Performance of assessment tools in predicting neural autoantibody positivity in patients with seizures.

BACKGROUND: The identification of patients with seizures of unknown etiology who would benefit from neural antibody testing necessitates effective assessment tools. The study aimed to compare the performance of the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score and the "Obvious" Indications for Neural Antibody Testing in Epilepsy or Seizures (ONES) checklist. We also intended to evaluate whether the performance of the tools varied by types of antibody. METHODS: Patients diagnosed with epilepsy, seizures, or status epilepticus of unknown etiology at West China Hospital from January 2019 to December 2021 were included. Paired serum/cerebrospinal fluid samples were analyzed for antineuronal and antiglial antibodies. The APE2 score and ONES checklist were applied, and their outcomes were compared to laboratory antibody test results. Possible false positive neuronal antibody results were excluded in sensitivity/specificity analysis reasonably. RESULTS: A total of 113 antibody-positive and 159 antibody-negative patients were enrolled in sensitivity/specificity analysis. The ONES checklist showed superior sensitivity than APE2 score (95.6 % vs.79.6 %, P < 0.001). Specificity was not statistically different (60.4 % vs. 57.9 %, P = 0.557). The negative predictive value (NPV) of ONES checklist was higher than that of APE2 score (94.8 % vs 80.7 %, P < 0.001). The positive predictive value of them was not statistically different (61.7 % vs 58.8 %, P = 0.557). APE2 score exhibited lower sensitivity for predicting LGI-Abs (52.9 % vs. 80.3 %, P = 0.022) compared to NMDAR-Abs. Similarly, ONES checklist showed lower sensitivity for LGI1-Abs than NMDAR-Abs (82.4 % vs. 100.0 %, P = 0.009). CONCLUSIONS: The ONES checklist demonstrates superior sensitivity for neural antibody positivity than APE2 score. Specificity of the two assessment tools was similar. ONES checklist performed better NPV than the APE2 score. Both assessment tools performed less well in predicting the presence of LGI1- Abs when compared to NMDAR-Abs.

Multi-Branch Attention Learning for Bone Age Assessment with Ambiguous Label.

Bone age assessment (BAA) is a typical clinical technique for diagnosing endocrine and metabolic diseases in children's development. Existing deep learning-based automatic BAA models are trained on the Radiological Society of North America dataset (RSNA) from Western populations. However, due to the difference in developmental process and BAA standards between Eastern and Western children, these models cannot be applied to bone age prediction in Eastern populations. To address this issue, this paper collects a bone age dataset based on the East Asian populations for model training. Nevertheless, it is laborious and difficult to obtain enough X-ray images with accurate labels. In this paper, we employ ambiguous labels from radiology reports and transform them into Gaussian distribution labels of different amplitudes. Furthermore, we propose multi-branch attention learning with ambiguous labels network (MAAL-Net). MAAL-Net consists of a hand object location module and an attention part extraction module to discover the informative regions of interest (ROIs) based only on image-level labels. Extensive experiments on both the RSNA dataset and the China Bone Age (CNBA) dataset demonstrate that our method achieves competitive results with the state-of-the-arts, and performs on par with experienced physicians in children's BAA tasks.

Construction and optimization of ecological security network in the Shule River Basin, China.

Construction and optimization of ecological security network is an efficient way to ensure regional ecological security and achieve sustainable development. Based on the morphological spatial pattern analysis method, circuit theory and other methods, we constructed the ecological security network of the Shule River Basin. The PLUS model was used to predict the land use change in 2030, with the aim to explore the current ecological protection direction and propose reasonable optimization strategies. The results showed that there were 20 ecological sources in the Shule River Basin, with a total area of 15774.08 km2, accounting for 12.3% of the total area of study area. The ecological sources were mainly distributed in the south part of the study area. A total of 37 potential ecological corridors were extracted, including 22 important ecological corridors, which showed the overall spatial characteristics of vertical distribution. Meanwhile, 19 ecological pinch points and 17 ecological obstacle points were identified. We predicted that the expansion of construction land would continue to squeeze the ecological space by 2030, and identified 6 warning areas of ecological protection space to effectively avoid conflicts between ecological protection and economic development. After optimization, 14 new ecological sources and 17 stepping stones were added, and the circuitry, ratio of line to node and connectivity index of the ecological security network increased by 18.3%, 15.5%, and 8.2% respectively compared with those before optimization, forming a structurally stable ecological security network. The results could provide scientific basis for ecological security network optimization and ecological restoration.

The Effects of Online Social Interactions on Life Satisfaction of Older Chinese Adults: New Insights Based on a Longitudinal Approach.

Population aging and digitalization have become universal phenomena. Over the past two decades, digital inclusion has started to play a crucial role in supporting successful aging. Based on a nationally representative sample of around 5200 older adults in China over the period of 2014-2018, we explore the effects of online social interactions (OSIs) on the life satisfaction of older adults. We find that OSIs can improve the levels of life satisfaction of older Chinese adults. Estimates from fixed effect and cross-lagged structural equation models further suggest that OSIs work by increasing physical activities, healthy time allocation, interpersonal trust, and informal social engagement and reducing loneliness. We also find that OSIs narrow the social inequality in life satisfaction across groups from rural-urban areas and groups with different social statuses. Moreover, a comparison among different online engagements shows that not all online activities positively affect older adults' life satisfaction. Different online activities have varying effects. Our results highlight that public digital interventions focusing on social functions can benefit the lives of older adults.

Does Internet Connect to Social Justice Perception in China?

The world has witnessed an important and dramatic transition during the past decades, with social and economic challenges related to the advancement of digital technologies. Meanwhile, inequalities of distributions of resources and opportunities obstinately exist around the world. This study innovates by utilizing household survey datasets to empirically evaluate the impact of Internet utilization on individual's perception toward social justice in China. Estimates suggest that Internet utilization generates a significant negative effect on perceived social justice (in general, -5%). In China, there are 1.032 billion Internet users by the end of 2021, accounting for 73% of the total population (China Internet Network Information Center). It suggests that 3.65% of the population, around 5 million people, might consider the current society is injustice if all circumstances remain unchanged. For robustness checks, we not only run multivariate regressions, implemented different model specification, and used alternative measures as well as datasets, but also approached instrumental variable estimation with regional rainfall for causal inference. Consistent conclusions are found. Also, we found stronger negative effects among male, eastern provinces, and urban area samples. To the end, our results shed lights on policy implication, for example, Internet associated public interventions can be focused on justice cultivation and information transparency.

Barriers to generic antiseizure medication use: Results of a global survey by the International League Against Epilepsy Generic Substitution Task Force.

The objective of this study was to identify and quantify barriers to generic substitution of antiseizure medications (ASM). A questionnaire on generic ASM substitution was developed by the International League Against Epilepsy (ILAE) Task Force on Generic Substitution. Questions addressed understanding of bioequivalence, standards for generic products, experiences with substitution, and demographic data. The survey was web-based and distributed to ILAE chapters, their membership, and professional colleagues of task force members. Comparisons in responses were between ILAE regions and country income classification. A total of 800 individuals responded, with 44.2% being from the Asia-Oceania ILAE Region and 38.6% from European Region. The majority of respondents had little or no education in generic substitution or bioequivalence. Many respondents indicated lack of understanding aspects of generic substitution. Common barriers to generic substitution included limited access, poor or inconsistent quality, too expensive, or lack of regulatory control. Increase in seizures was the most common reported adverse outcome of substitution. Of medications on the World Health Organization Essential Medication list, problems with generic products were most frequent with carbamazepine, lamotrigine, and valproic acid. Several barriers with generic substitution of ASM revolved around mistrust of regulatory control and quality of generic ASM. Lack of education on generic substitution is also a concern. Generic ASM products may be the only option in some parts of the world and efforts should address these issues. Efforts to address these barriers should improve access to medications in all parts of the world.

Epilepsy care during the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has affected the care of all patients around the world. The International League Against Epilepsy (ILAE) COVID-19 and Telemedicine Task Forces examined, through surveys to people with epilepsy (PWE), caregivers, and health care professionals, how the pandemic has affected the well-being, care, and services for PWE. The ILAE included a link on their website whereby PWE and/or their caregivers could fill out a survey (in 11 languages) about the impact of the COVID-19 pandemic, including access to health services and impact on mental health, including the 6-item Kessler Psychological Distress Scale. An anonymous link was also provided whereby health care providers could report cases of new-onset seizures or an exacerbation of seizures in the context of COVID-19. Finally, a separate questionnaire aimed at exploring the utilization of telehealth by health care professionals since the pandemic began was available on the ILAE website and also disseminated to its members. Seventeen case reports were received; data were limited and therefore no firm conclusions could be drawn. Of 590 respondents to the well-being survey (422 PWE, 166 caregivers), 22.8% PWE and 27.5% caregivers reported an increase in seizure frequency, with difficulty in accessing medication and health care professionals reported as barriers to care. Of all respondents, 57.1% PWE and 21.5% caregivers had severe psychological distress (k score >13), which was significantly higher among PWE than caregivers (p<0.01). An increase in telemedicine use during the COVID-19 pandemic was reported by health care professionals, with 40% of consultations conducted by this method. Although 74.9% of health care providers thought that this impacted positively, barriers to care were also identified. As we move forward, there is a need to ensure ongoing support and care for PWE to prevent a parallel pandemic of unmet health care needs.

Direct economic burden of patients with tuberculous meningitis in western China.

OBJECTIVE: To estimate the direct economic burden of tuberculous meningitis (TBM) in China for the first time. METHODS: Patients who were first diagnosed with TBM from December 2015 to December 2018 in Western China Hospital were enrolled. We retrospectively collected data on demographic and clinical features, resource utilization, costs, and long-term outcomes. The patients were followed up for 15-53 months. We performed a cost-of-illness study and analyzed the cost contributors with a generalized linear model. RESULTS: In total, the cases of 154 TBM patients (95 males, 59 females, aged 14-82 years) were reviewed. The average total direct cost per person was USD (United States dollars) 9,484 (range 1,822-67,285), with a mean direct medical cost of USD 8,901 (range 1,189-67,049). The average inpatient cost and drug cost after discharge were USD 6,837 (range 845-52,921) and USD 1,967 (range 0-60,423), respectively. The mean direct nonmedical cost was USD 583 (range 33-3,817), which accounted for 6.2% of the total direct cost. The average length of stay (LOS) in hospital was 25.0 days (range 6-152). A total of 117 of the patients (76.0%) had good outcomes (mRS = 0-2). There was no significant difference in the costs, LOS, or outcomes between rural and urban patients. Contributors to total direct cost were definite TBM, fever, coma, seizures, multidrug resistance, hydrocephalus, and poor long-term outcome. CONCLUSIONS: Although the accessibility of medical resources in remote and rural regions has significantly improved in China, the cost of TBM imposes a catastrophic burden on patients.

Direct economic burden of patients with autoimmune encephalitis in western China.

OBJECTIVE: To analyze the cost of autoimmune encephalitis (AE) in China for the first time. METHODS: Patients who were newly diagnosed with antibody-positive AE (anti-NMDA receptor [NMDAR], anti-γ aminobutyric acid type B receptor [GABABR], antileucine-rich glioma-inactivated 1 [LGI1], and anticontactin-associated protein-2 [CASPR2]) at West China Medical Center between June 2012 and December 2018 were enrolled, and a cost-of-illness study was performed retrospectively. Data on clinical characteristics, costs, and utilization of sources were collected from questionnaires and the hospital information system. RESULTS: Of the 208 patients reviewed, the mean direct cost per patient was renminbi (RMB) 94,129 (United States dollars [USD] 14,219), with an average direct medical cost of RMB 88,373 (USD 13,349). The average inpatient cost per patients with AE was RMB 86,810 (USD 13,113). The direct nonmedical cost was much lower than the direct medical cost, averaging RMB 5,756 (USD 869). The direct cost of anti-LGI1/CASPR2 encephalitis was significantly lower than that of anti-NMDAR encephalitis and anti-GABABR encephalitis. The length of stay in the hospital was significantly associated with the direct cost. CONCLUSIONS: The financial burden of AE is heavy for Chinese patients, and there are significant differences between different types of AE.

Telemedicine During the COVID-19 Pandemic: Experiences From Western China.

Disasters and pandemics pose unique challenges to health care delivery. As health care resources continue to be stretched due to the increasing burden of the coronavirus disease (COVID-19) pandemic, telemedicine, including tele-education, may be an effective way to rationally allocate medical resources. During the COVID-19 pandemic, a multimodal telemedicine network in Sichuan Province in Western China was activated immediately after the first outbreak in January 2020. The network synergizes a newly established 5G service, a smartphone app, and an existing telemedicine system. Telemedicine was demonstrated to be feasible, acceptable, and effective in Western China, and allowed for significant improvements in health care outcomes. The success of telemedicine here may be a useful reference for other parts of the world.

A quantitative assessment method for the space design of products based on ergonomics and virtual simulation.

Work spaces for assembly or maintenance operations are considered in the design stage of products. Maintenance space is a key factor in determining how well a product can be maintained. If the work space is sufficiently considered in the design stage, it will benefit both the user and the maintainer. From a maintenance perspective, this paper proposes a quantitative method to evaluate the maintenance space by virtual simulation and consideration of ergonomics. In this method, maintenance operations are concisely classified into three types. Based on the virtual simulation of the maintenance process and maintainer data, the swept volume of a hand is built using envelope theory. The operation range of the maintainer is derived by establishing a mathematical model for the upper limb. Combining the swept volume and operation range, the maintenance space can be quantitatively evaluated. A concise validation demonstrates that the proposed method is effective for evaluating the maintenance space to improve the space design. The proposed method could be applied to the space design of a complex product.

Diagnostic and treatment services for patients with Psychogenic Nonepileptic Seizures (PNES): A survey of health professionals in urban China.

PURPOSE: This study is intended to provide an overview of diagnostic and treatment services for patients with psychogenic nonepileptic seizures (PNES) across China. METHODS: Using a questionnaire devised by the PNES Task Force of Neuropsychiatry Commission of the International League Against Epilepsy (ILAE), we conducted a survey among Chinese health professionals at the Sixth Advanced International Course: Clinical Epileptology. Descriptive analyses were performed. RESULTS: Responses from 102 eligible clinicians were analysed. Responses were received from urban areas in 20 provinces/municipalities around China. Most respondents were neurologists. The results showed that hospitals in urban China were mostly well-equipped, and that health professionals' understanding of PNES largely reflected current international expert opinion. However, many of the participants would not actually make the diagnosis, and most provided neither follow-up nor treatment (especially psychotherapy) for patients with PNES. Only about one third of the patients diagnosed with PNES were estimated to receive at least one appointment for psychological treatment. In the opinion of the respondents, tacit trauma (neglect and stress) play an important role in the development of PNES. The main obstacles to patients with PNES accessing health services for their condition were thought to be lack of knowledge or awareness among health professionals, patients and society. CONCLUSION: Despite good access to equipment, diagnostic and treatment services for patients with PNES in China are currently deficient. Education programs about PNES with different target groups, and more effective referral and social security systems emerge as particular development needs from this survey.

PNES around the world: Where we are now and how we can close the diagnosis and treatment gaps-an ILAE PNES Task Force report.

An international consensus clinical practice statement issued in 2011 ranked psychogenic nonepileptic seizures (PNES) among the top three neuropsychiatric problems. An ILAE PNES Task Force was founded and initially charged with summarizing the current state of the art in terms of diagnosis and treatment, resulting in two publications. The first described different levels of diagnostic certainty. The second summarized current knowledge of management approaches. The present paper summarizes an international workshop of the ILAE PNES Task Force that focused on the current understanding and management of PNES around the world. We initially provide a knowledge update about the etiology, epidemiology, and prognosis of PNES-in adults and in special patient groups, such as children, older adults, and those with intellectual disability. We then explore clinical management pathways and obstacles to optimal care for this disorder around the world by focusing on a number of countries with different cultural backgrounds and at very different stages of social and economic development (United Kingdom, U.S.A., Zambia, Georgia, China, and Japan). Although evidence-based methods for the diagnosis and treatment of PNES have now been described, and much is known about the biopsychosocial underpinnings of this disorder, this paper describes gaps in care (not only in less developed countries) that result in patients with PNES not having adequate access to healthcare provisions. A range of challenges requiring solutions tailored to different healthcare systems emerges. Continued attention to PNES by the ILAE and other national and international neurologic, psychiatric, and health organizations, along with ongoing international collaboration, should ensure that patients with PNES do not lose out as healthcare services evolve around the world.

PET of Poly (ADP-Ribose) Polymerase Activity in Cancer: Preclinical Assessment and First In-Human Studies.

Purpose To demonstrate that positron emission tomography (PET) with fluorine 18 (18F) fluorthanatrace (FTT) depicts activated poly (adenosine diphosphate-ribose)polymerase (PARP) expression and is feasible for clinical trial evaluation. Materials and Methods All studies were conducted prospectively from February 2012 through July 2015 under protocols approved by the local animal studies committee and institutional review board. The area under the receiver operating characteristic curve (AUC, in g/mL· min) for 18F-FTT was assessed in normal mouse organs before and after treatment with olaparib (n = 14), a PARP inhibitor, or iniparib (n = 11), which has no PARP inhibitory activity. Murine biodistribution studies were performed to support human translational studies. Eight human subjects with cancer and eight healthy volunteers underwent imaging to verify the human radiation dosimetry of 18F-FTT. The Wilcoxon signed rank test was used to assess for differences among treatment groups for the mouse studies. Results In mice, olaparib, but not iniparib, significantly reduced the 18F-FTT AUC in the spine (median difference before and after treatment and interquartile range [IQR]: -17 g/mL· min and 10 g/mL · min, respectively [P = .0001], for olaparib and -3 g/mL · min and 13 g/mL · min [P = .70] for iniparib) and in nodes (median difference and interquartile range [IQR] before and after treatment: -23 g/mL · min and 13 g/mL · min [P = .0001] for olaparib; -9 g/mL · min and 17 g/mL · min [P = .05] for iniparib). The effective dose was estimated at 6.9 mSv for a 370-MBq 18F-FTT dose in humans. In humans, the organs with the highest uptake on images were the spleen and pancreas. Among five subjects with measurable tumors, increased 18F-FTT uptake was seen in one subject with pancreatic adenocarcinoma and another with liver cancer. Conclusion The results suggest that 18F-FTT uptake reflects PARP expression and that its radiation dosimetry profile is compatible with those of agents currently in clinical use. © RSNA, 2016 Online supplemental material is available for this article.

Smartphone applications for seizure care and management in children and adolescents with epilepsy: Feasibility and acceptability assessment among caregivers in China.

OBJECTIVE: to determine the feasibility as well as the attitudes among caregivers of children and adolescents with epilepsy in China towards the use of smart phone applications (apps) for the management of seizures. METHODS: The caregivers of children and adolescents with epilepsy, ages ranging from 0 to 15 years, were enrolled in the study from the Epilepsy Prevention and Cure Center of West China Hospital within the time period from June 2015 to December 2015. A 10-item questionnaire gauging the attitudes towards using apps for seizure management was administered to the 390 caregivers. Additionally, data on the demographic and clinic characteristics of the children and adolescents with epilepsy for each caregiver were also collected. RESULTS: The results indicated that approximately 99.2% of caregivers own a mobile phone, of which, 97.9% of these mobile phones were smart phones. Despite only 3.1% (12/390) of caregivers currently having an app regarding the management of a chronic illness, 70.2%(274/390) reported that they would use a free seizure management app. The results of the current study indicated that the likelihood of using such a free app increased if the participant was a male as opposed to a female (P=0.03) and among caregivers with a higher education level, a higher annual household income as well as stable job (P<0.001, P<0.001, P=0.02). No statistically significant difference was found in the likelihood of using such a free app among caregivers living in rural as opposed to urban areas (P=0.3). CONCLUSIONS: The results of this study imply a favorable attitude towards the use of apps for epilepsy and seizure management among caregivers. The use of such apps in China thus represents a promising strategy among caregivers for seizure management.

Assessment of Utilization and Cost-Effectiveness of Telemedicine Program in Western Regions of China: A 12-Year Study of 249 Hospitals Across 112 Cities.

BACKGROUND: The imbalance in healthcare between urban and rural areas is still a problem in China. In recent decades, China has aimed to develop telemedicine. We assessed the implementation, utilization, and cost-effectiveness of a large telemedicine program across western China. MATERIALS AND METHODS: In 2002-2013, a government-sponsored major telemedicine program was established by West China Hospital of Sichuan University (hub), covering 249 spoke hospitals in 112 cities throughout western China and in 40 medical expertise areas. We analyzed the cross-sectional data from 11,987 consultations conducted at West China Hospital using the telemedicine network over a 12-year period. The types of diseases as well as the diagnosis and treatment changes were assessed. We also performed a cost-savings analysis and a one-way sensitivity analysis. RESULTS: Of the 11,987 teleconsultations, we noted that neoplasms (19.4%), injuries (13.9%), and circulatory diseases (10.3%) were the three most common diagnoses. Teleconsultations resulted in a change of diagnosis in 4,772 (39.8%) patients, and 3,707 (77.7%) of them underwent major diagnosis changes. Moreover, it led to a change of treatment in 6,591 (55.0%) patients, including 3,677 (55.8%) changes not linked to diagnosis changes. The telemedicine network resulted in an estimated net saving of $2,364,525 (if the patients traveled to the hub) or $3,759,014 (if the specialists traveled to the spoke hospitals). CONCLUSIONS: The introduction of telemedicine in China, linking highly specialized major hospitals (hub) with hundreds of small rural hospitals (spoke), can greatly improve the quality, efficiency, and cost-effectiveness of healthcare delivery and utilization. This new Internet-based healthcare model should be utilized more widely in developing countries.

Lateral Penumbra Modelling Based Leaf End Shape Optimization for Multileaf Collimator in Radiotherapy.

Lateral penumbra of multileaf collimator plays an important role in radiotherapy treatment planning. Growing evidence has revealed that, for a single-focused multileaf collimator, lateral penumbra width is leaf position dependent and largely attributed to the leaf end shape. In our study, an analytical method for leaf end induced lateral penumbra modelling is formulated using Tangent Secant Theory. Compared with Monte Carlo simulation and ray tracing algorithm, our model serves well the purpose of cost-efficient penumbra evaluation. Leaf ends represented in parametric forms of circular arc, elliptical arc, Bézier curve, and B-spline are implemented. With biobjective function of penumbra mean and variance introduced, genetic algorithm is carried out for approximating the Pareto frontier. Results show that for circular arc leaf end objective function is convex and convergence to optimal solution is guaranteed using gradient based iterative method. It is found that optimal leaf end in the shape of Bézier curve achieves minimal standard deviation, while using B-spline minimum of penumbra mean is obtained. For treatment modalities in clinical application, optimized leaf ends are in close agreement with actual shapes. Taken together, the method that we propose can provide insight into leaf end shape design of multileaf collimator.

Periconceptional folic acid supplementation among pregnant women with epilepsy in a developing country: a retroprospective survey in China.

OBJECTIVE: The aims of this study were to investigate the implementation of guidelines on periconceptional folic acid supplementation among pregnant women with epilepsy (WWE) in China and to identify its potential correlations with selected sociodemographic and clinical factors. METHODS: A detailed investigation was conducted in China using a structured questionnaire from December 2013 to May 2014. Data on the awareness and use of folic acid supplementation, as well as sociodemographic and clinical characteristics, were collected from 153 pregnant WWE. Descriptive analysis, followed by univariate and multivariate logistic regression analyses, was applied to the data from this survey. RESULTS: Among the enrolled subjects, 67.3% became pregnant after the promulgation of the relevant guidelines. Only 26.2% of them knew the exact effects of folic acid, and 73.8% had taken folic acid at some point during periconception. In addition, the folic acid intake of most of these women (67.1%) did not exceed that of the average pregnant woman. The prevalence of folic acid supplementation for pregnant WWE three months before pregnancy was only 15.5%. There has been almost no improvement in the level of additional awareness and use of folic acid supplementation for WWE since the relevant guidelines were established in China. Pregnant WWE with higher education levels, those with a planned pregnancy, or those who live in urban areas were more likely to know about and implement folic acid supplementation during periconception. Moreover, pregnant WWE with a planned pregnancy or those living in cities seemed to have a higher folic acid intake and started folic acid supplementation earlier before conception. CONCLUSION: The extent of awareness and use of folic acid supplementation in pregnant WWE remains low in China. More efforts are needed to promote periconceptional folic acid supplementation for WWE, especially those with low education levels and those who live in rural areas. Planned pregnancy should be encouraged for WWE.

Assessment of the Zn-Co mixtures rhizotoxicity under Ca deficiency: using two conventional mixture models based on the cell membrane surface potential.

Toxicity assessment of Zn-Co mixtures involves multiple ions interactions. The negative potential (ψ0) at the cell membrane surface (CMs) concentrated cationic toxicants (denoted {M(2+)}0) and influenced the rhizotoxicity of Co(2+) or Zn(2+). The single and joint rhizotoxicity of Co(2+) and Zn(2+) to wheat (Triticum aestivum L.) were examined, coupled with different Ca(2+) levels. Joint effects of Zn(2+), Co(2+) and Ca(2+) were estimated by the linearly extended concentration addition (CA) and response addition (RA) models. Incorporation of Ca(2+) in single metal toxicity assessment significantly enhanced the prediction accuracy (r(2) increased from 0.948 to 0.550 for Zn(2+) and from 0.903 to 0.611 for Co(2+), respectively). ψ0 affected the multiple metals toxicity in both conventional mixture models (r(2)=0.814 for CA model and 0.820 for RA model). Concretely, {Zn(2+)}0 alleviated the toxicity of {Co(2+)}0, while {Co(2+)}0 had non-significant effect on {Zn(2+)}0 toxicity. Growth responses to {Ca(2+)}0 were substantially affected by {Zn(2+)}0 and {Co(2+)}0. Ca addition in medium decreased the {M(2+)}0 by reducing the ψ0 negativity, moreover this addition alleviated Ca deficiency at CMs induced by Zn(2+) (or Co(2+)). These consistent results from both extended CA and RA models indicated that ψ0 provided a novel sight for understanding the rhizotoxicity of multiple metals.