Supplemental Digital Content is available in the text. Visits to pediatric emergency departments (EDs) are increasing, leading to overcrowding, prolonged patient wait times, and negative patient experiences. In our system, these prolonged wait times and negative experiences notably impact mid-acuity patients. As such, we sought to decrease their time-to-first-provider from 92 to 60 minutes.After identifying inefficiencies in patient arrival, triage, and assessment, we redesigned our physical space and implemented a new triage process. Further, we deployed a new multidisciplinary front-end team consisting of a physician, nurses, and ED tech specialists to create and implement an initial management plan. Time-to-first-provider for mid-acuity patients was the main outcome measure. We examined ED length of stay (LOS) as a balancing measure. Post hoc, we measured time-to-first-nursing assessment and the proportion of high-acuity patients seen within 20 minutes as additional measures of the impact of these interventions on our system. All analyses were measured using statistical process control charts.During high patient volumes, we decreased the time-to-first-provider to 70 minutes, but exceeded our goal during low patient volumes (41 minutes). We observed a 5% decrease in LOS during both high and low patient volumes . There was a 60% increase in the time-to-first-nursing assessment.A new front-end process resulted in improved time-to-first-provider and LOS. The new process was associated with longer times for nursing assessments but did not negatively impact the rapid physician assessment of higher acuity patients. ED overcrowding threatens patient safety, negatively impacts patient experience, and creates a risk of clinical deterioration or prolonged pain.5Emergency department (ED) visits are increasing for the pediatric population.7 One institution attempted to decrease ED length of stay (LOS) by increasing efficiency with front-end processes such as in-room registration,7 while another trialed immediate bedding to decrease door-to-provider (physician or nurse practitioner) time and improve the patient experience.5 Rutman et al8 sought to redesign their front-end processes by using a registered nurse in the lobby and direct patient rooming: immediate, team-based assessment and the use of an early initiation team to begin orders when the primary team was not available.Several ED throughput improvement studies focus on early processes in the ED course to mitigate the impacts of overcrowding.9 The lowest acuity patients, ESI 5, are stable patients who can wait to see a provider and will not require ED resources.9 Mid-acuity patients (ESI 3) are stable but require ED resources. During our busiest periods, bed shortages adversely affect patient arrival-to-provider times, particularly for mid-acuity patients, which represent approximately 30% of our annual visits. These patients are negatively impacted by overcrowding and face longer wait times and delays in care than their more acute counterparts. Paradoxically, because we have separate processes for low-acuity patients who often do not require beds, our ESI 3 patients often have longer wait times. We performed this quality improvement effort specifically to decrease the time-to-first-provider for mid-acuity patients. Our primary aim was to decrease the time-to-first-provider from our baseline of 92–60 minutes.The Emergency Severity Index (ESI) defines patient acuity on a scale of 1–5, with ESI 1 as the highest acuity, unstable patients needing to be seen immediately.Children’s National Hospital ED is an urban, academic, tertiary care, Level 1 pediatric trauma center located in a free-standing children’s hospital. Board-certified pediatric emergency medicine (PEM) physicians, fellows, general pediatricians, advanced practice providers, and residents staff the ED. At our institution, “provider” is either a physician or an advanced practice provider. Additional clinical staff include ED nurses, ED tech specialists, and interpreters. The ED and waiting room accommodate 45,000 visits per year, but our annual volumes exceed 87,000 visits.In July 2016, we conducted a Kaizen event, an intense, week-long improvement session to perform process mapping and plan PDSA (Plan-Do-Study-Act) cycles to improve quality and safety. The team of stakeholders included ED physician and nursing leadership, staff nurses, nursing educators, ED tech specialists, and staff from patient registration, security, and patient experience. Focusing on front-end processes, we identified several inefficiencies regarding patient arrival, registration, triage, and assessment  physical space redesign and (2) front-end process change. The design of these interventions occurred in parallel, but the implementation of the new processes could not proceed until the space redesign was complete.In tandem with our efforts to improve the ED flow of low-acuity patients (ESI 4 and 5),We renovated our waiting room to improve the registration, triage, and assessment processes. The renovation increased the number of nurse assessment rooms from 4 to 7, and patient registration windows from 1 to 2. This change created 2 areas which could accommodate the updated registration and rapid triage (pivot) process outlined below. The resultant changes decreased the size of the waiting room by half but increased the number of front-end patient care rooms. Construction for the physical space redesign occurred from July 2016 to January 2017.The new front-end process had 2 components: (1) a new rapid triage (“pivot”) process and (2) a new multidisciplinary front-end team. Before the intervention, patients waited in line for a single registration clerk, then provided comprehensive clinical information to a single triage nurse, followed by a comprehensive nursing assessment, including vital signs, medication reconciliation, and required screenings. There was often unnecessary redundancy in the information provided to the triage and assessment nurses. After the intervention (February 2017), patients undergo quick registration by a registration clerk, which includes only essential, limited demographic information. Almost simultaneously, patients receive a rapid triage by the “pivot nurse.” When faced with high volumes of incoming patients, the nurse quickly pivots back and forth between patients undergoing registration at the 2 patient registration windows. The rapid evaluation by the pivot nurse captures a limited pertinent medical history and presenting complaint, allowing the assignment of an ESI triage level. In short, the pivot nurse performs a quick triage and assignment of patient acuity. To ensure an expeditious process for our Spanish language patients, we assigned a Spanish language interpreter to the front-end area (February 2017). After pivot, the assessment nurse obtains additional medical information and performs a thorough nursing assessment.http://links.lww.com/PQ9/A188) represents the job aid created for physicians. The front-end team consists of a front-end physician, either a subspecialist in PEM or senior pediatrician, a front-end flow coordinator (nurse), assessment nurses, and an ED tech specialist. To maximize communication, we co-located all members of the front-end team. After the pivot process, the front-end flow coordinator facilitates the movement of the patient from pivot to assessment rooms, where the assessment nurse obtains vital signs and a weight, documents the medication reconciliation and allergy profile, and completes all required patient screenings. The goal is for a simultaneously focused history and physical by the front-end physician during the nursing assessment, but this may not occur simultaneously depending on the front-end physician’s workload. The front-end physician initiates a preliminary management plan that may include lab testing, imaging, initial medical interventions, and possible redirection to consultant clinics such as dental or ophthalmology. We created a document template in the electronic health record (EHR) to document a brief assessment and preliminary plan, which facilitates communication between the front-end physician and the remainder of the ED team. Further, we assigned the front-end physician a designated phone number, so all team members had direct communication as needed. An ED tech specialist obtains intravenous access and laboratory studies, if needed, and escorts patients to other care areas. The front-end flow coordinator facilitates patient flow and assists in executing the preliminary management plan .Before implementation, we created job descriptions and job aids and provided education for all members of the front-end team. Table 1 . We excluded patients with missing data from the analysis for all measures. Also, patients with an arrival-to-first provider time or an LOS greater than the weekly 95% were excluded from the analysis because they represent human error.10 Because seasonal variation affects patient volumes, we separately analyzed high-volume (September to May) and low-volume months.The analyses of the outcome measure, the LOS balancing measure, and post hoc analysis of time-to-first-nursing assessment were limited to ESI 3 patients arriving from 3 11 An accompanying centerline shift and recalculation of control limits occurred if there were special cause variation and an associated change related to the system. This work is quality improvement and was approved as exempt from review by the institutional review board.Statistical process control charts, specifically X bar S charts, were used to analyze time measures, and we used a P chart for the proportion of ESI 2 patients seen by a physician within 20 minutes of arrival. We created all statistical process control charts with Minitab 17 Statistical Software (2010) . The baseline period was July 2016 through February 2017. Standard criteria identified special cause variation.During the high-volume periods, the baseline mean time-to-first-physician for ESI 3 patients was 92 minutes, which improved to a mean of 70 minutes after the introduction of the front-end team in February 2017  to the front-end assessment nurse, thereby delaying the nurse’s ability to assess patients rapidly. Similarly, with this new process, we pivot patients very close to their ED arrival. Before these interventions, patients spent longer in the line awaiting triage, particularly during our high-volume times. The combination of rapidly triaging patients closer to their actual arrival to the ED and shifting additional tasks to the assessment nurse likely increased the time-to-first-nursing assessment.There were unintended consequences of our interventions. Adding an additional physician in the patient’s ED course created the need for a physician handoff. We did not encounter safety issues as the EHR documentation and designated front-end physician phone limited communication barriers between the front-end physician and the remainder of the ED team. Also, we found that some patients, despite their ESI designation, did not require additional physician management beyond the history obtained by the front-end physician. For example, patients requiring laceration repairs or consults who provide definitive management of the presenting issue  were often managed by the front-end physician without requiring a handoff. This observation was an unanticipated additional benefit of the new process. Finally, decreasing the size of the waiting room created crowding, particularly in high-volume times. The front-end team, initially located in “off stage” areas away from patients, transitioned to working in “on stage” areas of the waiting room area to improve team communication and efficiency. We believe the benefits of an expeditious patient evaluation by a physician and decreased LOS outweighs the negative experience in a crowded waiting room.There are costs associated with implementing the interventions noted in this study. Teams will need to weigh the capital costs of an ED redesign and staffing of a front-end team against the opportunity to shorten ED LOS and improve the patient experience. Institutions with limited physical plant space and limited funding for the capital outlay should consider re-allocating nursing and physician staff and repurposing other sections of the ED to create a front-end team. Limiting these interventions to high-volume periods mitigates additional staffing costs.We acknowledge both the special cause variation and seasonality present in the data as a limitation of our work. Although trends in patient arrivals based on time of day or season  can be predicted, more minute variations cannot. Analyses to account for highly skewed data neither corrected nor eliminated this variation. We chose not to exclude these points as they truly reflect the performance of our system, not outliers caused by inaccurate data. In our system, this special cause variation is evidence that some patients receive a greater impact of the intervention; there is a subset of patients with very short time-to-first-provider and LOS. Some of the variability beginning in late 2018 can be attributed to a larger pool of physicians filling the front-end shift. We may have lost some physician performance consistency due to decreased oversight.These interventions represent a creative use of space and personnel in a pediatric ED with insufficient space for the volume of patients. Other institutions can easily adapt parts of these interventions to meet their needs. The change in initial nursing assessment (pivot) is hardwired into our system. Still, the institution of a front-end provider is turned on and off to meet the needs of our patient volumes, thus creating a sustainable intervention. Rapid evaluation by a physician early in the patient encounter can be applied to other EDs and other high-volume clinical settings. Further study should include a direct measurement of these interventions on the patient experience.The authors have no financial interest to declare in relation to the content of this article.


The long-term survival of cancer patients has significantly improved over the past years. Despite their therapeutic efficacy, various cancer therapies are associated with cardiotoxicity. Therefore, timely detection of cardiotoxic adverse events is crucial. However, the clinical assessment of myocardial damage caused by cancer therapy remains difficult.Essen Cardio-oncology Registry (ECoR). We included patients with all types of cancer. Plasma concentrations of cTnI and NT-proBNP were measured by radioimmunoassay, and two-dimensional left ventricular ejection fraction (2D-LVEF), diastolic function, and global longitudinal strain (GLS) were measured by transthoracic echocardiography. In 116 patients, assessment was conducted before the induction of cancer therapy and during a short-term follow-up period; n = 42 of these were treated for malignant melanoma, and n = 42 with serial measurements were under treatment for breast cancer.This retrospective study was performed to evaluate the diagnostic value of cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for monitoring cancer therapy-induced cardiomyopathy. A total of 485 cancer patients referred to our cardio-oncology unit between July 2018 and January 2020 were selected from our In cross-sectional data, elevated NT-proBNP was associated with reduced LVEF and pathological GLS in the total cohort. A total of 116 patients had serial LVEF and biomarker measurements, and changes in NT-proBNP and troponin correlated with changes in LVEF during follow-up investigations. Similar to the total cohort, a subgroup of patients treated for malignant melanoma showed a correlation between the change in cTnI and the change in LVEF. In a subgroup analysis of patients undergoing breast cancer therapy, a correlation between the change in NT-proBNP and the change in LVEF could be detected. Thirty patients presented with chemotherapy-induced cardiomyopathy, defined as a significant LVEF decrease (> 10%) to a value below 50%. The number of patients with increased cTnI and NT-proBNP was significantly higher in patients with chemotherapy-induced cardiomyopathy than in patients without cardiotoxicity. Patients with positive cTnI and NT-proBNP were more likely to have a history of coronary heart disease, atrial fibrillation, and arterial hypertension.Our data suggest that cardiac biomarkers play an important role in the detection of cancer therapy-induced cardiotoxicity. Larger systematic assessment in prospective cohorts is mandatory. The development of antineoplastic treatments over the past decades has improved the long-term survival of cancer patients . DespiteCardiac troponins are structural proteins of the contractile apparatus and are expressed almost exclusively in myocardial cells. Only a small proportion of troponins are expressed in the cytoplasm of myocytes. Integrated in the thin filament of the sarcomere of striated muscle, cardiac troponins are involved in electromechanical coupling . They coBrain natriuretic peptides (BNPs) are hormones released by ventricular cardiomyocytes in response to increased filling pressures and improve myocardial performance due to vasorelaxation and natriuresis . The proTo date, there is inconsistent evidence for conventional biomarkers as markers of cardiotoxicity in cancer patients. The aim of this retrospective investigation was to determine whether levels and changes in cTnI and NT-proBNP may correlate with the occurrence of LVEF reduction in cancer patients and to evaluate potential associations between biomarker levels and clinical data.Essen Cardio-oncology Registry' (ECoR). The inclusion criteria were as follows: cancer patients ≥ 18 years with a histologically confirmed diagnosis with Eastern Cooperative Oncology Group (ECOG) status I–II and planned or initiated cardiotoxic antitumor therapy . Bedridden patients with ECOG III-IV were excluded. In n = 116 patients, assessment was conducted before cancer therapy and during a short-term follow-up period (1–6 months after the start of antineoplastic treatment), while in the remaining patients, data from only one assessment were available. The choice of follow-up termination depended on the antineoplastic treatment and clinical indication and was left to the treating physician. As part of the presentation to our cardio-oncology unit, patients were clinically examined and interviewed to determine signs of heart failure and myocardial ischemia. On the basis of symptom burden, dyspnea and angina pectoris were classified according to the Canadian Cardiovascular Society (CCS) and the New York Heart Association (NYHA) classifications . The endocardial borders of the left ventricle were traced in 4-, 2-, and 3-chamber views, and Qlab software automatically tracked endocardial borders throughout the cardiac cycles. The software calculated myocardial strain by using the speckle-tracking method, and myocardial strain was defined as the change in an object's dimension in comparison to the object's original dimension. Moreover, diastolic dysfunction was assessed according to current recommendations  ultrasound machine. Echocardiographic analysis of cardiac structure and function was performed in accordance with the recommendations of the American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) . Left vendations . Therefondations . The exaPlasma concentrations of cTnI and NT-proBNP were measured by radioimmunoassay . cTnI was considered positive for values >6 ng/L and significantly elevated at a level >40 ng/L (99th percentile). NT-proBNP was considered positive at a level of >125 pg/ml.p value < 0.05 was considered statistically significant. Continuous variables are shown as the mean ± the standard deviation (SD).All data were pseudonymized (Microsoft GmbH). Statistical analysis was performed using GraphPad Prism software version 6.0 and IBM SPSS Statistics. The data were checked for normal distribution using the Kolmogorov-Smirnov test. Troponin and NT-proBNP values showed a non-normal distribution. Differences in proportions of dichotomous values between groups were compared with univariate and multivariate binary logistic regression analyses. Moreover, Spearman correlation analysis was performed to investigate the association between LVEF and biomarkers between baseline and follow-up investigations. Furthermore, a sensitivity and specificity analysis was performed. A A total of n = 485 patients were included from our ECoR cardio-oncology database, and n = 116 patients had serial measurements for LVEF and biomarkers. Characteristics of the study population are provided in p = 0.004) and NT-proBNP values  were more frequently observed in male patients. Age, systolic blood pressure, and heart rate did not show any detectable differences between patients with and patients without cTnI and NT-proBNP elevations.Univariate and bivariate analyses were performed to detect potential associations between the population characteristics and biomarkers, and the results are presented in p = 0.009), arterial hypertension  and atrial fibrillation . Multivariate analysis showed no significant association. Moreover, patients with coronary artery disease  and atrial fibrillation  had higher rates of positive troponin in univariate analysis.Patients with previously known or newly diagnosed cardiac comorbidities showed positive troponin and NT-proBNP values more frequently. Univariate analysis revealed significantly higher rates of positive NT-proBNP in patients with coronary artery disease . In addition, univariate analysis revealed higher rates of positive troponin in patients treated with anthracyclines, alkylating agents, taxane, PD1 inhibitors, and BRAF/MEK inhibitors.Moreover, univariate analysis showed significantly higher rates of positive troponin in patients treated with alkylating agents . Furthermore, an increased cTnI correlated significantly with LVEF reduction . The percentage of patients with positive cTnI and NT-proBNP was higher in patients with EF <40% and EF between 40% and 50% than in patients with EF > 50%  and NT-proBNP .Moreover, univariate binary logistic regression showed that the presence of diastolic dysfunction was associated with positive troponin . Moreover, univariate analysis showed an association between increased troponin and pathological GLS .GLS was performed in 210 patients. Seventy-four of them showed pathological strain values (defined as GLS > −20). Univariate and multivariate analyses showed a significant association between elevated NT-pro-BNP and pathological strain measurements  to a value below 50% . The numTroponin showed a high specificity of 95.47% with a low sensitivity of 13.64% for the detection of chemotherapy-related cardiotoxicity. Likewise, NT-proBNP showed a high specificity of 92.21% with a low sensitivity of 12.06% for the detection of chemotherapy-related cardiotoxicity.p = 0.012, r = 0.231) and between changes in NT-proBNP and changes in LVEF .To investigate a potential association between changes in biomarker values and the changes in LVEF between baseline and follow-up measurements, a Spearman rank correlation analysis was performed. The analysis showed a correlation between changes in cTnI and changes in LVEF , whereas no significant correlation could be found between the change in NT-proBNP and the change in LVEF . N = 42 patients with breast cancer therapy received a follow-up investigation. In this subgroup, a correlation for the change in NT-proBNP with the change in LVEF could be detected . There was no significant correlation between changes in cTnI and changes in NT-proBNP in breast cancer patients .A total of n = 42 patients treated with melanoma therapy received serial measurements of LVEF and cardiac biomarkers. Similar to the total cohort, melanoma patients showed a moderate correlation between the change in cTnI and the change in LVEF during follow-up  Conception and design: LH, MT. (II) Administrative support: TR, MT. (III) Provision of study materials or patients: LH, SM, R-IM, JP, AR. (IV) Collection and assembly of data: LH, SM, R-IM, JP, AR. (V) Data analysis and interpretation: LH, MT, AM. (VI) Manuscript writing: All authors. (VII) Final approval of manuscript: All authors.TR was funded by the German Research Foundation  (RA 964/12-2). SM was funded by the IFORES research grant from the Medical Faculty, University Duisburg-Essen, Germany.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


NSTEMI status and positive family history of cardiovascular diseases were only independent predictors of the highest tertile of dp-ucMGP levels. Among those with NSTEMI, patients at a high risk of in-hospital mortality (adjudicated by GRACE score) had significantly higher levels of dp-ucMGP compared to non-high-risk patients . Altogether, our findings suggest that higher dp-ucMGP levels likely reflect higher calcification burden in ACS patients and might aid in the identification of NSTEMI patients at increased risk of in-hospital mortality. Furthermore, observed dp-ucMGP levels might reflect differences in atherosclerotic plaque pathobiology between patients with STEMI and NSTEMI.Vascular calcification contributes to the pathogenesis of coronary artery disease while matrix Gla protein (MGP) was recently identified as a potent inhibitor of vascular calcification. MGP fractions, such as dephosphorylated-uncarboxylated MGP (dp-ucMGP), lack post-translational modifications and are less efficient in vascular calcification inhibition. We sought to compare dp-ucMGP levels between patients with acute coronary syndrome (ACS), stratified by ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) status. Physical examination and clinical data, along with plasma dp-ucMGP levels, were obtained from 90 consecutive ACS patients. We observed that levels of dp-ucMGP were significantly higher in patients with NSTEMI compared to STEMI patients (1063.4 ± 518.6 vs. 742.7 ± 166.6 pmol/L,  Acute coronary syndrome (ACS) represents a spectrum of clinical presentations associated with reduced myocardial blood flow . Even thAmong many other mechanisms, vascular calcification is a process of depositing calcium phosphate salts in the arterial wall and, therefore, contributes to the complex pathogenesis of coronary artery disease (CAD) ,4. CalciMatrix GLA protein (MGP), a vitamin K dependent protein, on the other hand, acts as a vascular calcification inhibitor ,10,11,12Furthermore, data suggest that neither the un-carboxylated (ucMGP) nor dephosphorylated form of MGP (dpMGP) exerts its inhibitory function on vascular calcification properly ,21. Of nSpecifically, with respect to different pathophysiological and prognostic characteristics of ACS with and without ST-segment elevation, in this study, the main goal was to compare dp-ucMGP plasma levels of consecutive patients with ST-elevation myocardial infarction (STEMI) and patients with non-ST-elevation myocardial infarction (NSTEMI) ,25. Furtp = 0.001), more of them had multi-vessel disease (p = 0.012) and they had higher creatinine levels (p = 0.045). On the other hand, a greater proportion of patients with STEMI had ST segment deviation in first contact ECG (p = 0.002), and more performed in-hospital percutaneous coronary interventions (PCIs) (p = 0.001) compared to NSTEMI patients.Most of the presented baseline characteristics of patients did not differ between patients with STEMI and patients with NSTEMI . Importap < 0.001)  .p = 0.030)  had significantly higher plasma levels of dp-ucMGP in comparison to patients without high risk of in-hospital mortality  .p = 0.014), GRACE score  and both urea  and creatinine serum levels  in whole ACS population (p = 0.033), urea  and creatinine serum levels , while in the STEMI subgroup, the significant correlation was observed for dp-ucMGP and age  and hemostatic parameters as reflected in prothrombin time-INR  and activated partial thromboplastin time (APTT) . Other variables showed no statistically significant correlations.The univariate Pearson’s correlation analysis showed that dp-ucMGP plasma levels positively correlated with age  in the whole ACS cohort, a univariate binary logistic regression was employed. This analysis showed that age, diabetes mellitus, acute kidney injury, positive family history of CVD, positive history of CVD-related hospitalizations, and NSTEMI status were single predictors of the highest tertile of plasma dp-ucMGP levels . HoweverAfter adjustment for confounding variables in the model of stepwise multivariable logistic regression, the dp-ucMGP plasma level as a continuous variable was significantly associated with positive NSTEMI status  .The present cross-sectional study provided several important results. One of the main findings is that the dp-ucMGP plasma levels were significantly higher among ACS patients with NSTEMI in comparison to patients with STEMI. In addition, after adjustment for confounding variables in the model of multivariable logistic regression, circulating dp-ucMGP was associated with positive NSTEMI status while, on the other hand, NSTEMI status and positive family history for CVD were the only independent predictors of the highest tertile of plasma dp-ucMGP levels in the multivariable-adjusted regression model performed across the whole cohort of patients. When further refined, it is those patients with NSTEMI at the highest risk of in-hospital mortality (estimated by the GRACE score) who had significantly higher plasma levels of dp-ucMGP compared to NSTEMI patients in the lower-risk categories. In addition, GRACE score values positively correlated with dp-ucMGP levels. Apart from the main findings, dp-ucMPG plasma levels have been shown to positively correlate with urea and creatinine levels, and this relationship was pronounced in NSTEMI but not STEMI patients. To the best of our knowledge, this is the first original study to compare the dp-ucMGP levels between patients with different subtypes of ACS.The observed difference in the dp-ucMGP plasma levels could likely be explained by differences in atherosclerotic plaque pathobiology between patients with STEMI and NSTEMI. In a recent study, Dong et al. demonstrated that patients with NSTEMI had a higher prevalence of calcified thick-cap fibroatheromas and larger superficial calcium percentage at the minimum lumen cross-sectional area (MLA) than patients with STEMI . IntravaFurthermore, in our study, we measured significantly higher dp-ucMGP plasma levels among NSTEMI patients at higher risk of in-hospital mortality  . This fiFinally, a positive correlation of circulating dp-ucMGP levels with established kidney status markers (urea and creatinine) that we observed is in line with conducted studies. In our study, this relationship was more pronounced among NSTEMI compared to STEMI patients. Schurgers et al. demonstrated that plasma dp-ucMGP levels augmented progressively with chronic kidney disease stage and in a recent study by Fain et al., authors reported higher dp-ucMGP levels in patients on hemodialysis ,45. Of nThe present study has several limitations. First, and the main limitation, is that the study is of cross-sectional design, which prevents us from making any causal inferences. Secondly, we performed only a single measurement of dp-ucMGP levels during the admission and evaluation of patients with ACS; therefore, we lack information on possible dp-ucMGP dynamics. Thirdly, given the complex immunopathological and pathophysiological development of ACS in temporal aspect and with respect to myocardial injury and plaque burden, it is likely that blood samples were taken heterogeneously at different time points and periods of admission of ACS patients; thus, the obtained dp-ucMGP levels might not uniformly reflect disease state. Furthermore, a group of healthy controls was not included in the present study. Finally, our study lacks mortality/morbidity outcomes, it was conducted in a single center and it included a relatively small number of participants.This cross-sectional study was performed at the University Hospital of Split during the period from June 2018 to July 2019.The study was approved by the Ethics Committee of University Hospital of Split and was conducted in accordance with all ethical principles of the Helsinki Declaration from 2013. Before enrolling in the study, every participant was informed about the procedures, course and purpose of this research and each of them individually signed an informed written consent.The present study included 90 consecutive patients ≥18 years of age diagnosed with ACS, 46 of which were patients with STEMI and 44 were patients with NSTEMI. Patients were diagnosed and treated in accordance with European Society of Cardiology (ESC) guidelines for treatment of STEMI and NSTEMI ,28. ExclFor the body weight (kg) and height (cm) measurements, we used a calibrated scale  and the BMI was calculated by the body weight (kg) being divided by height-squared (m2 waist circumference (cm) was measured while standing at the mid-point between the inferior tip of the ribcage and the superior aspect of the iliac crest, while hip circumference (cm) was measured at the point providing maximum circumference over the buttocks, using a tape measure. Waist-to-hip ratio (WHR) was calculated by dividing the waist by the hip circumference.Physical examination and medical history items were directly collected from all patients included in the study in the first 24 h of admission. For the body weight (kg) and height (cm) measurements, we used a calibrated scale  and the BMI was calculated by the body weight (kg) being divided by height-squared (m2 waist circumference (cm) was measured while standing at the mid-point between the inferior tip of the ribcage and the superior aspect of the iliac crest, while hip circumference (cm) was measured at the point providing maximum circumference over the buttocks, using a tape measure. WHR was calculated by dividing the waist by the hip circumference. A transthoracic echocardiography (TTE) examination was performed in the first 24 h of admission. All measurements were taken while patients were at rest and in the left lateral decubitus position; LV ejection fraction (LVEF) was measured several times by the 2D biplane method, according to the modified Simpson’s rule, and the average value was recorded. All images were acquired using the Vivid 9 ultrasound system  and stored/analyzed on the Echo PAC workstation . The severity of heart failure and left ventricular dysfunction was clinically assessed by using Killip classification, while in-hospital mortality risk was assessed by the GRACE score ,29. The ®  and Prism 6 for Windows® . Categorical data were shown as absolute numbers (N) and percentages (%), while continuous data were shown as mean ± standard deviation (SD) or median (interquartile range). The normality of data was assessed with the Kolmogorov–Smirnov test. Differences between two principal groups of interest (STEMI vs. NSTEMI cohort) were assessed by using independent samples t-test and Mann–Whitney U test for continuous variables and Chi-squared (χ2) test for categorical variables or Fisher’s exact test, where appropriate. For the association of plasma dp-ucMGP levels with continuous baseline anthropometric, clinical, and laboratory parameters, a Pearson’s bivariate correlation analysis was used. In this analysis, the respective r correlation coefficient (rho) and two-tailed significance (p) values were reported. To determine which clinical variables would be independent predictors of the highest tertile of plasma dp-ucMGP levels (>940 pmol/L) in the whole ACS cohort, a univariate binary logistic regression was employed. This analysis evaluated relevant clinical variables such as age, sex, BMI, diabetes mellitus, arterial hypertension, dyslipidemia, acute kidney injury, positive family history for cardiovascular disease (CVD), positive history of CVD-related hospitalizations, left-ventricular ejection fraction (LVEF), multivessel disease and NSTEMI status as single predictors of highest tertile of plasma dp-ucMGP levels. Variables significant (p < 0.05) in the univariate regression model were entered in the stepwise multivariable regression model. Finally, to determine if the dp-ucMGP levels were independently associated with positive NSTEMI status, the stepwise multivariable logistic regression analysis was used and was adjusted for potential confounding variables at baselines such as age, sex, body mass index (BMI), systolic blood pressure, renal function (serum creatinine), C-reactive protein, left ventricular ejection fraction (LVEF), and relevant comorbidities encompassing arterial hypertension, type II diabetes mellitus, dyslipidemia and smoking. For this analysis, respective odds ratios (ORs), 95% confidence intervals (CIs), and two-tailed p-values were reported. Results with p-value <0.05 were considered statistically significant in all analyses.Data were analyzed by using SPSS Statistics for WindowsIn this study, for the first time, we demonstrated that the dp-ucMGP plasma levels are higher in ACS patients with NSTEMI in comparison to STEMI. Furthermore, among patients with NSTEMI, higher plasma levels of dp-ucMGP were associated with a greater risk of in-hospital mortality, which is consistent with the previous data that suggest that high dp-ucMGP levels reflect mortality rates in CVDs. Nevertheless, these findings should be supported with additional evidence in future, well-designed studies.


Risk of dementia is both racially and spatially patterned. Less is known about sex/gender differences in pathways linking birth place to late-life cognitive outcomes in older non-Latino Blacks. The 1464 Black men and women included in these analyses were Northern Manhattan residents. Cox regressions revealed that Stroke-Belt South (SB) and Non-Stroke-Belt South (NSB) birth was associated with a higher dementia risk, adjusted for birth year, childhood SES, and risk of death. Compared to Northern-born (NB) men, SB men had the highest risk, followed by NSB women and SB women, while NSB men and NB women had a similar risk to NB men. The higher risk for SB men and NSB women remained after adjusting for education, adult income, and CVD burden. Future work should identify why birth in the SB is uniquely detrimental for cognitive health among Black men, while birth in NSB has the strongest impact on Black women.


Central nervous system (CNS) tumors are a leading source of morbidity and mortality worldwide. Today, different strategies have been developed to allow targeted and controlled drug delivery into the brain. Gene therapy is a system based on the modification of patient's cells through the introduction of genetic material to exert a specific action. Administration of the foreign genetic material can be done through viral-mediated delivery or non-viral delivery via physical or mechanical systems. For brain cancer specifically, gene therapy can overcome the actual challenge of blood brain barrier penetration, the main reason for therapeutic failure. Chitosan (CS), a natural based biodegradable polymer obtained from the exoskeleton of crustaceans such as crab, shrimp, and lobster, has been used as a delivery vehicle in several non-viral modification strategies. This cationic polysaccharide is highly suitable for gene delivery mainly due to its chemical properties, its non-toxic nature, its capacity to protect nucleic acids through the formation of complexes with the genetic material, and its ease of degradation in organic environments. Recent evidence supports the use of CS as an alternative gene delivery system for cancer treatment. This review will describe multiple studies highlighting the advantages and challenges of CS-based delivery structures for the treatment of brain tumors. Furthermore, this review will provide insight on the translational potential of various CS based-strategies in current clinical cancer studies. Specifically, CS-based nanostructures including nanocapsules, nanospheres, solid-gel formulations, and nanoemulsions, also microshperes and micelles will be evaluated. Cancer is the second most frequent cause of mortality following cardiovascular disease, and has surpassed it in high and middle-income countries , 2. AlthNano-delivery systems have been shown to be a promising strategy against multiple types of cancer , 8. The In CNS cancers, one of the main challenges is the administration of chemotherapeutic agents and the successful action of the drug in the desired area. For brain tumors, selective penetration of the BBB is a limiting factor for successful eradication of cancer cells . ChitosaIn this review, we will highlight the recent advances in CS-based gene and drug delivery systems using nanotechnology for the treatment of brain cancer.Brain tumors are one of the most devastating types of cancer, with the most malignant form having a median survival of ~15 months. Brain tumors can be primary, meaning they arise from the native cells of the brain, or they can be metastatic, arising from tumors that have spread from other organs. Brain tumors have an annual incidence of about 22 people per 100,000 in the United States, with incidence increasing with age . InteresGliomas, or tumors arising from glial cells, account for over 75% of malignant adult brain tumors. These tumors are classified by the World Health Organization (WHO) by histopathological features and molecular findings. Diffuse gliomas can be stratified by their cell origin through histological characterization . The celThe current standard of care for GBM involves a combinatorial strategy of surgical resection, chemotherapy, and radiation treatment . The addIn contrast to viral vectors, non-viral delivery systems are better tolerated, can carry large amounts of nucleic acid and have a higher safety index due to their transient expression compared to stable modifications . CS is aElectroporation: An electrical pulse is applied to the cells to increase the permeability of the cell membrane facilitating uptake of DNA strands  is rapidly broken down by nucleases , a linear polysaccharide highly biodegradable and one of the most abundant polymers in nature (second only to cellulose) . PartialDue to its ability to modulate the inflammatory response, CS has been used for the repair of damaged tissue  by promoting formation of granular tissue after injury . AdditioS. aureus, P. aeruginosa, P. mirabilis, and E. Coli  and increased permeability in the bacteria cellular membrane impairing nutrient uptake . Interes E. Coli ; causing E. Coli .2 functional groups that act as readily accessible moieties for functional modifications. This enables tuning for efficient cross-linking, controlled drug release profile, enhanced electrostatic interaction, and increased solubility. The degree of deacetylation and molecular weight ratio of CS-nitrogen to phosphate-cargo make CS a suitable biomaterial that could be utilized for nanoparticle synthesis and nanomaterial fabrication for the delivery of therapeutic agents , and a polymeric shell  and galectin-1, leading to chemotherapy resistance. Amplification of EGFR is found in > 50% of GBM cases and presents a logical molecular target for GBM therapy . Given tin vivo . Data su in vivo , 63.vβ3 integrins on endothelia and is highly expressed in many tumor vasculature beds but largely absent in normal tissue. Hyper-vascularized tumors, such as brain cancers, would benefit from nano-platforms that incorporate integrin targeting strategies for gene or drug delivery. To bypass limitations of chemotherapeutic delivery to the BBB, dual functionalized liposomes were developed to mitigate transportation of doxorubicin and erlotinib to tumor cells. Liposomes were surface modified with transferrin enabling their translocation across endothelial cells lining the blood vessels, and whose surface exhibits high transferrin receptor expression. Additionally, a cell penetrating PFVYLI peptide was coated on the surface to enhance liposomal uptake by U87 human GBM commercial cell line. GBM cells were seeded in PLGA-chitosan scaffold serving as an in vitro porous scaffold 3D platform to study the functional translocation and cellular uptake of coated liposomes. Tumor cells seeded in the PLGA-chitosan scaffold resulted in 52% cell death. This study offers a 3D based platform that acts as a sufficient surrogate to study nanoparticle uptake and translocation in 3D models of brain tumors  (PLGA) modified CS nanoparticles (CSNPs) were conjugated with Arg-Gly-Asp RGD-linked peptide and loaded with clinically approved paclitaxel (PTX) chemotherapeutic drug for GBM therapy. The PTX-PLGA-CSNP-RGD particle, prepared by emulsion-solvent evaporation, displayed optimal tumor targeting and uptake via integrin receptor mediated endocytosis, induced cell-cycle arrest at G2/M, and increased lung tumor cell death . While an tumors .Brain targeted chitosan-coated nanoparticles is further shown to enhance particle uptake by human blood-brain barrier cerebral microvessel endothelial cells (hCMECs) via receptor mediated endocytosis. Further evaluation into the mechanisms enabling this translocation revealed a preferential cellular uptake pathway implicating the transferrin receptor with subsequent nanoparticle internalization via receptor-mediated endocytosis .in vivo brain pharmacokinetics of conventional GBM chemotherapy, such as TMZ, was shown to be significantly enhanced when polyamidoamine (PAMAM) dendrimer is coated with chitosan and conjugated to TMZ. Chitosan-coated PAMAM conjugated to TMZ improved GBM tumor targeting in U-251 and T-98G cell lines at lower TMZ concentrations. In vivo pharmacokinetics exhibited sustained release with a half-life of 22.74 h in chitosan-coated dendrimer compared to free drug  at 15.35 h. Reported work revealed that chitosan-anchored nanoparticles are sufficient at delivering chemotherapy across the BBB and enhanced tumor cell cytotoxicity ex vivo (Improved  ex vivo .in vitro for intracellular delivery of Pseudovirus (pSV)-luciferase (surrogate gene) to neural stem cells and spinal cord slices along with direct injection into the spinal cord in vivo. HA signals through CD44 and the receptor for hyaluronan mediated motility (RHAMM) on neural stem cells, regulating proliferation and angiogenesis and mediating the radial migration of spinal cord neurons. CS-TPP/HA resulted in higher gene transfection efficiency, less toxicity, and more retention time of CS nanosphere in vitro and in vivo compared to PEI or naked-DNA alone, suggesting a viable carrier for gene delivery to neural stem cells using CS nanospheres.Similarly, CS nanospheres were constructed by complexing pDNA with CS tripolyphosphate (TPP) and hyaluronic acid (HA) via ionotropic gelation. Ionic gelation permits the formation of sol-gel transition, and TPP stabilizes the complex in biological fluids and decreases particle size . ResultaRetinoic acid (RA), a derivative of vitamin A, activates Notch signaling response pathways in glioma initiating stem cells, prompting lineage specific differentiation and arrest at the G0/S phase . Strategin vivo in rats (Nanoemulsions are the product of the mixing of two immiscible liquids into a single phase through the use of a surfactant . The res in rats . Additio in rats , suggestin vitro (in vivo compared to free drug and controls (in vivo over time (Micelles are particles 10–100 nm in diameter formed by amphiphilic molecules self-assembling by turning hydrophobic compartments inward and hydrophilic compartments outward in solution . Similarin vitro . The usecontrols . Adding controls . This mever time . Based oIn conclusion, CS has been widely used in several health care materials and extensively studied; chitosan-coated material may offer novel and improved approaches toward the delivery of cancer therapeutics . Its bioML-V, RA, EN, CR-L, and RS-E contributed conception and design of the study. ML-V, RA, EN, and CR-L wrote the first draft of the manuscript and sections of the manuscript. HG-C, AQ-H, WF, and AF contributed reviewing the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Staphylococcus infections. Diminished susceptibility to DAP is emerging among Staphylococcus epidermidis strains although mechanisms for non-susceptibility (NS) remain poorly understood. We report a case of persistent S. epidermidis bacteremia in which loss of DAP susceptibility arose during prolonged treatment. Whole genome sequencing identified two mutations, Q371del and P415L, in a single-affected gene, WalK, that coincided with the emergence of DAP-NS. Protein modeling of the mutations predicted a disruption of WalK protein configuration. The emergence of mutations in a single-gene during DAP exposure raises concerns in an era of increasingly treatment-resistant infections.Daptomycin (DAP) is key in treating multidrug-resistant Staphylococcus infections. We identified variants in the WalK gene that were coincident with resistance in a clinical Staphylococcus epidermidis infection. Clinicians, hospital epidemiologists, and microbiology laboratories need to be aware of the potential for the evolution of drug resistance during prolonged daptomycin therapy.Lay summary: Daptomycin is an important antibiotic for fighting  Staphylococci (CoNS), including S. epidermidis, are capable of biofilm production, and are therefore one of the most common causes of endovascular device-related bloodstream infection (BSI) . Fr. Frde noPipeline . These sPipeline . Both vaccessed) . PROVEANWalK (P415L) arose coinciding with the loss of DAP susceptibility in an MDR-S. epidermidis (ST2) blood stream infection after prolonged DAP exposure. To the best our knowledge, this is the first report of in vivo induction of the WalK mutation in a CoNS clinical isolate that is absent in other heterogenous mutations [in vivo mutation resulting from antibiotic pressure was the most likely explanation for clinical failure owing to the emergence of a DAP-NS S. epidermidis strain. In addition, a previous study has shown that in vitro selection for DAP-NS resulted in a V500F WalK, further supporting the relevance of Q371del/P415L for phenotypic loss of DAP susceptibility [WalK/R sensing system and DAP resistance among CoNS , which thereby provides information for a tailored therapeutic response.The utility of genomic and bioinformatic approaches for the surveillance, identification, and prediction of antibiotic resistance is being increasingly recognized as an aid or alternative to traditional clinical microbiology , 24. In S. epidermidis bacteremia. Our findings suggest that DAP promoted the Q371del/P415L WalK mutation, but given that other environmental triggers, like detergents and divalent metals, may also regulate WalKR; further investigations into the range of hospital chemical inducers of reduced susceptibility to vancomycin and DAP are warranted.Clinicians, hospital epidemiologists, and microbiology laboratories need to be aware of the potential for drug-resistance development on therapy. Daptomycin dosing is undergoing scrutiny for MRSA and Enterococcal infections, and our data support the consideration of using higher than manufacturer label (6 mg/kg) when treating high-burden endovascular device-related eoaa031_Supplementary_DataClick here for additional data file.


This may reflect tumor infiltration that is not visible in conventional imaging, and may therefore reveal important information for personalized treatment decisions.Diffusion tensor imaging (DTI), and fractional-anisotropy (FA) maps in particular, have shown promise in predicting areas of tumor recurrence in glioblastoma. However, analysis of peritumoral edema, where most recurrences occur, is impeded by free-water contamination. In this study, we evaluated the benefits of a novel, deep-learning-based approach for the free-water correction (FWC) of DTI data for prediction of later recurrence. We investigated 35 glioblastoma cases from our prospective glioma cohort. A preoperative MR image and the first MR scan showing tumor recurrence were semiautomatically segmented into areas of contrast-enhancing tumor, edema, or recurrence of the tumor. The 10th, 50th and 90th percentiles and mean of FA and mean-diffusivity (MD) values  were collected for areas with and without recurrence in the peritumoral edema. We found significant differences in the FWC–FA maps between areas of recurrence-free edema and areas with later tumor recurrence, where differences in noncorrected FA maps were less pronounced. Consequently, a generalized mixed-effect model had a significantly higher area under the curve when using FWC–FA maps (AUC = 0.9) compared to noncorrected maps (AUC = 0.77,  Glioblastoma is the most aggressive primary brain tumor, with a median survival rate of only 15 months despite intensive treatment that usually consists of surgery and subsequent radiochemotherapy . ConsequIn a retrospective study from 2017, Bette et al. detected that, in nonenhancing peritumoral edema, FA values were significantly lower in regions with later tumor recurrence than in regions without. This was measured in comparison to the contralateral, nonaffected side to consider regional differences . Howeverb-values), and can be retrospectively applied to any diffusion MRI data [A strategy to reduce this uncontrolled variability is to eliminate the free-water signal stemming from the edema , with frMRI data .In this study, we evaluated the benefit of this novel approach for the free-water correction of DTI data for the prediction of later tumor recurrence from the first preoperative MR scan. Thus, we aimed to discover alterations in the peritumoral edema that are not visible in conventional imaging, but probably indicate tumor infiltration.Here, we comparatively investigated the prognostic potential of FA with and without free-water correction, as well as changes in mean diffusivity (MD) and tissue-volume fraction estimated by the ANN model. We identified a significant difference in free-water-corrected FA values in regions with later tumor recurrence and those of pure edema. Such differentiation, obtained directly from preoperative MR scans, has the potential to provide crucial information for personalized treatment decisions. Furthermore, analysis did not show any significant prognostic potential of MD changes and estimated tissue-volume fractions.The ANN we developed was trained to estimate fractions of water and tissue, respectively, in each voxel. Using this information, we generated tissue-volume maps that visualized the tissue fraction in each voxel. We analyzed these data to identify if there were significant differences in the amount of tissue in the area of peritumoral edema on preoperative MR images where later tumor recurrence occurred. However, there were no significant differences in the 10th, 50th or 90th percentile of tissue-volume-fraction values . Thus, wp90 = 0.04648400 when comparing pure edema with edema showing later recurrence, with lower MD values in areas of later recurrence. As we expected, there were no significant differences without applying free-water correction (p90 = 0.16753559).Next, we examined mean-diffusivity (MD) values after performing free-water elimination as described in Visual comparison of standard and free-water-corrected FA maps revealed a relevant recovery of FA information, especially in areas with large partial volume contamination, such as peritumoral edema and the borders of the ventricles, leading to a visual improvement of FA maps . This rep10 = 0.00112, p50 = 0.00314, and p90 = 0.00007, as well as in the mean values .In contrast, the original, noncorrected FA maps only showed differences in the 90th percentile, while the 10th and 50th percentiles were not significantly different between both areas  for radiotherapy is defined by a mostly uniform margin of 1.0–2.5 cm set around the area of residual T1 enhancement (if present) and the surgical bed to account for invisible tumor infiltration, following the guidelines of the European Society for Radiotherapy and Oncology (ESTRO) Advisory Committee on Radiation Oncology Practice (ESTRO-ACROP) . This vohttps://github.com/mmromero/dry).As demonstrated by Bette et al., we find lower FA values in areas of later tumor recurrence . ThroughAs opposed to previous studies, we unbiasedly analyzed the entire peritumoral edema using tumor segmentation and nonlinear image registration, whereas earlier works focused on individually drawn regions of interest (ROI) in the contralateral hemisphere. Coupled with algorithmic strategies for automated brain-tumor segmentation that we actively develop , this opIn contrast to FA values, MD values did not reveal additional information about the peritumoral edema and later recurrence after performing free-water correction. In general, MD values can perfectly describe isotropic diffusion but not the whole properties of anisotropic diffusion . In mostOur study has two important limitations. First, it was conducted in a single center. Though the ANN should be able to generalize to DTI data from different centers with comparable performance, this needs to be demonstrated in future multicenter studies. Second, this is retrospective analysis in spite of a prospective observational cohort. Although we included all patients with available data, we cannot exclude a selection bias towards patients with local recurrences.b = 800s/mm2) and one nondiffusion-weighted volume (Nb = 32), T2 turbo spin echo (T2w), T2-FLAIR, nonenhanced and contrast-enhanced T1 (CE-T1w). All patients underwent gross-total tumor resection following this initial MRI, and all cases were confirmed by histopathological study as IDH-wildtype glioblastoma according to the 2016 WHO classification of brain tumors [We investigated 35 glioblastoma cases from our prospective glioma cohort that was approved by the local ethics committee. All patients were scanned in a 3 T whole-body MRI scanner . The protocol consisted of DTI  with 32 directions , two hidden layers with Nb/2 and Nb/4, respectively, and a single output unit yielding the estimate of tissue-volume fraction. The model is freely available at https://github.com/mmromero/dry.Free-water correction of preoperative DTI data was performed using a model based on an artificial neural network (ANN), as previously described . In brieIn DTI, the diffusion tensor basically describes the 3D diffusion phenomenon of water molecules by using a matrix of numbers derived from measurements of at least six or more applied diffusion gradients. After analytical diagonalization of the diffusion tensor, a 3D shape is formed by calculating three eigenvectors that are perpendicular to each other. MD is simply the mean of these three eigenvalues, whereas FA represents a ratio of diffusion coefficients with lower values, describing nearly isotropic diffusion, and higher ones, characterizing extremely anisotropic diffusion restricted along two of the three eigenvector directions ,22.Here, robust estimation of tensors by outlier rejection (RESTORE) was employed for tensor estimation, and subsequent MD and FA calculation both from the uncorrected and free-water-corrected DTI data .To apply these methods for tumor-recurrence prediction, we assessed peritumoral edema for alterations in MD and FA values before and after free-water correction. In particular, we automatically extracted the 10th, 50th, and 90th percentile, as well as the mean of MD and FA values  from areas with and without later tumor recurrence in peritumoral edema. We employed Wilcoxon’s rank-sum test to compare MD and FA values from peritumoral edema with and without later tumor recurrence. In line with analysis by Bette et al. , we randCorrecting the free-water contamination of DTI using an artificial neural network has the potential to relevantly improve tumor delineation in the first preoperative MR scan, which may not only inform more accurate surgery planning, but also help to generate personalized radiotherapy plans that spare more healthy tissue while allowing for dose escalation in areas that are prone to tumor recurrence. This could possibly lead to prolonged progression-free and overall survival in glioblastoma patients, and highlights the potential of AI-driven image analysis.


Optimal balance control is of paramount importance for function recovery after total joint arthroplasty (TJA). The study objective of this meta-analysis was to assess the short- and mid-term effects of proprioceptive and balance training for patients undergoing TJA.Electronic searches were conducted from PubMed, Cochrane library, and Embase databases to identify eligible RCTs through May 2020. Standard mean difference (SMD) with 95% confidence interval (95%CI) was applied to calculate pooled effect estimates between proprioceptive and balance training and control group. Main outcomes were self-reported functionality, balance, pain, quality of life, and function (range of motion).Seven randomized controlled trials were finally included in this meta-analysis. Pooled results found that balance and proprioceptive trainings have a positive role in improving self-reported functionality at short-term after TJA. Moreover, balance and proprioceptive trainings were associated with an increase of the balance at short- and mid-term after TJA. These results were further confirmed by subgroup analysis between preoperative and postoperative administration of balance and proprioceptive trainings.Our meta-analysis suggests that balance and proprioceptive trainings after TJA improved self-reported functionality and balance. These improvements were maintained at mid-terms. More research is needed to confirm balance and proprioceptive trainings for pain and quality of life for TJA. Osteoarthritis (OA) is the most prevalent joint disease characterized by joint pain, tenderness, and stiffness that finally can lead to the loss of joint function –3. JointThe results of joint arthroplasty procedures are overall satisfactory . HoweverTo optimize joint arthroplasty, it is necessary to explore additional effective rehabilitation protocols. Proprioceptive training has been investigated as a mean to achieve complete rehabilitation. Studies examining proprioceptive training following joint arthroplasty have produced conflicting results. Jogi et al.  revealedTherefore, this review and meta-analysis systematically assessed the effect of proprioceptive training in patients undergoing total joint arthroplasty (TJA), in terms of post-operative self-reported functionality, balance, pain, quality of life, and postoperative function (range of motion).This meta-analysis was carried out in accordance with the recommendations of the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .Three electronic databases  were used for article retrieval. Two reviewers independently searched these databases from inception to May 20, 2020. The search criteria “proprioceptive training”, “balance exercise”, “education”, “training”, “total knee arthroplasty/replacement”, “TKA”, “TKR”, “total hip arthroplasty/replacement”, “THA”, and “THR” were used in keywords for search. No restrictions were applied for the country, year of publication, publication status, type of study, or language. And the reference lists were also manually reviewed to find relevant studies that were not found during the database searches.Inclusion criteria were based on the PICOS strategy: (P) adult patients with knee or hip joint degenerative disease and received TKA or THA; (I) intervention group was proprioceptive training; (C) comparison group was standard procedure or no intervention; (O) outcomes including self-reported functionality (SRF), quality of life (QoL), Biodex Balance System (BBS), pain (P), balance (B), and knee function (KF); (S) randomized controlled trials (RCTs).Exclusion criteria for this meta-analysis were as follows: (1) studies without available data; (2) abstract of full text was not available; (3) non-RCTs; (4) review manuscripts; (5) non-relevant studies.General information of the included studies was extracted by using a standardized data extraction form and recorded into Excel . Study data extracted included first author, publication year, participants , number of patients, mean age of patients, female patients (%), study type, intervention, comparison, and outcomes. If differences in opinion existed, the diagnosis was decided by their discussion and to reach total agreement.Two reviewers (Wen-chao Zhang and Deng Xiao) independently complete the process of quality assessment. The following aspects will be assessed: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. Each aspect was classified as “low,” “high,” or “unclear” according to Cochrane Collaboration Handbook recommendations.Finally, quality of evidence was generated according to GRADE  methodology and performed by utilizing the GRADE Pro GDT software. A total of four categories were used: high, moderate, low, or very low.P < 0.05 was considered statistically significant. The I2 value was used to assess the degree of heterogeneity . Publication bias was assessed by visual inspection of the funnel plot, and we accepted that a symmetrical funnel plot was likely to indicate low publication bias. A subgroup analysis was performed by duration of follow-up: early period (6–12 weeks), mid-term (6–12 months), and long-term (> 12 months). Another subgroup analysis was conducted by the timing of the intervention: preoperative intervention and postoperative intervention.The statistical analysis was performed using the Stata 12.0 software . Pooled data were assessed by standard mean difference (SMD) with 95% confidence intervals (CIs), and The initial literature search retrieved 535 relevant articles. After duplicates were discarded, 415 studies were screened. After reviewing the abstracts, 408 articles were excluded because they did not meet inclusion and exclusion criteria; therefore, leaving 7 studies that matched the selection criteria and were suitable for meta-analysis  showed that there was statistically significance between balance and proprioceptive trainings and controls, but no significant difference in preoperative intervention .Results of the subgroup analysis are presented in Table The GRADE working group grade level of evidence is low for ROM and QoL and moderate for pain, self-reported functionality, and balance Table . PublicaThis meta-analysis appraised the effects of balance and proprioceptive trainings in patients undergoing TJA. Based on the pooled effects, balance and proprioceptive trainings enhanced the early postoperative functional outcomes after TJA. What’s more, follow-up evaluations confirmed that the promotion effects of balance and proprioceptive trainings for balance were maintained at mid-term. In subgroup analysis, postoperative balance and proprioceptive trainings were associated with better functional outcomes in TJA patients.A major strength of this meta-analysis is that we assessed the most important clinical outcome, self-reported functionality, and balance at early period and mid-term follow-up. Another strength of this meta-analysis was the good stability of the results, which is reflected in subgroup analysis.Previous study has reported that proprioceptive inaccuracy is the main cause of functional deterioration. According to the theory mentioned above, well-targeted post-operative proprioceptive intervention can further enhance the patients’ functional performance and quality of life. An observational study has pointed out that game-based balance exercises could improve motor performance and postural control in long-term follow-up . KakavasAnother important finding from our analysis is that balance and proprioceptive trainings showed no benefit for pain, range of motion, and quality of life at early period and mid-term follow-up. Appropriately 30% of patients experience moderate to severe pain at 1 year after surgery . SeveralConsistent with pain outcome, balance and proprioceptive trainings also have no effects on the quality of life after TJA compared with standard procedures. TJA itself could significantly improve the quality of life in TJA patients. There was no further improvement in balance and proprioceptive trainings than that of standard procedures. Due to the low number of these studies, more studies are needed to confirm and elucidate this finding. These results were clinically important as balance and proprioceptive trainings only have benefit for improving balance and self-reported functionality. These improvement effects were maintained at mid-term follow-up. Moreover, postoperative balance and proprioceptive trainings was superior than preoperative balance and proprioceptive trainings in terms of the balance and self-reported functionality. One important consideration was that TJA surgeries have vital influence on the proprioception. Thus, postoperative balance and proprioceptive trainings could improve the balance and functionality at some extent. Lee et al.  includedTo prevent selection bias within this meta-analysis, only RCTs were included for final analysis. However, some potential limitations in this study were inevitable. Firstly, the duration, timing, and type of the balance and proprioceptive trainings differed across studies. This may affect the final results; in addition, some important data  were lacking, hampering analysis. Secondly, small sample size of the included studies may render the results underpowered. Thirdly, the heterogeneous outcomes were also a limitation. Subgroup analysis was performed to assess the robustness of results; however, not all planned subgroup analyses could be performed, due to insufficient data reporting. Thus, the heterogeneity could not always be explained. Fourth, the data for pain and other adverse effects was limited, and these results need for more studies to validate. Lastly, the clinical relevance of self-reported functionality and balance remain challenging due the short-term follow-up duration.Our meta-analysis suggests that balance and proprioceptive trainings after TJA improved self-reported functionality and balance. These improvements were maintained at mid-terms and postoperative balance and proprioceptive trainings. However, balance and proprioceptive trainings have no effects on pain relieving, functional recovery, and quality of life after TJA. Considering these effects of balance and proprioceptive trainings, more studies are needed to identify the balance and proprioceptive trainings for pain control and functional outcomes.


Curvature is a fundamental morphological descriptor of cellular membranes. Cryo-electron tomography (cryo-ET) is particularly well-suited to visualize and analyze membrane morphology in a close-to-native state and molecular resolution. However, current curvature estimation methods cannot be applied directly to membrane segmentations in cryo-ET, as these methods cannot cope with some of the artifacts introduced during image acquisition and membrane segmentation, such as quantization noise and open borders. Here, we developed and implemented a Python package for membrane curvature estimation from tomogram segmentations, which we named PyCurv. From a membrane segmentation, a signed surface (triangle mesh) is first extracted. The triangle mesh is then represented by a graph, which facilitates finding neighboring triangles and the calculation of geodesic distances necessary for local curvature estimation. PyCurv estimates curvature based on tensor voting. Beside curvatures, this algorithm also provides robust estimations of surface normals and principal directions. We tested PyCurv and three well-established methods on benchmark surfaces and biological data. This revealed the superior performance of PyCurv not only for cryo-ET, but also for data generated by other techniques such as light microscopy and magnetic resonance imaging. Altogether, PyCurv is a versatile open-source software to reliably estimate curvature of membranes and other surfaces in a wide variety of applications. Membrane curvature plays a central role in many cellular processes like cell division, organelle shaping and membrane contact sites. While cryo-electron tomography (cryo-ET) allows the visualization of cellular membranes in 3D at molecular resolution and close-to-native conditions, there is a lack of computational methods to quantify membrane curvature from cryo-ET data. Therefore, we developed a computational procedure for membrane curvature estimation from tomogram segmentations and implemented it in a software package called PyCurv. PyCurv converts a membrane segmentation, i.e. a set of voxels, into a surface, i.e. a mesh of triangles. PyCurv uses the local geometrical information to reliably estimate the local surface orientation, the principal (maximum and minimum) curvatures and their directions. PyCurv outperforms well-established curvature estimation methods, and it can also be applied to data generated by other imaging techniques. PLOS Computational Biology Methods paper.This is a Membranes define the limits of the cells and encompass compartments within eukaryotic cells, helping to maintain specific micro-environments with different shapes and functions. Membrane curvature is important for many cellular processes, including organelle shaping, vesicle formation, scission and fusion, protein sorting and enzyme activation , 2. TherCryo-electron tomography (cryo-ET) enables an accurate three-dimensional (3D) visualization and analysis of the subcellular architecture at molecular resolution –6 and ismissing wedge n→vi of ii casts a vote to the central vertex v, where the votes are collected into a 3x3 symmetric matrix Bv 40]) agairh-1 should be excluded from the analysis.Curvature is a local property, so its value on discrete surfaces depends on the definition of a neighborhood. Robustness to noise increases with the neighborhood size by averaging the contributions of the neighboring triangles. However, features smaller than the neighborhood are averaged out. Therefore, the neighborhood size defines the scale of the features that can be analyzed. To achieve more reliable results for cryo-ET segmentations that contain holes, curvature values at surface borders and/or higher than PyCurv was already applied in a cryo-ET study in yeast proposing that cER membrane curvature plays a key role in the regulation of ER-to-PM lipid homeostasis at membrane contact sites . MoreoveS1 Videomembrane and compartment segmentations of the cortical ER, generated surface, normals estimated by Vector Voting (VV) and curvedness estimated by Augmented Vector Voting (AVV) algorithms.The visualization of PyCurv processing workflow, as described in (MP4)Click here for additional data file.


Cisplatin and its analogues are widely used as chemotherapeutic agents in clinical practice. After being intravenously administrated, a substantial amount of platinum will bind with proteins in the blood. This binding is vital for the transport, distribution, and metabolism of drugs; however, toxicity can also occur from the irreversible binding between biologically active proteins and platinum drugs. Therefore, it is very important to study the protein-binding behavior of platinum drugs in blood. This review summarizes mass spectrometry-based strategies to identify and quantitate the proteins binding with platinum anticancer drugs in blood, such as offline high-performance liquid chromatography/inductively coupled plasma mass spectrometry (HPLC–ICP-MS) combined with electrospray ionization mass spectrometry (ESI-MS/MS) and multidimensional LC–ESI-MS/MS. The identification of in vivo targets in blood cannot be accomplished without first studying the protein-binding behavior of platinum drugs in vitro; therefore, relevant studies are also summarized. This knowledge will further our understanding of the pharmacokinetics and toxicity of platinum anticancer drugs, and it will be beneficial for the rational design of metal-based anticancer drugs. Cisplatin , which wThe pharmacokinetics of platinum anticancer drugs have been extensively studied. The differences among them were attributed to the different leaving groups. The formulation and protein-binding behavior of platinum drugs in plasma have a great impact on their pharmacokinetics, for example renal excretion rate ,17,18. G2) for the area under the plasma concentration-time curve (AUC), and the AUC of carboplatin is closely correlated with its clinical parameters, including toxicity and response [After intravenous infusion, cisplatin rapidly diffuses into tissues, and more than 90% binds to plasma protein . More spresponse ,19,25,26response . Oxaliplatin, another commonly used antitumor drug, binds to protein at a high ratio; moreover, it can bind to erythrocytes . The maxAlthough early studies on cisplatin’s mechanism of action suggested that DNA binding is the main reason for its antitumor activity ,30, onlyDeveloped in the 1980s, ICP-MS is a method for the analysis of inorganic elements and isotopes. It combines the high-temperature ionization characteristics of inductively coupled plasma with the sensitivity and fast scanning of mass spectrometers through a unique interface. Due to its low detection limit and excellent separation power when combined with separation techniques such as liquid chromatography (LC) and capillary electrophoresis (CE), ICP-MS has become the preferred choice in metallomic analysis ,53. AlthSize-exclusion chromatography (SEC) is usually used in LC–ICP-MS systems to separate intact proteins on the basis of their molecular weight. For example, it can be used to characterize the protein-binding properties of platinum-based and ruthenium-based drugs ,55,56. RLaser ablation (LA)–ICP-MS is an imaging method for inorganic elements . It reliESI-MS is widely used in proteomics studies. Complete molecular information can be obtained from complex biological samples using this method. ESI-MS can be used to determine the stoichiometric ratio of metal drugs to biomolecules, identify the binding site of metals on biomolecules through fragments, and perform large-scale proteomics analysis. Small molecules, DNA bases, and the amino acid side chains of intact proteins can all function as metal ligands. For small biomolecules, such as peptides, metal adducts can be detected on the basis of unique isotope patterns ,64. HoweEscherichia coli after trypsin digestion [Multidimensional protein identification technology (MudPIT) is based on the combination of two-dimensional liquid chromatography (reverse-phase or strong cation exchange) and ESI tandem mass spectrometry. It is suitable for comprehensive metabolomics and proteomics analyses of biological samples in a single experiment. It has been successfully used to determine the protein-binding sites of cisplatin in human serum and of the ruthenium(II) complex in igestion ,65.Because clinically used platinum anticancer drugs are administered intravenously, their interactions with proteins in blood should be fully considered because they influence their transport, distribution, and toxicity. Some high-abundance serum proteins are responsible for the transport of small molecules, for example, human serum albumin can transport fatty acids, amino acids, and metal ions in body fluids. Various studies on the interactions of antitumor platinum complexes with plasma proteins have been performed using spectroscopic techniques, including circular dichroism (CD), fluorescence, and NMR spectroscopy ,67,68, wWith the emergence of mass spectrometric and separation techniques, such as electrospray ionization mass spectrometry, inductively coupled plasma mass spectrometry, and chromatography, more detailed information about the protein-binding behavior of platinum drugs in serum can be obtained ,72. ExteIn order to identify the protein-binding behavior of platinum drugs, it is necessary to evaluate the stability of platinum–protein adducts during sample preparation ,78. MedeThereafter, Will et al. characterized the cisplatin-binding sites in human serum proteins by combining multidimensional liquid chromatography with ESI tandem mass spectrometry . FirstlyTo identify low-abundance binding proteins in serum, Moraleja et al. developed a shotgun method that includes peptide-based non-gel isoelectric focusing (IEF) separation . Cisplat194Pt–HSA spike, which could be very useful for clinic analysis.The quantification of Pt–protein adducts is necessary for assessing the dose-dependent response to treatment of individual patients. After identification of the major binding proteins in blood, quantitative analysis of the binding becomes possible. For example, a novel method was developed by Janez et al. for speciation of Pt in human serum . The sepPharmacokinetic studies of platinum drugs are mainly based on the determination of total platinum content in blood and urine. The methods most commonly used for platinum content determination are atomic absorption spectroscopy and the more sensitive ICP-MS method, which can be easily coupled with liquid chromatography. Combined with gel chromatography and reverse-phase chromatography, ICP-MS can be used to directly analyze the protein bound to Pt in plasma and detect the possible metabolites of platinum drugs. For example, Allain et al. monitored the binding of oxaliplatin to plasma proteins and the penetration of red blood cells (RBCs) using LC coupled with ICP-MS . The bio−1·min−1, whereas that for γ-globulin was 1.01 M−1·min−1. These studies can help us to understand how carboplatin interacts with plasma proteins in human blood.Carboplatin is a second-generation platinum antitumor drug, commonly used to treat malignant tumors. In order to study the interactions between carboplatin and plasma proteins, Xie et al. developed an SEC–ICP-MS method to analyze the plasma of patients receiving chemotherapy, with the aim of monitoring and identifying the complexes formed between plasma proteins and carboplatin . The resOxaliplatin is widely used in the treatment of cancer; however, its toxicity limits its clinical application. Peng et al. used nano-electrospray tandem mass spectrometry to characterize the intact hemoglobin tetramer and its interaction with oxaliplatin . The fra195Pt signals shown above. This method was also used to detect protein targets in cisplatin-incubated renal tubular epithelial cells. To identify the binding proteins of cisplatin in the serum of living animals, Gordaliza et al. developed a new method. Generally, the proteins were separated via gel electrophoresis, and the platinum-containing proteins were detected using LA–ICP-MS, followed by subsequent proteomic analysis of the band using nLC–ESI-linear ion trap quadrupole (LTQ)-Fourier transform (FT)-MS/MS . Two-dimIn another study, Kato et al. used ICP-MS to study the protein-binding properties of albumin with cisplatin, carboplatin, and oxaliplatin and measure their real-time concentration in rat plasma . For in 2+, {(NH3)Pt}2+, {(NH3)2Pt}2+ and {(NH3)2PtCl}+ with additional mass of 193, 210, 227 and 263 respectively are set as variable modification of peptide for cisplatin. Considering the complexity of blood proteome, false-positive results will occur, especially those peptides with the same mass but different elemental compositions as that of platinated peptide. Thus, the proteomic search engine cannot effectively exclude false positive results. Consequently, manually checking the isotope pattern of modified peptides is the only way to exclude false-positive results; typical isotope patterns of a platinated peptide and free peptide are shown in The protein binding with platinum anticancer drugs is usually identified by finding the peptides that are platinated. As mentioned in 2 tool developed by Dyson et al. [2 and SNAP can only be used to match and assign the binding sites of drugs on known peptides or proteins. SNAP–LC has been used to identify the binding sites of platinum, iridium, and osmium complexes on a model protein after nanoLC–MS/MS analysis [2 tool has been utilized to locate the modification sites of cisplatin on ubiquitin using top-down CID–MS/MS [Recently, bioinorganic chemists have made some attempts to develop data processing software. A typical example is the Apmn et al. ,86. It in et al. . This alanalysis ,88,89. TID–MS/MS . 2 and SNAP. According to the similarity between experimental isotopes and theoretical isotopes, false-positive results can be excluded. This combination speeds up the data process for identifying proteins binding with platinum drugs in blood.To efficiently identify proteins modified by metal drugs in complex matrixes, the combination of an open search engine with an isotopic matching tool is necessary. Identifying the potentially modified protein is the first step, after which an automatic verification step should be conducted with the help of software such as ApmPlatinum-based anticancer compounds are widely used for the treatment of cancer. The interactions of platinum-based drugs with proteins in the blood are vital for their uptake, distribution, metabolism, bioavailability, and toxicity. The LC–ICP-MS method was initially commonly used for the identification and quantification of binding proteins for platinum drugs in blood via comparison with standard proteins; however, the combination of multidimensional LC with ESI-MS/MS is being increasingly used. Since predominantly high-abundance proteins are identified, several attempts have been made to identify low-abundance protein targets, with no satisfactory results being achieved so far due to the restrictions of analytical methods and data processing software. Nevertheless, with the development of separation techniques and bioinformatics tools, the comprehensive characterization of binding targets for metal drugs in blood will become possible in the future. Mass-spectrometry-based analytical methods have superior selectivity and sensitivity; when combined with multidimensional separation methods and efficient software, they can play an even greater role in identifying the protein targets of metal-based drugs both in vitro and in vivo, which will be helpful to understand the pharmacokinetics and toxicity of metal-based drugs and optimize their structures.


Objective: The aim of this retrospective study was to investigate the relationship between serum systemic autoantibodies and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.Methods: Thirty-nine patients with anti-NMDAR encephalitis were examined for serum systemic autoantibodies , in comparison with 39 neuromyelitis optica spectrum disorder (NMOSD) and 78 healthy controls. Clinical features, cerebrospinal fluid characteristics, and outcomes were compared between the two subgroups of anti-NMDAR patients with positive and negative systemic autoantibodies, respectively.Results: Anti-NMDAR encephalitis patients had higher frequency of positive serum systemic autoantibodies than healthy controls  and lower frequency than NMOSD . No patients were diagnosed comorbidities with non-organ-specific autoimmune diseases. Consciousness disturbance was more frequent in autoantibodies positive group than in the negative group . Autoantibody positive group had a poorer outcome than autoantibody negative group . There was a negative correlation between serum autoantibodies and outcomes in anti-NMDAR encephalitis patients .Conclusion: Our data demonstrated serum systemic autoantibodies were more frequent in anti-NMDAR encephalitis patients than in healthy controls and less frequent than NMOSD, which were associated with higher severity of disease. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis (AE) related to antibody-mediated synaptic dysfunction, which is characterized by the subacute development of psychosis, epileptic seizures, memory deficit, autonomic instability, and a decrease in the level of consciousness . The disPrevious reports have demonstrated the intertwining relationships between systemic immune abnormalities and immune-mediated neurological disorders, such as neuromyelitis optica spectrum disorder (NMOSD), and multiple sclerosis , 6. ReceTherefore, this study aims to analyze serum systemic autoantibodies in patients with anti-NMDAR encephalitis, and determine the association with clinical characteristics in the patients.This retrospective study enrolled 39 patients with anti-NMDAR encephalitis who were admitted to the Third Affiliated Hospital of Sun Yat-sen University from February 2016 to December 2017. Anti-NMDAR encephalitis was defined according to diagnostic criteria . A commeGender, age, clinical manifestations, time from onset to hospitalization, length of hospital stay, and length of follow-up were recorded. Examinations including brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) were reviewed. The patients received first-line immunotherapy [steroids and intravenous immunoglobulin (IVIg) with or without plasma exchange], second-line immunotherapy (rituximab with or without cyclophosphamide). The patients' neurological function and outcome were evaluated using the modified Rankin Scale (mRS) at admission and at discharge.Systemic autoantibodies  tests were measured on Tenfly Phoenix Auto Blot Analyzer  at the clinical rheumatology immunology laboratory of the Third Affiliated Hospital of Sun Yat-sen University . The samt-test. Qualitative data were analyzed with the χ2 test or Fisher's exact test. The relationship of two variables was analyzed using Spearman's rank test. Values of p < 0.05 were considered statistically significant. Statistical analysis was performed by SPSS version 22.0 .All quantitative data in this study are presented as mean ± standard deviation (SD) or median (range). Quantitative data were processed using the Mann-Whitney U-test or Student's p = 0.001), which less frequent in anti-NMDAR encephalitis patients than in NMOSD .Baseline characteristics were presented in As shown in p > 0.05). However, consciousness disturbance was more frequent in autoantibodies positive group than in the negative group . No difference was found in MRI findings (p > 0.05). Autoantibody positive group had a poorer outcome than autoantibody negative group  .As shown in findings , CSF abn= 0.043) . The relIn the present study, we found that anti-NMDAR encephalitis patients had higher frequency of positive serum systemic autoantibodies than healthy controls and lower frequency than NMOSD. We also found ANA was the most common serum autoantibodies in anti-NMDAR encephalitis. However, no patients were diagnosed comorbidities with non-organ-specific autoimmune diseases. Furthermore, good outcomes in anti-NMDAR encephalitis patients were significantly negatively associated with the serum autoantibodies. To the best of our knowledge, this is the first study to analyze serum systemic autoantibodies in patients with anti-NMDAR encephalitis.Autoantibodies are the result of a failure of the immune system to discriminate between “self” and “non-self,” which target a person's own antigen . AutoantThis study also compared the characteristics of anti-NMDAR encephalitis patients according to serum systemic autoantibodies status. In our study, more than one half of anti-NMDAR encephalitis patients had consciousness disturbance. And a study conducted by Lin et al. showed that consciousness disturbance is typically severe syndrome , which iAnti-NMDAR encephalitis is a treatable and even curable disease. In our present study, nearly 80% had good outcome (mRS < 2) at discharge, which is consistent with previous researches , 30. TheWe are aware that this study has some limitations. First, the sample size was relatively small. Second, we only detected systemic autoantibodies in the serum, not in the CSF, which result could strengthen our findings. Third, as a retrospective study, bias is inevitable.In conclusion, our data demonstrated serum systemic autoantibodies were more frequent in anti-NMDAR encephalitis patients than in healthy controls and less frequent than NMOSD, which were associated with higher severity of disease.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University. The need for obtaining written informed consent from patients or their family members was waived by the same committee.BZ, YY, YL, and ZL designed the research. LA performed the experiments and analyzed the data. XM wrote the main manuscript text and prepared the figures. BZ edited and revised the manuscript. All authors reviewed and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.