Identification of a de novo CACNA1B variant and a start-loss ADRA2B variant in paroxysmal kinesigenic dyskinesia.

Paroxysmal kinesigenic dyskinesia (PKD) represents the most prevalent form of paroxysmal dyskinesia, characterized by recurrent and transient attacks of involuntary movements triggered by a sudden voluntary action. In this study, whole-exome sequencing was conducted on a cohort of Chinese patients to identify causal mutations. In one young female case, a de novo CACNA1B variant (NM_000718.3:exon3:c.479C > T:p.S160F) was identified as the causative lesion. This finding may broaden the phenotypic spectrum of CACNA1B mutations and provide a prospective cause of primary PKD. Additionally, a novel start-loss variant (NM_000682.7:c.3G > A) within ADRA2B further denied its association with benign adult familial myoclonic epilepsy, and a KCNQ2 E515D variant that was reported as a genetic susceptibility factor for seizures had no damaging effect in this family. In sum, this study established a correlation between CACNA1B and primary PKD, and found valid evidence that further negates the pathogenic role of ADRA2B in benign adult familial myoclonic epilepsy.

Calcified apoptotic vesicles from PROCR+ fibroblasts initiate heterotopic ossification.

Heterotopic ossification (HO) comprises the abnormal formation of ectopic bone in extraskeletal soft tissue. The factors that initiate HO remain elusive. Herein, we found that calcified apoptotic vesicles (apoVs) led to increased calcification and stiffness of tendon extracellular matrix (ECM), which initiated M2 macrophage polarization and HO progression. Specifically, single-cell transcriptome analyses of different stages of HO revealed that calcified apoVs were primarily secreted by a PROCR+ fibroblast population. In addition, calcified apoVs enriched calcium by annexin channels, absorbed to collagen I via electrostatic interaction, and aggregated to produce calcifying nodules in the ECM, leading to tendon calcification and stiffening. More importantly, apoV-releasing inhibition or macrophage deletion both successfully reversed HO development. Thus, we are the first to identify calcified apoVs from PROCR+ fibroblasts as the initiating factor of HO, and might serve as the therapeutic target for inhibiting pathological calcification.

Meta-analysis comparing different ultrasound detection methods to accurately assess wound healing and scar formation after caesarean section.

The accurate assessment of wound healing post-caesarean section, especially in twin pregnancies, remains a pivotal concern in obstetrics, given its implications for maternal health and recovery. Traditional methods, including conventional abdominal ultrasonography (CU), have been challenged by the advent of transvaginal ultrasonography (TU), offering potentially enhanced sensitivity and specificity. This meta-analysis directly compares the efficacy of TU and CU in evaluating wound healing and scar formation, crucial for optimizing postoperative care. Results indicate that TU is associated with significantly better outcomes in wound healing, demonstrated by lower REEDA scores (SMD = -20.56, 95% CI: [-27.34.20, -13.77], p < 0.01), and in scar formation reduction, evidenced by lower Manchester Scar Scale scores (SMD = -25.18, 95% CI: [-29.98, -20.39], p < 0.01). These findings underscore the potential of integrating TU into routine post-caesarean evaluation protocols to enhance care quality and patient recovery.

Maternal exposure to ambient ozone and fetal conotruncal heart defects in China: A multicenter cohort study.

BACKGROUND: The relationships between maternal genetic and environmental exposure and conotruncal heart defects (CTDs) have been extensively investigated. Nevertheless, there is limited knowledge regarding the impact of ozone (O3) on the risk of CTDs. OBJECTIVE: To explore the correlation between maternal exposure to O3 and CTDs in China. METHODS: Pregnant women who underwent fetal echocardiography at Beijing Anzhen Hospital between January 2013 and December 2021 were enrolled. Their sociodemographic characteristics and lifestyle information, along with fetal data, were systematically collected. Fetal echocardiography was used to detect CTDs. Maternal exposure to ambient O3 during the embryonic period, the first trimester, the three months preceding the last menstrual period, and the perinatal period was estimated using residential addresses or hospital addresses associated with prenatal visits. The concentration of O3 was divided by quartiles, with the first quartile serving as a reference. Adjusted logistic regression models were employed to examine the associations between every 10 µg/m3 increase or quartile increase in ambient O3 exposure and CTDs. RESULTS: Among 24,278 subjects, 1069 exhibited fetuses with CTDs. Maternal exposure to ambient O3 during three pregnancy periods was associated with increased CTD risk. The adjusted odds ratio (OR) and 95% confidence interval (CI) were 1.271 (1.189-1.360) per 10 µg/m3 increase in O3 during the perinatal period. For each quartile of O3, the risk increased with increasing exposure concentration, particularly during the perinatal period (OR = 2.206 for quartile 2, 2.367 for quartile 3, and 3.378 for quartile 4, all P<0.05). CONCLUSIONS: Elevated maternal exposure to O3 during pregnancy, particularly in the perinatal period, is linked to an increased risk of fetal CTDs. Further longitudinal analyses are needed to validate these results.

Impact of long-term mining activity on groundwater dynamics in a mining district in Xinjiang coal Mine Base, Northwest China: insight from geochemical fingerprint and machine learning.

Long-term coal mining could lead to a serious of geo-environmental problems. However, less comprehensive identification of factors controlling the groundwater dynamics were involved in previous studies. This study focused on 68 groundwater samples collected before and after mining activities, Self-Organizing Maps (SOM) combining with Principal Component Analysis (PCA) derived that the groundwater samples were classified into five clusters. Clusters 1-5 (C1-C5) represented the groundwater quality affected by different hydrochemical processes, mainly including mineral (carbonate and evaporite) dissolution and cation exchange, which were controlled by the hydrochemical environment at different stages of mining activities. Combining with the time-series data, the Extreme Gradient Boosting Decision Trees (XGBoost) derived that the mine water inflow (feature relative importance of 40.0%) and unit goaf area (feature relative importance of 29.2%) were dominant factors affecting the confined groundwater level, but had less or lagged impact on phreatic groundwater level. This was closely related to the height of the water flow fractured zone and hydraulic connection between aquifers. The results of this study on the coupled evolution of groundwater dynamics could enhance our understanding of the effects of mining on aquifer systems and contribute to the prevention of water hazards in the coalfields.

Investigating the nexus of metabolic syndrome, serum uric acid, and dementia risk: a prospective cohort study.

BACKGROUND: The global dementia prevalence is surging, necessitating research into contributing factors. We aimed to investigate the association between metabolic syndrome (MetS), its components, serum uric acid (SUA) levels, and dementia risk. METHODS: Our prospective study comprised 466,788 participants without pre-existing MetS from the UK Biobank. We confirmed dementia diagnoses based on the ICD-10 criteria (F00-03). To evaluate the dementia risk concerning MetS, its components, and SUA levels, we applied Cox proportional hazards models, while adjusting for demographic factors. RESULTS: Over a median follow-up of 12.7 years, we identified 6845 dementia cases. Individuals with MetS had a 25% higher risk of all-cause dementia (hazard ratio [HR] = 1.25, 95% confidence interval [CI] = 1.19-1.31). The risk increased with the number of MetS components including central obesity, dyslipidemia for high-density lipoprotein (HDL) cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides. Particularly for those with all five components (HR = 1.76, 95% CI = 1.51-2.04). Dyslipidemia for HDL cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides were independently associated with elevated dementia risk (p < 0.01). MetS was further linked to an increased risk of all-cause dementia (11%) and vascular dementia (VD, 50%) among individuals with SUA levels exceeding 400 µmol/L (all-cause dementia: HR = 1.11, 95% CI = 1.02-1.21; VD: HR = 1.50, 95% CI = 1.28-1.77). CONCLUSIONS: Our study provides robust evidence supporting the association between MetS, its components, and dementia risk. These findings emphasize the importance of considering MetS and SUA levels in assessing dementia risk, offering valuable insights for prevention and management strategies.

Magnetic Resonance-Guided Focused Ultrasound for Treatment of Essential Tremor: Ventral Intermediate Nucleus Ablation Alone or Additional Posterior Subthalamic Area Lesioning?

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) for treatment of essential tremor (ET) traditionally targets the ventral intermediate (Vim) nucleus. Recent strategies include a secondary lesion to the posterior subthalamic area (PSA). OBJECTIVE: The aim was to compare lesion characteristics, tremor improvement, and adverse events (AE) between patients in whom satisfactory tremor suppression was achieved with lesioning of the Vim alone and patients who required additional lesioning of the PSA. METHODS: Retrospective analysis of data collected from ET patients treated with MRgFUS at St Vincent's Hospital Sydney was performed. Clinical Rating Scale for Tremor (CRST), hand tremor score (HTS), and Quality of Life in Essential Tremor Questionnaire (QUEST) were collected pre- and posttreatment in addition to the prevalence of AEs. The lesion coordinates and overlap with the dentatorubrothalamic tract (DRTT) were evaluated using magnetic resonance imaging. RESULTS: Twenty-one patients were treated in Vim only, and 14 were treated with dual Vim-PSA lesions. Clinical data were available for 29 of the 35 patients (19 single target and 10 dual target). At follow-up (mean: 18.80 months) HTS, CRST, and QUEST in single-target patients improved by 57.97% (P < 0.001), 36.71% (P < 0.001), and 58.26% (P < 0.001), whereas dual-target patients improved by 68.34% (P < 0.001), 35.37% (P < 0.003), and 46.97% (P < 0.005), respectively. The Vim lesion of dual-target patients was further anterior relative to the posterior commissure (PC) (7.84 mm), compared with single-target patients (6.92 mm), with less DRTT involvement (14.85% vs. 23.21%). Dual-target patients exhibited a greater proportion of patients with acute motor AEs (100% vs. 58%); however, motor AE prevalence was similar in both groups at long-term follow-up (33% vs. 38%). CONCLUSION: Posterior placement of lesions targeting the Vim may confer greater tremor suppression. The addition of a PSA lesion, in patients with inadequate tremor control despite Vim lesioning, had a trend toward better long-term tremor suppression; however, this approach was associated with greater prevalence of gait disturbance in the short term.

Longitudinal enlargement of choroid plexus is associated with chronic lesion expansion and neurodegeneration in RRMS patients.

BACKGROUND AND OBJECTIVE: We explored dynamic changes in the choroid plexus (CP) in patients with relapsing-remitting multiple sclerosis (RRMS) and assessed its relationship with chronic lesion expansion and atrophy in various brain compartments. METHODS: Fifty-seven RRMS patients were annually assessed for a minimum of 48 months with 3D FLAIR, pre- and post-contrast 3D T1 and diffusion-weighted magnetic resonance imaging (MRI). The CP was manually segmented at baseline and last follow-up. RESULTS: The volume of CP significantly increased by 1.4% annually. However, the extent of CP enlargement varied considerably among individuals (ranging from -3.6 to 150.8 mm3 or -0.2% to 6.3%). The magnitude of CP enlargement significantly correlated with central (r = 0.70, p < 0.001) and total brain atrophy (r = -0.57, p < 0.001), white (r = -0.61, p < 0.001) and deep grey matter atrophy (r = -0.60, p < 0.001). Progressive CP enlargement was significantly associated with the volume and extent of chronic lesion expansion (r = 0.60, p < 0.001), but not with the number or volume of new lesions. CONCLUSION: This study provides evidence of progressive CP enlargement in patients with RRMS. Our findings also demonstrate that enlargement of the CP volume is linked to the expansion of chronic lesions and neurodegeneration of periventricular white and grey matter in RRMS patients.

RTN3 deficiency exacerbates cisplatin-induced acute kidney injury through the disruption of mitochondrial stability.

Reticulum 3 (RTN3) is an endoplasmic reticulum (ER) protein that has been reported to act in neurodegenerative diseases and lipid metabolism. However, the role of RTN3 in acute kidney injury (AKI) has not been explored. Here, we employed public datasets, patient data, and animal models to explore the role of RTN3 in AKI. The underlying mechanisms were studied in primary renal tubular epithelial cells and in the HK2 cell line. We found reduced expression of RTN3 in AKI patients, cisplatin-induced mice, and cisplatin-treated HK2 cells. RTN3-null mice exhibit more severe AKI symptoms and kidney fibrosis after cisplatin treatment. Mitochondrial dysfunction was also found in cells with RTN3 knockdown or knockout. A mechanistic study revealed that RTN3 can interact with HSPA9 in kidney cells. RTN3 deficiency may disrupt the RTN3-HSPA9-VDAC2 complex and affect MAMs during ER-mitochondrion contact, which further leads to mitochondrial dysfunction and exacerbates cisplatin-induced AKI. Our study indicated that RTN3 was important in the kidney and that a decrease in RTN3 in the kidney might be a risk factor for the aggravation of AKI.

Ordered mesoporous silica microspheres for supercritical fluid chromatography.

Herein, silica microspheres with ordered mesopores are synthesized and applied as a stationary phase for supercritical fluid chromatography (SFC). The excellent particle monodispersity and pore orderliness coupled with the rapid analytes diffusion of the supercritical fluid lead to an ultra-high column efficiency of 340 000 plate per m.

Social support systems involved in suicide prevention and intervention among adolescents: A Delphi study in Shanghai.

The rotes of attempted and completed suicide among adolescents are increasing globally. Social support can help decrease the risk of adolescent suicide, but this aspect has been rarely studied in China. The present study aimed to use the Delphi methodology to establish a set of guidelines for the development of social support resources, with the goal of collectively reducing suicide risks among adolescents in Shanghai. We commenced the study in April 2021, established a research team, searched the keywords using Web of Science from 2016 to 2021 and ultimately designed a pre-evaluation index. Next, following Donabedian's Structure-Process-Outcome model, the research developed a questionnaire comprising 3 level-1, 12 level-2, and 73 level-3 indicators. Ten experts were enlisted to conduct three rounds of e-mail inquiries in order to finalize the indicator system, resulting in 2 level-1, 11 level-2, and 52 level-3 indicators, as well as expert consensus. Our findings indicate that the social support systems should include parents, schools, psychiatric hospitals, social organizations, and government departments, with the government sector being the most important ((M = 9.4). Furthermore, our study revealed that school counselors and psychologists play similar roles to psychiatrists within the interdisciplinary team (M ± S = 9.2 ± 1.1). As per the expert consensus, social support systems should strengthen government-led and interdisciplinary collaboration, prioritize suicide prevention in schools and encourage greater involvement from social organizations.

Impaired cerebellar plasticity hypersensitizes sensory reflexes in SCN2A-associated ASD.

Children diagnosed with autism spectrum disorder (ASD) commonly present with sensory hypersensitivity or abnormally strong reactions to sensory stimuli. Such hypersensitivity can be overwhelming, causing high levels of distress that contribute markedly to the negative aspects of the disorder. Here, we identify a mechanism that underlies hypersensitivity in a sensorimotor reflex found to be altered in humans and in mice with loss of function in the ASD risk-factor gene SCN2A. The cerebellum-dependent vestibulo-ocular reflex (VOR), which helps maintain one's gaze during movement, was hypersensitized due to deficits in cerebellar synaptic plasticity. Heterozygous loss of SCN2A-encoded NaV1.2 sodium channels in granule cells impaired high-frequency transmission to Purkinje cells and long-term potentiation, a form of synaptic plasticity important for modulating VOR gain. VOR plasticity could be rescued in mice via a CRISPR-activator approach that increases Scn2a expression, demonstrating that evaluation of a simple reflex can be used to assess and quantify successful therapeutic intervention.

Interorgan communication in neurogenic heterotopic ossification: the role of brain-derived extracellular vesicles.

Brain-derived extracellular vesicles participate in interorgan communication after traumatic brain injury by transporting pathogens to initiate secondary injury. Inflammasome-related proteins encapsulated in brain-derived extracellular vesicles can cross the blood‒brain barrier to reach distal tissues. These proteins initiate inflammatory dysfunction, such as neurogenic heterotopic ossification. This recurrent condition is highly debilitating to patients because of its relatively unknown pathogenesis and the lack of effective prophylactic intervention strategies. Accordingly, a rat model of neurogenic heterotopic ossification induced by combined traumatic brain injury and achillotenotomy was developed to address these two issues. Histological examination of the injured tendon revealed the coexistence of ectopic calcification and fibroblast pyroptosis. The relationships among brain-derived extracellular vesicles, fibroblast pyroptosis and ectopic calcification were further investigated in vitro and in vivo. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk reversed the development of neurogenic heterotopic ossification in vivo. The present work highlights the role of brain-derived extracellular vesicles in the pathogenesis of neurogenic heterotopic ossification and offers a potential strategy for preventing neurogenic heterotopic ossification after traumatic brain injury. Brain-derived extracellular vesicles (BEVs) are released after traumatic brain injury. These BEVs contain pathogens and participate in interorgan communication to initiate secondary injury in distal tissues. After achillotenotomy, the phagocytosis of BEVs by fibroblasts induces pyroptosis, which is a highly inflammatory form of lytic programmed cell death, in the injured tendon. Fibroblast pyroptosis leads to an increase in calcium and phosphorus concentrations and creates a microenvironment that promotes osteogenesis. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk suppressed fibroblast pyroptosis and effectively prevented the onset of heterotopic ossification after neuronal injury. The use of a pyroptosis inhibitor represents a potential strategy for the treatment of neurogenic heterotopic ossification.

Global burden of pancreatic cancer attributable to metabolic risks from 1990 to 2019, with projections of mortality to 2030.

OBJECTIVE: Metabolic risks play a key role in the progression of pancreatic cancer. This study aimed to present global, regional and national data on mortality and disability-adjusted life-year (DALY) for pancreatic cancer attributable to metabolic risk and to forecast mortality to 2030 using data from the Global Burden of Disease (GBD). METHODS: Data on mortality and DALYs due to pancreatic cancer attributable to metabolic risks were obtained from GBD 2019. Metabolic risks include high fasting plasma glucose (FPG) and high body mass index (BMI). Total numbers and age-standardized rates per 100,000 people for mortality and DALYs were reported by age, sex, region and country/territory from 1990 to 2019. The "Bayes age-period-cohort" method was used for projections of mortality to 2030. RESULTS: Globally, there was a 3.5-fold increase in the number of pancreatic cancer deaths attributable to metabolic risk, from 22,091 in 1990 to 77,215 in 2019. High-income North America and Central Europe had the highest age-standardized mortality rates (ASMRs) of pancreatic cancer attributable to high FPG and high BMI in 2019, respectively. From 1990 to 2019, the global ASMR of pancreatic cancer attributable to high FPG and high BMI increased. Countries with high healthcare access quality had much higher age-standardized DALY rates. In the next 10 years, the ASMR of pancreatic cancer attributable to high FPG and high BMI will continue to increase. CONCLUSION: Pancreatic cancer mortality and DALYs attributable to metabolic factors remain high, particularly in high-income regions or countries. Studies on the metabolic mechanism of pancreatic cancer and effective treatment strategies are needed.

Eliminating the Scattering of Thin Film Structures.

Rendering invisibility in the wide application scenarios has seen a surge in interest in recent years. Though various approaches have been proposed to realize concealments under different conditions, achieving polarization-independent invisibility for large objects remains a big challenge. Here, we propose to attain invisibility of a large dielectric slab with polarization constraints being totally lifted. This is accomplished by employing an antiscattering coating made of anisotropic metamaterials. We show that by tailoring the electric resonance of a triangular mushroom structure, antiphase electric dipole moment can be induced, resulting in an antipolarization response of the whole metamaterial coatings. By putting the proposed coatings on both sides of a large dielectric slab, a neutralization effect of the total polarization is observed, leading to the peculiar phenomenon of full-polarization invisibility. Our results are validated through full-wave simulations and experimental measurements. Remarkably, the intrinsic null-polarization property of the coating-slab-coating structure guarantees the invisibility feature of a large-scale bulk made by simply stacking the sandwiched composites, which facilitates the application of invisibility in practical scenarios such as the invisibility cloaks and the reflectionless antenna radomes.

Development and Evaluation of a Quantitative Systems Pharmacology Model for Mechanism Interpretation and Efficacy Prediction of Atezolizumab in Combination with Carboplatin and Nab-Paclitaxel in Patients with Non-Small-Cell Lung Cancer.

Immunotherapy has shown clinical benefit in patients with non-small-cell lung cancer (NSCLC). Due to the limited response of monotherapy, combining immune checkpoint inhibitors (ICIs) and chemotherapy is considered a treatment option for advanced NSCLC. However, the mechanism of combined therapy and the potential patient population that could benefit from combined therapy remain undetermined. Here, we developed an NSCLC model based on the published quantitative systems pharmacology (QSP)-immuno-oncology platform by making necessary adjustments. After calibration and validation, the established QSP model could adequately characterise the biological mechanisms of action of the triple combination of atezolizumab, nab-paclitaxel, and carboplatin in patients with NSCLC, and identify predictive biomarkers for precision dosing. The established model could efficiently characterise the objective response rate and duration of response of the IMpower131 trial, reproducing the efficacy of alternative dosing. Furthermore, CD8+ and CD4+ T cell densities in tumours were found to be significantly related to the response status. This significant extension of the QSP model not only broadens its applicability but also more accurately reflects real-world clinical settings. Importantly, it positions the model as a critical foundation for model-informed drug development and the customisation of treatment plans, especially in the context of combining single-agent ICIs with platinum-doublet chemotherapy.

A system review of central nervous system tumors on children in China: epidemiology and clinical characteristics.

BACKGROUND: Central nervous system (CNS) tumors are the most common solid tumors in children and the leading cause of cancer-related death in the latter. Currently, the incidence rate exceeds that of leukemia and ranks first in the incidence of malignant tumors in children. METHODS: The epidemiological data on childhood CNS tumors were collected from the Chinese Cancer Registry Annual Report. The annual percent change (APC) of incidence and mortality-rate changes were estimated via Joinpoint regression. Due to a lack of pertinent data, we performed a system review on the clinical-pathological characteristics in Chinese publications. RESULTS: There was no significant increase in the incidence rate (APC: -0.1, 95% CI: -1.5 to 1.3), but there was a significant increase in the mortality rate (APC: 1.8, 95% CI: 0.3 to 3.4) for childhood CNS tumors. In the subgroup analysis, there were significant increases in both the incidence and mortality rates in rural areas (APC in the incidence: 6.2, 95% CI: 2.4 to 10.2; APC in mortality: 4.4, 95% CI: 0.4 to 8.4). The most common location and type of childhood CNS were, respectively, the cerebral hemisphere (25.5%, 95% CI: 21.7% to 29.4%) and astrocytomas (26.8%, 95% CI: 23.9% to 29.6%). CONCLUSIONS: The epidemiological trends, and the relevant prediction, highlighted the need to pay continual attention to childhood CNS tumors, and the clinicopathology evinced its own distinctive characteristics. Timely detection and effective treatment must be further promoted regarding childhood CNS tumors with a view to decreasing the disease burden, especially in rural areas.

Coherent X-ray Spectroscopy Elucidates Nanoscale Dynamics of Plasma-Enhanced Thin-Film Growth.

Sophisticated thin film growth techniques increasingly rely on the addition of a plasma component to open or widen a processing window, particularly at low temperatures. Taking advantage of continued increases in accelerator-based X-ray source brilliance, this real-time study uses X-ray Photon Correlation Spectroscopy (XPCS) to elucidate the nanoscale surface dynamics during Plasma-Enhanced Atomic Layer Deposition (PE-ALD) of an epitaxial indium nitride film. Ultrathin films are synthesized from repeated cycles of alternating self-limited surface reactions induced by temporally separated pulses of the material precursor and plasma reactant, allowing the influence of each on the evolving morphology to be examined. During the heteroepitaxial 3D growth examined here, sudden changes in the surface structure during initial film growth, consistent with numerous overlapping stress-relief events, are observed. When the film becomes continuous, the nanoscale surface morphology abruptly becomes long-lived with a correlation time spanning the period of the experiment. Throughout the growth experiment, there is a consistent repeating pattern of correlations associated with the cyclic growth process, which is modeled as transitions between different surface states. The plasma exposure does not simply freeze in a structure that is then built upon in subsequent cycles, but rather, there is considerable surface evolution during all phases of the growth cycle.