Bile duct ligation impairs visual acuity in rats by ammonia- and bilirubin-induced retinal degeneration.

Patients with hepatic failure are often accompanied by hepatic retinopathy, but the cellular and molecular mechanisms underlying the hepatic retinopathy remain unclear. In this study, we investigated how liver failure leads to hepatic retinopathy using bile duct ligation (BDL) rats as a cholestasis animal model. Light-dark box test was used to assess sensitivity to light, indexed as visual acuity. On D28 post-BDL, rats were subjected to light-dark box test and blood samples were collected for biochemical analyses. The rats then were euthanized. Liver, spleen and both side of eye were quickly harvested. We showed that BDL impaired rat sensitivity to light, significantly decreased the thickness of inner nuclear layer (INL), outer nuclear layer (ONL) and total retina, as well as the retinal cell numbers in ONL and ganglion cell layer (GCL). The expression of rhodopsin (RHO), brn-3a and GPX4 was significantly decreased in retina of BDL rats, whereas the expression of cleaved caspase 3, 8, 9, bax/bcl-2, RIP1, GFAP, and iba-1, as well as TUNEL-positive cells were significantly increased. In cultured retinal explant, we found that NH4Cl (0.2, 1, 5 mM) concentration-dependently impaired activity of retinal explant, decreased thickness of INL and ONL, downregulated expression of brn-3a, RHO and GFAP, increased expression of cl-caspase 3 and TUNEL-positive cell numbers, with NH4Cl (5 mM) almost completely disrupting the structure of the cultured retina; bilirubin (1 µM) significantly upregulated GFAP expression, whereas high level (10 µM) of bilirubin downregulated expression of GFAP. We further demonstrated in vivo that hyperammonemia impaired rat sensitivity to light, decreased thickness of INL and ONL, downregulated expression of RHO, brn-3a, GFAP and increased expression of cl-caspase 3; hyperbilirubinemia impaired rat sensitivity to light, upregulated expression of GFAP and iba-1. In conclusion, BDL impaired rat visual acuity due to the elevated levels of ammonia and bilirubin. Ammonia induced loss of retinal ganglion cells and rod photoreceptor cells via apoptosis-mediated cell death. Bilirubin impaired retinal function via activating microglia and Müller cells.

Short Chain Chlorinated Paraffins Impaired Spermatogenesis Process in Mice via Inhibiting α-KG/TET Enzyme Activity.

Short chain chlorinated paraffins (SCCPs) are widely found in various environmental media and potentially threaten human health. However, the toxicity mechanisms of SCCPs to the male reproductive system remain unclear. In this study, male BALB/c mice and GC-1 cells were used to investigate the reproductive toxicity of SCCPs and their molecular mechanisms. SCCPs decreased the content of the tricarboxylic acid cycle intermediate α-KG in testicular cells, thus inhibiting the activity of the DNA demethylase TET enzyme and resulting in an increase in the overall methylation level of the testicular genome. Correspondingly, the promoter demethylation and expression of spermatogenesis-related genes Rbm46, Sohlh1, Kit, and Dmrt1 were significantly reduced by SCCPs, which further prevented the transformation of spermatogonia to spermatocytes and reduced sperm quality in mice. The in vitro experiments suggested that the TGFß pathway activated by oxidative stress might be an essential reason for inhibiting the tricarboxylic acid cycle and the reduction of α-KG content in testicular cells induced by SCCPs. Overall, this study reveals a novel metabolic regulatory mechanism of SCCPs-induced spermatogenesis disorders, which provides an essential theoretical basis for the prevention of reproductive toxicity of SCCPs.

Anterior decompression and posterior total laminectomy with fusion for ossification of the cervical posterior longitudinal ligament.

Aims: Surgical approaches to cervical ossification of the posterior longitudinal ligament (OPLL) remain controversial. The purpose of the present study was to analyze and compare the long-term neurological recovery following anterior decompression with fusion (ADF) and posterior laminectomy and fusion with bone graft and internal fixation (PLF) based on > ten-year follow-up outcomes in a single centre. Methods: Included in this retrospective cohort study were 48 patients (12 females; mean age 55.79 years (SD 8.94)) who were diagnosed with cervical OPLL, received treatment in our centre, and were followed up for 10.22 to 15.25 years. Of them, 24 patients (six females; mean age 52.88 years (SD 8.79)) received ADF, and the other 24 patients (five females; mean age 56.25 years (SD 9.44)) received PLF. Clinical data including age, sex, and the OPLL canal-occupying ratio were analyzed and compared. The primary outcome was Japanese Orthopaedic Association (JOA) score, and the secondary outcome was visual analogue scale neck pain. Results: Compared with the baseline, neurological function improved significantly after surgery in all patients of both groups (p < 0.001). The JOA recovery rate in the ADF group was significantly higher than that in the PLF group (p < 0.001). There was no significant difference in postoperative cervical pain between the two groups (p = 0.387). The operating time was longer and intraoperative blood loss was greater in the PLF group than the ADF group. More complications were observed in the ADF group than in the PLF group, although the difference was not statistically significant. Conclusion: Long-term neurological function improved significantly after surgery in both groups, with the improvement more pronounced in the ADF group. There was no significant difference in postoperative neck pain between the two groups. The operating time was shorter and intraoperative blood loss was lower in the ADF group; however, the incidence of perioperative complications was higher.

Increased peripheral leukocyte aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis: A study based on clinical evidence.

Whether the dynamic development of peripheral inflammation aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis (IVT), remains unclear and warrants further study. In this study, total of 1034 patients with acute ischemic stroke who underwent IVT were enrolled. Serum leukocyte variation (whether increase from baseline to 24 h after IVT), National Institutes of Health Stroke Scale (NIHSS), infarct volume, early neurologic deterioration (END), the unfavorable outcome at 3-month (modified Rankin Scale [mRS] score ≥3) and mortality were recorded. Serum brain injury biomarkers, including Glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), S100ß, neuron-specific enolase (NSE), were measured to reflect the extent of brain injury. We found that patients with increased serum leukocytes had elevated brain injury biomarkers (GFAP, UCH-L1, and S100ß), larger infarct volume, higher 24 h NIHSS, higher proportion of END, unfavorable outcome and mortality. Furthermore, an increase in serum leukocytes was independently associated with infarct volume, 24 h NIHSS, END, and unfavorable outcome at 3 months, and serum UCH-L1, S100ß, and NSE levels. These results suggest that an increase in serum leukocytes indicates severe brain injury and may be used to predict the outcome of patients with ischemic stroke who undergo IVT.

A macroscopic magneto-optical response resulting from local effects in ferronematic liquid crystals.

This study investigates the magneto-optical response of liquid crystals (LCs) with planar anchoring in the presence of γ-Fe2O3 magnetic nanoparticles (MNPs). This research demonstrates the formation of novel magnetic composite chains of LCs wrapped around γ-Fe2O3 MNP chains within the LC matrix under an applied magnetic field. These composite chains exhibit a distinct magneto-optical response, characterized by changes in birefringence and dichroism as the magnetic field direction is altered. Based on experimental findings, a two-subsystem model and an effective volume fraction of composite chains are proposed to describe the magneto-optical behavior of the γ-Fe2O3 MNP-doped LCs. The first subsystem comprises the LC matrix, which retains its inherent anisotropic optical properties and does not respond to the applied magnetic field. The second subsystem consists of the magnetic composite chains, which exhibit a distinct magneto-optical response due to their rotational alignment with the magnetic field. The difference in absorbance, 2αdd, which corresponds to dichroism, decreases with increasing magnetic field angle Θ, indicating a corresponding change in dichroism. This interplay between the two subsystems leads to the macroscopic magneto-optical response observed in the γ-Fe2O3 MNP-doped LCs. Due to the stability of the composite chains, the magneto-optical response is stable and can be reversed.

Analysis of Variable Frequency Stimulation Sacral Neuromodulation for Different Genders: A Chinese Multicentric Prospective Clinical Study.

AIM: Sacral neuromodulation (SNM) is widely recognized as the essential treatment modality for patients suffering from various lower urinary tract disorders, particularly overactive bladder (OAB). This prospective study recruited patients who underwent variable frequency SNM treatment at six Chinese medical centers, aiming to evaluate the gender-specific effects of this intervention and provide precise guidance on its application for clinical management. METHODS: This prospective study was managed by Beijing Hospital, and six Chinese medical centers participated in this prospective research. Inclusion and exclusion criteria were established to screen patients based on the indication for SNM. During the research, all patients were required to record 72-h voiding diaries, urgency scores, and visual analogue scale (VAS) scores to reflect their disease symptoms. Additionally, subjective questionnaire surveys such as OAB symptom score (OABSS) and quality-of-life (Qol) score were recorded to reflect the patients' quality of life and treatment satisfaction. RESULTS: In this study, 52 patients (male patients: 25; female patients: 27) with OAB symptoms agreed to undergo variable frequency stimulation SNM therapy and finally convert to Stage II. Regarding the baseline outcomes, no significant differences were observed between the male and female groups. In terms of postoperative indicators, male patients showed a greater improvement in Qol scores compared to their female counterparts (20.06 ± 13.12 vs. 40.83 ± 26.06, p = 0.005). The results from VAS scores indicated that pain remission was more pronounced in male patients than in female patients (0.31 ± 0.87 vs. 1.67 ± 2.16, p = 0.02). Importantly, there was a statistically significant disparity in urinary urgency between males and females (male patients: 1.19 ± 1.56; female patients: 2.17 ± 1.52, p = 0.04). CONCLUSIONS: In our study, we found that variable frequency SNM treatment yielded sex-specific differences in therapeutic effects, with male patients having a better outcome in some metrics. This suggests that a patient's sex may influence when variable frequency SNM is used, and in the patient's follow-up. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ChiCTR2000036677.

Quantitatively predicting effects of exercise on pharmacokinetics of drugs using a physiologically based pharmacokinetic model.

Exercise significantly alters human physiological functions, such as increasing cardiac output and muscle blood flow, decreasing glomerular filtration rate (GFR) and liver blood flow, thereby, altering absorption, distribution, metabolism and excretion of drugs. In this study, we aimed to establish a database of human physiological parameters during exercise and to construct equations for the relationship between changes in each physiological parameter and exercise intensity, including cardiac output, organ blood flow (e.g. muscle blood flow and kidney blood flow), oxygen uptake, plasma pH and GFR, etc. The polynomial equation was used for illustrating the relationship between the physiological parameters (P) and heart rate (HR), which served as an index of exercise intensity. Pharmacokinetics of midazolam, quinidine, digoxin and lidocaine during exercise were predicted by a whole body physiologically based pharmacokinetic (WB-PBPK) model and the developed database of physiological parameters following administration to 100 virtual subjects. The WB-PBPK model simulation results showed that most of the observed plasma drug concentrations fell within 5th-95th percentiles of the simulations, and the estimated peak concentrations and area under the curve of drugs were also within 0.5-2.0 folds of observations. Sensitivity analysis showed that exercise intensity, exercise duration, medication time and alterations in physiological parameters significantly affected drug pharmacokinetics, and the net effect depending on drug characteristics and exercise conditions. In conclusion, pharmacokinetics of drugs during exercise could be quantitatively predicted using the developed WB-PBPK model and database of physiological parameters. Significance Statement This study simulated real-time changes of human physiological parameters during exercise in the WB-PBPK model and comprehensively investigated pharmacokinetic changes during exercise following oral and intravenous administration. Furthermore, the factors affecting pharmacokinetics during exercise were also revealed.

Astrocyte-derived clusterin disrupts glial physiology to obstruct remyelination in mouse models of demyelinating diseases.

Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models.

Cis-regulatory elements driving motor neuron-restricted viral payload expression within the mammalian spinal cord.

Spinal motor neuron (MN) dysfunction is the cause of a number of clinically significant movement disorders. Despite the recent approval of gene therapeutics targeting these MN-related disorders, there are no viral delivery mechanisms that achieve MN-restricted transgene expression. In this study, chromatin accessibility profiling of genetically defined mouse MNs was used to identify candidate cis-regulatory elements (CREs) capable of driving MN-selective gene expression. Subsequent testing of these candidates identified two CREs that confer MN-selective gene expression in the spinal cord as well as reduced off-target expression in dorsal root ganglia. Within one of these candidate elements, we identified a compact core transcription factor (TF)-binding region that drives MN-selective gene expression. Finally, we demonstrate that selective spinal cord expression of this mouse CRE is preserved in non-human primates. These findings suggest that the generation of cell-type-selective viral reagents, in which cell-type-selective CREs drive restricted gene expression, will be valuable research tools in mice and other mammalian species, with potentially significant therapeutic value in humans.

[Retracted] miRNA­490­3p promotes the metastatic progression of invasive ductal carcinoma.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the western blotting data shown in Fig. 2D, the cell migration and invasion assay data in Fig. 3C, the mouse imaging pictures in Fig. 4C and D, and the H&E­stained images in Fig. 4E and F were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had already been submitted or published elsewhere prior to the submission of this paper to Oncology Reports. Given that the abovementioned data had already apparently been submitted or published prior to the receipt of this paper at Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 45: 706­716, 2021; DOI: 10.3892/or.2020.7880].

Record of microplastic deposition revealed by ornithogenic soil and sediment profiles from Ross Island, Antarctica.

Microplastics (MPs) are a global concern as an emerging pollutant, and the investigation on MPs in Antarctic aids in informing their global pollution assessments. Therefore, there are urgent scientific concerns regarding the environmental behavior, origins, influencing factors, and potential hazards of MPs in Antarctica. This study presents the characteristics of MPs from one ornithogenic sediment profile (coded CC) and two ornithogenic soil profiles (coded MR1 and MR2) from ice-free areas on Ross Island, Antarctica. We explored the potential sources of MPs and the main influencing factors for deposition based on their distribution with depth in the profiles. Through laser-infrared imaging spectroscopy (LDIR), a total of 30 polymer types were identified in all samples, with polyethylene terephthalate (PET) and polyvinyl chloride (PVC) as the dominant types, accounting for more than 70% of the total. The abundance of MPs in the CC sediment profile ranged from 2.83 to 394.18 items/g, while in MR1 and MR2 soil profiles, the abundance ranged from 2.25 to 1690.11 and 8.24 to 168.27 items/g, respectively. The size of MPs was mainly concentrated in the range of 20-50 µm, and possible downward movement of certain polymer types was revealed. From the perspective of temporal variation, we suggest that MPs were heavily influenced by local human activities including scientific research, fishing, and tourism, balanced by protective regulations, while no solid evidence was obtained to support strong influence from biological transport through penguins. This research enhances our understanding on the environmental behavior of MPs in the terrestrial systems of remote polar regions.

Elucidating the genotoxicity of Fusobacterium nucleatum-secreted mutagens in colorectal cancer carcinogenesis.

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) is one of the key tumorigenic bacteria in colorectal cancer (CRC), yet how F. nucleatum is involved in colorectal cancer carcinogenesis remains unknown. RESULTS: In the present study, we carried out PathSeq analysis on RNA sequencing data from the 430 primary colon adenocarcinomas in TCGA database to assess the relationship between patients' survival and F. nucleatum abundance. Among patients with cecum and ascending colon tumors, we found that F. nucleatum transcriptome abundance is positively correlated with mutation load. We further demonstrated that patients with both high tumoral abundance of F. nucleatum and high mutation load exhibited poorer survival and DNA damage. We furthermore determined that F. nucleatum-conditioned medium (Fn. CM) induces DNA damage in both in vitro and in vivo studies. In addition, two F. nucleatum-secreted mutagens, namely DL-homocystine and allantoic acid, were identified to lead to DNA damage. CONCLUSIONS: Our finding delineates the genotoxicity of F.nucleatum-secreted mutagens, which provides a basis for further work to investigate the role of F. nucleatum in the pathogenicity of CRC.

Free-standing cubic gauche nitrogen stable at 760 K under ambient pressure.

Cubic gauche nitrogen (cg-N) has received wide attention for its exceptionally high energy density and environmental friendliness. However, traditional synthesis methods for cg-N predominantly rely on high-pressure techniques or the utilization of nanoconfined effects using highly toxic and sensitive sodium azide as precursor, which substantially restrict its practical application. On the basis of the first-principles simulations, we found that adsorption of potassium on the cg-N surface exhibits superior stabilization compared to sodium. Then, we chose safer potassium azide as precursor for synthesizing cg-N. Through plasma-enhanced chemical vapor deposition treatment, the free-standing cg-N was successfully synthesized without the need for high-pressure and nanoconfined effects. It demonstrated excellent thermal stability up to 760 K, and then rapid and intense thermal decomposition occurred, exhibiting typical thermal decomposition behaviors of high-energy-density materials. The explosion parameters were also measured using laser-induced plasma spectroscopy. Our work has substantially promoted the practical application of cg-N as HEDMs.

Naringin safeguards vertebral endplate chondrocytes from apoptosis and NLRP3 inflammasome activation through SIRT3-mediated mitophagy.

AIM: The degradation of the cartilage endplate (CEP) plays a critical role in the initiation and progression of intervertebral disc degeneration (IVDD), a disease closely associated with inflammation and oxidative stress. Naringin (NGN), a flavonoid compound derived from citrus fruits, has been shown to exhibit significant anti-inflammatory and antioxidant properties. This suggests a promising avenue for NGN's application in IVDD therapy. This study aims to elucidate the therapeutic effects and underlying mechanisms of NGN on CEP degeneration, contributing to the formulation of evidence-based treatment strategies for IVDD. METHODS: In vivo, we developed an intervertebral disc degeneration (IVDD) model in mice by excising the bilateral facet joints and surrounding ligaments, and evaluated the effects of naringin using HE staining and Micro-CT analysis. In vitro, endplate chondrocytes were isolated and subjected to TBHP to replicate the IVDD pathological condition. The protective effects of NGN on these cells were confirmed through immunofluorescence, Western Blot, and flow cytometry. RESULTS: In vivo, NGN effectively mitigated IVDD progression and CEP calcification in mice. In vitro, NGN enhanced mitophagy and suppressed NLRP3 inflammasome activation through the SIRT3/FOXO3a/Parkin pathway. Furthermore, NGN safeguarded chondrocytes against apoptosis and calcification triggered by oxidative stress, in addition to mitigating the degradation of the extracellular matrix. However, silencing SIRT3 negated NGN's protective influence on chondrocytes. CONCLUSION: Our study demonstrated that NGN effectively shields chondrocytes from apoptosis and NLRP3 inflammasome activation by facilitating SIRT3-mediated mitophagy. These insights could pave the way for innovative approaches in the prevention and management of IVDD.

Persistent Gene Flow Suggests an Absence of Reproductive Isolation in an African Antelope Speciation Model.

African antelope diversity is a globally unique vestige of a much richer world-wide Pleistocene megafauna. Despite this, the evolutionary processes leading to the prolific radiation of African antelopes are not well understood. Here, we sequenced 145 whole genomes from both subspecies of the waterbuck (Kobus ellipsiprymnus), an African antelope believed to be in the process of speciation. We investigated genetic structure and population divergence and found evidence of a mid-Pleistocene separation on either side of the eastern Great Rift Valley, consistent with vicariance caused by a rain shadow along the so-called 'Kingdon's Line'. However, we also found pervasive evidence of both recent and widespread historical gene flow across the Rift Valley barrier. By inferring the genome-wide landscape of variation among subspecies, we found 14 genomic regions of elevated differentiation, including a locus that may be related to each subspecies' distinctive coat pigmentation pattern. We investigated these regions as candidate speciation islands. However, we observed no significant reduction in gene flow in these regions, nor any indications of selection against hybrids. Altogether, these results suggest a pattern whereby climatically driven vicariance is the most important process driving the African antelope radiation, and suggest that reproductive isolation may not set in until very late in the divergence process. This has a significant impact on taxonomic inference, as many taxa will be in a gray area of ambiguous systematic status, possibly explaining why it has been hard to achieve consensus regarding the species status of many African antelopes. Our analyses demonstrate how population genetics based on low-depth whole genome sequencing can provide new insights that can help resolve how far lineages have gone along the path to speciation.

Simultaneously Predicting Pharmacokinetics of Loratadine and Desloratadine in Children Using a Whole-Body Physiologically Based Pharmacokinetic Model.

Loratadine is metabolized to desloratadine. Both of them have been used for allergy treatment in children. Anatomical, physiological, and biological parameters of children and clearance of drugs vary with age. We aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model to simultaneously predict the pharmacokinetics of loratadine and desloratadine in children. Following validation using 11 adult data sets, the developed PBPK model was extrapolated to children. Plasma concentrations following oral loratadine or desloratadine to children of different ages were simulated and compared with six children data sets. After scaling anatomy/physiology, protein binding, and clearance, pharmacokinetics of the two drugs in pediatric populations were satisfactorily predicted. Most of the observed concentrations fell within the 5th-95th percentile range of the simulations in 1000 virtual children. The predicted area under the concentration-time curve (AUC) and Cmax fell within 0.5-2.0-fold range of the observations. Oral doses of loratadine or desloratadine for children of different ages were simulated based on similar AUCs following 10 mg of loratadine or 5 mg of desloratadine for adults. Pediatric PBPK model was successfully developed to simultaneously predict plasma concentrations of loratadine and desloratadine in children of all ages. The developed pediatric PBPK model may also be applied to optimize pediatric dosage.

Factors influencing value co-creation in cultural and creative enterprises: An empirical study.

The empirical validation of the relationship among the capabilities of cultural and creative enterprises (CCE), customer co-creation value, and enterprise value remains insufficient. Therefore, clarifying the essential capabilities for increasing enterprise and customer value is essential. This study explores the factors that influence value co-creation in cultural and creative enterprises and examines how this influences enterprise and customer value. To measure this, a structured questionnaire was distributed to cultural and creative practitioners in Shanghai, China, and AMOS 24.0 was used for structural equation modelling of the obtained survey data. The results confirm the positive impacts of cooperative innovation capability, customer-linking, and service capability on creating enterprise and customer value. Additionally, the results indicate an interactive relationship between enterprise value creation and customer co-creation value in this context. This study provides management insights for product innovation and to enhance customer service and competitive advantage.

Changes in patterns of multimorbidity and associated with medical costs among Chinese middle-aged and older adults from 2013 to 2023: an analysis of repeated cross-sectional surveys in Xiangyang, China.

Background: Multimorbidity has become a major public health problem among Chinese middle-aged and older adults, and the most costly to the health care system. However, most previous population-based studies of multimorbidity have focused on a limited number of chronic diseases, and diagnosis was based on participants' self-report, which may oversimplify the problem. At the same time, there were few reports on the relationship between multimorbidity patterns and health care costs. This study analyzed the multimorbidity patterns and changes among middle-aged and older people in China over the past decade, and their association with medical costs, based on representative hospital electronic medical record data. Methods: Two cross-sectional surveys based on representative hospital data were used to obtain adults aged 45 years and older in Xiangyang in 2013 (n = 20,218) and 2023 (n = 63,517). Latent Class Analysis was used to analyze changes in the patterns of multimorbidity, gray correlation analysis and ordered logistics model were used to assess the association of multimorbidity patterns with medical expenses. The diagnosis and classification of chronic diseases were based on the International Classification of Diseases, Tenth Revision codes (ICD-10). Results: The detection rate of chronic disease multimorbidity has increased (70.74 vs. 76.63%, p < 0.001), and multimorbidity patterns have increased from 6 to 9 (2013: Malignant tumors pattern, non-specific multimorbidity pattern, ischemic heart disease + hypertension pattern, cerebral infarction + hypertension pattern, kidney disease + hypertension pattern, lens disease + hypertension pattern; new in 2023: Nutritional metabolism disorders + hypertension pattern, chronic lower respiratory diseases + malignant tumors pattern, and gastrointestinal diseases pattern) in China. The medical cost of all multimorbidity patients have been reduced between 2013 and 2023 (RMB: 8216.74 vs. 7247.96, IQR: 5802.28-15,737 vs. 5014.63-15434.06). The top three specific multimorbidity patterns in both surveys were malignancy tumor pattern, ischemic heart disease + hypertension pattern, and cerebral infarction + hypertension pattern. Hypertension and type 2 diabetes are important components of multimorbidity patterns. Compared with patients with a single disease, only lens disorders + hypertension pattern were at risk of higher medical costs in 2013 (aOR:1.23, 95% CI: 1.03, 1.47), whereas all multimorbidity patterns were significantly associated with increased medical costs in 2023, except for lens disorders + hypertension (aOR:0.35, 95% CI: 0.32, 0.39). Moreover, the odds of higher medical costs were not consistent across multimorbidity patterns. Among them, ischemic heart disease + hypertension pattern [adjusted odds ratio (aOR):4.66, 95%CI: 4.31, 5.05] and cerebral infarction + hypertension pattern (aOR: 3.63, 95% CI: 3.35, 3.92) were the two patterns with the highest risk. Meanwhile, men (aOR:1.12, 95CI:1.09, 1.16), no spouse (aOR:1.09, 95CI: 1.03, 1.16) had a positive effect on medical costs, while patients with total self-pay (aOR: 0.45, 95CI: 0.29, 0.70), no surgery (aOR: 0.05, 95CI: 0.05, 0.05), rural residence (aOR: 0.92, 95CI: 0.89, 0.95), hospitalization days 1-5 (aOR: 0.04, 95CI: 0.04, 0.04), and hospitalization days 6-9 (aOR: 0.15, 95CI: 0.15, 0.16) had a negative impact on medical costs. Conclusion: Multimorbidity patterns among middle-aged and older adults in China have diversified over the past decade and are associated with rising health care costs in China. Smart, decisive and comprehensive policy and care interventions are needed to effectively manage NCDS and their risk factors and to reduce the economic burden of multimorbidity on patients and the country.

Metal ions overloading and cell death.

Cell death maintains cell morphology and homeostasis during development by removing damaged or obsolete cells. The concentration of metal ions whithin cells is regulated by various intracellular transporters and repositories to maintain dynamic balance. External or internal stimuli might increase the concentration of metal ions, which results in ions overloading. Abnormal accumulation of large amounts of metal ions can lead to disruption of various signaling in the cell, which in turn can produce toxic effects and lead to the occurrence of different types of cell deaths. In order to further study the occurrence and development of metal ions overloading induced cell death, this paper reviewed the regulation of Ca2+, Fe3+, Cu2+ and Zn2+ metal ions, and the internal mechanism of cell death induced by overloading. Furthermore, we found that different metal ions possess a synergistic and competitive relationship in the regulation of cell death. And the enhanced level of oxidative stress was present in all the processes of cell death due to metal ions overloading, which possibly due to the combination of factors. Therefore, this review offers a theoretical foundation for the investigation of the toxic effects of metal ions, and presents innovative insights for targeted regulation and therapeutic intervention. HIGHLIGHTS: • Metal ions overloading disrupts homeostasis, which in turn affects the regulation of cell death. • Metal ions overloading can cause cell death via reactive oxygen species (ROS). • Different metal ions have synergistic and competitive relationships for regulating cell death.