Epidemiological Characteristics of Fracture Among Children Aged 6-17 Years - China, 2019-2021.

What is already known about this topic?: Fractures are a common and serious injury among children. While many studies have utilized clinical data, there is a lack of large-scale community-based research in China. What is added by this report?: This cross-sectional study provides national and regionally representative data on the prevalence of fractures among Chinese children aged 6-17 years (6.93%), with higher rates observed in males than in females (8.13% vs. 5.71%) and in rural areas compared to urban areas (7.22% vs. 6.62%). The most common site of fracture was the upper limbs (4.24%, accounting for 63.0% of fractures). What are the implications for public health practice?: The need to enhance awareness of fracture prevention is critical, particularly for children in rural areas and males in middle childhood. We recommend that local authorities increase investments in educational programs and child safety oversight. Additionally, promoting balanced diets for children, training in proper exercise techniques, and reinforcing participation in outdoor sports are essential.

Multidimensional role of adapalene in regulating cell death in multiple myeloma.

Aims: Multiple myeloma (MM) remains a challenging condition to cure, with persistent drug resistance negating the benefits of treatment advancements. The unraveling complexities in programmed cell death (PCD), inclusive of apoptosis, autophagy, and ferroptosis, have highlighted novel therapeutic avenues. Our study focuses on deciphering how adapalene (ADA), a small molecule compound, accelerates the demise of MM cells via targeting their compensatory survival mechanisms. Methods: To assess the impact of ADA on MM, we employed flow cytometry and trypan blue exclusion assays to determine cell viabilities across MM cell lines and primary patient samples post-treatment. To delineate ADA's therapeutic targets and mechanisms, we conducted RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), molecular docking, and molecular dynamics simulations. We further designed pre-clinical trials emphasizing MM, exploring the efficacy of ADA as a standalone and in combination with bortezomib (BTZ). Results: ADA elicited a dose-responsive induction of MM cell death. Building upon ADA's anti-MM capabilities as a single agent, we proposed that ADA-BTZ co-treatment might amplify this lethality. Indeed, ADA and BTZ together greatly potentiated MM cell death. ADA proved beneficial in restoring BTZ susceptibility in BTZ-resistant relapsed or refractory MM (RRMM) patient cells. Molecular simulations highlighted ADA's high affinity (-9.17 kcal/mol) for CD138, with MM-GBSA revealing a binding free energy of -27.39 kcal/mol. Detailed interaction analyses indicated hydrogen-bonding of ADA with CD138 at the Asp35 and Gln34 residues. Additionally, ADA emerged as a versatile instigator of both ferroptosis and apoptosis in MM cells. Furthermore, ADA disrupted activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway triggered by BTZ, fostering cell death in BTZ-resistant MM subsets. Conclusion: ADA demonstrates a comprehensive capability to orchestrate MM cell death, exerting pronounced anti-MM activity while disrupting NF-κB-related drug resistance. ADA sensitization of MM cells to BTZ unravels its potential as a novel therapeutic drug for MM management.

Low-dose doxorubicin loaded extracellular vesicles combined Fas/FasL pathway-mediated chemo-sensitization and immunotherapy against tumor.

The clinical application of doxorubicin (DOX) is mainly restricted by its serious side effects, poor drug delivery efficiency, and limited immunogenic death (ICD) effect. To improve DOX-based chemotherapy and ameliorate its adverse effects, we utilized 3LL cell-derived extracellular vesicles to encapsulate DOX and sodium nitroprusside (SNP) to obtain DOX/SNP@CM, which could effectively target the tumor site by harnessing the inherent homologous targeting property of tumor cell membranes. DOX performed its role on chemotherapy, and SNP successfully respond to the intracellular GSH to continuously generate nitric oxide (NO). The in situ-produced NO upregulated the Fas expression on the tumor cell surface, thereby sensitizing the Fas/FasL pathway-mediated tumor cell apoptosis of DOX. Furthermore, NO also boosted the intratumoral infiltration of cytotoxic T cells by promoted ICD effect towards tumor cells. Importantly, the anti-tumor immunity tightly cooperated with Fas/FasL mediated tumor cell apoptosis by NO-mediated manipulation on Fas/FasL interaction, collectively making DOX/SNP@CM exert significant tumor growth inhibition with low-dose DOX. Remarkably, DOX and SNP both are widely used clinical medicines, ensuring DOX/SNP@CM a potential opportunity for future practical applications.

Deficiency of CAMSAP2 impairs olfaction and the morphogenesis of mitral cells.

In developing olfactory bulb (OB), mitral cells (MCs) remodel their dendrites to establish the precise olfactory circuit, and these circuits are critical for individuals to sense odors and elicit behaviors for survival. However, how microtubules (MTs) participate in the process of dendritic remodeling remains elusive. Here, we reveal that calmodulin-regulated spectrin-associated proteins (CAMSAPs), a family of proteins that bind to the minus-end of the noncentrosomal MTs, play a crucial part in the development of MC dendrites. We observed that Camsap2 knockout (KO) males are infertile while the reproductive tract is normal. Further study showed that the infertility was due to the severe defects of mating behavior in male mice. Besides, mice with loss-of-function displayed defects in the sense of smell. Furthermore, we found that the deficiency of CAMSAP2 impairs the classical morphology of MCs, and the CAMSAP2-dependent dendritic remodeling process is responsible for this defect. Thus, our findings demonstrate that CAMSAP2 plays a vital role in regulating the development of MCs.

Multi-ion detection chemosensor based on rhodamine for turn-on fluorescence sensing and bioimaging of Fe3+, Al3+, Cr3+, and Hg2+ under different channels.

A novel rhodamine-based multi-ion fluorescent sensor, RGN, was designed and synthesized for the highly selective detection of mercury ions (Hg2+) in ethanol and water systems, as well as trivalent cations (Fe3+, Al3+, and Cr3+) in acetonitrile and water systems using a two-step Schiff base reaction method. Nuclear magnetic titration experiments and theoretical calculations demonstrated that the sensor achieved the detection of the aforementioned metal ions through the fluorescence turn-on phenomenon induced by lactam ring-opening. Density functional theory (DFT) calculation results showed decreased HOMO-LUMO energy gaps and increased dipole moments, indicating the effective coordination of the sensor with the corresponding metal ions to form more stable complexes, thereby achieving detection objectives. Furthermore, the fluorescence turn-on sensor RGN exhibited relatively low detection limits, with limits of detection (LOD) for Fe3+, Al3+, Cr3+, and Hg2+ being 10.20 nM, 14.66 nM, 58.78 nM, and 73.33 nM, respectively. Finally, practical applications of sensor RGN in environmental water samples, L929 cells, and zebrafish were demonstrated, indicating its potential for detecting and tracking Fe3+, Al3+, Cr3+, and Hg2+ in environmental samples and biological systems, with prospects for biomedical applications in the diagnosis and treatment of heavy metal ion-induced diseases.

Clinical efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapy for relapsed/refractory multiple myeloma: a systematic review and meta-analysis.

Background: The low rates of durable response against relapsed/refractory multiple myeloma (RRMM) in recent studies prompt that chimeric antigen receptor (CAR)-T cell therapies are yet to be optimized. The combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high clinical efficacy in several clinical trials for RRMM. We here conducted a meta-analysis to confirm its efficacy and safety. Methods: We collected data from Embase, Web of Science, PubMed, CNKI, Wanfang and Cochrane databases up to April 2023. We extracted and evaluated data related to the efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapies in RRMM patients. The data was then analyzed using RevMan5.4 and StataSE-64 software. PROSPERO number was CRD42023455002. Results: Our meta-analysis included 12 relevant clinical trials involving 347 RRMM patients who were treated with combined anti-BCMA and anti-CD19 CAR-T cell therapies. For efficacy assessment, the pooled overall response rate (ORR) was 94% (95% CI: 91%-98%), the complete response rate (CRR) was 50% (95% CI: 29%-71%), and the minimal residual disease (MRD) negativity rate within responders was 73% (95% CI: 66%-80%). In terms of safety, the pooled all-grade cytokine release syndrome (CRS) rate was 98% (95% CI: 97%-100%), grade≥3 CRS rate was 9% (95% CI: 4%-14%), and the incidence of neurotoxicity was 8% (95% CI: 4%-11%). Of hematologic toxicity, neutropenia was 82% (95% CI: 75%-89%), anemia was 71% (95% CI: 53%-90%), thrombocytopenia was 67% (95% CI: 40%-93%) and infection was 42% (95% CI: 9%-76%). The median progression-free survival (PFS) was 12.97 months (95% CI: 6.02-19.91), and the median overall survival (OS) was 26.63 months (95% CI: 8.14-45.11). Conclusions: As a novel immunotherapy strategy with great potential, the combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high efficacy in RRMM, but its safety needs further improvement. This meta-analysis suggests possible optimization of combined CAR-T therapy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023455002.

The NAC056 transcription factor confers freezing tolerance by positively regulating expression of CBFs and NIA1 in Arabidopsis.

Freezing stress can seriously affect plant growth and development, but the mechanisms of these effects and plant responses to freezing stress require further exploration. Here, we identified a NAM, ATAF1/2, and CUC2 (NAC)-family transcription factor (TF), NAC056, that can promote freezing tolerance in Arabidopsis. NAC056 mRNA levels are strongly induced by freezing stress in roots, and the nac056 mutant exhibits compromised freezing tolerance. NAC056 acts positively in response to freezing by directly promoting key C-repeat-binding factor (CBF) pathway genes. Interestingly, we found that CBF1 regulates nitrate assimilation by regulating the nitrate reductase gene NIA1 in plants; therefore, NAC056-CBF1-NIA1 form a regulatory module for the assimilation of nitrate and the growth of roots under freezing stress. In addition, 35S::NAC056 transgenic plants show enhanced freezing tolerance, which is partially reversed in the cbfs triple mutant. Thus, NAC056 confers freezing tolerance through the CBF pathway, mediating plant responses to balance growth and freezing stress tolerance.

Bifunctional iRGD-Exo-DOX crosses the blood-brain barrier to target central nervous system lymphoma.

Central nervous system lymphoma (CNSL) is a type of hematological tumor. Treatment of CNSL is difficult due to the existence of the blood-brain barrier (BBB). Here, we used exosomes (Exos), a type of extracellular vesicle, and iRGD to construct a new drug carrier system and use it to load doxorubicin (DOX). The results of in vitro and in vivo experiments showed that the iRGD-Exo-DOX system can efficiently and securely transport DOX through the BBB and target tumor cells. The results suggest that iRGD-Exo-DOX may cross the BBB through brain microvascular endothelial cell-mediated endocytosis. Together, our study indicates an impactful treatment of central nervous system tumors.

Construction and validation of an 18F-FDG-PET/CT-based prognostic model to predict progression-free survival in newly diagnosed multiple myeloma patients.

OBJECTIVE: To investigate the relationship between 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) related parameters and the prognosis of multiple myeloma and to establish and validate a prediction model regarding the progression-free survival (PFS) of multiple myeloma. METHODS: A retrospective analysis of 126 newly diagnosed multiple myeloma patients who attended Nanjing Drum Tower Hospital from 2014-2021. All patients underwent PET/CT before treatment and were divided into a training cohort (n = 75) and a validation cohort (n = 51). Multivariate Cox proportional hazard regression analysis incorporated PET/CT-related parameters and clinical indicators. A nomogram was established to individually predict PFS in MM patients. The model was evaluated by calculating the C-index and calibration curve. RESULTS: Here, 4.2 was used as the cut-off value of SUVmax to divide patients into high and low groups. PFS significantly differed between patients in the high-SUVmax group and low-SUVmax group, and SUVmax was an independent predictor of PFS in newly diagnosed multiple myeloma (NDMM) patients. Univariate and multivariate cox regression analysis suggested that lactate dehydrogenase (LDH), bone marrow plasma cell (BMPC), and SUVmax affected PFS. These factors were incorporated to construct a nomogram model for predicting PFS at 1 and 2 years in NDMM patients. The C-index and calibration curves of the nomogram exhibited good accuracy and consistency, and the DCA curves suggested that the model had good clinical utility. CONCLUSION: The PET/CT parameter SUVmax is closely related to the prognosis of myeloma patients. The nomogram constructed in this study based on PET/CT-related parameters and clinical indicators individually predicts the PFS rate of NDMM patients and enables further risk stratification of NDMM patients.

Preparation of cellulose-based flexible SERS and its application for rapid and ultra-sensitive detection of thiram on fruits and vegetables.

In response to the prevalent issue of thiram as a common pesticide residue on the surface of fruits and vegetables, our research team employed an acidic hydrated metal salt low co-fusion solvent to dissolve cellulose lysis slurry. Subsequently, a regenerated cellulose membrane (RCM) was successfully prepared via sol-gel method. Uniformly sized Ag nanoparticles (NPs) were deposited on RCM utilizing the continuous ion layer adsorption and reaction (SILAR) technique. The resulting Ag NPs/RCM flexible surface-enhanced Raman spectroscopy (SERS) substrates exhibited a minimum detection limit of 5 × 10-9 M for Rhodamine 6G (R6G), demonstrating good uniformity (RSD = 4.86 %) and reproducibility (RSD = 3.07 %). Moreover, the substrate displayed a remarkable sensitivity of 10-10 M toward thiram standard solution. Given its inherent flexibility, the substrate proves advantageous for the detection of three-dimensional environments such as fruit and vegetable surfaces, and its practicality has been confirmed in the detection of thiram residue on apples, tomatoes, pears, and other fruits and vegetables.

Identification of a novel fusion gene, RARA::ANKRD34C, in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia that is distinguished by the chromosomal translocation t(15;17)(q24;q21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA). Recently, we identified a novel fusion gene in APL, RARA::ankyrin repeat domain 34C (ANKRD34C), identified its functions by morphological, cytogenetic, molecular biological and multiplex fluorescence in situ hybridization analyses, and demonstrated the potential therapeutic effect clinically and experimentally of all-trans retinoic acid (ATRA); the findings have important implications for the diagnosis and treatment of atypical APL.

Prevalence of Vitamin A Deficiency in Children Aged 6 to 17 Years - Western and Central Rural Areas, China, 2012-2021.

What is already known about this topic?: Vitamin A deficiency (VAD) is a leading global nutritional concern, ranking among the top four major nutritional deficiencies worldwide. The prevalence of VAD is unevenly distributed across various regions, both within China and globally. What is added by this report?: The report adds valuable insights into the vitamin A nutritional status of rural students aged 6-17 years who participated in the Nutrition Improvement Programme for Rural Compulsory Education Students (NIPRCES). Over the decade from 2012 to 2021, there was a modest improvement in vitamin A status. The prevalence of VAD and sub-clinical VAD (SVAD) declined as the students aged. Throughout the majority of the survey years, the incidence of VAD was higher among males and western regions compared to females and central regions, respectively. What are the implications for public health practice?: A comprehensive approach, incorporating dietary diversification, nutrition education, and food fortification, should be implemented to prevent VAD and SVAD especially in males, younger children and children in western areas.

Electrophysiological assessment of radial shock wave therapy for carpal tunnel syndrome.

This study presents an electrophysiological assessment of radial extracorporeal shock wave therapy on patients with carpal tunnel syndrome (CTS). Sixteen CTS subjects received radial extracorporeal shock wave therapy once a week for five consecutive weeks. Outcome performance was assessed using the Boston Carpal Tunnel Questionnaire (BCTQ) and electrodiagnostic measurements including a nerve conduction study of the median nerve and a compound muscle action potential (CMAP) scan of the abductor pollicis brevis muscle. The BCTQ and the sensory conduction test measurements were all statistically improved after the treatment. However, the motor conduction test measurements were not significantly different before and after the treatment. The CMAP scan examination revealed MScanFit motor unit number estimation (MUNE) was significantly higher after the treatment, while no significant change was found in StairFit MUNE and step index. These results confirmed the effectiveness of shock wave therapy for treating CTS symptoms and the associated sensory property changes. The reasons for the inconsistencies from different CMAP scan processing methods are worthwhile targets for further investigation.

Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers.

Targeting the intrinsic apoptotic pathway regulated by B-cell lymphoma-2 (BCL-2) antiapoptotic proteins can overcome the evasion of apoptosis in cancer cells. BCL-2 inhibitors have evolved into an important means of treating cancers by inducing tumor cell apoptosis. As the most extensively investigated BCL-2 inhibitor, venetoclax is highly selective for BCL-2 and can effectively inhibit tumor survival. Its emergence and development have significantly influenced the therapeutic landscape of hematological malignancies, especially in chronic lymphocytic leukemia and acute myeloid leukemia, in which it has been clearly incorporated into the recommended treatment regimens. In addition, the considerable efficacy of venetoclax in combination with other agents has been demonstrated in relapsed and refractory multiple myeloma and certain lymphomas. Although venetoclax plays a prominent antitumor role in preclinical experiments and clinical trials, large individual differences in treatment outcomes have been characterized in real-world patient populations, and reduced drug sensitivity will lead to disease recurrence or progression. The therapeutic efficacy may vary widely in patients with different molecular characteristics, and key genetic mutations potentially result in differential sensitivities to venetoclax. The identification and validation of more novel biomarkers are required to accurately predict the effectiveness of BCL-2 inhibition therapy. Furthermore, we summarize the recent research progress relating to the use of BCL-2 inhibitors in solid tumor treatment and demonstrate that a wealth of preclinical models have shown promising results through combination therapies. The applications of venetoclax in solid tumors warrant further clinical investigation to define its prospects.

Establishing a Mouse Model of Chlorpromazine-Induced Corneal Trigeminal Denervation.

Purpose: This study aimed to establish a mouse model of chlorpromazine-induced corneal trigeminal denervation (CCTD). Methods: Retrobulbar chlorpromazine injections were administered to 6- to 8-week-old C57BL/6j mice to induce corneal denervation. Additionally, apoptosis was assessed in isolated primary trigeminal ganglion cells after culturing in a conditioned medium containing chlorpromazine. Finally, the success rate of model generation, mortality and complication rates, and model-preparation learning curves were compared between the CCTD model and the electrocoagulation and axotomy models. Results: Chlorpromazine retrobulbar injections resulted in trigeminal denervation, leading to a reduced blink reflex, corneal nerve density, and corneal epithelium thickness. Furthermore, 90% (9/10) of the mice developed epithelial defects, accompanied by increased apoptosis and inhibited proliferation of corneal epithelial cells. In vitro, trigeminal ganglion cell apoptosis increased after culturing in a conditioned medium containing chlorpromazine. Moreover, the CCTD model exhibited a higher success rate, longer survival rate, and lower complication rate compared to the electrocoagulation and axotomy models. Crucially, the learning curve demonstrated that the method used to generate the CCTD model was easy to learn. Conclusions: The CCTD model is a user-friendly mouse model for studying corneal trigeminal denervation that offers a less invasive alternative to existing models. Translational Relevance: The CCTD model serves as a valuable tool for investigating the functional mechanisms of corneal trigeminal nerves and their interactions with corneal cells.

Semi-supervised enhanced discriminative local constraint preserving projection for dimensionality reduction of medical hyperspectral images.

Microscopic hyperspectral images has the advantage of containing rich spatial and spectral information. However, the large number of spectral bands provides a significant amount of spectral features, but also leads to data redundancy and noise, which seriously affect the recognition and classification performance of the images, as well as increasing the requirements for computation and storage. To address this issue, we propose a dimensionality reduction algorithm named enhanced discriminant local constraint preserving projection (EDLCPP). Specifically, the global spectral attention mechanism focuses on important bands, the high discriminability sample selection module measures the discriminability of samples using a modified average neighborhood margin, the graph construction module preserves the local geometric relationship and discriminant information, and the graph embedding module embeds the constructed graphs into a low-dimensional space to obtain the projection matrices. Experimental results on eight cholangiocarcinoma (CCA) hyperspectral images, Bloodcell1-3, and Bloodcell2-2 datasets have demonstrated the effectiveness of the proposed method.

A novel polyhedral oligomeric silsesquioxane nanohybrid fluorescent sensor designed based on an osmotic mechanism for specific detection and intelligent scavenging of magnesium ions.

BACKGROUND: Mg2+ has long been recognized as one of the most vital cations due to its diverse physiological and pathological roles, making it indispensable in both biomedical and biological research. Organic fluorescent sensors are commonly employed for Mg2+ detection, but they often lack high selectivity and exhibit poor hydrophilicity, limiting their biomedical applications. RESULTS: Herein, we introduced a novel organic-inorganic hybrid fluorescence sensor, PFHBS, constructed on the POSS nanoplatforms. The efficient connection between PEGylated POSS and the small molecule sensor FHBS through Click chemistry enhances the selectivity and reduces interference, making this chemical sensor ideal for the accurate detection of Mg2+. Furthermore, the incorporation of POSS amplifies the ligand field effect of FHBS, making it more conducive to Mg2+ capture. The modification of PEG chains enhances the sensor's amphiphilicity, facilitating efficient cell penetration and effective Mg2+ detection at the biological level. SIGNIFICANCE: Finally, relying on spontaneous permeation, coupled with its strong ligand field effect and excellent cell permeability, the chemosensor demonstrates the capability to intelligently remove excess Mg2+ from the body. It has been successfully applied to mitigate renal overload resulting from acute Mg2+ poisoning.

Clinical characteristics and proposed mechanism of pediatric spinal cord injury resulting from backbend practice.

Objective: Pediatric spinal cord injury without radiographic abnormality (SCIWORA) caused by backbend practice is increasing. This study proposed an underlying 'combined injury mechanism' related to the spinal cord and femoral nerve overstretching. Methods: Pediatric patients diagnosed with backbend-associated SCIWORA at the China Rehabilitation Research Center during 2017-2021 were recruited. Clinical and imaging data were collected, and each patient's clinical course and prognosis were determined. Healthy dancers were recruited to simulate the backbend, obtain images, and estimate the spinal cord and femoral nerve stretch ratio. A model for the 'combined injury mechanism' was established using 4-week-old SD rats. Results: Forty-two SCIWORA female patients with an average age of 6 (SD 1) years and an average hospitalization time of 91 (SD 43) days were assessed. The primary initial symptom was pain in the back and/or lower extremities (33, 79%). The average time from injury onset to severe paralysis was 2.0 (SD 0.6) hours. Most patients had complete paraplegia (32, 76%), and neurological levels were distributed mainly in thoracic segments (38, 91%). Patients with elicited tendon reflexes on admission tended to have an incomplete spinal cord injury (p = 0.001) and improved motor recovery (p = 0.018). After one year, the most common complications were scoliosis (31, 74%) and abnormal hips (14, 33%). Injury of the caudal spinal cord torn by nerve roots was confirmed by surgical exploration in a case. The thoracic spinal cord and femoral nerves were overstretched by 148.8 ± 3.6% and111.7 ± 4.0%, respectively, in a full backbend posture. The 'combined injury mechanism' was partially replicated in the animal model. Conclusion: Spinal overstretch and transient dislocation are considered the primary mechanisms by which SCIWORA occurs in children. Overstretching the femoral nerve aggravates spinal cord injuries caused by backbend practice.