{"title":"Cerebrospinal fluid biomarkers for normal pressure hydrocephalus","authors":"Derya Kaya, Ahmet Turan Isik","doi":"10.1016/j.bionps.2023.100071","DOIUrl":"https://doi.org/10.1016/j.bionps.2023.100071","url":null,"abstract":"<div><p>Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible disease characterized by gait disturbance, a frontal-subcortical pattern of cognitive impairment, and urinary incontinence with disproportionately enlarged ventricles. Its prevalence rises with aging. Patients with iNPH are treated with shunt placement, and predicting the surgical outcome is not always easy. Cerebrospinal fluid (CSF) has inevitably been an attractive matrix for biomarker identification in both the diagnosis and treatment of iNPH and the disease may have individual CSF composition changes. Additionally, in order to detect iNPH earlier, implement treatment faster, and have better therapeutic effects, the incorporation of CSF biomarkers in the diagnostic and treatment process is essential. In this review, CSF biomarkers of Alzheimer’s disease pathology, axonal damage, neuronal damage, astroglial dysfunction, myelin damage, inflammation, and extracellular matrix protein remodeling have been evaluated and tried to emphasize those of which have highly consistent findings in the studies. CSF samples collected only at a single time point may not be sufficient to identify a promising marker in such a dynamic and used to be a common comorbid condition to other neurodegenerative diseases. These confounders demonstrate the limitations of using solely biomarkers to diagnose the disease and to foresee the outcome of the shunt surgery. Therefore, CSF samples collected antemortem at different time points and biopsy-confirmed iNPH patients with and without other neurodegenerative diseases would fill the gaps in identifying a valid biomarker. Longitudinal observations of shunt responders and non-responders in multicenter with well-defined cohorts are also needed to understand iNPH-specific markers. Finally, biomarkers of a bioinformatic approach that includes micro-RNAs, extracellular vesicles, metabolomics, the microbiome, or else are warranted to identify novel and useful diagnostic and prognostic biomarker tools in iNPH.</p></div>","PeriodicalId":52767,"journal":{"name":"Biomarkers in Neuropsychiatry","volume":"9 ","pages":"Article 100071"},"PeriodicalIF":0.0,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50187064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rui Liu , Ernest V. Pedapati , Lauren M. Schmitt , Rebecca C. Shaffer , Elizabeth G. Smith , Kelli C. Dominick , Lisa A. DeStefano , Grace Westerkamp , Paul Horn , John A. Sweeney , Craig A. Erickson
{"title":"Reliability of resting-state electrophysiology in fragile X syndrome","authors":"Rui Liu , Ernest V. Pedapati , Lauren M. Schmitt , Rebecca C. Shaffer , Elizabeth G. Smith , Kelli C. Dominick , Lisa A. DeStefano , Grace Westerkamp , Paul Horn , John A. Sweeney , Craig A. Erickson","doi":"10.1016/j.bionps.2023.100070","DOIUrl":"10.1016/j.bionps.2023.100070","url":null,"abstract":"<div><h3>Objective</h3><p>Fragile X Syndrome (FXS) is the leading monogenic cause of intellectual disability and autism spectrum disorder. Currently, there are no established biomarkers for predicting and monitoring drug effects in FXS, and no approved therapies are available. Previous studies have shown electrophysiological changes in the brain using electroencephalography (EEG) in individuals with FXS and animal models. These changes may be influenced by drug therapies. In this study, we aimed to assess the reliability of resting-state EEG measures in individuals with FXS, which could potentially serve as a biomarker for drug discovery.</p></div><div><h3>Methods</h3><p>We collected resting-state EEG data from 35 individuals with FXS participating in placebo-controlled clinical trials (23 males, 12 females; visit age mean+/-std 25.6 +/−8.3). The data were analyzed for various spectral features using intraclass correlation analysis to evaluate test-retest reliability. The intervals between EEG recordings ranged from same-day measurements to up to six weeks apart.</p></div><div><h3>Results</h3><p>Our results showed high reliability for most spectral features, with same-day reliability exceeding 0.8. Features of interest demonstrated ICC values of 0.60 or above at longer intervals. Among the features, alpha band relative power exhibited the highest reliability.</p></div><div><h3>Conclusion</h3><p>These findings indicate that resting-state EEG can provide consistent and reproducible measures of brain activity in individuals with FXS. This supports the potential use of EEG as an objective biomarker for evaluating the effects of new drugs in FXS.</p></div><div><h3>Significance</h3><p>The reliable measurements obtained from power spectrum-based resting-state EEG make it a promising tool for assessing the impact of small molecule drugs in FXS.</p></div>","PeriodicalId":52767,"journal":{"name":"Biomarkers in Neuropsychiatry","volume":"9 ","pages":"Article 100070"},"PeriodicalIF":0.0,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43207735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lea Daou , Alaeddine El Alayli , Fadi Constantinos , Georgette Dib , Marc Barakat
{"title":"Can neurocognitive assessment be a lower-cost substitute for biomarkers in predicting progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD)? A narrative review","authors":"Lea Daou , Alaeddine El Alayli , Fadi Constantinos , Georgette Dib , Marc Barakat","doi":"10.1016/j.bionps.2023.100069","DOIUrl":"https://doi.org/10.1016/j.bionps.2023.100069","url":null,"abstract":"<div><p>The challenge to find the best predictors of conversion from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD) has been ongoing at least for the last decade. Nonetheless, clinicians still lack, to date, a robust predictive tool for identifying individuals who will go through this conversion. In this narrative review, we reported the sensitivity and specificity of biomarkers and neurocognitive assessment in predicting the progression from MCI to AD. Given that biomarkers do not necessarily provide a better predictive accuracy as showcased by the numbers in this study, cognitive tests seem like a more cost-effective, less invasive, and easily accessible option. They also offer the added benefit of measuring functional cognitive impairment. However, it remains clear that efforts are still needed to come up with more accurate, sensitive, and specific predictors.</p></div>","PeriodicalId":52767,"journal":{"name":"Biomarkers in Neuropsychiatry","volume":"9 ","pages":"Article 100069"},"PeriodicalIF":0.0,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50187067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jana Harenbrock , Heinz Holling , Graham Reid , Ivan Koychev
{"title":"A meta-analysis of the relationship between sleep and β-Amyloid biomarkers in Alzheimer’s disease","authors":"Jana Harenbrock , Heinz Holling , Graham Reid , Ivan Koychev","doi":"10.1016/j.bionps.2023.100068","DOIUrl":"https://doi.org/10.1016/j.bionps.2023.100068","url":null,"abstract":"<div><p>Sleep has an important role for long-term memory consolidation. As deficits in learning and memory are clinical characteristics of Alzheimer’s disease (AD), it has been suggested that disruptions in sleep-mediated consolidation processes are related to AD. Indeed, sleep disruptions and sleep disorders are often comorbid with AD and perhaps precede the onset of AD symptoms as a risk factor. Additionally, research has shown that sleep disruptions and disorders are associated with accumulation of β-amyloid (AB), a neuropathologic hallmark and biomarker of AD. However, the studies that have investigated the relationship between sleep disturbances and AB burden have been heterogenous in design and quality, leaving it unclear whether the overall effect is statistically significant. As such, this paper investigated the relationship between sleep disturbances and AB burden by meta-analytically integrating reported correlations that have been published to date. Results revealed that higher levels of cerebral AB (lower AB42/40 ratios) were related to shorter sleep durations, highlighting the importance of total sleep time in supporting the clearance of AB during slow-wave sleep. Herein we also controlled for heterogeneity in the included studies by conducting several moderator analyses, showing an important role for age, sex, cognitive impairment, sleep disorders, and education in influencing the associations between sleep disturbances and AB.</p></div>","PeriodicalId":52767,"journal":{"name":"Biomarkers in Neuropsychiatry","volume":"9 ","pages":"Article 100068"},"PeriodicalIF":0.0,"publicationDate":"2023-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50187063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A narrative review and discussion of concepts and ongoing data regarding quantitative EEG as a childhood mood disorder biomarker","authors":"Serhiy Y. Chumachenko , Molly McVoy","doi":"10.1016/j.bionps.2022.100060","DOIUrl":"https://doi.org/10.1016/j.bionps.2022.100060","url":null,"abstract":"<div><h3>Background</h3><p>As the need for prompt identification and management of childhood mood. disorders continues to grow, increasing interest has shifted towards potential objective. biomarkers. One modality that has shown promise as a biomarker has been quantitative electroencephalography or qEEG. In this review, we expand on our previous investigation into qEEG biomarker research for child mood disorders and potential challenges faced in ongoing development.</p></div><div><h3>Ongoing research into qEEG:</h3><p>Since our last systematic review, qEEG biomarker research of childhood major depressive disorder remained sparse, with only one novel awake qEEG investigation in children despite ongoing adult depression qEEG research. For bipolar disorder, previously identified qEEG researchers have continued investigation into Bipolar II diagnosis identification, Bipolar I versus II diagnostic discrimination, and general bipolar biomarker utilization.</p></div><div><h3>Challenges faced by qEEG:</h3><p>While the nature of qEEG as a data-driven, easily performed, and easily analyzable biomarker is promising, challenges to clinical utilization remain, including direct anatomical correlation and generation of patientfacing clinically tested and usable tools. However, preliminary general utilization of qEEG in clinical settings with childhood mood disorder has shown excellent efficacy, and ongoing research to address these limitations is feasible and ongoing.</p></div><div><h3>Conclusions</h3><p>While qEEG biomarker research in child mood disorders has remained slow, there is a clear need and strong ongoing potential for future investigations.</p></div>","PeriodicalId":52767,"journal":{"name":"Biomarkers in Neuropsychiatry","volume":"8 ","pages":"Article 100060"},"PeriodicalIF":0.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50190117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Biomarkers in frontotemporal dementia: Current landscape and future directions","authors":"Abbott Gifford , Nathan Praschan , Amy Newhouse , Zeina Chemali","doi":"10.1016/j.bionps.2023.100065","DOIUrl":"10.1016/j.bionps.2023.100065","url":null,"abstract":"<div><p>Frontotemporal dementia (FTD) is one of the most common neurodegenerative diseases, encompassing a myriad of different, clinically distinct subtypes which all target the frontoinsular region. FTD is characterized by a decline in behavioral, language, and executive functions. Due to its proximity to similar diseases, both in symptomology and mechanism, FTD remains challenging to diagnose conclusively. As a result, searching for distinct biomarkers that allow clinicians to differentiate between FTD and other neurocognitive disorders is extremely important. This review examines studies published in the past decade to evaluate which current biomarkers are the most clinically viable and where future research might lead. Genetic screening for FTD, specifically the three most common mutations to the TDP-43, MAPT, and PGRN genes, show promising predictive ability and could help patients access treatment in the early stages of the disease. In addition, serum and CSF biomarkers can help clinicians track the disease process and show good specificity when differentiating between FTD, primary psychiatric disorders, and other neurodegenerative diseases, especially when coupled with imaging techniques such as MRI and PET. Lastly, recent advances in machine learning may allow future researchers and clinicians to comprehensively analyze FTD's biochemical and imaging fingerprint, leading to increasingly accurate and timely diagnosis. Further work must be focused on transitioning the understanding of FTD biomarkers from research to concrete tools available to clinicians and patients, with the hopes of advancing the quality of care available to those suffering from FTD.</p></div>","PeriodicalId":52767,"journal":{"name":"Biomarkers in Neuropsychiatry","volume":"8 ","pages":"Article 100065"},"PeriodicalIF":0.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44262302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maísa Braga Aguiar, Gabriela Haas Henrique Barros, Gisele W.B. Colleoni, Maysa Seabra Cendoroglo, Clineu de Mello Almada Filho
{"title":"Association between C-reactive protein, neutrophils, lymphocytes, cognition, and functional capacity in an oldest old population","authors":"Maísa Braga Aguiar, Gabriela Haas Henrique Barros, Gisele W.B. Colleoni, Maysa Seabra Cendoroglo, Clineu de Mello Almada Filho","doi":"10.1016/j.bionps.2023.100067","DOIUrl":"10.1016/j.bionps.2023.100067","url":null,"abstract":"<div><p>Systemic inflammatory processes can cause changes in cognition and functional capacity in the general population. Currently there are no accessible biomarkers capable of early detection and monitoring of such pathologies, and only few studies involving older than 80 years-old population were done. The C-reactive protein (CRP) and blood counts are low-cost tests that are often performed in routine basis. From the blood counts it is possible to evaluate the absolute count of neutrophils and lymphocytes, which are peripheral blood inflammatory markers. With these results, it is also possible to evaluate the neutrophils to lymphocytes ratio (NLR). Therefore, these tests may be potential biomarkers in the evaluation of the development of dementia, mild cognitive disorder, and functional dependence, with the possibility of assisting in the clinical management and prevention of such pathologies.</p></div><div><h3>Objective</h3><p>To evaluate the association between cognition and functional capacity with C-reactive protein, absolute neutrophil count, lymphocyte count, and NLR in a population of elderly people aged 80 years and older.</p></div><div><h3>Methods</h3><p>Observational analytical cross-sectional study conducted in the cohort of the Longevous Project of the Discipline of Geriatrics and Gerontology of UNIFESP. Complete blood counts (CBC) and CRP were collected from 244 patients included in the study between 2010 and 2013. Gender and the presence of hypertension and diabetes mellitus were also characterized. Associations between the absolute values of neutrophils and lymphocytes and the NLR with cognitive tests (mini mental state examination, MMSE, and clock drawing test, CDT) and with functional capacity (basic activities of daily living, BADL or Katz score, and instrumental activities of daily living, IADL or Lawton score) were performed using nonparametric Mann-Whitney and Kruskall-Wallis statistical tests.</p></div><div><h3>Results</h3><p>We found no associations between the markers obtained by the CBC and the cognitive assessment tests. We also found no association between the CRP and the MMSE. However, we obtained a statistically significant difference between the CRP marker and the CDT, with P = 0.003. There was no statistically significant difference between markers obtained by CBC or CRP with the BADLs. But we observed a statistically significant association between the IADLs and the absolute count of neutrophils and lymphocytes, respectively P = 0.0379 and 0.0190.</p></div><div><h3>Conclusion</h3><p>The presented results contribute to the hypothesis that serum inflammatory biomarkers can be useful in the assessment of health outcomes. We identified that patients with lower functional capacity for IADLs have higher absolute neutrophil and lymphocyte counts when compared to patients with higher functional capacity. In addition, we identified that patients with low performance on CDT have CRP at higher levels when compared to patie","PeriodicalId":52767,"journal":{"name":"Biomarkers in Neuropsychiatry","volume":"8 ","pages":"Article 100067"},"PeriodicalIF":0.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42759522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthew Luebke , Manisha Parulekar , Florian P. Thomas
{"title":"Fluid biomarkers for the diagnosis of neurodegenerative diseases","authors":"Matthew Luebke , Manisha Parulekar , Florian P. Thomas","doi":"10.1016/j.bionps.2023.100062","DOIUrl":"10.1016/j.bionps.2023.100062","url":null,"abstract":"<div><p>In this review, we evaluate the role of fluid biomarkers related to neurodegenerative diseases. Such conditions present diagnostic challenges due to phenotypic heterogeneity, longitudinal evolution, overlap between diagnostic entities, and variability in progression. Biomarkers can potentially provide insight into diagnosis, progression, prognostication, and treatment efficacy. This review covers recent advances in fluid biomarkers including beta-amyloid, tau protein, neurofilament light chain, alpha-synuclein and glial fibrillary protein, and briefly touches upon imaging biomarkers. For each biomarker, we discuss the pathophysiological correlates, clinical uses, accuracy, and limitations.</p></div>","PeriodicalId":52767,"journal":{"name":"Biomarkers in Neuropsychiatry","volume":"8 ","pages":"Article 100062"},"PeriodicalIF":0.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41573218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jennifer Abi Gerges , Issam Chalhoub , Carl Atallah , Rita Khoury
{"title":"Biomarkers of chronic traumatic encephalopathy: A state-of-the art review","authors":"Jennifer Abi Gerges , Issam Chalhoub , Carl Atallah , Rita Khoury","doi":"10.1016/j.bionps.2023.100066","DOIUrl":"10.1016/j.bionps.2023.100066","url":null,"abstract":"<div><p>Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition that occurs several years following repetitive mild concussive or sub concussive brain injuries. To date, it is a post-mortem diagnosis. Traumatic encephalopathy syndrome (TES) is a framework that was developed as a clinical predictor of CTE in living individuals. Development of biomarkers of CTE, detectable through imaging or bodily fluids will aid improve the diagnostic accuracy of CTE in life, and help develop prevention and therapeutic strategies. This article reviews biomarkers investigated to date, and discusses challenges and future avenues in this burgeoning field.</p></div>","PeriodicalId":52767,"journal":{"name":"Biomarkers in Neuropsychiatry","volume":"8 ","pages":"Article 100066"},"PeriodicalIF":0.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45978084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Walaa G. El Sheikh , Bshara Sleem , Firas Kobeissy , Maya Bizri
{"title":"Biomarkers of delirium and relation to dementia among the elderly in the intensive care unit: A narrative review","authors":"Walaa G. El Sheikh , Bshara Sleem , Firas Kobeissy , Maya Bizri","doi":"10.1016/j.bionps.2023.100064","DOIUrl":"https://doi.org/10.1016/j.bionps.2023.100064","url":null,"abstract":"<div><p>Delirium is a neuropsychiatric disorder highly prevalent in the intensive care unit (ICU), especially among elderly patients. Symptoms develop suddenly over a short period of time in the form of a fluctuating mental state marked by severe inattention and disturbance in cognition. Dementia, on the other hand, develops over a long period of time as a result of a neurodegenerative disorder. In this review, we aim to identify overlapping biomarkers between delirium and dementia to have a better understanding of the underlying pathophysiological mechanisms relating these two disorders. Overlapping biomarkers included low levels of albumin and IGF-1, a presence of the APOE ε4 allele (APOE ε4 +), as well as higher levels of of AβN-40, S100β, procalcitonin, IL-1β, NfL, prolactin, creatinine, MMP-9, and homocysteine. We put forward several hypotheses on the convergence of the pathophysiology of these two disorders. It is plausible that ICU-acquired delirium arises as a sign of prodromal dementia or as a result of chronic systemic inflammation and concomitant neuroinflammation due to an increase in S100β proteins in the brain as a byproduct of chronic glial activation. Simultaneously, accumulation of creatinine may render the functioning of the kidneys sub-optimal, which can have deleterious effects on cognitive functioning, while lower serum albumin can increase the risk of Aβ accumulation in the brain and therefore increase the likelihood of delirium and future dementia. Moreover, homozygosity in the APOE ε4 allele coupled with elevated plasma CRP might increase the risk of delirium and trigger the onset of Alzheimer’s disease (AD). Therapeutic approaches targeting the above biomarkers need to be the subject of further investigation, especially among those exhibiting persistent delirium.</p></div>","PeriodicalId":52767,"journal":{"name":"Biomarkers in Neuropsychiatry","volume":"8 ","pages":"Article 100064"},"PeriodicalIF":0.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50190107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}