Sleep deprivation disrupts visual attention; however, the effects of chronic poor sleep quality on it are not understood. The dorsal attention network (DAN) and the ventral attention network (VAN) are involved in visual attention and search (VSA), with the DAN being important for the serial attention network and the VAN for parallel “pop-out” visual search.The aim of the study was to evaluate correlation of sleep quality with visual attention and search, functional, and tracts’ properties of the DAN and VAN.We recruited 79 young male subjects and assessed their sleep quality using the Pittsburgh Sleep Quality Index (PSQI), dividing subjects into poor sleepers (PSs) and good sleepers (GSs) based on a cutoff of 5. Daytime sleepiness, sleep hygiene, depression, and anxiety levels were also evaluated. We assessed VSA using a computerized match-to-sample (MTS) task. We extracted functional networks and tracts of the VAN and DAN and statistically assessed group differences in task performance and imaging covarying age, depression, and anxiety. An interaction model with MTS × group was also done on imaging.p < 0.001). No between-group differences were seen in task performance and functional or tract properties of the attention networks. Interaction analysis showed that the task performance was highly reliant on the DAN in PSs and on the VAN in GSs.In total, 43.67% of subjects were PSs. Sleep quality significantly correlated with daytime sleepiness, sleep hygiene, depression, and anxiety (all Our findings show no association between sleep quality and VSA in task performance and imaging correlates of the attention network. However, unlike the GS group, poor sleep quality is associated with VSA being more reliant on the DAN than on the VAN. Proper sleep is required to maintain optimal cognitive function. Lack of nighttime sleep, even for one night, has detrimental effects on several cognitive functions, especially sustained attention and vigilance, but other cognitive aspects are also involved, including executive function and sensory perception  . EvaluatVisual search is a complex behavior requiring working memory, scenery-related information processing , and attention. Two models are proposed for visual search. In the “serial” search (inefficient), the subject screens each object independently, matching it with the sample presented or asked. However, it seems that, in real-life situations, we usually implement the “parallel” strategy ; despite being overtly attended to one location in space, the attention is covertly scanning the periphery and nearby, searching for the target stimuli, and changing the overt attention toward the target upon finding it . In a prIn this study, we first aimed to examine the effects of chronic poor sleep quality on a complex attention task, visual search and attention, controlling for major confounds such as depression and anxiety. Next, we examined the effects of chronic poor sleep quality on neuroimaging correlates of visual attention using fMRI to identify the DAN and the VAN and using DWI to delineate fibers connecting these two networks . Finally, using an interaction model, we attempted to identify the association between sleep quality × brain findings and task outcomes.In total, 79 subjects were recruited via local flyers and online advertisements using Twitter and Telegram channels in the city of Tehran, Iran [mean age (SD) = 24.10 (4.16)]. The inclusion criteria for this study were being men, being 20–40 years of age, having no current or previously untreated psychiatric or neurologic disorders, with no prior history of head trauma leading to loss of consciousness, with no history of claustrophobia, and with no current signs or symptoms of or admission history due to COVID-19. This study was approved by the Ethics Review Board of Iran University of Medical Sciences, Tehran, Iran, with the ID IR.IUMS.REC.1400.026.Subject demographics including age, handedness, education, marital status, smoking behavior, and any drugs taken or discontinued were acquired. To assess sleep, we used the Persian-translated and validated versions of the Pittsburgh Sleep Quality Index (PSQI) , EpworthDepression and anxiety are major contributors and are also affected by sleep quality. We used Beck Depression Inventory II (BDI-II)  to evaluWe used the match-to-sample (MTS) task of the Cambridge Neuropsychological Test Automated Battery (CANTAB) for visual search and attention . In thisWe chose this task for several reasons: First, it can be easily performed irrespective of subjects’ education or prior experience. Second, it can assess two complex functions, namely, visual search and visual attention, at the same time. Third, in many tasks, the subjects’ hand movement time cannot be separated from the reaction time; however, in the MTS of CANTAB, the subjects had to hold the mouse button until they have found a match, release it, and touch the target on a touch screen. Thus, the interval between stimulus presentation and mouse click release is considered the reaction time. Of note, it is different from the delayed match-to-sample task, in which working memory load becomes increasingly important. Since previous studies have shown the association between working memory dysfunction and poor sleep quality , we chos3 × 0.8 mm3 × 0.8 mm3), T2 SPACE , resting-state fMRI , diffusion MRI , and 3 b0s with opposite phase-encoding direction from the main DWI sequence (phase-encoding direction: PA). To minimize the possibility of subjects falling asleep under the scanner, which can affect our functional data, we acquired the resting-state fMRI sequence with subjects with open eyes and the third protocol  with a duration of 6:08 mins.All imaging acquisitions were carried out in a single session using a 3T Siemens Prisma MRI scanner located at the National Brain Mapping Laboratory (NBML), Tehran University, Tehran, Iran. The imaging protocols were as follows: T1 MPRAGE  were fed into the i et al. , to impri et al. . The defi et al. , and thei et al. . The powi et al. . We extr1 (RRID:SCR_009550)  Gaussian kernel. The results of preprocessing were inspected individually to have structural and functional data aligned and normalized. We applied fMRI denoising using the CompCor method   using rer method  and regr2 , especially on the right side. So, we considered the spatial regions of this component to include both attention networks, DAN and VAN   tool in CONN. We estimated the median number of components of all subjects’ rest fMRI data to be 16 using GIFT toolbox v 3.0c2 . Group-lortices) .p-value threshold < 0.001 and a cluster-wise FDR-corrected p < 0.05 were considered significant.To evaluate between-group differences, we used a general linear model (GLM) with age, depression, and anxiety scores (both state and trait) as covariates in the identified spatial component of the VAN and DAN. Moreover, group × MTS score interaction analysis was also performed with the same covariates in the same networks to find group-related differences in behavior and baseline function correlates. Results with a voxel U test based on the distribution of data. We assessed the correlation between the PSQI total score and components with ESS, SHI, BDI, STAI-T, and STAI-S using Pearson’s or Spearman’s formula based on data distribution. We also used the GLM to assess any association between PSQI components and MTS scores, irrespective of the group, and adjusting for age and scores of depression and anxiety.We used R version 4.0.4 embedded within RStudio . BetweenDifferences in fiber properties of SLFs and AF between PSs and GSs were evaluated using the same GLM, with age, BDI, and STAI scores as covariates. We also applied an interaction model with MTS measures as the outcome and group × fiber properties as the predicting variable covarying age, BDI, and STAI scores.The mean (SD) of the education years of the subjects was 12.20 (0.34). Of the 79 subjects, total PSQI scores could be calculated for 71 subjects; 31 subjects had a PSQI total score > 5, indicating a poor sleep quality prevalence of 43.67% in our sample. Although there is no consensus regarding the BDI-II cutoff for depression, using the suggested cutoff of 13   indicaten = 39) were randomly matched by MatchIt . While using a GLM with age, BDI, and STAI parameters as covariates, there were no significant associations between MTS task parameters  and PSQI scores  . Group dWithout any prior history of claustrophobia or any fears of the dark or closed spaces, 4 subjects, all in the PS group, developed claustrophobia either at the beginning or even prior to the start of the T1 acquisition . Overall, 35 subjects completed the MRI session.https://identifiers.org/neurovault.collection:11254).After adjusting for age, depression, and anxiety scores, no differences were found between PS and GS in fiber properties of bilateral SLFs and right AF . Moreovehttps://identifiers.org/neurovault.collection:11254).Overall, 30 subjects (13 PSs and 17 GSs) could successfully complete both MRI and MTS tasks. We found significant group × MTS measure interactions for MTS total correct and right SLF3 AD, MTS mean correct RT with left SLF1 AD, right SLF2 FA, right AF FA, MTS mean RT change with right AF FA, and right SLF2 FA . MoreoveIn this study, we investigated the associations between sleep quality and visual search and attention, using a computerized task (CANTAB match-to-sample), as well as structural and functional correlates of visual attention in two attention networks . In our sample, 43.67% of subjects reported poor sleep quality during the last month based on the PSQI. Poor sleep quality was also correlated with poor sleep hygiene and more daytime sleepiness. It was also highly associated with depression and anxiety. Despite our expectations, we found no associations between sleep quality (based on the PSQI) and visual search and attention, neither in the task nor in the imaging correlates of visual attention covarying for age, depression, and anxiety scores. However, by implementing an interaction model, we found that visual search and attention are highly associated with the DAN  in the PS group and with the VAN in the GS group.vice versa  in the poor sleeper and the VAN (SLF2 and SLF3 and TPJ) in the good sleeper group. It is a multi-modal finding, found using both fMRI and DWI analysis. Despite not explicitly and overtly implementing a serial visual search task, we believe that this finding probably reflects a higher load on the DAN in PSs and not using the VAN by this group for visual search. Also, since it seems that the serial and parallel search strategies are more reliant on the DAN and VAN, respectively , this fi2 and a total diffusion direction of 64, as well as the recent TRACULA method, for our analysis can somehow address the cross-fiber issue.Although our study investigates the association between sleep quality and visual search and attention in a task, as well as functional and structural connections of the attention network, it is faced with limitations. The major limitation is the sample size of 39 subjects. Nonetheless, we limited our sample to only include right-handed male subjects to decrease the between-subject variability in the brain and behavior. However, future studies must use a larger sample size including both major genders. For example, we are aware that the ENIGMA-Sleep study is a multi-center study currently conducted to overcome the limitations of small-sample studies . MoreoveIn conclusion, to our knowledge, this study is the first to investigate visual attention and search in chronic poor sleep. Significant associations of sleep quality were found neither in a visual search and attention task nor in dorsal and ventral attention networks and fibers connecting them. However, we found that task performance is highly reliant on the DAN in the PS group and on the VAN in the GS group, probably reflecting higher cognitive demand in the DAN or implementing different search strategies  in subjects with poor sleep. Future studies with larger sample sizes using separate serial and parallel visual search task designs are suggested.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Review Board of the Iran University of Medical Sciences, Tehran, Iran. The patients/participants provided their written informed consent to participate in this study.AA contributed to the design of the study, data collection, imaging analysis, statistical analysis, and wrote the manuscript. SN contributed to idea formation, designing the study, data collection, and wrote the manuscript. Both authors contributed to the article 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Inflammation plays a pivotal in the occurrence and development of coronary heart disease (CHD). We aim to investigate the association between the Dietary Inflammatory Index (DII) and CHD in the present study. In this cross-sectional study, adult participants from the National Health and Nutrition Examination Survey (NHANES) (1999–2018) were enrolled. The social demographic information, lifestyle factors, blood biochemical measurements, dietary information, and CHD status of all the participants were systematically collected. Multivariable logistic regression was adopted to investigate the association between the risk of CHD and the DII. Besides, restricted cubic spline (RCS) analysis was used to explore whether there was a nonlinear association of the DII and CHD. Subgroup analysis stratified by sex, age, race/ethnicity, and BMI was conducted to evaluate the association of the DII and CHD among different populations. A total of 45,306 adults from NHANES (1999–2018) were included. Compared with individuals without CHD, the DIIs of the participants with CHD were significantly elevated. A positive association was observed between the DII and CHD in multivariable logistic analysis after adjusting for age, sex, race/ethnicity, education levels, smoking, drinking, diabetes, hypertension, and body mass index (BMI). Results of RCS analysis suggested a nonlinear relationship between the DII and CHD. In addition, the increment of the DII had a greater impact on female individuals compared with male individuals. The DII is closely associated with the risk of CHD. For better prevention and treatment of CHD, more attention should be paid to controlling dietary inflammation. Coronary heart disease (CHD) is a chronic complex disease with high morbidity and mortality, mainly caused by atherosclerotic lesions in coronary vessels, eventually leading to myocardial infarction (MI) and stroke . CoronarCHD is closely associated with unhealthy eating habits, which can be achieved through the influence of chronic inflammation. Inflammation is of great importance for the occurrence and development of CHD. Numerous researchers have investigated the association between eating habits and CHD risk. High-fat diet is one of the key factors that induce inflammation. Besides, obesity caused by a high-fat diet is often accompanied by a series of chronic inflammatory diseases, such as type 2 diabetes and hypertension, eventually leading to CHD ,9. ConsuConsidering inflammation as a fundamental component of atherosclerosis, measuring inflammation levels is likely to be useful for predicting and protecting CHD. The Dietary Inflammatory Index (DII) was first proposed by Shivappa et al. in 2014 based on the summary of published literatures . The DIINevertheless, to our knowledge, relatively few researchers have investigated the association between the DII and CHD. Therefore, we conducted this cross-sectional study to explore the association between the DII and the prevalence of CHD in a large multiracial cohort in the US, which may be helpful for the prevention and treatment of CHD. http://www.cdc.gov/nchs/nhanes.htm (accessed on 1 August 2022)). All participants enrolled in NHANES provided written informed consent, and the whole procedures were approved by the Institutional Review Board of the Centers for Disease Control and Prevention. An analysis of 10 consecutive NHANES circles from 1999/2000 to 2017/2018 was conducted in the present study. The exclusion criteria were as follows: (1) participants’ age < 18 or ≥ 80 years, (2) participants with missing CHD status, (3) participants with no DII, or missing dietary information  is a program designed to measure the health and nutrition status of adults and children in the US. A mass of data in the NHANES database has been analyzed extensively, which is of great help in unraveling the etiologies, understanding the epidemiology, and searching for novel biomarkers of different diseases ,15,16. Tormation .The Nutrition Methodology Working Group of the survey collected all of the dietary information in the mobile examination center (MCE) through 24 h dietary recall interviews. We calculated the DII based on 28 dietary components and following the protocol reported by Shivappa et al. . There wSimilar to previous published articles based on NHANES, CHD was mainly adjudicated by the history of CHD . In the Age, race/ethnicity, and education levels were obtained from the demographic questionnaires. Diabetes history, alcohol consumption, and smoking status were also adopted from the health questionnaires. Race/ethnicity was classified as non-Hispanic white, non-Hispanic black, Mexican American, other Hispanic, and others. Education was categorized into three levels: below high school, high school, and above high school. After at least 8 h of an overnight fast, blood samples were collected and used to examine the levels of TG, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), red blood cells (RBC), white blood cells (WBC), platelet (PLT), neutrophil (NE), lymphocyte (LY), hemoglobin, glycosylated hemoglobin (HbA1c), and fasting blood glucose (FBG). The estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. The NHANES website provided the detailed procedures in collecting blood biochemical measurements .2. Subgroup analysis, stratified by sex, age, race/ethnicity, and BMI, was conducted to evaluate the heterogeneity among different populations. The correlation between the DII and HEI was investigated using “Sperman” method. We also conducted multivariable logistic regression including both the DII and HEI to explore the association between the HEI and CHD risk. A two-sided p-value < 0.05 was considered significant. All statistical analyses were conducted using the R software .Continuous variables were presented as the mean ± standard deviation (SD)  or the median (interquartile range) (skewed distribution). We compared baseline characteristics among individuals with and without CHD based on independent t tests, chi-square test, and Mann––Whitney U test. Multivariable logistic regression was adopted to investigate the relationship between the risk of CHD and DII after adjusting for confounding factors . Restricted cubic spline (RCS) analysis (with three piecewise points) was used to evaluate the nonlinear associations between the DII and CHD risk. Obesity was defined as BMI ≥ 30.0 kg/mA total of 45,306 participants from NHANES (1999–2018) were enrolled in the present study , of whomp for nonlinear = 0.023). The risk of CHD increased rapidly with the increase in DII, especially if the DII was greater than 2  (p for interaction = 0.11) (p for interaction = 0.012) (p for interaction = 0.032)  B. Howeve = 0.11) C. We als= 0.012) D. In add= 0.032) E.p < 0.001). However, results of multivariable logistic analysis including both the DII and HEI demonstrated that, after adjusting for confounding factors, the DII had a close association with CHD, but the association between the HEI and CHD was not observed in either the continuous or category variable , which is often used in evaluating the quality of diet in previous studies. We explored the correlation between the DII and HEI in the same population, as shown in variable . The DIIIt is gradually recognized that chronic inflammation plays a critical role in diverse pathological states and chronic diseases. Inflammation–endothelial dysfunction interaction initiates and propitiates atherosclerosis. The DII is a literature-derived tool that measures the inflammatory potential of a person’s diet. In this cross-sectional study, we explored the relationship between the DII and the prevalence of CHD based on a large population from NHANES. The main findings are as follows: (1) The DIIs in participants with CHD were significantly higher compared with those without CHD; (2) the DII had a positive association with the prevalence of CHD. The association of the DII and CHD was in a nonlinear pattern; and (3) compared with males, females were more sensitive to the DII. Moreover, the increment in the DII was more closely associated with the risk of CHD among individuals with normal weight and in the non-Hispanic black population. However, we can only draw correlation conclusions, considering that this study is a cross-sectional study. More prospective studies are needed to further investigate the association between the DII and CHD.Unhealthy eating habits lead to chronic systemic inflammation, which is one of the most important characteristics of metabolic diseases . ProinflNevertheless, the association between the DII and CHD has not been reported yet. In the current study, our results based on 45,306 adults from NHANES showed significant increases in DII levels of patients with CHD. Inflammation plays a crucial role in atherosclerosis, which is one of the pivotal mechanisms of CHD . We founRCS, a widely used method, was applied to analyze the nonlinear relationship between variables and outcomes ,42,43. RThere are several advantages and implications of our study. First, it was adequate to provide reliable conclusion and precise statistical power, considering the large-scale sample size included. Second, our study adopted RCS analysis and further demonstrated the nonlinear associations between the DII and CHD, and the trends of RCS curves and cutoff values may provide new evidence for health policy makers. However, several limitations of this study also have to be clarified. First, causal associations could not be determined, considering the research type of cross-sectional study. More prospective studies are needed to determine the exact relationship between the DII and CHD. Second, there may be subjective bias due to the self-reported CHD status and covariates from the NHANES database. Third, there are large ethnic differences in diet, physical activity, genetic variants, lipid metabolism, and susceptibility to cardiovascular disease. Therefore, whether the conclusion in the present study based on US participants could be applicable to other populations needs to be further explored in a future work.We retrospectively analyzed 45,036 adults in the US from NHANES and found that the increment in the DII closely was associated with the risk of CHD. The association between the DII and CHD was in a nonlinear pattern, and the increment of the DII had a greater impact on female individuals compared with male individuals. Our results may be helpful to public health policy makers in developing rational approaches to prevent CHD by controlling dietary inflammation, but further studies are still needed.


As one of the most common diseases, major depressive disorder (MDD) has a significant adverse impact on the li of patients. As a mild form of depression, subclinical depression (SD) serves as an indicator of progression to MDD. This study analyzed the degree centrality (DC) for MDD, SD, and healthy control (HC) groups and identified the brain regions with DC alterations.t-tests were used for further analysis to explore the brain regions with changed DC. Receiver operating characteristic (ROC) curve analysis of single index and composite index features was performed to analyze the distinguishable ability of important brain regions.The experimental data were composed of resting-state functional magnetic resonance imaging (rs-fMRI) from 40 HCs, 40 MDD subjects, and 34 SD subjects. After conducting a one-way analysis of variance, two-sample For the comparison of MDD vs. HC, increased DC was found in the right superior temporal gyrus (STG) and right inferior parietal lobule (IPL) in the MDD group. For SD vs. HC, the SD group showed a higher DC in the right STG and the right middle temporal gyrus (MTG), and a smaller DC in the left IPL. For MDD vs. SD, increased DC in the right middle frontal gyrus (MFG), right IPL, and left IPL, and decreased DC in the right STG and right MTG was found in the MDD group. With an area under the ROC (AUC) of 0.779, the right STG could differentiate MDD patients from HCs and, with an AUC of 0.704, the right MTG could differentiate MDD patients from SD patients. The three composite indexes had good discriminative ability in each pairwise comparison, with AUCs of 0.803, 0.751, and 0.814 for MDD vs. HC, SD vs. HC, and MDD vs. SD, respectively.Altered DC in the STG, MTG, IPL, and MFG were identified in depression groups. The DC values of these altered regions and their combinations presented good discriminative ability between HC, SD, and MDD. These findings could help to find effective biomarkers and reveal the potential mechanisms of depression. People with major depressive disorder (MDD) often feel terrible or sad, and lose enjoyment in their daily lives. MDD can cause suicidal thoughts in patients and put their lives at risk , 2. SubcAt present, the pathogenesis of MDD and SD is unclear. One study showed altered activation of the medial prefrontal network regions in MDD . The braResting-state functional magnetic resonance imaging (rs-fMRI) is a relatively common means of medical check-up often used in studies of depression. Images are obtained by collecting blood oxygen level dependent images with patients in a resting state during an MRI scan , 13. Rs-Graph theory is another method to investigate the spontaneous neural activity of the brain from the perspective of a network , 23. In The degree centrality (DC) index is an important part of graph theory and network analyses. The degree is a node property, and centrality determines the importance of nodes in a network , 29, 30.Alterations in functional brain networks have been proven to exist in MDD and SD –36. A feIn this study, we compared DC values in different groups and aimed to find and analyze brain regions with abnormal DC values. This study included preprocessing of MRI data, brain network construction, DC calculation, statistical analysis, a summary of DC alterations, and receiver operating characteristic (ROC) curve comparisons.Diagnostic and Statistical Manual of Mental Disorders , 34 with SD , and 40 HCs  collected from the Guangzhou First People’s Hospital of Guangzhou Medical University. The patients in the MDD group were diagnosed by experienced psychiatrists referring to the Structured Clinical Interview guided by the fifth version of the isorders . The Hamisorders  scores oisorders , 44, andVolunteer recruitment and image data collection were completed under the supervision of the Medical Ethics Committee of the affiliated Guangzhou First People’s Hospital of Guangzhou Medical University. All subjects were fully aware of the whole data-collection process, and all signed informed consent forms and provided permission for their information to be used.All data were collected using an MRI scanner . To reduce the impact of head movement on data quality, foam pads were used to hold patients’ heads in place, and headphones were used to reduce noise from the equipment. All patients met the resting-state scanning conditions, i.e., closing their eyes and staying relaxed and awake during imaging. An experienced doctor reviewed the MRI results to make sure there was no structural damage in the brain.The scan parameters for the rs-fMRI images were as follows: repetition time (TR), 2,500 ms; flip angle (FA), 90°; echo time (TE), 21 ms; dimension of the matrix, 64 × 64; field of view (FOV), 200 mm × 200 mm; voxel size, 3.5 mm × 3.1 mm × 3.1 mm; slices, 42 with no gap; and echo-planar imaging sequence. There were 200 time points (or volumes) of rs-fMRI data for each subject. Parameters of the T1-weighted images were as follows: FA, 7°; TR, 2,530 ms; TE, 2.34 ms; slice thickness, 1.0 mm with no gap; FOV, 256 mm × 224 mm; and magnetization-prepared rapid acquisition gradient-echo sequences.The four main procedures of this study are presented in The preprocessing step was completed using the Data Processing Assistant for Resting-state fMRI software .1.DICOM images were converted to NIFIT format.2.To ensure that the MRI equipment was in normal working condition and the subjects had adapted to the scanning process, the first 10 time points were abandoned.3.The slice-timing step used the middle slice as the reference to eliminate any difference between slices due to acquisition times as much as possible.4.Slight head movements caused by breathing, heartbeats, or other factors are inevitable. Patients with total scan time <3 min after scrubbing all time points with framewise displacement (FD) >0.2 mm  or max h5.To make the brain images of different subjects more standardized, echo-planar imaging images were registered with T1 images.6.The brain of each patient was segmented using the “New Segment + DARTEL” method.7.Covariables  were removed to reduce the impact on analysis results.8.Spatial normalization is necessary and it resampled each voxel in the brain to 3 mm × 3 mm × 3 mm.9.A temporal bandpass filter was applied (0.01–0.08 Hz).10.Gaussian smoothing was conducted for further noise reduction; the kernel parameter was full width at half-maximum with a size of 6 mm × 6 mm × 6 mm.The Graph Theoretical Network Analysis (GRETNA) toolbox  was usedThere is a lack of a clear standard to select a specific sparsity threshold , whereasCD(Ni) is the DC value of the node iN, g represents how many nodes the graph network has, dij represents how many edges the network has between iN and other g-1 nodes and i≠j exclude the connection of Ni with itself.where t-test was performed to analyze the BDI-II scores in the comparison of SD patients and HC subjects.For all subjects, demographic data were analyzed using the relevant statistical module of the Statistical Product and Service Solutions software (SPSS), software program . When comparing the differences in age and education time, a one-way analysis of variance (ANOVA) was carried out, while the sex differences were obtained by a Chi-squared test. A two-sample p < 0.05, (post-hoc t-tests (two-sample t-tests) were carried out for the pairwise comparison with a Bonferroni correction (p < 0.05). To ensure the quality and accuracy of the statistical analysis for DC, the age, gender, educational level, and head motion were taken as the covariate in the statistical analysis during the ANOVA analysis and the pairwise two-sample t-test . Finally, brain regions with aberrant DC were identified.Statistical analysis was conducted using the GRETNA toolbox. To identify brain regions with significant DC values in the three groups, a one-way ANOVA analysis  was perp < 0.05) were extracted for ROC analysis . The logistic regression model is obtained by the following equation:In the dichotomous task of distinguishing MDD from HC, we defined iz is the intermediate variable parameter , 0a is the regression constant, ia is the regression coefficient of the j-th variable , Xij is the i-th value of the j-th variable vector, and iP is regression prediction probability of disease probability in the i-th sample.where Finally, the ROC curves of the composite index were analyzed. ROC curves were compared to analyze distinguishability. Similarly, we compared the ROC curves of every single index with abnormal DC values and the composite index for SD vs. HC and MDD vs. SD using the same method. For the ROC curve analysis, we mainly used the area under the curve (AUC) to analyze the ability to differentiate. In addition, other important measures, such as sensitivity, specificity, and cut-off values, were calculated. Youden’s index represents the ability to distinguish two groups and was used to determine cut-off values.p > 0.05) was found. The symptom scores  of the MDD group were significantly different from those of the HC group (p < 0.001).With the standard of scrubbing  and max head movement removal (translation >2 mm and rotation >2°), we ruled out two MDD, eight SD, and seven HC subjects before further data analysis. According to one-way ANOVA analysis, brain regions with obvious changes in DC included the right MFG, right superior temporal gyrus (STG), right middle temporal gyrus (MTG), and the left and right inferior parietal lobules (IPLs). According to the comparison results, the alteration tendency of DC in three different stages for each important brain region is summarized in We compared the ROC curves of brain regions with aberrant DC using the single index and the composite index regressed by the single index, separately. For the aberrant brain regions in each comparison, the AUC value, cut-off point, sensitivity, and specificity of ROC analysis are given in p < 0.0001]. Conversely, the distinguishing ability of the right IPL was not good, with an AUC of 0.615 , while the AUC of the composite index was 0.803 . Thus, according to the AUC >0.7 rule, the right STG and the composite index showed good discriminative ability.The ROC results of the right STG, right IPL, and the composite index of the right STG and right IPL for MDD vs. HC are shown in p = 0.0396), the right MTG presented an AUC of 0.669 , and the left IPL presented an AUC of 0.688 , while the AUC of the composite index was 0.751 . The DC value of the composite index had a good discriminative ability.For the comparison between the SD and HC groups, the ROC results of the right STG, right MTG, and left IPL and the composite index of these regions combined are shown in p = 0.0050), 0.681 , 0.704 , 0.695 , and 0.651 , respectively. Additionally, the AUC of the composite index was 0.814 . As such, the right MTG and the composite index showed good discriminative ability.For the comparison between the MDD and SD patient groups, the ROC results of the right MFG, right STG, right MTG, left IPL, and right IPL and the composite index of these regions combined are shown in We identified aberrant DC and summarized a tendency for DC alteration by comparing three groups  for the first time in the existing study. Notably, the MFG, STG, MTG, and IPL are important areas of the brain that displayed changed DC values. The ROC curve analysis showed that the right STG performs well for the differentiation between MDD and HC groups, and the right MTG could effectively distinguish the MDD and SD groups. All three composite indexes had a good discriminative ability when distinguishing two groups in each pairwise comparison. These findings have implications for the study of depression and will be further discussed and analyzed below.In each group of comparison experiments, the DC value of the right STG was significantly changed. For both the MDD group and the SD group, the right STG presented an increased DC trend. For the comparison of DC in the MDD and SD groups, the right STG showed a decreased tendency in the MDD group.As one of the important brain regions, the STG plays a key role in dealing with tasks related to social cognition, emotional processing, and language expression , 56. MDDIn our study, the right STG in the MDD and SD groups presented a higher DC. Zhang et al.  observedThe right MTG in the SD subjects showed higher DC values in the three groups. In our previous studies, the FCs based on the region of interest of the posterior parietal thalamus (PPtha) were investigated because PPtha is an important brain region associated with depression , 65. TheIn SD patients, the FC, ReHo, and DC all showed decreasing tendencies in the MTG in the MDD group. Therefore, the function of the MTG might be further damaged in more severe stages of depression. As one of the most important areas in the temporal cortex, the MTG is usually associated with the neural response to negative stimuli , 67. In p > 0.05).As shown in The DC in the right STG could be used to differentiate MDD from HC (AUC = 0.779). These results indicated that DC changes in the right STG can be considered an indicator of depression. The importance of DC in the STG has been emphasized because of its good discriminative ability. Similarly, the DC in the right MTG could be used to distinguish MDD from SD (AUC = 0.704). This indicates that changes in DC in the right MTG could be imaging biomarkers for distinguishing MDD from SD.Logistic regression was used to regress the brain regions with significant differences in each comparison as one composite index and the three composite indexes had a good discriminative ability. This suggests that depression may not be caused by dysfunction or changes in a single brain region; instead, multiple brain regions and their interactions contribute to depressive symptoms. The diverse features can be used to take multiple aspects of the disease into account to estimate and classify MDD and SD. We can use machine learning models to conduct a comprehensive analysis of multiple features to obtain higher classification accuracy.This work still has shortcomings. First, the accuracy of the statistical results was limited because the sample size was small. Second, we could not study the developmental trajectories of the same patients at different stages of depression because the multistage data for the same group of subjects was unavailable. In future work, data from the Strategic Research Program for Brain Sciences dataset  and the This study analyzed the alterations in DC for patients with MDD and SD compared to HCs based on rs-fMRI data. Brain regions with altered DC values included the MFG, STG, MTG, and IPL. In the DC analysis, the right STG showed significant changes in the three pairwise comparisons. The alteration tendency for DC alteration of five important brain regions was identified. The DC of the right STG showed a good differentiation ability in the comparison between MDD patients and HCs, while the DC of the right MTG showed a good differentiation ability to distinguish MDD patients from SD patients. The three composite indexes showed good discriminative ability. These findings may help to explore patterns of functional brain networks in depressed people or identify biological markers of depression.qisl@bmie.neu.edu.cn.The datasets presented in this article are not readily available because the sharing of data must be approved by the Medical Ethics Committee. Requests to access the datasets should be directed to SQ, The studies involving human participants were reviewed and approved by Medical Ethics Committee of the affiliated Guangzhou First People’s Hospital of Guangzhou Medical University. The patients/participants provided their written informed consent to participate in this study.LY performed the experiments and analyzed the data along with CJ and SQ. SQ, YY, and XW conceived the study, presented the results, and wrote the manuscript along with LY. XR collected and analyzed the data. YT and CL supervised the algorithm development and analyzed the data. All authors read and approved the final manuscript.


Studies reporting on rehabilitation specifically designed for older adults—testing for at least one domain that affects rehabilitation or assessments for admission to inpatient rehabilitation—were also included. Results were described both quantitatively and narratively. (5) Results: 1404 articles were identified through selected databases and registers, and these articles underwent a filtering process intended to identify and remove any duplicates. This process reduced the number to 1186 articles. These, in turn, were screened for inclusion criteria, as a result of which 37 articles were included in the final review. The majority of assessments for geriatric rehabilitation were carried out by a multidisciplinary team. Multiple studies considered more than one domain during assessment, with a high percentage evaluating a specific outcome measure used in geriatric rehabilitation. The most common domains assessed were function, cognition and medical status—with communication, vision and pain being the least common. A total of 172 outcome measures were identified in this review, with MMSE, BI, FIM and CCI being the most frequent. (6) Conclusions: This review highlights the lack of standardised approaches in existing assessment processes. Generally, older-adult-rehabilitation assessments struggle to capture rehabilitation potential in a holistic manner. Hence, a predictive model of rehabilitation for assessing patients at the initial stages would be useful in planning a patient-specific programme aimed at maximising functional independence and, thus, quality of life. Over the last decade, the number of persons in Malta aged >60 has increased by almost 34,000, accounting for approximately 18.9% of the total population at the end of 2020 [The increase in the older-adult population stresses the importance of improved healthcare services to detect vulnerable individuals in the community as early as possible. Due to the effects of ageing, functional decline and increasing rates of disability, older adults are at an increased risk of hospitalisation, care and admission to long-term facilities. Following an acute event that would lead to hospitalisation, older adults could benefit from an inpatient rehabilitation phase, which could eventually help them, as far as possible, to return to their previous physical function ,5. The pGeriatric rehabilitation (GR) is an inpatient programme that applies a multidisciplinary-team approach, typically consisting of a consultant geriatrician, skilled nursing staff, a physiotherapist, an occupational therapist and a social worker. It could also include a speech therapist, psychologist, podiatrist and dietician . The mulAccording to the World Health Organization (WHO) the aim of rehabilitation is to maximise functional independence and facilitate psychosocial adjustments to residual disability, to allow the patient to function successfully within the community ,9,10. ThTaking all the above into consideration, this review seeks to provide an overview of the assessments in place for admitting patients to inpatient GR, and which domains are considered for rehabilitation. This review will provide the basis for the setting up of an expert panel, which would enhance the robustness of the design and development of a prediction model for GR.A review search was conducted as the starting point for the current study. An electronic, seven-step search string was developed, with guidance from an experienced librarian . The samSearches, title and abstract screening were carried out by a single researcher (FM), whereas full-text screening and data extraction was completed by FM and reviewed by two other researchers . Any divergent opinions, such as the relevance of particular studies to inpatient rehabilitation, were resolved through discussions among the research team members. A sample of excluded articles is presented in This review included studies that focused on rehabilitation assessments and measures delivered in hospitals in community settings. There is a divergence of views as to what constitutes the age of an older person. Some countries consider admission to geriatric rehabilitation wards at the age of 60 years and older. This review is based on that position for the sake of completeness. Rehabilitation targeted adults aged >60  sufferinStudies that presented primary research, including randomized controlled trials, non-randomised control trials, quasi-experimental studies, pre-test/post-test studies, prospective and retrospective cohort studies, case-control studies and individual case reports were also included.The review excluded studies using outcome measures specific to conditions such as stroke, traumatic brain injuries, intensive care, palliative and end-of-life care, amputee rehabilitation, burns, substance-abuse care and specific post-COVID-19 or cardiopulmonary rehabilitation.Studies that did not have an age restriction or a threshold of 60 years, studies that did not focus on patient evaluation measures, and studies that incorporated assessments involving digital technology or virtual reality were eliminated from the study.Opinion pieces, editorials and books were also omitted from this review.Outcomes of interest included the following: measures of physical function and activities of daily living (PADLs and IADLs); cognitive outcome measures; and other outcome measures that had an effect on rehabilitation provided to older adults, based on the domains stated in the WHO ICF framework ,10.All the studies were uploaded on Mendeley, a reference management software, with duplicate articles being removed. The studies were screened by title and abstract to identify those which met the inclusion criteria. The full text was then analysed by author, publication year, country of publication, study type and design, participant demographics, outcome measures used and clinician assessment and results. Results were described both quantitatively and narratively, noting emergent themes and taking into account the rehabilitation definition stated in the WHO ICF framework ,10. A syThe quality of the studies was evaluated and marked as ‘yes’ or ‘no’, noting any missing information that could affect the quality of the results presented in this review. A high number of ‘yes’ values indicated that the study had a good level of transparency in the method. A table representing a sample of bias is presented in In total, 1404 articles were identified through the selected databases and registers. After removing duplicates, a new total of 1186 articles was obtained, all of which were duly screened. Following inclusion-criteria screening, 37 articles were selected in the final review. This is shown in The 37 studies were conducted between 1969 and 2021, five of which were published during 2020—the highest number since 1969. More than half of the 37 studies were carried out in Europe .The Journal of Rehabilitation Medicine numbered the highest number of articles , followed by the Journal of Gerontology  and Age & Ageing . The most common type was prospective longitudinal observational studies, followed by prospective cohort studies . The majority of the articles took place in a GR setting , included a sample size between 200 and 299 patients  and had a data-collection phase of 10 to 19 months .Twenty-nine studies considered consecutive admissions to GR units, without specifying age limitation, while sixteen studies included patients aged >65 years. Studies included patients with general mobility problems, post-orthopaedic interventions, stroke rehabilitation and rehabilitation following post-acute respiratory problems. However, they still focused on assessment measures of GR. Most excluded patients with medical instability  or with moderate-to-severe cognitive impairment . Two studies (5.4%) excluded participants from residential homes, while eight retrospective studies (21.6%) excluded participants with missing reported data.Only a small number of the 37 selected studies provided a definition of rehabilitation, whereas most of them described other aspects of GR. The descriptions and definitions were heterogenous and lacked consensus.Studies described the goal of rehabilitation as restoring functional independence and facilitating psychosocial adjustments to residual disability ,13,14,15In some of the consulted studies, GR was affected by functional status, the presenting condition and comorbidities, age, cognition, social support and nutritional status ,29,30. CThe fact that GR primarily uses an MDT approach became evident upon noting which professional carried out the assessment. The highest percentage was completed by the MDT , while in some studies, the researchers performed the assessment  or collected data. In 18.9% of the studies (n = 7), it was not specified which clinician was involved. Others included physicians and geriatricians , occupational therapists , nurses  and physiotherapists . However, there were no details or explanations as to how the final decision of acceptance or rejection of inpatient GR was made. Although the clinicians were mentioned in most studies, it was unclear as to how or who rated RP affecting GR admission.Some studies ,14,23,33The timings of the assessments that were carried out also varied. These were mostly performed at multiple time points, with more than half made at admission and discharge , whereas another 21.6% (n = 8) were carried out at admission, discharge and at follow-up post-discharge. Only five studies (13.5%) included comparator groups—that is, included a control group—for comparison between assessments and interventions.In their respective assessments, the studies evaluated for this review measured rehabilitation differently from each other. This divergence proved to be very challenging in combining the findings in a systematic review or meta-analysis. The aims and hypotheses of the various studies were noted, and the main themes were extracted. The aims were mostly to evaluate which factors tend to impact rehabilitation. The studies looked at factors including frailty , cognition , pre-function , medical status  and patient goals . A total of 16.2% (n = 6) looked at factors impacting rehabilitation post-hip-fracture surgery. Some of the studies evaluated the use of specific outcome measures, while others used assessment tools to evaluate inpatient rehabilitation outcomes. Others investigated the relationships between function and mortality, age and rehabilitation and clinicians’ predictions of patient rehabilitation .The assessments included the various domains constituting the definition of rehabilitation endorsed by the WHO in its ICF framework, and other sub-domains that were extracted from the studies. The majority looked at patient demographics and characteristics , which included information such as gender, age, pre-admission living arrangements and settings. The most prevalent domains assessed for admission to GR are listed in A total of 172 outcome measures were used in the studies that met the criteria. Three of the studies each used a specific instrument to assess GR, namely, Minimum Data Set for Post-Acute Care (MDS-PAC) , HospitaThe majority of the remaining studies used more than one outcome measure from multiple domains during the assessment. Function was measured in most assessments (83.8%), followed by cognition (78.4%), with both domains being also commonly assessed in conjunction (67.6%). This summary of domain combinations is shown in All domains included other outcome measures. The cognition domain also included the Abbreviated Mental Test (AMT), which was used in three studies (8.1%); the Short Portable Mental Status Questionnaire (SPMSQ), which was employed in two studies (5.4%); and another 10 outcome measures that were used once (2.7% each).Following the Barthel Index (BI) and the Functional Independence Measure (FIM) in most studies, three studies (8.1%) used a function-assessment sheet, designed by the clinicians in a hospital setting. However, no details of what the score sheet entailed were provided in the study report. Another 11 outcome measures were used once in different studies (2.7% each).Medical assessments were used in 23 articles (62.2%) including comorbidities, number of medications and the admitting condition; once again, measures varied. Following the Charlson Comorbidity Index (CCI), the Cumulative Illness Rating Scale (CIRS) was used in four studies (10.8%) and nine other outcome measures were used once (2.7% each). The physical domain was assessed in 16 articles 43.2%). In none of these articles was it assessed on its own, but was combined with other domains. Six of these articles (16.2%) used a single outcome measure from the physical domain, with other outcome measures from other domains. The single outcome measures used were: POMA , the MDS3.2%. In Thirteen articles (35.1%) investigated behaviour during assessment. Following the Geriatric Depression Scale (GDS), the Confusion Assessment Method (CAM) was used in three studies (8.1%), the Center for Epidemiologic Studies Depression Scale (CES-D) was used in two studies (5.4% each), and five other outcome measures were used once (2.7% each).Various outcome measures were used to assess patient quality of life and its effect on GR . Two studies (5.4%) used a clinician-designed questionnaire based on ICF standards, but no specific information was provided in either study. Two further studies used the EQ-5D-3L, a questionnaire with a visual analogue scale (VAS) format, comprising questions of five domains being “mobility, self-care, usual activities, pain/discomfort and anxiety/depression” . The remFour studies (10.8%) included nutrition in their assessment. These used the Mini Nutritional Assessment , the Malnutrition Screening Tool  and the Communication and vision assessments were carried out in two studies (5.4%), both of which formed part of an instrument that was being validated for the assessment of GR and RP, assessing multiple domains. These instruments were MDS-PAC and GEMS ,29. AnotThe respective numbers of outcome measures employed for each domain are listed in Through this scoping review, the research team could establish that it is not yet possible to provide a watertight definition of GR and determine the factors that would condition RP. The diversity of the studies prevents a definitive answer at this time. There were significant discrepancies in the definition of rehabilitation and, in most cases, an absence of a clear definition was noted. A considerable number of different outcome measures and multiple domains were used . There wFor successful GR, discharge planning should ideally start at the early stages of patient admission to hospital. This would help in developing a patient-specific plan of treatment, thus facilitating discharge and ensuring that the patient’s needs are met . AssessiThe studies lacked standardised assessments of social support and environment. However, most pointed out that, in the case of patients residing in the community and enjoying a good level of support, it is reasonable to predict GR success. This also included the patient’s and carer’s wishes and rehabilitation goals ,33,35. CThe studies illustrate the value of assessing comorbidities, as they are likely to affect GR success ,30,37,47The above-mentioned domains were in agreement with the Comprehensive Geriatric Assessment (CGA) and WHO ICF ,10, whicOn the basis of the studies, the CGA and the WHO ICF, it is evident that using a single domain as an assessment of GR would fail to produce a correct prediction of rehabilitation success, and that a holistic approach would need to be adopted in addressing this complex field. Although there was no standardisation in the studies and no statistical significance could be noted through this review, it was apparent that function and cognition are the two main domains that tend to be assessed in conjunction for determining RP and have the greatest effect on rehabilitation success.This review followed a predetermined protocol and employed a thorough search technique ,49. The This review evaluated publications that were selected according to focused inclusion and exclusion criteria that were, in turn, aligned with a GR setting. Studies that included specialist rehabilitation or technology were excluded, due to specific specialist outcome measures and rehabilitation protocols. It is not to be excluded that outcome measures common to those studied in this review are also used in specialist settings. However, the linking of the GR setting and RP did not allow those publications to be included here.The data presented by the various studies were summarised using quantitative measures, when possible. These tables and figures were intended to provide a summary, as the diversity of the studies was not conducive to undertaking an explanatory meta-analysis.It proved to be a challenging task to identify studies that mentioned which outcome measures and assessment methods were used to assess RP and criteria for GR inpatient admission. This may be due to a limitation in the search terms and truncations used. However, it also sheds light on the lack of literature and consensus in GR decision-making and standardised frameworks available. Given the large body of literature on the subject, GR remains a challenging area to research and, while every attempt was made to identify the most pertinent studies, the presence of equally pertinent studies is not to be excluded.This review did not set out to eliminate existing discrepancies in admission standards for inpatient geriatric rehabilitation (GR). However, it contributes to summarising the currently available research, highlighting the absence of standardised approaches and highlighting the necessity of achieving such standardisation.Inpatient GR requires extensive resources and the involvement of multidisciplinary teams (MDT). This places a substantial expense on any healthcare system. The large number of outcome measures identified in this study highlights the complexities of this patient population. Moreover, the lack of consensus in standardised assessments for inpatient GR admission presents the MDT with a challenge in defining and understanding RP, and in accepting patients for GR.Current assessments and approaches struggle to evaluate older adults in a holistic manner. They view certain domains of rehabilitation, such as cognition and physical function, but fail to consider others, thus also compromising inpatient GR success.A standardised predictive model of rehabilitation, encompassing a holistic approach including outcome measures based on all the major domains, could have a positive impact on the GR admission system, and would allow an equitable chance for all older adults to be referred for inpatient GR. A standardised assessment process for GR could facilitate further research that would evaluate the effectiveness of GR in reducing hospital readmissions, decrease mortality rates and improve patient function. Further research is necessary towards managing this increasingly indispensable area of clinical practice.


Negative symptoms have long been conceptualized as a core aspect of schizophrenia. Despite widespread recognition of the status of these symptoms as independent dimensions of schizophrenia, they are sometimes difficult to distinguish from depression or cognitive impairment. Therefore, objective assessment of schizophrenia symptoms is critical by obtaining a valid and reliable Indonesian version of the SANS instrument. This study aimed to determine the content validity, concurrent, internal consistency reliability, inter-rater, cut-off value, sensitivity, and specificity of the SANS instrument.This is a diagnostic study using the cross-sectional method to determine the relationship between the SANS and PANSS instruments on the negative symptom subscale. It was located at the Prof. Dr. M. Ildrem Mental Hospital of North Sumatera Province.p < 0.001) with a strong correlation (r = 0.763). Additionally, the consistency reliability test had a very high internal score , the overall inter-rater reliability test was “very good” (ICC = 0.985), and the cut-off value was 10.5 with sensitivity and specificity values of 72.9 and 77.9%, respectively.Of the 400 subjects, 67.5% were males, and the median age of the subjects was 37 years (18–45). The results of the content validity test were good (mean I-CVI=1.00), and the concurrent validity test comparing the SANS and PANSS instruments on the negative symptom subscale obtained significant results (The Indonesian version of the SANS instrument is valid and reliable for measuring negative symptoms in people with schizophrenia in Indonesia. Schizophrenia is a mental disorder characterized by positive symptoms comprising delusions, hallucinations, and disorganized speech, negative symptoms, including flat affect, avolition, speech, and language poverty, social withdrawal, and cognitive deficits covering attention deficit, and impaired executive function . In 2013Negative symptoms have long been conceptualized as a core aspect of schizophrenia. Despite widespread recognition of these symptoms as an independent dimension of schizophrenia, they are sometimes difficult to distinguish from depression or cognitive impairment. Additionally, the pathogenetic mechanisms remain unknown, available treatments' effectiveness was far from satisfactory, and these symptoms were considered difficult to assess reliably. Furthermore, the main function of negative symptoms in the patient's functional outcome was often overlooked or unknown –6.Positive and Negative Syndrome Scale (PANSS), the Scale for Assessment of Positive Symptoms (SAPS), and the Scale for the Assessment of Negative Symptoms (SANS) have been developed to assess symptoms of schizophrenia objectively. Because this scale is sensitive to changes in symptoms, it is considered the “gold standard” in studies for the treatment of schizophrenia  and good overall internal consistency of the items (Cronbach's = 0.885). Therefore, the SANS is a valid and reliable scale to measure the development of predominantly negative symptoms in schizophrenic patients .Many studies have validated SANS into several versions in different countries. Previous studies conducted by Philips et al. validated SANS and measured the validity and reliability of the Chinese version of the SAPS and SANS. In this study, the overall score of the Chinese version of the SANS had high inter-rater reliability 0.93), test-retest reliability 0.88), and good overall internal consistency of the items (Cronbach = 0.96)  criteria, aged 18–45 years. Additionally, this study had the following exclusion criteria: having a general medical condition that can affect the subject's psychotic condition and a history of other psychiatric disorders.A sample size is suggested according to the following scale, 50 subjects (very poor), 100 subjects (poor), 200 subjects (enough), 300 subjects (good), 500 subjects (very good), and 1,000 subjects or more (excellent) . A largeThis study began with study preparation, including asking permission to translate and testing the validity and reliability of SANS to Nancy Andreas through electronic mail (e-mail). The next step was to obtain a research permit from the Head of the Department of Psychiatry, Faculty of Medicine, the Universitas Sumatera Utara before conducting the process of cross-cultural adaptation. This process aimed to achieve different language versions of the English instrument conceptually equivalent in each of the target countries/cultures. Therefore, the instrument should be natural and acceptable and practiced similarly. The focus was on cross-cultural and conceptual, not linguistic/literal equivalence. An excellent method to achieve this goal was to use forward and backward translations. The process used adaptations recommended by the Institute for Work and Health (IWH) as follows: , 13 StagFurthermore, Stage II was a synthesis of two translations involving a third person who acted as a mediator in discussing the differences to produce one translation . Stage IThis study was conducted using the final result of the Indonesian version of the SANS translation. After receiving detailed explanations, subjects who met the inclusion criteria filled out a written informed consent form. When it was impossible to fill out the consent form, the consent of the subject's family was obtained. Then, the diagnosis of schizophrenia was made using the ICD-10 diagnostic criteria. Next, the exclusion of other psychiatric disorders was assessed using the Mini International Neuropsychiatric Interview Version ICD-10 (MINI ICD-10). Before the examination, the assessor was trained or equalized the perception of items on the measurement scale and then examined with SANS and the Indonesian version of the negative scale PANSS with the help of a psychiatrist assessor at Prof. Dr. M. Ildrem Psychiatric Hospital Medan, North Sumatera. The negative scale SANS and PANSS questionnaire data were obtained before analyzing and processing.Statistical Package for Social Science (SPSS) program to process the data. Additionally, it received approval from the Research Ethics Committee at the University of North Sumatera with letter number 209/KEP/USU/2021.Data were collected, tabulated, and statistically processed. The validity test was assessed by qualitative assessment of each instrument item by three experts in psychiatry. In the concurrent validity test, the Pearson correlation test was performed when the data distribution was normal; otherwise, the Spearman correlation test was performed to find the correlation coefficient between the numerical variables (SANS) and the negative symptom subscale of PANSS. The reliability test was measured by the internal consistency reliability of each statement item by calculating Cronbach's alpha and inter-rater reliability by the intra-class correlation coefficient (ICC). This study used the Demographic characteristics analyzed were age, gender, last education, employment status, marital status, ethnicity, Body Mass Index (BMI), duration of schizophrenia, and the onset of illness. The age, BMI, duration of illness, and disease onset were numerical scale variables. The Kolmogorov–Smirnov analysis was the normality test because there were more than 50 subjects. The mean and standard deviation presented when the data was normally distributed; otherwise, it presented in median and percentile. Gender, latest education, employment status, marital status, and ethnicity were categorical variables presented in a frequency distribution.Content validity was accessed using a quantitative approach through an assessment of the measuring instrument conducted by several experts called the panel, who understand and explore the construct of the instrument assessed. Three experts conducted the validity of the SANS instrument and assessed each item using four value scales. This included a value of 4 when the item was very relevant, a value of 3 when the item was relevant, a value of 2 that was somewhat relevant but should be improved, and a value of 1 when the item was not relevant. The conformity assessment can be repeated .Content Validity Ratio (CVR) was used to measure the agreement between raters/experts on the importance of certain instrument items. Content Validity Ratio (CVR) was calculated by the formula (ne – N/2)/(N/2), where ne was the number of experts who answered “quite relevant” and “very relevant,” namely scores 3 and 4, and N was the number of experts. I-CVI is the number of experts rated “fairly relevant” and “very relevant,” divided by the number of experts who participated in the assessment. The I-CVI score for good content validity was at least 0.78 for six experts or more and a score of 1.00 for three to five experts . Therefore, the relationship between linear variables was obtained before conducting the Spearman correlation test.The concurrent validity test compared the Indonesian version of the scale for assessing negative symptoms (SANS) scores with a standard gold instrument. This study used the Indonesian PANSS negative symptom subscale (PANSS-NS) instrument. The normality test used was the Kolmogorov–Smirnov test because the number of participants was more than 50, and both results were p-value < 0.001, indicating that the correlation between the SANS and PANSS-NS scores was significant. Furthermore, the Spearman correlation value of 0.763 indicated a strong positive correlation.The reliability of the SANS instrument was measured using an inter-rater reliability design. This approach was preferred over test-retest because the assessment depended on observations of patient behavior compared to self-reports and subjective complaints. Primarily, it determined how well two or more independent observers or raters will agree on some aspect of the patient's behavior. Furthermore, the test-retest design provides an additional source of variance, such as changes in patient behavior over time, giving rise to an undesirable source of variance. This did not allow a net assessment of variance between rater observations. Furthermore, the inter-rater reliability design was preferred because assessing the observed variance was the main objective .Inter-rater  measurement test on the SANS instrument used the ICC. In examining the reliability, the rule of thumb should involve a minimum of 30 samples assessed by a minimum of 3 raters . A totalThe receiver operating characteristic (ROC) and (AUC) were inseparable methods. The ROC method results from a trade-off between the sensitivity and specificity values at various alternative intersection points presented in the graph. The AUC was the result of the region generated from the ROC curve.p < 0.001. Furthermore, the hypothesis test compared the AUC obtained by the index to the AUC of 50%, with a p-value of <0.05, which indicated that the AUC value of the SANS instrument was significantly different from that of 50%. However, the AUC value was satisfactory because it was more significant than the expected minimum value.In The AUC score of 86.0% was good, meaning that when a negative symptom score was used to assess the symptoms in 100 subjects, the examination will give the correct conclusion for 86 people.Obtaining a valid and accurate Indonesian version of the SANS instrument is crucial for objective assessment of schizophrenia symptoms. As mentioned before, the purpose of this study was to establish the SANS instrument's content validity, concurrent, internal consistency reliability, inter-rater, cut-off value, sensitivity and specificity. The subjects were people with schizophrenia aged 18–45 years to minimize bias due to secondary negative symptoms caused by non-schizophrenic diseases or a degenerative process . DemograThree experts conducted the content validity test to find the values of I-CVI, S-CVI, CVR, S-CVI/UA, and S-CVI/Ave. r value = 0.76 with a p-value of <0.001, as shown in p < 0.001) at admission and discharge from the hospital, with positive correlation results and weak to moderate correlation strength (r = 0.17–0.46).The concurrent validity test used the Spearman correlation test to determine the correlation between the Indonesian version of the SANS and the standard gold instrument. This study used the negative symptom subscale PANSS instrument, and the SPSS calculation obtained an p = 0.002) with a negative correlation and moderate correlation strength (r = −0.48). The difference in the results obtained is possible because of an ethnocentric bias, differences in the gold standard instruments used, and the tests conducted . The size of the AUC area will show the validity of the conclusions given by a diagnostic instrument for clinical purposes. The AUC of 86.0% is a good value, meaning that when a negative symptom score is used to diagnose the negative symptoms from 100 subjects, then the right conclusion can be obtained about 86 people. Sensitivity is the ability of an instrument to show positive results in a genuinely positive population, while specificity is the ability of an instrument to show negative results in a genuinely negative population , pulation .In This study has implemented the content and concurrent validity test, internal consistency, and inter-rater reliability test. Additionally, this study obtained good AUC values with the ROC method, cut-off values, and sensitivity and specificity values of the Indonesian version of the SANS instrument. Contrarily, the limitation of this study was that it used non-probability sampling method and was only conducted in one particular area or place due to the current pandemic conditions.p < 0.001), with a strong correlation (r = 0.763). Furthermore, the reliability test for internal consistency was very high , the overall item inter-rater reliability test was “very good” (ICC = 0.985), and the cut-off value was 10.5 with a sensitivity and specificity of 72.9 and 77.9%, respectively. In conclusion, the Indonesian version of the SANS instrument is valid and reliable for measuring negative symptoms in people with schizophrenia.This study showed that the content validity test was good (mean I-CVI = 1.00), and the concurrent validity test that compared the SANS and PANSS instruments on the negative symptom subscale obtained significant results (The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.The studies involving human participants were reviewed and approved by Study Ethics Committee at the Universitas Sumatera Utara. The patients/participants provided their written informed consent to participate in this study.MA, EE, VC, and MS were involved and contributed equally to the study. RH and AK conducted forward translation. All authors contributed to the article and approved the submitted version.


Glioma-associated macrophage/microglia (GAM) represents a key player in shaping a unique glioma ecosystem to facilitate tumor progression and therapeutic resistance. Numerous studies have been published concerning GAM, but no relevant bibliometric study has been performed yet. Our bibliometric study aimed to comprehensively summarize and analyze the global scientific output, research hotspots, and trendy topics of publications on GAM over time. Data on publications on GAM were collected using the Web of Science (WoS). The search date was 16 January 2022, and the publications were collected from 2002 to 2021. Totally, 1,224 articles and reviews were incorporated and analyzed in the current study. It showed that the annual publications concerning GAM kept increasing over the past 20 years. The United States had the largest number of publications and total citations. Holland, Kettenmann, and Gutmann were the top three authors in terms of citation frequency. Neuro-oncology represented the most influential journal in GAM studies, with the highest H-index, total citations, and publication numbers. The paper published by Hambardzumyan in 2016 had the highest local citations. Additionally, the analysis of keywords implied that “prognosis,” “tumor microenvironment,” and “immunotherapy” might become research hotspots. Furthermore, trendy topics in GAM studies suggested that “immune infiltration,” “immune microenvironment,” “bioinformatics,” “prognosis,” and “immunotherapy” deserved additional attention. In conclusion, this bibliometric study comprehensively analyzed the publication trend of GAM studies for the past 20 years, in which the research hotspots and trendy topics were also uncovered. This information offered scholars critical references for conducting in-depth studies on GAM in the future. Glioma has been considered to be the majority of primary intracranial malignancies, with poor prognosis, high recurrence, and mortality rate. Although great progress has been made in advanced multimodality regimens, the clinical outcomes of patients with glioma remained dismal , 2. In lIt has been well-accepted that the tumor microenvironment (TME) plays a pivotal role in sustaining the malignant proliferation and progression of GBM . The TMEBibliometrics represents a branch of library science that uses mathematical and statistical measurements to analyze publications quantitatively and qualitatively . Based oWe searched the Web of Science (WoS) on 16 January 2022 to collect GAM-related studies between 2002 and 2021. The database source was limited to Science Citation Index Expanded. The search strategy was presented as follows: TS = glioma-associated macrophage OR TS = glioma AND (tumor-associated macrophage OR tumor-associated microglia OR TAM) OR TS = glioblastoma-associated macrophage OR TS = GBM-associated macrophage OR TS = (glioblastoma OR GBM) AND (tumor-associated macrophage OR tumor-associated microglia OR TAM).The publication types were limited to “article” and “review,” which were written in English. The meeting abstract, editorial material, book chapter, letter, and others were excluded. Duplicate and inaccurate raw data were removed by the analyzing tool automatically. Eventually, a total of 1,224 publications were incorporated and analyzed in the current study. All the information, including titles, authors, affiliations, sources, countries, keywords, publication year, and references, was retrieved for subsequent bibliometric analysis.The R software (version 4.1.2) and the “BiblioShiny” package were used to construct the basic analysis of all enrolled publications. “BiblioShiny” is the tool under the package that is designed for non-coders to provide methods for complete bibliometric analysis. It enables the generation of multiple results in the form of tables and graphs, which are not common in other software . To optiThe number of articles and citations were applied as the bibliometric indicators. Briefly, productivity was measured by the number of publications (NP). The impact was measured by the number of total citations (TC) and average article citations per year (AC). H-index was used to predict future achievement and evaluate academic achievements by integrating productivity and impact. Besides, the latest impact factor (IF) based on the latest Journal Citation Reports was also chosen as an indicator reflecting the quality and impact of medical sources.To comprehend the most highlighted keywords in the GAM field intuitively and quickly, a word cloud was constructed to extract the author's keywords. To deeply understand the categories and main information of the GAM field, a co-occurrence analysis of the author's keywords was carried out. Furthermore, the analysis of the most locally cited publications can be an important tool to measure the contribution of an article in a selected field, which may facilitate the researchers in finding innovative studies. Additionally, the trend topics analysis can help us to understand the research trends in the recent 20 years, thereby predicting future research hotspots.Until 16 January 2022, a total of 1,224 publications on GAM met our inclusion criteria and were eligible for subsequent bibliometric analyses, including 1,053 original articles and 171 reviews. The detailed process for screening and enrollment is presented in Since 2002, the number of publications in the GAM field has elevated from 11 to 253 in 2021. As shown in As depicted in The top 20 most cited countries measured by the number of citations are shown in In GAM-related publications, a total of 6,884 listed authors were retrieved for the subsequent analysis. Neuro-oncology had the largest number regarding the TCs , with Cancer Research  and Clinical Cancer Research  ranking second and third, respectively. Meanwhile, Neuro-oncology also shared the highest H-index  have reached a balance between the yield and quality of studies on GAM. Paying attention to these top sources will facilitate us in grasping the frontiers of the research field of GAM, and publishing articles in these journals will contribute to the academic dissemination of our own research results. Of the top three authors in the GAM field, two are from the United States, and they all focused on the interaction between GAM and other components in the glioma microenvironment (According to the analysis of countries, the United States ranked first in terms of TC and NP, suggesting that it was a highly productive and influential country in GAM-related research . Howeverironment , 28–30. As shown in the red cluster presented in in vitro experiments on cell lines such as THP-1 and RAW264.7. The THP-1 cell line was cultured from the blood of a boy with acute monocytic leukemia, and RAW264.7 represents a mouse leukemia cell line of monocyte (in vitro study could not accurately reflect the actual functional status of GAM (in vivo experiments are an urgent need for exploring the heterogeneity of GAM. Meanwhile, emerging evidence has implied that GAM in glioma could not be simply divided into M1 and M2 subtypes, which came from in vitro experiments (The heterogeneity of GAM in the glioma microenvironment also represented a research focus according to the blue cluster in monocyte –38. Uponmonocyte . Using cs of GAM . For exas of GAM . Thus, meriments . In GBM eriments . With theriments . Ochockaeriments . Therefovia activating the α6β1 integrin/AKT pathway (The cross-talk between GAM and CSC is a topic of great concern . Increas pathway . Mirrori pathway . Thus, f+ T cells are rare in GBM tissues, they cannot mediate effective antitumor immune responses (In recent years, immunotherapies-related studies have become a trendy topic according to esponses . Therefoesponses . Future Similarly, the expression of PD-1 and PD-L1 on GAM has been a focus in this field, as presented by the purple cluster in Nonetheless, this study had several limitations. First, merely original articles and review articles written in English were included. Second, analysis based on the R package “BiblioShiny” might omit some information since it could not analyze the full text of enrolled publications. Third, only data obtained from the WoS database were included in this study; other databases need to be analyzed in a future study. Finally, the database updates continuously and only relevant records from 2002 to 2021 were taken into consideration in the current study. Therefore, a discrepancy might exist between the bibliometric analysis and the real status of publications on GAM.In conclusion, we performed an integrated bibliometric analysis of publications on GAM regarding different countries, authors, and sources, with the comprehensive mapping of the research hotspots over the past 20 years. Moreover, we also predicted the research trends of GAM-related studies. We hope our study can reflect the current status and novel directions for GAM research, thereby facilitating scholars to obtain more innovative research and rapid development in this field.The original contributions presented in the study are included in the article/Y-yL, R-qY, and L-yL conceived the bibliometric analysis. J-lL, Y-xL, and B-YT were responsible for the data interpretation. Y-yL and R-qY co-wrote the paper. H-yL and ZL undertook data collection. The final manuscript was approved by LC and Y-mY. All authors contributed to the article and approved the submitted version.


Age was positively correlated to disease duration and severity in MS . No differences emerged for quantitative and qualitative IIS determinations. (4) Discussion: Although the main difference between males and females concerns the function of BCSFB assessed by QAlb, this sexual dimorphism does not affect the determination of the IIS evaluated both by quantitative and qualitative methods.(1) Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that mainly affects young adults and females more than males. The detection of intrathecal IgG synthesis (IIS) on cerebrospinal fluid (CSF) analysis supports the diagnosis of MS. A sexual dimorphism has recently been described in CSF protein content. (2) Methods: Clinical and laboratory data from 340 MS patients  and 89 people with clinically isolated syndrome (CIS)  were retrospectively analyzed to assess the presence of variables affected by sex and age. (3) Results: In MS, the albumin quotient (QAlb), reflecting the blood–CSF barrier (BCSFB) function, was higher in males (5.6 vs. 4.34) and correlated to age with a constant difference between sexes (F = 41.71). In CIS patients, QAlb increased with age only in males ( Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) . It mainAlmost 85% of people with MS have a relapsing-remitting course characterized by clinical relapses alternating with phases of well-being . BesidesThe first clinical manifestation of MS is known as CIS , which by definition implies a monophasic condition . MS diagCSF is a watery fluid that permeates the entire CNS. It is mainly produced in the choroid plexuses of the cerebral ventricles and is largely similar to a plasma ultrafiltrate in that most CSF proteins are plasma-derived ,11. For In recent years, the existence of sexual dimorphism at the level of CSF protein content has become increasingly evident, and in particular, these sex-related differences seem to concern all the concentrations of plasma-derived proteins ,15,16,17In light of the discrepancies between males and females in the onset and course of multiple sclerosis and of the effects of sex and age on CSF protein content and BCSFB permeability, this study aims to investigate whether sex and age have an impact on CSF analysis used to support the diagnosis of MS.Anonymized clinical and laboratory data were collected retrospectively from patients admitted to the three centers participating in the study: (i) Ferrara, northern Italy; (ii) San Giovanni Rotondo, southern Italy; and (iii) Ulm, Germany. The study was approved by the Medical Ethics in Research Committee of the coordinating center of Ferrara, “Comitato Etico di Area Vasta Emilia Centro della Regione Emilia-Romagna” . Sampling, analysis, and data collection were performed with the approval of the respective local ethics committees in all participating centers, and informed consent was obtained from each patient upon admission.All pre-analytical and analytical procedures were performed according to good clinical practice and following international guidelines ,20,21. TThe “time of the study”, for all patients, refers to the moment they underwent lumbar puncture for diagnostic purposes.Three different cohorts of patients were included in this study.Cohort 1 included patients hospitalized from 2005 to 2017 at the “S. Anna” University Hospital , in Ferrara, northern Italy. Data from 266 patients with a definitive diagnosis of MS were included in the study. Patients with CIS were not included in this cohort.Cohort 2 included patients hospitalized from 2013 to 2020 at the Hospital “Casa sollievo della sofferenza” in San Giovanni Rotondo (FG), southern Italy. Seventy-six MS patients were identified, and data were collected for the study. Moreover, in this case, CIS patients were excluded.Cohort 3 included patients hospitalized from 2004 to 2011 at the Department of Neurology, University Hospital Ulm, Ulm, Germany. Data from 89 CIS patients were collected and included in the study.None of the patients included in the study had received treatment with immunosuppressants or immunomodulatory drugs, including steroids, at the time of sampling.For MS patients, relapse was defined as the onset of new or recurrent signs or symptoms or the worsening of already present neurological abnormalities persisting for at least 24 h in the absence of fever and preceded by at least 1 month of stable or improved neurological state . For allPaired CSF and serum samples were obtained during hospitalization as a part of the diagnostic work-up. The quantitative analysis consisted of the evaluation of the BCSFB permeability with the use of QAlb and in the determination of an IIS through mathematical indexes. Albumin quotient was calculated according to the formula: Normal QAlb values were considered as <6.5 for patients aged 15–40 years, <8.0 for patients aged 41–60 years, and <9.0 for patients over 60 years ,23,24. ACSF/[IgG]serum × 1000;Quantification of the IIS was done with both linear and hyperbolic mathematical formulas as follows:To calculate the IgG intrathecal fraction (IF)The Normal limits were considered 0.7 and 0 for IgG index and IF, respectively.Qualitative analysis consisted of the research of IgG OCBs in CSF with the use of the “gold standard” of isoelectric focusing on an agarose gel followed by IgG-specific immunofixation. The following CSF patterns were considered: pattern 1 = absence of IgG OCBs; pattern 2 = 2 or more CSF-restricted IgG OCBs; pattern 3 = 2 or more CSF-restricted IgG OCBs with additional identical IgG OCBs in CSF and serum; pattern 4 = 2 or more identical IgG OCBs in CSF and serum; and pattern 5 = some identical IgG OCBs in CSF and serum in a restricted pH range. Only patterns 2 and 3 were considered suggestive of an intrathecal IgG synthesis . https://www.graphpad.com/quickcalcs/kappa1/ (accessed on 24 May 2022).After checking for normality with the Kolmogorov–Smirnov test, the majority of continuous variables presented a non-normal distribution . A non-parametric approach was adopted: data were reported as the median and interquartile range (IQR), and Mann–Whitney test was used for all comparisons. Categorical variables were reported as counts (percentages), and the Fisher’s exact test was used to test significance. Correlations were investigated with the Spearman test. In regression analysis, F-test was used to compare the fits of linear models. The agreement with quantitative and qualitative methods for the determination of an IIS was calculated through the Cohen’s kappa coefficient with a free available tool : https:/p-values < 0.05 were considered statistically significant. Prism 9 for MacOS  was used for the statistical analysis.Kappa values were interpreted as follows: 0.00–0.20, slight agreement; 0.21–0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, substantial agreement; and 0.81–1.00, almost perfect agreement. Two-tailed The demographic and clinical characteristics of the study population are reported in p > 0.05). The same variables showed no sex-related differences between MS patients in cohort 1 and 2 . Owing to this lack of differences, cohorts 1 and 2 were merged in all subsequent analyses.Cohort 1 and cohort 2 included patients with MS, while cohort 3 included patients with CIS. At the study time, there were no differences between males and females within the three cohorts of patients for age, clinical activity, disease duration, and severity , and the percentage of people with an altered QAlb, suggestive of BCSFB impairment, was greater in male MS patients compared to females (33.0 vs. 10.4%). There were no differences between male and female patients for the presence of an IIS using either mathematical formulas or the research of CSF-restricted IgG OCB in MS and CIS subgroups. The comparisons between MS and CIS subjects, grouped by sex, showed higher QAlb values in females with CIS than in MS (5.2 vs. 4.34). Other comparisons between MS and CIS groups did not reach a statistical significance for the quantitative and qualitative determination of an IIS.p > 0.05).To investigate a possible role of an altered BCSFB permeability, MS patients were grouped by the presence or absence of an altered QAlb, and differences in EDSS and disease duration were checked in patients analyzed as a whole and grouped by sex. As reported in In MS patients, age, expressed in years, was correlated to disease duration and disease severity, scored by EDSS . r = 0.3502 and p < 0.0001) in male  and in female subgroups . Age was also positively correlated to EDSS in the whole MS group  in male  and female subgroups . EDSS and disease duration were positively correlated to each other in the overall population and in female subgroup , while they did not correlate in male subgroup.Age positively correlated to disease duration in MS patients analyzed as a whole  and Reiber’s hyperbolic formula were used to calculate the intrathecal fraction (IF) . r = 0.1807 and p = 0.0008) and in male  and female subgroups . In a simple linear regression model, the regression line was constantly higher in male than in female MS patients . Age was also positively correlated to QAlb in CIS patients analyzed as a whole  and in the male subgroup . In CIS patients, simple linear regression analysis was not performed due to the lack of correlation between age and QAlb in the female subgroup. A weak statistical significance was found for a positive correlation between age and the linear IgG index in male CIS patients . All other correlations between age and quantitative indexes of IIS did not yield statistically significant results in both MS and CIS patients . As reported in p > 0.05). While grouping patients by the presence or absence of CSF-restricted OCB, there were no differences in age in MS and CIS patients analyzed as a whole and grouped by sex (data not shown).The “gold standard” of the CSF-restricted IgG OCB was used to assess the presence of an IIS in MS and CIS patients. As reported in The performance of the two mathematical indexes for the quantitative determination of an IIS, the linear IgG index  and Reiber’s hyperbolic formula , were determined in MS and CIS patients . For both formulas, the “gold standard” of the CSF-restricted IgG OCB was used to calculate: (i) concordance through the Cohen’s kappa, (ii) sensitivity, (iii) specificity, and (iv) positive and (v) negative predictive value . In MS patients, the IgG index reached a moderate agreement with the gold standard only in females (kappa = 0.407), but in general, both indexes showed a slight agreement or a fair agreement with the gold standard . In CIS patients, concerning the gold standard, both indexes showed a slight agreement in all subgroups . In MS patients, the average sensitivity of the IgG index and the Reiber’s formula was 0.6699 and 0.6241, respectively, while in CIS subjects, they were 0.4749 and 0.4338, respectively. In both MS and CIS patients, the specificity of the two indexes was always equal to or greater than 0.9 , and the PPV was never less than 0.97 , while the NPV showed lower value, especially in the CIS population .In this study, we applied, for the first time, a sex-specific approach to a retrospective study of the laboratory results of CSF analysis performed to support the diagnosis of MS. If, on the one hand, our results substantially confirm that the main difference between males and females concerns the BCSFB function assessed by QAlb, on the other hand, they demonstrate that this sexual dimorphism does not affect the determination of the intrathecal IgG synthesis evaluated both by quantitative and qualitative methods. Moreover, our results show that age has a different effect on the increase in BCSFB function in the two sexes, with a greater impact in males than females in both MS and CIS patients.Gender medicine is considered the study of how diseases differ between men and women in terms of prevention, clinical symptoms, therapeutic approach, prognosis, and psychological and social impact and is a relatively recent cultural approach that is not yet fully applied. This way of carrying out biomedical research has made it possible to highlight differences that were previously existent but which had not yet been taken into consideration. In the case of CSF analysis for the classification of the neurological patient, a sex-specific approach to laboratory data has, in recent years, shown a greater permeability of BCSFB in males compared to females with a consequent increase in protein transferred from the blood to CSF ,17,18,19Irrespective of the underlying pathophysiology, which remains to be clarified, this sexual dimorphism impacts daily clinical practice. In fact, male patients are likely to receive a laboratory report suggesting altered BCSFB function three times more often than females regardless of the disorder they suffer from .CSF analysis is a widely used laboratory tool to support the diagnosis of neurological disorders and plays a particularly important role in supporting the diagnosis of MS . QuantitIn our two patient populations, each analyzed as a whole, we confirmed the role of age in increasing BCSFB function. However, when patients were grouped by sex, we found that this aging effect was less evident or even absent in women with MS or CIS, respectively. These data confirm that the use of the same thresholds as a function of age for the QAlb values in the two sexes can create criticalities and evaluation disparities ,18,19.Age was also correlated to disease duration and severity in overall MS population as well as in male and female subgroups, confirming an effect of aging on disease progression . DespiteFinally, our results seem to indicate that the IIS, detected through the gold standard of CSF-restricted OCB, was not influenced by either sex or age. Although a lower percentage of positivity emerges in females over 40 years of age (76%) compared to the average of the other subgroups , this reduced positivity in women does not, however, reach statistical significance. Previous studies associated the absence of CSF-restricted OCB with increasing age, without a gender specificity ,35, or wTo its observational and retrospective nature, this study has some limitations. First of all, as already pointed out, an analysis of the MRI data is lacking, Furthermore, data on the clinical evolution of the various patients were not collected, and it was therefore not possible to evaluate the long-term effects of the sex-related differences that emerged.Taken together, our data confirm the need to review the thresholds used for the assessment of QAlb according to the patient’s sex to avoid a potential underestimation of the BCSFB function in women and/or an overestimation in men. Furthermore, our data show a different role played by age on BCSFB function in the two sexes, with a greater impact on the male sex. Finally, the presence of this sexual dimorphism at the level of CSF protein content does not seem to influence the determination of the intrathecal synthesis of IgG carried out with both quantitative and qualitative methods.In an era of cost-effective personalized medicine, future studies on the role of sex-related differences in CSF protein content are recommended. In addition, application of a sex-specific approach is advisable for all studies looking for soluble biomarkers, especially those biomarkers that are related to BCSFB function.