiomics allowed short-term survival prediction with accuracy 0.80 and AUC 0.84. These findings may aid clinicians in tailoring therapeutic approaches based on cortical characteristics, potentially enhancing the efficacy of current and future treatment modalities.

Ventral Tegmental Area Glutamatergic Neurons Facilitated Emergence From Isoflurane Anesthesia Involves Excitation of Lateral Septum γ-Aminobutyric Acid-ergic Neurons in Mice.

BACKGROUND: Ventral tegmental area (VTA) glutamatergic neurons promote wakefulness in the sleep-wake cycle; however, their roles and neural circuit mechanisms during isoflurane (ISO) anesthesia remain unclear. METHODS: Fiber photometry and in vivo electrophysiology were used to observe the changes in neuronal or terminal activity during ISO anesthesia and arousal processes. Optogenetic and anesthesia behaviors were used to investigate the effects of VTA glutamatergic neurons and their projections to the lateral septum (LS) during ISO anesthesia and arousal. Anterograde and retrograde tracings were performed to identify the connections between VTA glutamatergic neurons and the LS. RESULTS: Population activity and firing rates of VTA glutamatergic neurons decreased during ISO anesthesia (ISO: 95% confidence interval [CI], 0.83-2.06 Spikes.s-1 vs wake: 95% CI, 3.53-7.83 Spikes.s-1; P =.0001; n = 34 from 4 mice). Optogenetic activation of VTA glutamatergic neurons reduced the burst-suppression ratio in electroencephalography (laser: 95% CI, 13.09%-28.76% vs pre: 95% CI, 52.85%-71.59%; P =.0009; n = 6) and facilitated emergence (ChR2: 95% CI, 343.3-388.0 seconds vs mCherry: 95% CI, 447.6-509.8 seconds; P < .0001; n = 11/12) from ISO anesthesia. VTA glutamatergic neurons monosynaptically innervated LS γ-aminobutyric acid (GABA)-ergic neurons. The activity of VTA glutamatergic terminals in the LS decreased during ISO anesthesia, and optogenetic activation of the VTA glutamatergic terminals in the LS facilitated emergence from ISO anesthesia. Furthermore, optogenetic activation of VTA glutamatergic terminals increased the firing rates of LS γ-aminobutyric acid-ergic (GABAergic) neurons (laser: 95% CI, 0.85-4.03 Spikes.s-1 vs pre: 95% CI, 0.24-0.78 Spikes.s-1; P =.008; n = 23 from 4 mice) during ISO anesthesia. CONCLUSIONS: VTA glutamatergic neurons facilitated emergence from ISO anesthesia involving excitation of LS GABAergic neurons.

Metabolic heterogeneity in different subtypes of malformations of cortical development causing epilepsy: a proton magnetic resonance spectroscopy study.

Background: The most common subtypes of malformations of cortical development (MCDs) are gray matter heterotopia (GMH), focal cortical dysplasia (FCD), and polymicrogyria (PMG). This study aimed to characterize the possible neurometabolic abnormalities and heterogeneity in different MCDs subtypes using proton magnetic resonance spectroscopy (1H-MRS). Methods: In this prospective cross-sectional study, we recruited 29 patients with MCDs and epilepsy, including ten with GMH, ten with FCD, and nine with PMG, as well as 25 age- and sex-matched healthy controls (HC) from the Epilepsy Center of West China Hospital of Sichuan University between August 2018 and November 2021. Inclusion criteria for the patients were based upon typical magnetic resonance imaging (MRI) findings of MCDs and full clinical assessment for epilepsy. Single-voxel point-resolved spectroscopy was used to acquire data from both the lesion and the normal-appearing contralateral side (NACS) in patients and from the frontal lobe in HC. Metabolite measures, including N-acetyl aspartate (NAA), myoinositol (Ins), choline (Cho), creatine (Cr), and glutamate + glutamine (Glx) concentrations, were quantitatively estimated with linear combination model (LCModel) software and corrected for the partial volume effect of cerebrospinal fluid (CSF). Results: The NAA concentration was lower and the Ins concentration was higher in the MCDs lesions than in the NACS and in HC (P=0.002-0.007), and the Cho and Cr concentrations were higher in MCDs lesions than in HC (P=0.001-0.016). Moreover, the Cho concentration was higher in NACS than in HC (P=0.015). In the GMH lesions, the only metabolic alteration was an NAA reduction (GMH_lesion vs. HC: P=0.001). In the FCD lesions, there were more metabolite abnormalities than in the other two subtypes, particularly a lower NAA and a higher Ins than in HC and NACS (P=0.012-0.042). In the PMG lesions, Cr (lesion vs. HC or NACS: P=0.017-0.021) and Glx (lesion vs. NACS: P=0.043) were increased, while NAA was normal. Correlation analysis revealed that the Cr concentration in MCDs lesions was positively correlated with seizure frequency (r=0.411; P=0.027). Conclusions: Based upon 1H-MRS, our study demonstrated that different MCDs subtypes exhibited variable metabolic features, which may be associated with distinct functional and cytoarchitectural properties.