Hetero-Nucleation Induced [111]-Oriented Mixed Halide Perovskite for Stable Pure Red Light-Emitting Diodes.

Mixed halide 3D perovskites are promising for bright, efficient, and wide-color gamut light-emitting diodes (LEDs) due to their excellent carrier transport, high luminescence, and easily tunable bandgaps. However, serious halide ion migration inside mixed halide 3D perovskite results in poor operational and spectral stability of the as-fabricated LEDs. Here, a hetero-nucleation crystallization strategy is reported to grow [111]-orientation preferred mixed halide 3D perovskite CsPbI3-xBrx thin films for stable pure red LEDs. This hetero-nucleation crystallization is enabled by the addition of phosphoric acid (H3PO4) complexation, which promotes the growth of small perovskite grains into large grains with uniform [111]-orientation. The obtained [111]-orientation preferred film exhibits excellent stability under light or electric field stimulus as revealed by model analysis and experimental results compared to that of [001]-orientation preferred film. Thus, based on the [111]-orientation preferred film, the fabricated LED exhibits an external quantum efficiency of 22.8%, a maximum brightness of 12 000 cd m-2, and a half-life time of 4080 min under 1.5 mA cm-2. More importantly, the electroluminescence spectrum of the device remains stable during the continuous operation of 4080 min, showcasing the significant spectral stability improvement enabled by the hetero-nucleation induced [111]-orientation strategy.

May Measurement Month 2020: An Analysis of Blood Pressure Screening Results From China.

We reported the blood pressure data obtained in the May Measurement Month (MMM) China project in 2020 during the COVID-19 control period. The study participants were adults (≥ 18 years), ideally in whom blood pressure had not been measured in the previous year. Blood pressure was measured three times consecutively with a 1-min interval in the sitting position, using a validated automated BP monitor (Omron HEM-7081IT), and transmitted to a central database via a smartphone app. The measurement was performed at 136 sites across 29 China provinces. The 100 728 participants had a mean (±SD) age of 45.6 (±18.3) years and included 56 097 (55.7%) women. The mean systolic/diastolic blood pressure was 120.0/76.9 mm Hg. The proportion of hypertension was 28.9% (n  =  29 135), and the awareness, treatment, and control rates of hypertension were 45.3% (n = 13 212), 39.7% (n =  1573), and 24.4% (n = 7101), respectively. After adjustment for age, gender, and use of antihypertensive medication, systolic/diastolic BP were significantly higher with cigarette smoking (n = 8070, +0.5/+1.0 mm Hg, p < 0.05), mild (n = 4369, +1.2/+1.3 mm Hg, p < 0.001) and moderate or heavy alcohol drinking (n = 3871, +0.4/+0.7 mm Hg, p < 0.05), and overweight (+1.8/+1.4 mm Hg, p < 0.001) and obesity (+2.3/+1.5 mm Hg, p < 0.001). In conclusion, our study provided unique blood pressure data during the COVID-19 period, and suggested that hypertension management might have been even more challenging when the medical professionals had to shift their focus on other urgencies.

Analysis of low-density lipoprotein receptor gene mutations in a family with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a common monogenic autosomal dominant disorder, primarily mainly caused by pathogenic mutations in the low-density lipoprotein receptor (LDLR) gene. Through phenotypic-genetic linkage analysis, two LDLR pathogenic mutations were identified in FH families: c.G1027A (p.Gly343Ser) and c.G1879A (p.Ala627Thr). MATERIALS AND METHODS: Whole exome sequencing was conducted on the proband with familial hypercholesterolemia to identify the target gene and screen for potential pathogenic mutations. The suspicious responsible mutation sites in 14 family members were analyzed using Sanger sequencing to assess genotype-phenotype correlations. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to evaluate LDLR mRNA and protein expression. In parallel, bioinformatics tools were employed to predict structural and functional changes in the mutant LDLR. RESULTS: Immunofluorescence analysis revealed no significant difference in the intracellular localization of the p.Gly343Ser mutation, whereas protein expression of the p.Ala627Thr mutation was decreased and predominantly localized in the cytoplasm. Western blotting has showed that protein expression levels of the mutant variants were markedly declined in both cell lysates and supernatants. Enzyme linked immunosorbent assay has demonstrated that LDLR protein levels in the supernatant of cell culture medium was not significant different from those of the wild-type group. However, LDLR protein levels in the cell lysate of both the Gly343Ser and Ala627Thr variants groups were significantly lower than those in the wild-type group. Bioinformatic predictions further suggested that these mutations may affect post-translational modifications of the protein, providing additional insight into the mechanisms underlying the observed reduction in protein expression. CONCLUSIONS: In this study, we identified two heterozygous pathogenic variants in the LDLR gene, c.G1027A (p.Gly343Ser) and c.G1879A (p.Ala627Thr), in a family with familial hypercholesterolemia. We also conducted preliminary investigations into the mechanisms by which these mutations contribute to disease pathology.

Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer's disease: a multi-omics Mendelian randomization study.

BACKGROUND: Mitochondrial dysfunction (MD) is increasingly recognized as a key pathophysiological contributor in Alzheimer disease (AD). As differential MD genes expression may serve as either a causative factor or a consequence in AD, and expression of these genes could be influenced by epigenetic modifications or interact with inflammatory cytokines, hence, the precise role of MD in AD remains uncertain. METHODS: Meta-analysis of brain transcriptome datasets was conducted to pinpoint differentially expressed genes (DEGs) associated with MD in AD. We utilized three-step SMR to analyze the AD genome-wide association study summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs from the blood and brain tissues, respectively. Through SMR and colocalization analysis, we further explored the interactions between brain eQTLs and inflammatory cytokines. RESULTS: Five datasets were meta-analyzed to prioritize 825 DEGs in AD from 1339 MD-related genes. Among these, seven genes from blood samples such as NDUFS8 and SPG7 and thirty-two genes from brain tissue including CLU and MAPT were identified as candidate AD-causal MD genes and regulated by methylation level. Furthermore, we revealed 13 MD gene expression-inflammatory pathway pairs involving LDLR, ACE and PTPMT1 along with interleukin-17C, interleukin-18 and hepatocyte growth factor. CONCLUSIONS: This study highlighted that the AD-causal MD genes could be regulated by epigenetic changes and interact with inflammatory cytokines, providing evidence for AD prevention and intervention.

Population pharmacokinetic study in children with vascular anomalies: body weight as a key variable in predicting the initial dose and dosing frequency of sirolimus.

Background: The main challenges faced when using sirolimus in children with vascular anomalies (VAs) still include significant pharmacokinetic (PK) variability, uncertainty in the target concentration range, as well as inconsistencies in initial dosing and dosing frequency. The aim of this study is to establish a new population pharmacokinetic (PPK) model for children with VAs to guide the individualized use of sirolimus. Methods: A PPK study was performed using data from children with VAs who received sirolimus between July 2017 and April 2022. A nonlinear mixed-effect modeling with a one-compartment model structure was applied. Monte Carlo simulation was employed to propose specific dosing recommendations to achieve the target trough concentrations (C trough) of 5-15 ng/mL. Results: In total, 134 blood concentrations from 49 pediatric patients were used to characterize the sirolimus pharmacokinetics. Covariate analysis identified body weight (BW) as a significant factor affecting clearance (CL) in the final PPK model. The typical clearance rate and distribution volume, standardized to a BW of 16 kg, were 4.06 L/h (4% relative standard error, RSE) and 155 L (26% RSE), respectively. Optimal dosing regimens were simulated for different BWs. For a twice-daily regimen, the recommended doses were 0.05, 0.06, 0.07, and 0.08 mg/kg/day for BW of <10, 10-20, 20-40, and ≥40 kg, respectively; for a once-daily regimen, the recommended doses were 0.06, 0.07, 0.08, and 0.09 mg/kg/day for BW of <10, 10-30, 30-50, and ≥50 kg, respectively. Notably, sirolimus C trough could be maintained between 5-15 ng/mL across various dosing frequencies based on the recommended dosing regimen. Conclusion: We established a PPK model of sirolimus for children with VAs and proposed an initial dosing strategy. Integrating initial dose and medication frequency recommendations into sirolimus' guidelines will broaden its clinical options and simplify the clinical management for childhood VAs.

Therapeutic Drug Monitoring for Sirolimus in Children with Vascular Anomalies: What Can We Learn from a Retrospective Study.

Objectives: Sirolimus (SRL), a mammalian target of rapamycin inhibitor, has been widely used to treat patients with vascular anomalies (VAs). The objectives of this study were to summarize the routine blood SRL monitoring data for VAs children, to investigate the factors contributing to the variable blood SRL concentrations and to evaluate the efficacy and safety of SRL therapy. Methods: VAs patients with routine blood SRL monitoring from July 2017 to April 2022 at the Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University were retrospectively collected. Clinical data were obtained from the hospital information system. Results: In total, 67 children (35 females) were enrolled. The therapeutic drug monitoring data showed that the range of measured blood trough concentrations (Ctrough) was 3.6-46.8 ng/mL. At the initial measurements, only 33% of patients were in the target concentration range (10-15 ng/mL). But this proportion became 54% at the last measurements. The whole blood-Ctrough-to-daily dose (Ctrough/Dose) ratio was significantly associated with age and body weight (BW). The patients' laboratory results did not change significantly after SRL treatment. Although the incidence of adverse events was relatively high (44.8%), most of them were mild and tolerable. 70.3% patients had total responses to SRL, whereas 29.7% children exhibited stable disease or progressive disease. No significant differences were found in Ctrough between the total response group and non-response group. Conclusions: This retrospective study revealed a high variability in SRL blood concentrations in Chinese children with VAs. Of note, pediatric patients with older age and a higher BW had a lower Ctrough/Dose ratio. It is a concern whether the range of 10-15 ng/mL is feasible for Chinese children based only on our study. Further studies recruiting more patients are required to redefine the target reference range for children with VAs.

Disambiguating Clinical Abbreviations by One-to-All Classification: Algorithm Development and Validation Study.

Background: Electronic medical records store extensive patient data and serve as a comprehensive repository, including textual medical records like surgical and imaging reports. Their utility in clinical decision support systems is substantial, but the widespread use of ambiguous and unstandardized abbreviations in clinical documents poses challenges for natural language processing in clinical decision support systems. Efficient abbreviation disambiguation methods are needed for effective information extraction. Objective: This study aims to enhance the one-to-all (OTA) framework for clinical abbreviation expansion, which uses a single model to predict multiple abbreviation meanings. The objective is to improve OTA by developing context-candidate pairs and optimizing word embeddings in Bidirectional Encoder Representations From Transformers (BERT), evaluating the model's efficacy in expanding clinical abbreviations using real data. Methods: Three datasets were used: Medical Subject Headings Word Sense Disambiguation, University of Minnesota, and Chia-Yi Christian Hospital from Ditmanson Medical Foundation Chia-Yi Christian Hospital. Texts containing polysemous abbreviations were preprocessed and formatted for BERT. The study involved fine-tuning pretrained models, ClinicalBERT and BlueBERT, generating dataset pairs for training and testing based on Huang et al's method. Results: BlueBERT achieved macro- and microaccuracies of 95.41% and 95.16%, respectively, on the Medical Subject Headings Word Sense Disambiguation dataset. It improved macroaccuracy by 0.54%-1.53% compared to two baselines, long short-term memory and deepBioWSD with random embedding. On the University of Minnesota dataset, BlueBERT recorded macro- and microaccuracies of 98.40% and 98.22%, respectively. Against the baselines of Word2Vec + support vector machine and BioWordVec + support vector machine, BlueBERT demonstrated a macroaccuracy improvement of 2.61%-4.13%. Conclusions: This research preliminarily validated the effectiveness of the OTA method for abbreviation disambiguation in medical texts, demonstrating the potential to enhance both clinical staff efficiency and research effectiveness.

Direct conversion of human umbilical cord mesenchymal stem cells into dopaminergic neurons for Parkinson's disease treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits due to the depletion of nigrostriatal dopamine. Stem cell differentiation therapy emerges as a promising treatment option for sustained symptom relief. In this study, we successfully developed a one-step differentiation system using the YFBP cocktail (Y27632, Forskolin, SB431542, and SP600125) to effectively convert human umbilical cord mesenchymal stem cells (hUCMSCs) into dopaminergic neurons without genetic modification. This approach addresses the challenge of rapidly and safely generating functional neurons on a large scale. After a 7-day induction period, over 80 % of the cells were double-positive for TUBB3 and NEUN. Transcriptome analysis revealed the dual roles of the cocktail in inducing fate erasure in mesenchymal stem cells and activating the neuronal program. Notably, these chemically induced cells (CiNs) did not express HLA class II genes, preserving their immune-privileged status. Further study indicated that YFBP significantly downregulated p53 signaling and accelerated the differentiation process when Pifithrin-α, a p53 signaling inhibitor, was applied. Additionally, Wnt/ß-catenin signaling was transiently activated within one day, but the prolonged activation hindered the neuronal differentiation of hUCMSCs. Upon transplantation into the striatum of mice, CiNs survived well and tested positive for dopaminergic neuron markers. They exhibited typical action potentials and sodium and potassium ion channel activity, demonstrating neuronal electrophysiological activity. Furthermore, CiNs treatment significantly increased the number of tyrosine hydroxylase-positive cells and the concentration of dopamine in the striatum, effectively ameliorating movement disorders in PD mice. Overall, our study provides a secure and reliable framework for cell replacement therapy for Parkinson's disease.

Precipitation-induced biomass enhancement and differential allocation in Inner Mongolia's herbaceous and shrub communities.

Changes in precipitation patterns induced by global climate change have profound implications for the structure and function of grassland ecosystems. However, the relationship between plant diversity and ecosystem function across different grassland types, particularly those with varying plant compositions and dominant species, remains inadequately understood. To address this knowledge gap, a five-year experimental manipulation of precipitation was conducted within herbaceous and shrub communities in the desert grasslands of Inner Mongolia. We found that increased precipitation significantly enhances aboveground biomass (AGB), belowground biomass (BGB), and community total biomass (CTB) in both herbaceous and shrub communities. In herbaceous communities, increased precipitation led to a disproportionate increase in both aboveground and belowground biomass, supporting the optimal allocation hypothesis. Structural equation modeling (SEM) further elucidated that precipitation regulates AGB and CTB through species richness and functional traits in herbaceous communities. In shrub communities, precipitation influences AGB, BGB, and CTB by affecting species richness and soil water content. This study highlights the critical role of precipitation in shaping biomass dynamics and allocation strategies within herbaceous and shrub communities in desert steppe of Inner Mongolia. These findings provide essential insights into the potential responses of desert grassland ecosystems to ongoing climate change.

Integrating clinical and biochemical markers: a novel nomogram for predicting lacunes in cerebral small vessel disease.

Background: Lacunes, a characteristic feature of cerebral small vessel disease (CSVD), are critical public health concerns, especially in the aging population. Traditional neuroimaging techniques often fall short in early lacune detection, prompting the need for more precise predictive models. Methods: In this retrospective study, 587 patients from the Neurology Department of the Affiliated Hospital of Hebei University who underwent cranial MRI were assessed. A nomogram for predicting lacune incidence was developed using LASSO regression and binary logistic regression analysis for variable selection. The nomogram's performance was quantitatively assessed using AUC-ROC, calibration plots, and decision curve analysis (DCA) in both training (n = 412) and testing (n = 175) cohorts. Results: Independent predictors identified included age, gender, history of stroke, carotid atherosclerosis, hypertension, creatinine, and homocysteine levels. The nomogram showed an AUC-ROC of 0.814 (95% CI: 0.791-0.870) for the training set and 0.805 (95% CI: 0.782-0.843) for the testing set. Calibration and DCA corroborated the model's clinical value. Conclusion: This study introduces a clinically useful nomogram, derived from binary logistic regression, that significantly enhances the prediction of lacunes in patients undergoing brain MRI for various indications, potentially advancing early diagnosis and intervention. While promising, its retrospective design and single-center context are limitations that warrant further research, including multi-center validation.

HGF Facilitates the Repair of Spinal Cord Injuries by Driving the Chemotactic Migration of MSCs Through the ß-Catenin/TCF4/Nedd9 Signaling Pathway.

Transplanted mesenchymal stem cells (MSCs) can significantly aid in repairing spinal cord injuries (SCI) by migrating to and settling at the injury site. However, this process is typically inefficient, as only a small fraction of MSCs successfully reach the target lesion area. During SCI, the increased expression and secretion of hepatocyte growth factor (HGF) act as a chemoattractant that guides MSC migration. Nonetheless, the precise mechanisms by which HGF influences MSC migration are not fully understood. This study focused on unraveling the molecular pathways that drive MSC migration towards the SCI site in response to HGF. It was found that HGF can activate ß-catenin signaling in MSCs either by phosphorylating LRP6 or by suppressing GSK3ß phosphorylation through the AKT and ERK1/2 pathways, or by enhancing the expression and nuclear translocation of TCF4. This activation leads to elevated Nedd9 expression, which promotes focal adhesion formation and F-actin polymerization, facilitating chemotactic migration. Transplanting MSCs during peak HGF expression in injured tissues substantially improves nerve regeneration, reduces scarring, and enhances hind limb mobility. Additionally, prolonging HGF release can further boost MSC migration and engraftment, thereby amplifying regenerative outcomes. However, inhibiting HGF/Met or interfering with ß-catenin or Nedd9 signaling significantly impairs MSC engraftment, obstructing tissue repair and functional recovery. Together, these findings provide a theoretical basis and practical strategy for MSC transplantation therapy in SCI, highlighting the specific molecular mechanisms by which HGF regulates ß-catenin signaling in MSCs, ultimately triggering their chemotactic migration.

CYP2C19 genotype and sodium channel blockers in lacosamide-treated children with epilepsy: two major determinants of trough lacosamide concentration or clinical response.

Background: The widespread clinical use of lacosamide (LCM) has revealed significant individual differences in clinical response, with various reported influencing factors. However, it remains unclear how genetic factors related to the disposition and clinical response of LCM, as well as drug-drug interactions (DDIs), exert their influence on pediatric patients with epilepsy. Objectives: To evaluate the impact of genetic variations and DDIs on plasma LCM concentrations and clinical response. Design: Patients with epilepsy treated with LCM from June 2021 to March 2023 in the Children's Hospital of Nanjing Medical University were included in the analysis. Methods: The demographic information and laboratory examination data were obtained from the hospital information system. For the pharmacogenetic study, the left-over blood specimens, collected for routine plasma LCM concentration monitoring, were used to perform genotyping analysis for the selected 26 single nucleotide polymorphisms from 14 genes. The trough concentration/daily dose (C 0/D) ratio and efficacy outcomes were compared. Results: Patients achieved 90.1% and 68.9% responder rates in LCM mono- and add-on therapy, respectively. The genetic variant in the CYP2C19 *2 (rs4244285) was associated with a better responsive treatment outcome (odds ratio: 1.82; 95% confidence interval: 1.05-3.15; p = 0.031). In monotherapy, 36% of patients were CYP2C19 normal metabolizers (NMs), 49% were intermediate metabolizers (IMs), and 15% were poor metabolizers (PMs) carrying CYP2C19 *2 or *3. Of note, the C 0/D ratios of IMs and PMs were 9.1% and 39.6% higher than those of NMs, respectively. Similar results were in the add-on therapy group, and we also observed a substantial decrease in the C 0/D ratio when patients were concomitant with sodium channel blockers (SCBs). Conclusion: This study was the first to confirm that CYP2C19 *2 or *3 variants impact the disposition and treatment response of LCM in children with epilepsy. Moreover, concomitant with SCBs, particularly oxcarbazepine, also decreased plasma LCM concentration.

CYP2C19 genotype and sodium channel blockers in lacosamide-treated children with epilepsy: two major determinants of plasma lacosamide concentration or treatment efficacy This study examined the impact of genetic factors and drug combinations on the effectiveness and plasma concentrations of lacosamide, an antiseizure medication, in patients under 18. Analyzing blood samples from 316 patients at the Children's Hospital of Nanjing Medical University, researchers discovered that genetic variations in the CYP2C19 (i.e. *2 and *3), along with metabolic capacity, and co-medication with sodium channel blockers, all influence plasma lacosamide concentration. Understanding these genetic influences could inform personalized dosing strategies, improving the medication's management for pediatric epilepsy patients.

A national-wide survey on clinical implementation of PGx testing into precision therapeutics for Chinese children: a long way before standard clinical practice.

BACKGROUND: Pharmacogenetics/pharmacogenomics (PGx) focuses on the genetic variation that causes the heterogeneity of pharmacokinetics and drug response among individuals and has the potential to predict individual efficacy and/or side effects. This study aims to investigate and understand the implementation of genetic testing for the personalized medication (GTPM) in children's hospitals in Mainland China. METHODS: A survey was conducted on 50 children's hospitals from 31 provinces, municipalities, and autonomous regions across Mainland China, and statistical analysis and recommendations were made. RESULTS: Questionnaire response was rate of 76.0% (38/50). Data from 15 hospitals conducting GTPM were included in this study, but only 6 hospitals had offered PGx tests for no less than five drug-related genes, and only 5 hospitals had covered more than ten drugs, which was a small scale overall. 20.0% of the laboratories did not conduct internal quality control, and 33.3% did not participate in inter-laboratory quality assessment. 46.7% of the practitioners did not receive external training. The primary goal for GTPM was to optimize drug dosage in the 15 hospitals, while the main challenge for GTPM was the implementation cost. CONCLUSION: Although GTPM in pediatrics has made major progress in Mainland China in recent years, there were still various problems in terms of software, hardware configuration, personnel allocation, business scale, quality control, and result interpretation. This requires joint efforts of health administration, medical insurance departments, researchers, and hospitals to promote and improve GTPM.

Febrile young infants and the association with enterovirus infection.

BACKGROUND: Enterovirus is a common pediatric infectious disease, but the epidemiological data in young infants were lacking. This study aims to evaluate the role of enterovirus in febrile young infants and identify risk factors for severe infections. METHODS: We enrolled febrile infants younger than 90 days admitted to National Taiwan University Hospital from January 2010 to June 2021. Enterovirus infection was confirmed via viral isolation or pan-enterovirus PCR. Central nervous system involvement was defined by positive culture or PCR in cerebrospinal fluid. Severe complications included sepsis, hepatic failure, myocarditis, shock, encephalitis, acute kidney injury, respiratory failure, and multiorgan failure. RESULTS: Out of 840 febrile infants, 17.4% (n = 146) had enterovirus infection. Among these, 46% (n = 67) presented with meningitis and/or encephalitis. Early-onset enterovirus infection within the first two weeks of life was significantly linked to increased risks of anemia (hemoglobin <9 g/dL), ICU admission, central nervous system involvement, shock, hepatic failure, and mortality. Multivariable logistic regression identified high-risk serotypes (aOR 17.4, [95% CI 1.58, 191.5], p = 0.019) and hemoglobin <9 g/dL (aOR 44.9, [95% CI 5.6, 357.6], p < 0.001) as significant risk factors for severe complications. CONCLUSIONS: Enterovirus accounted for 17.4% of the etiology in febrile young infants and the case-fatality rate was 2%. Febrile young infants who had risk factors of enterovirus infection should consider viral culture or PCR examination for confirmation.

A small step toward precision dosing of caffeine in preterm infants: An external evaluation of published population pharmacokinetic models.

BACKGROUND: Several population pharmacokinetic (PopPK) models of caffeine in preterm infants have been published, but the extrapolation of these models to facilitate model-informed precision dosing (MIPD) in clinical practice is uncertain. This study aimed to comprehensively evaluate their predictive performance using an external, independent dataset. METHODS: Data used for external evaluation were based on an independent cohort of preterm infants. Currently available PopPK models for caffeine in preterm infants were identified and re-established. Prediction- and simulation-based diagnostics were used to assess model predictability. The influence of prior information was assessed using Bayesian forecasting. RESULTS: 120 plasma samples from 76 preterm infants were included in the evaluation dataset. Twelve PopPK models of caffeine in preterm infants were re-established based on our previously published study. Although two models showed superior predictive performance, none of the 12 PopPK models met all the clinical acceptance criteria of these external evaluation items. Besides, the external predictive performances of most models were unsatisfactory in prediction- and simulation-based diagnostics. Nevertheless, the application of Bayesian forecasting significantly improved the predictive performance, even with only one prior observation. CONCLUSIONS: Two models that included the most covariates had the best predictive performance across all external assessments. Inclusion of different covariates, heterogeneity of preterm infant characteristics, and different study designs influenced predictive performance. Thorough evaluation is needed before these PopPK models can be implemented in clinical practice. The implementation of MIPD for caffeine in preterm infants could benefit from the combination of PopPK models and Bayesian forecasting as a helpful tool.

Analysis of lake changes and their influence factors in the three river regions from 2000 to 2020 in the Sanjiangyuan Region, China.

An important factor for investigating climate change in the Sanjiangyuan is the evolution of the spatio-temporal pattern of lakes in this region. The present study used the Google Earth Engine (GEE) platform to extract lakes from 2000 to 2020. The present approach created a lake distribution dataset yearly and analyzed spatial and temporal patterns over 20 years. The analysis of lakes focused on the reaction of the Sanjiangyuan Lakes area to changes in climate, glaciers, and permafrost. The findings indicated that the Sanjiangyuan region contains 143 lakes, the majority of which are predominantly small, measuring 1-10 km2. The small lakes account for 60.14 % of the total and are primarily located in the source regions of the Yangtze River and Yellow River. The findings demonstrated that the Sanjiangyuan lakes experienced a significant expansion over the past two decades, particularly from 2011 to 2020. These lakes are divided into expanded, atrophic, and stable categories. Expanded lakes showed significant inter-annual trends in expansion, while atrophic lakes showed smaller fluctuations. The area of stable lakes experienced a consistent decline after 2010, despite a consistent expansion tendency from 2001 to 2010. Moreover, the results indicated that alterations in the size of glaciers and ice reserves in the Sanjiangyuan region have had the greatest influence on the fluctuation in lake area. Among the factors that affect the climate, temperature had the most significant effect on the change in lake area, followed by precipitation.

Glucocorticoid signaling mediates stress-induced migraine-like behaviors in a preclinical mouse model.

BACKGROUND: Stress is one of the most common precipitating factors in migraine and is identified as a trigger in nearly 70% of patients. Responses to stress include release of glucocorticoids as an adaptive mechanism, but this may also contribute to migraine attacks. Here, we investigated the role of glucocorticoids on stress-induced migraine-like behaviors. METHODS: We have shown previously that repeated stress in mice evokes migraine-like behavioral responses and priming to a nitric oxide donor. Metyrapone, mifepristone, and corticosterone (CORT) were used to investigate whether CORT contributes to the stress-induced effects. Facial mechanical hypersensitivity was evaluated by von Frey testing and grimace scoring assessed the presence of non-evoked pain. We also measured serum CORT levels in control, stress, and daily CORT injected groups of both male and female mice. RESULTS: Metyrapone blocked stress-induced responses and priming in male and female mice. However, repeated CORT injections in the absence of stress only led to migraine-like behaviors in females. Both female and male mice showed similar patterns of serum CORT in response to stress or exogenous administration. Finally, administration of mifepristone, the glucocorticoid receptor antagonist, prior to each stress session blocked stress-induced behavioral responses in male and female mice. CONCLUSIONS: These findings demonstrate that while CORT synthesis and receptor activation is necessary for the behavioral responses triggered by repeated stress, it is only sufficient in females. Better understanding of how glucocorticoids contribute to migraine may lead to new therapeutic opportunities.

Dual concentric echo sign of ultrasound in primary hyperparathyroidism: The clinical and histopathologic features and differentiation from lymph nodes.

Context: Ultrasound (US) is the most economical and widely used method for detecting lesions in parathyroid regions. Identifying typically parathyroid adenomas as hypoechoic nodules with clear margins. However, 10 % of lesions exhibit atypical features, such as the dual concentric sign, and the cognition of them still needs to be improved. Objective: To promote understanding of clinical and histopathological features for parathyroid lesions with the dual concentric echo sign and to investigate its pathogenesis and methods for distinguishing from cervical lymph nodes to improve US diagnostic accuracy. Methods: Retrospectively, patients were categorized into three groups: Group 1, with 36 patients showing parathyroid lesions with dual concentric echo signs; Group 2, with 40 patients displaying classic hypoechoic parathyroid lesions; and Group 3, comprising 36 patients with identified lymph nodes, which were all examined from January 2018 to December 2019. The clinical data on demographics, clinical symptoms, serum levels, histopathologic findings, and US image characteristics were thoroughly reviewed. Results: According to the clinical data, no significant differences in demographics or lesion sizes were observed in Group 1 and Group 2 (p > 0.05). No significant variances were noted in biochemical markers, including PTH, T-25OHD, and ALP. However, a notable difference was identified in adjusted serum calcium levels, which were significantly lower in Group 1 compared to Group 2 (p < 0.05). Additionally, the proportion of asymptomatic patients was significantly higher in Group 1 compared to Group 2 (p < 0.05). Pathological examination revealed that all lesions with dual concentric echo signs were parathyroid adenomas. The isoechoic central region predominantly corresponded to areas of loose edema, while the hypoechoic peripheral layer was primarily associated with chief and/or oncocytic cells. By comparing the ultrasonography of Groups 1 and 3, the parathyroid lesions with dual concentric echo signs exhibited significant distinctions from lymph nodes in size, blood flow classification, vascular distribution, and anatomical location (p < 0.05). Conclusion: The parathyroid lesions with dual concentric echo signs in US corresponded to specific histopathological manifestations and relatively mild clinical features in the patients, this finding may increase the likelihood of incidental detection of parathyroid lesions by US. Attention to the details of size, location, and blood flow, especially, may aid US physicians in differentiating parathyroid adenomas from cervical lymph nodes.

Spatiotemporal expression analysis of jasmonic acid and saponin-related genes uncovers a potential biosynthetic regulation in Panax notoginseng.

BACKGROUND: Sanqi, the root of Panax notoginseng, has long been recognized for its therapeutic effects on cardiovascular diseases. Saponins, including ginsenosides and notoginsenosides, are the main bioactive components of P. notoginseng. The biosynthesis of saponins is closely related to the defense responses orchestrated by endogenous hormones. RESULTS: To provide new insights into the underlying role of phytohormone jasmonic acid (JA) in the synthesis and regulation of saponins, we performed an ultra-performance liquid chromatography analysis of different tissues of P. notoginseng aged 2-4 years. Moreover, by combined evaluation of saponin content and transcriptome profiling of each tissue, the spatial and temporal distribution of saponins was analyzed. N notoginsenoside R1, ginsenoside Rb1 and ginsenoside Rd accumulated in the underground tissues, including the root, tuqi, fibril and rhizome. In agreement with this data, the corresponding genes of the endogenous hormone JAs, especially coronatine insensitive 1 (COI1) and myelocytomatosis proteins 2 (MYC2), were predominantly expressed in the underground tissues. The tissue- and age-specific distribution of saponins was consistent with the expression of genes involved in JA biosynthetic, metabolic and signaling pathways. CONCLUSION: The present study has revealed the temporal and spatial effects of endogenous phtohormones in the synthesis and regulation of notoginsenosides, which will provide a significant impact on improving the ecological planting technology, cultivating new high-quality varieties and protecting the rare resources of medicinal P. notoginseng. © 2024 Society of Chemical Industry.