This study aimed to compare the functional connectivity (FC) assessed during acute stress and recovery after stress using the Montreal imaging stress task (MIST) in adults in their 20s and 30s with Korean Perceived Stress Scale (PSS) scores between 15 and 19 points inclusive. Four seed networks, including the salience network, default mode network, frontoparietal network, and dorsal attention network, were specified to extract the results. Healthy male and female adults who were required to make an effort to relieve stress were exposed to acute stress tasks, and the most common FCs were observed in the salience network, default mode network, and frontoparietal network during the stress and recovery phases. Compared to the stress phase, the increased effect size was significantly different in the recovery phase. In the stress phase, characteristically common FCs were observed in the dorsal attention network. During the recovery period, Salience network  and Salience network /Salience network , Salience network (AInsula) and Salience network (RPFC), and Default Mode network (posterior cingulate) cortex, PCC) and fronto-parietal network  FC were characteristically observed. Stress is a major risk factor for psychiatric disorders. There are many kinds of stress: acute, chronic, psychological, physical, and so on. Acute stress is a short-term response to a sudden, specific challenge or demand, such as a job interview, car accident, or public-speaking event. This type of stress is normal and often motivating, but can become problematic if it becomes chronic . ChronicStudies have demonstrated the patterns of brain activity associated with stress . Among tStudies have shown that exposure to stress can lead to changes in FC within the brain, particularly in the amygdala and other regions involved in the stress response, such as the hypothalamus, insula, and anterior cingulate cortex. For example, studies have reported increased FC between the amygdala and hypothalamus during exposure to acute stress, suggesting that stress leads to a heightened emotional and physiological response ,11. AddiBy comparing the FC in the stress and recovery periods, researchers can identify the specific brain regions and connections that are affected by stress, and the mechanisms by which they recover. Furthermore, comparisons of FC during stress and recovery can help to identify potential compensatory mechanisms that may be involved in the recovery process, as well as potential targets for interventions aimed at improving the brain’s resilience to stress. In conclusion, comparing the FC in the stress and recovery periods is important for understanding the changes in brain activity that occur in response to stress, and for identifying potential targets for interventions to improve stress resilience.This study aims to compare the FC assessed during acute stress and recovery after stress using the Montreal imaging stress task (MIST) in adults in their 20s and 30s with stress scores between 15 and 19 points inclusive.In this study, 37 healthy adult men and women (24.4 ± 4.3 years), right-handed, with normal cognitive abilities, were tested. Recruited subjects ranged in age from 20 to 33 years, and were 20 females (24.6 ± 4.2 years) and 17 males (25.1 ± 3.0 years). To measure the stress level, Korean perceived stress scale (PSS)  was usedThe acute stress-induced task was presented using the MIST paradigm. MIST was designed by Dedovic et al.  to inducTo induce stress, the participants were asked to calculate the arithmetic operations by difficulty level with a time limit of 3 s, and whether the answers were correct and their average scores were provided. In addition, they were asked to maintain a pre-intervention total score of 95 points.The study design is presented in Images were scanned with a 3T MRI system  using a standard 16-channel head coil. Single-shot echo-planar fMRI scans were acquired in 29 continuous slices, parallel to the anterior commissure–posterior commissure line. The parameters for fMRI were: TR/TE, 2000/20 ms; FOV, 240 mm; flip angle, 77°; matrix, 128 × 128; slice thickness, 3 mm; and voxel size, 3.0 mm × 3.0 mm × 3.0 mm. Anatomical images were obtained using a T1-weighted 3D MPRAGE sequence with the following parameters: TR/TE, 1900/2.52 ms; FOV, 256 mm; flip angle, 9°; matrix, 256 × 256; slice thickness, 1 mm; and voxel size, 1.0 × 1.0 × 1.0 mm.https://www.fil.ion.ucl.ac.uk/spm/software/spm12/; Wellcome Department of Cognitive Neurology, London, UK). All functional images were aligned with the anatomic images of the study using affine transformation routines built into the SPM 12 program. Time series of images acquired from the same participant were realigned using a least-squares approach and a 6-parameter (rigid body) spatial transformation. The first image in the list specified by the user was used as a reference to which all subsequent scans were realigned. The realigned scans were co-registered with the participant’s anatomic images obtained during each session and normalized to a template image in SPM 12, which uses the space defined by the Montreal Neurologic Institute. Motion correction was performed using a Sinc interpolation. Time-series data were filtered with a 240 s high-pass filter to remove artifacts due to cardiorespiratory and other cyclical influences. Additionally, the co-registered T1 and T2 images were used in a multichannel segmentation routine to extract probabilistic maps of six tissue classes: gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), bone, soft tissue, and residual noise. The functional map was smoothened with an 8 mm isotropic Gaussian kernel before statistical analysis. Statistical analysis was performed at the group level using a general linear model and the theory of Gaussian random fields implemented in SPM 12.The fMRI data were analyzed with the Statistical Parameter Mapping (SPM 12) software, version 12 (https://web.conn-toolbox.org/), which was implemented in the SPM 12 software. ROI-to-ROI analysis was conducted to examine which FC was implicated in inter-individual variations using the CONN toolbox. We predefined 105 ROIs in the CONN toolbox based on the Harvard–Oxford cortical and subcortical structural atlases (https://neurovault.org/collections/262/). The brainstem and cerebellum were excluded. We selected statistically significant ROI-to-ROI connections that correlated with the performance of the recognition tests by cluster-level inferences based on spatial pairwise clustering statistics (SPC) [p < 0.01 (uncorrected). The resulting suprathreshold areas defined a series of non-overlapping clusters. Cluster-level FDR-corrected p < 0.05 was applied.To process the fMRI data, we used the functional connectivity (CONN) toolbox (cs (SPC)  with deft-test (IBM SPSS Statistics 27) was performed to examine whether the effect size differs by phase.The effect size of FC, which was common in the stress phase and the recovery phase, was extracted, and paired FC was obtained from the data measured during the stress and recovery phases . FCs thap = 0.01), DMN (PCC) and FPN  (p = 0.035), SN  and SN  (p = 0.045), and FPN  and SN (ACC) (p = 0.008).FCs that were specifically observed in the stress phase included the DMN (PCC) and SN (ACC), DAN  and DAN , and SN  and FPN .In the recovery phase, connectivity between the SN (ACC) and FPN , SN  and SN (ACC)/RPFC, L), SN  and SN , and SN  and frontoparietal network  was observed, while FC of FPN  and SN , was observed. FC of the DMN (MPFC) and SN (ACC)/FPN , and DMN (PCC) and FPN /SN  was observed.The DMN, SN, DAN, and FPN are four different brain networks that have been implicated in the regulation of stress. The DMN is a network of brain regions that is active during rest and deactivated during task performance. Acute stress has been found to increase FC within the DMN and decrease FC between the DMN and task-positive network (TPN), which is a network of brain regions that is active during task performance ,20. ThesStudies have found that acute stress leads to alterations in FC in various brain networks, including the DMN, SN, and central executive network ,31. ThesThis study compared the effect sizes of common FCs in the stress and recovery phases, and showed that the effect sizes of the connection within the SN , and between the DMN (PCC) and FPN , and FPN  and SN (ACC) increased during the recovery phase compared to the stress phase. This suggests that the FC between these brain regions  during the rest period after stress-inducing tasks may be stronger compared to that during the tasks themselves. This increased FC could indicate a heightened state of recovery and restoration in the brain after stress.This study demonstrated that when stress was induced, FCs between the DMN (PCC) and SN (ACC), within the DAN , and between the SN  and FPN  were specifically observed. In terms of the FC between the DMN and SN during stress, some studies have found that the connectivity between the PCC, a key node in the DMN, and the ACC, a key node in the SN, increases during stress, while others have found that this connectivity decreases. In terms of the FC between the DAN and SN, some studies have found that the connectivity between the IPS in the DAN and the SMG in the SN increases during stress, while others have found that it decreases. When considering the FC between the FPN and SN, some studies have found that the connectivity between the PCC in the FPN and the SMG in the SN increases during stress, while others have found that it decreases. In conclusion, the FC between different brain networks during stress-inducing tasks is still an active area of research, and the results are not yet consistent across studies. Further research is needed to fully understand the underlying mechanisms and to determine the generalizability of these findings.Studies have found that performing MIST leads to alterations in FC in the DMN, which is a network of brain regions that is active during rest and deactivated during task performance. Specifically, MIST has been found to increase FC within the DMN and decrease the same between the DMN and TPN . These cHealthy adults who are required to make an effort to relieve stress were exposed to acute stress tasks and the most common FCs were observed in the SN, DMN, and FPN during the stress and recovery phases. Compared to the stress phase, the increased effect size was significantly different in the recovery phase. In the stress phase, characteristically common FCs were observed in the DAN. During the recovery phase, FCs were observed within the SN / RPFC; A Insula and RPFC), and between the DMN (PCC) and FPN (LPFC). Compared to previous studies, our findings suggest a complex network of interactions between different brain regions during the post-stress recovery phase. The FC between the SN and FPN suggests a role for these regions in modulating the effects of stress . SimilarThe comparison of FC in the stress and recovery phases is important because it provides insight into the changes in brain function that occur as a response to stress, and how the brain returns to a state of homeostasis during recovery. The common FC patterns in both phases suggest the presence of similar neural networks involved in the stress and recovery processes. The differences in FC between the stress and recovery phases, such as the decrease in the within-DAN  and SAN -FPN  connectivity in the stress phase and the emergence of new functional connections in the recovery phase, suggest the presence of dynamic changes in brain function as a response to stress and recovery.These findings have implications for the understanding of stress-related disorders and the development of potential treatments. For example, changes in FC in the stress and recovery phases may be used as markers of stress-related disorders and their severity, and interventions that target specific FC patterns may be used to alleviate symptoms and improve recovery.There are several limitations to this study that should be considered. First, the sample size of the study is relatively small, which may limit the generalizability of the results to other populations. Second, the study only included individuals who experienced acute stress, which may not fully capture the effects of chronic stress or stress experienced in different contexts. Additionally, the exclusion and inclusion criteria of the study were not well-defined, which may have introduced confounding factors into the analysis.A study on the differences in brain neural mechanisms during stress and recovery after stress through a comparative study between a normal group and a group with a high-stress index  is needed. In addition, in stress studies, considering the effects of many comorbid factors , it is thought that further research is needed to extract conclusions that can generalize the neural mechanisms of the brain caused by stress.


Psoriasis vulgaris is a chronic skin disease which is related to cardiovascular and metabolic diseases. In the pathogenesis of these diseases, adipokines, including retinol binding protein-4 (RBP-4), play crucial roles. Studies have also shown that RBP-4 might be a meaningful factor in psoriasis however, relying on the analysis of a single study have some drawbacks.To evaluate the association between RBP-4 and psoriasis vulgaris more comprehensively.p < 0.05 was defined as significance.Six databases were searched to obtain relevant publications. The selection of the included studies was based on a criteria. The standardized mean difference (SMD) was used for analysis. A value of p < 0.05). In five studies containing the data of RBP-4 levels before and after treatment, no significance was found, either for RBP-4 levels in the after-treatment group and control group in these five studies (p > 0.05). Subgroup analysis was conducted based on the therapy method. Patients with systematic treatment showed a significant decrease of BRP-4 level after the treatment .Seven studies were included, with 271 cases and 235 controls. In the comparison between patients and controls, the merged data suggested that levels of RBP-4 were significantly higher in patients (SMD = 0.61, 95%CI: 0.14, 1.07, For patients with psoriasis vulgaris, RBP-4 levels are elevated, and systematic treatment can lower these levels. RBP-4 might act as a key indicator for the diagnosis, efficacy assessment, and comorbidity monitoring of the patients. Further studies with well-designed protocols and enlarged populations are still needed. Psoriasis is a chronic skin disease associated with the immune system. Worldwide, psoriasis affects about 125 million people. Males and females are equally affected, while adults are more affected compared with children , 4. SeveIn the pathogenesis of CVD and metabolic diseases, adipokines play a crucial role in regulation and mediation , 11. RetIn total, six databases—PubMed, Ovid, EBSCO, Web of Science, Sinomed, and CNKI—were searched up to 31 January 2022. The words searched for were “Retinol Binding Protein-4” and “Psoriasis.” In PubMed, the search strategy was “((((Retinol Binding Protein-4[Title/Abstract]) OR (Retinol Binding Protein 4[Title/Abstract])) OR (RBP-4[Title/Abstract])) OR (RBP4[Title/Abstract])) AND (Psoriasis [Title/Abstract]).”published studies on the relationship between retinol binding protein-4 and psoriasis vulgaris;case–control or cohort studies;patients with psoriasis vulgaris were included in the case group;healthy subjects or subjects without related diseases were included in the control group;the level of serum retinol binding protein-4 levels was demonstrated, or enough information was provided to calculate the levels for both groups;the method and unit of measurement for RBP-4 detection were provided andthe language was Chinese or English.We formulated inclusion and exclusion criteria for the selection. Publications meeting the following requirements were included:publications from conferences, case series or reports, review articles, commentary articles, animal studies, or graduation theses;duplicates of previous publication (s);cases with patients with other types of psoriasis, including erythrodermic psoriasis, generalized pustular psoriasis, or psoriasis arthritis; andthe level of retinol binding protein-4 was not provided or could not calculated.Publications with at least one of the following items were excluded:There were two investigators (GG and YC) who conducted the selection based on the criteria independently. When disagreement occurred, another investigator (HC) would check the selection and make the final decision.The following information was extracted from each included study: (1) first author’s name and publication year, defined as Study ID; (2) country where the study was conducted; (3) gender of the subjects in both groups; (4) sample size in both groups; (5) age of the subjects in both groups; (6) treatment methods and duration of the study with comparison before and after treatment; (7) method and unit of measurement for RBP-4 detection; (8) levels of RBP-4 in both groups.The extraction was completed by two investigators (GG and YC). Then, another investigator (HC) checked the information and made modifications.The types of study were limited to case–control and cohort studies, so the Newcastle–Ottawa Scale (NOS) was applied to evaluate the study quality . AssessmTo evaluate relationships, the standardized mean difference (SMD) was used. In different studies, the units of measurement used in the detection of RBP-4 varied, and the standardized mean difference (SMD) was used to evaluate the relationship, in order to eliminate the influence brought by the measurements and units. The form of Mean ± SD was used in the data combination procedure of analysis. If the original data in the publication was not in the form of Mean ± SD, the methods from Luo and Wan were applied for calculation and transformation , 16.2 test and Q-statistical test were employed to test the heterogeneity. With a value of p > 0.10 and I2 < 50%, no significance was shown in the heterogeneity, thus the fixed-effects model was applied. Conversely, the random-effects model was applied if heterogeneity was found to be significant. For the comparisons with significant heterogeneity, subgroup analysis was introduced to find the source of heterogeneity. Sensitivity analysis was performed to test the influence of a single study to the total effect of synthesis. In this procedure, every study included in the comparison was ignored one by one. If five studies or more were included in a comparison, funnel plots were performed to estimate the publication bias. For all comparisons, a value of p < 0.05 was defined as statistical significance , Africa (Egypt), and Asia (China). The methods of detection were all ELISA. Five studies investigated the changes in RBP-4 levels before and after treatment . The spep < 0.05; All seven studies reported the levels of RBP-4 in patients with psoriasis vulgaris and in control subjects. The heterogeneity between the included studies was significant, so the random-effects model was applied. The merged data suggested that the levels of RBP-4 were significantly higher in patients with psoriasis vulgaris , although no significance was shown in the total effect. Moreover, there was one study that included patients under different treatment methods (p < 0.05; In the comparison between the levels before and after treatment, the methods were different, so subgroup analysis was conducted based on topical or systematic therapy. When all the five studies were included, patients undergoing systematic treatment showed a significant decrease (SMD = −0.64, 95%CI: −1.26, −0.03,  methods ; and it p of the total effect was equal to 0.05, with SMD = 0.56, 95%CI: 0.01, 1.12. At the same time, when the other six studies were ignored separately, the value of p of the total effect was not altered, which indicated the results were robust and credible in these seven studies.In the comparison between the levels in cases and in controls, when the 2013 Romani et al. study was ignored, the value of p < 0.05 (p of the total effect in five studies, this indicated the results in these comparisons were not completely robust. However, the value of p was 0.03, which is approximate to 0.05, and when the other four studies were ignored separately, the value of p was not altered. Additionally, the sample size in this study was not the largest; therefore, no potential impact was considered on the final results. All three comparisons included at least five studies. The funnel plots were all generally symmetrical, indicating a low publication bias (In the comparison between the levels before and after the treatment, when the 2016 Coban et al. study was ignored, a significant decrease was shown after treatment, with SMD = −0.52, 95%CI: −0.99, −0.04, p < 0.05 . Since iion bias .In this study, we investigated the relationship between retinol binding protein-4 and psoriasis vulgaris through meta-analysis. Our study included seven published studies, comprising 271 psoriasis patients and 235 control subjects. We found that levels of RBP-4 were significantly higher in patients with psoriasis vulgaris, and for patients with systematic treatment, a significant decrease of RBP-4 level was shown. Beyond skin lesions, psoriasis also affects multiple organs or systems such as cardiovascular diseases or metabolic diseases, in which RBP-4 plays vital roles , 25. TheThe efficacy evaluation of psoriasis is relatively simple to conduct, and is assessed from the changes in plaques and the life quality of patients. However, biomarkers are still needed to assess the underlying inflammation and long-term efficacy, or to predict the efficacy in refractory or severe patients. Additionally, certain indicators can reflect the condition of the patients with comorbidities; for example, a recent study found that gingival crevicular fluid miRNAs from periodontitis patients were associated with cardiovascular disease risk . As a reFrom the comparison of levels in patients at baseline and in controls in the seven studies, we found that the levels of RBP-4 increased significantly in patients with psoriasis vulgaris compared with control subjects. In previous studies, different results have been shown. For example, Gul et al.  and RomaThere were five studies included that contained the data of RBP-4 level before and after treatment. Therefore, we compared the RBP-4 levels before and after treatment, and no significance was found. Then, when we compared the levels in patients after treatment to the levels in control subjects in these five studies, no significance was found either. Since the level of RBP-4 was higher than that in controls according to our previous analysis with seven studies, we further conducted subgroup analysis by topical or systematic therapy and found that the levels decreased significantly in patients undergoing systematic treatment compared with before the treatment. Additionally, we excluded the study with mixed methods , and sigBiologic therapy of psoriasis has experienced rapid development in recent years . In our In this study, three comparisons were conducted: the levels of RBP-4 in patients at baseline and in controls in seven studies; the levels of RBP-4 in patients after and before treatment in five studies; and the levels of RBP-4 in patients after treatment and in controls in five studies. The heterogeneities were all significant, so subgroup analysis was needed. When we performed subgroup analysis by different region, we found that the levels of RBP-4 were not elevated significantly in patients in Asia and Europe. Region could be a source of the heterogeneity. Among different regions, there might be differences in genetic backgrounds , 37, whiSome limitations existed in this study. First, the sensitivity analysis showed that the results were not perfectly robust, and further studies with more cases including the levels before and after topical/systematic treatments are needed. Secondly, the relationship between severity and RBP-4 levels was not analyzed, because the original datasets were not attainable. For the same reason, the relationship between the efficacy and changes was not investigated. Additionally, it would be more beneficial to analyze RBP-4 in psoriasis patients with different comorbidities, especially cardiovascular disease and metabolic diseases. Additionally, in the subgroup analysis based on treatment, further classification of specific treatment methods was not possible to conduct due to the limited studies. In conclusion, larger sample sizes with different treatment strategies with different comorbidities and documenting detailed before/after levels of RBP-4 would help generate more thorough and robust results.For patients with psoriasis vulgaris, the levels of retinol binding protein-4 are elevated, and systematic treatment can lower RBP-4 levels. As RBP-4 plays an important role in psoriasis, CVD, and metabolic disease, it might act as a key indicator for the diagnosis and efficacy assessment of psoriasis and especially for the mutual pathogenic factors of the comorbidities in psoriasis patients, which might help contribute to future mutually beneficial treatment strategies. Therefore, further studies with well-designed protocols and enlarged populations are still needed.The original contributions presented in the study are included in the article/GG and YC conducted the literature research and data extraction. GG wrote this manuscript. HC designed the study, edited the manuscript, evaluated methodological quality, analyzed the data, and created all the figures and tables. All 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.


It is common practice to associate schizophrenia (SCZ) patients with substance use. The most commonly used substances in China are tobacco and alcohol. However, few studies have focused on alcohol consumption itself in patients with SCZ. Thus the purpose of this study was to detect the prevalence of alcohol use and associated clinical factors in Chinese patients with SCZ.A total of 616 male inpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for SCZ participated in this study. A detailed questionnaire, including data on alcohol consumption was used to collect demographic and clinical information on all patients. The five-factor model of the positive and negative syndrome scale (PANSS) was adopted to assess psychiatric symptoms.p = 0.004), more likely to have suicide attempts (p = 0.002) and suicidal ideation (p = 0.001), more severe positive (p < 0.001) and depressive symptoms (p = 0.034), but less severe negative symptoms (p = 0.04).In this study, 31.49% of SCZ inpatients had a history of alcohol use, and 82.9% of these patients abstained from alcohol use after the onset of SCZ. Compared to nondrinkers, patients who drank were more likely to smoke (These findings suggest that alcohol use is common during the lifetime of SCZ patients and that alcohol use may be associated with clinical symptoms in SCZ patients. Schizophrenia (SCZ) is a disabling psychiatric disorder with a high level of morbidity and mortality , 2. PatiPatients with psychiatric disorders are more likely to consume alcohol and become addicted compared to the general population . In addiPrior studies have demonstrated that alcohol can promote dopamine release, and long-term alcohol use can result in down regulation of dopamine receptors, which persists even during abstinence , 22. TheDespite the multifaceted effects of alcohol on SCZ patients, there is a lack of studies examining alcohol use in Chinese patients with SCZ. Because of the very low rate of alcohol consumption among women  compared to men , in the general Chinese population , only maN = (Zcrit)2P(1 − P)/D2, where N is the sample size of a study group. Zcrit value is given in the table of standard normal deviations corresponding to selected significance criteria and confidence interval (CI), Zcrit value of 1.96 at 95% CI, and D is tolerable error, which usually takes the value of 0.1P. Previous data has estimated the prevalence of schizophrenia patients with a history of alcohol consumption at P = 36.5%  18 to 75 years old, Chinese male; (2) confirmation of diagnostic criteria for schizophrenia, independently assessed by one of the four psychiatrists according to the Chinese version of the Structured Clinical Interview for DSM-5 (SCID); (3) continuous type, with a disease course of at least 2 years; (4) were on stable doses of antipsychotic medication for no less than 6 months prior to their participation in the present study.Each subject was assisted by trained researchers to complete a detailed questionnaire, including background information, social-demographic characteristics, alcohol use history, smoking status, suicidal behavior, and physical fitness.In the inpatient setting, patients experienced a similar environment, they received three meals per day, engaged in similar activities, and were restricted from using substances other than tobacco according to a fixed schedule.Prior to the start of this study, the Institutional Review Board of Beijing Huilongguan Hospital approved the study, and all participants signed a written informed consent form.Using a questionnaire, frequency of alcohol consumption (days per week) and number of standard drinks consumed  were measured. If a person consumed no more than two drinks of alcohol per day, they were classified as moderate drinkers for the purpose of assessing psychiatric symptoms. Furthermore, binge drinking refers to consuming five or more drinks on an occasion for men. Lifetime drinkers were defined as subjects who drank alcohol at least once a week for at least 6 months .A current smoker was defined as someone who smokes more than one cigarette per day in the past year . SuicidaThe positive and negative syndrome scale (PANSS) was adopted for the purpose of assessment psychiatric symptoms . The fivPANSS was assessed by four psychiatrists specially trained in standardized use. The inter-class correlation coefficient for the PANSS was greater than 0.8 during the repeated assessment.Analysis of variance (ANOVA) was conducted on demographic and clinical characteristics of drinkers and nondrinkers for continuous variables and chi squared for categorical variables. Analysis of covariance (ANCOVA) were conducted to control for the effects of related variables. Additional binary regression analysis was used to assess factors related to alcohol use history. Bonferroni corrections were applied to each trial to adjust for multiple testing. Statistical significance was set at 0.05 (two-tailed), and all statistical analyses were performed by R v. 3.6.2.Detailed types of alcohol consumption behaviors before and after illness onset are shown in p < 0.01) than those without a history of drinking. In addition, compared to nondrinkers, former drinkers were found to have more severe positive symptoms and depressive symptoms, while negative symptoms were less severe .In F = 13.38, p = 0.000), and the depression factor  remained significant between the 2 groups. Only differences in suicidal ideation and positive symptoms passed Bonferroni correction. In addition, after adjusting for age, age of onset, and types of antipsychotic medication, additional binary regression analysis confirmed that lifetime alcohol use was associated with smoking status , suicidal ideation  and positive symptoms .After adjusting for age, disease course, and antipsychotic medications, differences in positive symptoms , but there were no significant differences in any other variables between the two groups. In addition, 39.4% were on clozapine, and there were no significant differences in any variables between the clozapine and non-clozapine groups .Antipsychotic data were available for 616 patients, including 577 patients treated with atypical antipsychotics , 36 patients treated with typical antipsychotics , and 3 patients treated with unrecorded antipsychotics. No patient was on a combination of antipsychotics. The clinical characteristics of patients treated with typical and atypical anti psychotics were compared after adjusting for age and age at first hospitalization. The equivalent doses of antipsychotics were calculated by using chlorpromazine as the standard comparative drug . ResultsTo the best of our knowledge, this was the first study to investigate the effects of lifetime alcohol consumption on SCZ inpatients in China. This study revealed three main findings: (1) patients with a history of alcohol use were more likely to be smokers; (2) patients with a history of alcohol use had a higher incidence of suicidal behavior; (3) the positive symptom and depressive factor scores of drinkers were significantly higher than the nondrinkers’ scores, although the negative symptom score was significantly lower than that of nondrinkers.The current study found that 31.49% of the patients had a history of alcohol use, which is consistent with previous studies. In the general Chinese population, the current rate of male alcohol drinkers is 55.6% , which iSmoking in this study was closely linked to drinking behavior. These relationships were found not only in China , 41, butp = 0.002) and suicidal ideation (p = 0.001) between alcohol drinkers and non-drinkers, further regression analysis showed that lifetime drinking was not significantly associated with suicidal thoughts, as the p-value in the regression analysis was not less than 0.05 (p = 0.057). However, this result suggests that lifelong drinkers were more prone to suicidal behavior (suicide attempts or thoughts) than patients with no history of alcohol consumption. Alcohol use is common among suicide attempts  for the publication of any potentially identifiable images or data included in this article.XZ: study design. ML: study conduct. XW and ZW: data analysis. LW and YT: manuscript preparation. XL: data interpretation. ML, XW, ZW, XL, LW, YT, and XZ: manuscript revision. All authors contributed to the article and approved the submitted version.This work was supported by CAS Pioneer Hundred Talents Program and the National Natural Science Foundation of China (81371477), Capital Health Development Research Project (2016-4-2131), Beijing Excellent Talent Cultivation Funding Project (2016000021469G174). Design of the study, collection, analysis, interpretation of data, and writing were not influenced by the funding body.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.


Leonurus cardiaca L. extracts. The influence of the extraction method , as well as of the extract concentration on the characteristics of the nanoparticles, was studied using analytical methods, such as UV-Vis spectrometry, X-ray diffraction, dynamic light scattering, and transmission electron microscopy. Experimental data suggest that use of lower extract concentration leads to smaller dimensions nanoparticles, the same effect using the extract obtained by microwave-assisted extraction. The smallest recorded crystallite sizes (by X-ray diffraction) were under 3 nm. The antioxidant properties (determined by the DPPH assay) and the antimicrobial potential (determined against Gram-negative and Gram-positive strains) are enhanced by the phytosynthesis process (as demonstrated by the comparison of the nanoparticles’ properties with the parent extracts). The present work could also represent an important step in obtaining nanoparticles with enhanced properties and controlled morphologies, but also offers information on the phytosynthesis of metallic nanoparticles using low extract concentrations. The present work describes, for the first time in the literature, the phytosynthesis of silver nanoparticles using  The amazing world of plants offers new possibilities to obtain specific materials with a vast range of potential applications. Nowadays, plant-derived materials are used in various areas, from novel therapeutic instruments for disease treatment to environmental applications or development of sensory materials ,2,3. Duegreen synthesis methods, of particular interest is the phytosynthesis process  [During the present nanotechnological area, metallic or metal oxides nanoparticles find extensive application in different areas, from advanced sensors  to envirxtracts) ,16.Recent studies presented phytosynthesis of nanoparticles, such as noble metals, copper, zinc, iron, etc., with potential anticancer, antibacterial, antioxidant, anti-inflammatory, and antiviral properties, thus proposing them as good candidates in medical therapies ,18. The Leonurus (family Lamiaceae), Leonurus cardiaca L. is a perennial plant growing up to 1 m tall, with aerial stems growing from rhizomes and lobed leaves covered with bristles; it has pink flowers, grouped in clusters in the leaf axils [Known as the motherwort, belonging to the genus af axils ; the plaaf axils ,25. Moreaf axils , immunomaf axils , antimicaf axils , antioxiaf axils  effects,All these properties, and many others, are in strong correlation with the composition of the plant. Generally speaking, the composition of motherwort is dominated by furan diterpenes, alkaloids, sterol, iridoids, flavonoids, and minerals ; literatLeonurus genus (Leonurus japonicus Houtt.) was proven to be successfully applied for the phytosynthesis of silver nanoparticles with enhanced antibacterial properties [L. cardiaca aerial parts (as a source of bioactive compounds).Up to date, another species from the operties . In thisL. cardiaca extracts for the phytosynthesis of noble metal nanoparticles and presenting their characterization. The current study details the obtaining of the natural extracts, their analytical characterization, as well as the influence of the extract concentration on the characteristics of the obtained nanoparticles.Besides the complex biological activity of the plant itself, its rich composition in phytoconstituents recommends this plant for the synthesis of metallic nanoparticle with antimicrobial properties . One of L. cardiaca) was collected in the Bucharest area, Romania, from plants grown from certified seeds , and the extraction was performed using a UN 110 oven , in the following conditions: extraction time 3 h, extraction temperature 70 °C. The obtained extract was encoded Lt.The first extraction procedure selected was the microwave-assisted extraction; the vegetal material and solvent mixture (ethanol: water = 1:1) was subjected to microwave heating using an Ethos Easy Advanced Microwave Digestion System , under the following parameters: extraction time 30 min., extraction temperature 70 °C, microwave power 800 W. The extract was encoded Lmw. In both cases, the ratio vegetal material/solvent was 1/12 (w/v); after natural cooling to room temperature, the extracts were filtered using filter paper and reduced using a Laborota 4000 rotary evaporator . The extracts were further lyophilized , and the obtained powders were stored for further use. The second extraction method selected was the The ethanol used as solvent was reagent quality , while the bidistilled water was obtained in the laboratory using a GFL 2102 water still .The composition of the extracts was evaluated using phytochemical assays , as well as high-precision liquid chromatography (HPLC), for the quantification of selected compounds. All reagents were used as received, without further purification.The results of the phytochemical assay (methods being previously exhaustively presented by our group ) are expHigh-Performance Liquid Chromatography analyses were performed using a chromatograph equipped with a diode-array detector , using a method previously described . The comFor compositional evaluation, the lyophilized extracts were diluted with bidistilled water to reach a final concentration of 5 mg/mL.−3 M silver nitrate solution, Chimreactiv, Bucharest, Romania), in equal volumes, under natural light, at room temperature. No stirring was applied to the mixture. The encodings of the obtained samples are presented in For the NPs phytosynthesis, the dried extracts were redissolved in bidistilled water at five concentrations ; the resulting solutions were mixed with the metallic salt precursor , to estimate the NPs dimensions, and to evaluate the stability of the NPs solutions (by recording the UV-Vis spectra of the NPs solution after 9 months from the synthesis) . For the-Dynamic light scattering (DLS), for the determination of the NPs’ hydrodynamic diameter ; for DLS-Kα radiation (1.54059 Å), 2θ/θ scanning mode; the diffractograms were recorded between 7 and 90° (2θ). Components were identified by comparison with ICDD data , using the equipment’s software , while the crystallite size was determined using the Debye–Scherrer Equation (1):Dp = the average size of the crystallites, K—the Scherrer constant (K = 0.94), β = the width at half-height of the diffraction maximum, θ = the Bragg angle, λ = the wavelength—1.54059 Å).X-ray diffraction (XRD), for the determination of the crystallin structure and crystallite size , using a-Transmission Electron Microscopy (TEM) for the visualization of selected NPs, using a Tecnai G2 F20 TWIN Cryo-TEM equipment , at an accelerating voltage of 300 kV and a resolution of 1 Å. The microscope was equipped with an energy dispersive X-ray spectroscopy (EDX) accessory , allowing the evaluation of the elemental composition of the samples.The development of the NPs was monitored using the following analytical techniques: The antioxidant properties of both the extracts and the nanoparticles solutions were determined using the DPPH  assay, by measuring the discoloration of the stable free radical solution , as previously exhaustively presented by our group ,42. The Escherichia coli (Gram (-) bacterium) and Enterococcus faecalis (Gram (+) bacterium). These microorganisms were chosen because of their pathogenicity.The antibacterial testing of the s”mple’ studied in this manuscript was carried out on two bacterial strains Enterococcus faecalis can be spread from person to person. Many countries have adopted strict regulations on tap and bottled water, as well as bathing water, in order to avoid the contamination with E. faecalis [Enterococcus faecalis is commonly found in enterococcal infections (80–90%), and its increasing resistance to antibiotics has made it a bacterium of concern, as nosocomial infections are a real health problem. E. faecalis has a natural resistance to certain antibiotics, such as cephalosporins, and is tolerant to penicillin. Several studies [faecalis . This bafaecalis ,45. Ente studies ,47 show Escherichia coli  produce a powerful toxin known as Shiga toxin, which can cause fatal infections [E. coli strains [Some types of fections . Other ifections . Nosocom strains .All the antimicrobial determinations were performed in triplicate. Distilled water was used as a negative control and gentamicin sulfate  at a concentration of 10 µg/mL was used as a positive control. All bacteria strains were grown in Luria Bertani Agar  plates incubated at 37 °C. The antibacterial assay was performed by the agar well diffusion method . Brieflyp ≤ 0.05. Results shown for the determinations represent mean ± standard error of the mean (SE) of independent determinations. OriginPro 2018 Data Analysis and Graphing Software v. 95E  was used for all the graphic representation.The results obtained after multiple parallel determinations (detailed for each method) were analyzed for statistical significance using analysis of variance (one-way ANOVA) and the Tukey test to determine significant differences between means. Significant differences were set at As previously mentioned, the NPs characteristics are in strong dependency with the composition of the extracts used for phytosynthesis. In order to obtain an image on this parameter, the general composition of the extracts was evaluated by means of total phenolic content and total flavonoids content, while the selected components were quantified by HPLC . However, the results are similar to those obtained by Armatu et al. [w/v), the two results are similar. By comparing the results of the phytochemical assays with the literature data ,53,54 reu et al. , the totEchinacea purpurea L. flowers [The differences recorded could be e”plained, besides the influence of local environmental factors, by the value of the cultivar and the particular conditions on harvesting time, as well as by the mild extraction conditions and the solvents used in the present study, which could negatively influence the amount of extracted phytoconstituents. However, we can conclude that the motherwort grown in native conditions presents a lower intake of active constituents, especially when speaking of total phenolics, and at the same time, a higher intake of total flavonoids; this is a very interesting observation, as our group also presented the same conclusion regarding the composition of  flowers . Achyranthes aspera L., the value of TPC is dependent on two parameters that were varied in the present study: extraction method and extraction time. As the cited authors observed a higher value for the microwave extraction, compared with ultrasound extraction and continuous shaking extraction, most probably in our case, the difference between the TPC extraction efficiency of the two methods is counterbalanced by the influence of the extraction time . As such, most probably, the extraction time using microwave-assisted extraction should be increased in order to reach higher TPC values. However, this hypothesis should be thoroughly verified in future studies, as the extraction parameters are unique for each vegetal material. Regarding the total flavonoid content, also influenced by the extraction method and extraction time as demonstrated by Nurcholis et al. [Comparing the two extraction methods, it can be observed that the classical temperature extraction leads to higher total phenolics content, compared with the microwave extraction, while the difference between the two methods, in terms of total flavonoids, is not statistically significant. Regarding these differences, it is known that the value of TPC, due to the presence of a hydroxyl group, is dependent on the solvent’s polarity . In our s et al. , we coulL. cardiaca used in the present study. For the discussions regarding the HPLC quantification of the selected compounds, the same literature data previously cited will be used. By comparing our results with the ones presented by Angeloni et al. , it can In terms of flavonoids, our study identified higher contents in rutin, hyperoside, and catechin, compared to the study of Koshovyi et al. . Other fmw), while the flavonoids have an irregular distribution, with some being present in higher quantities in Lt , while others  being found in higher quantities in Lmw. These results can be correlated with the phytochemical assays previously discussed.When comparing the two extraction methods, it can be observed that the phenolic acids are usually in higher quantities in the extract obtained by temperature extraction , with the exception of caffeic acid (significantly higher in the microwave-obtained extract). The anthocyanidins are usually in higher amounts in the extract obtained via the microwave method  present in some of the samples. In evaluating the results obtained, it is important to remember that DLS determines the hydrodynamic diameter, which is usually larger than the actual particle diameter, especially for the phytosynthesized NPs . What neE. purpurea extracts [The value of the polydispersity index (PdI), with most of the samples having PdI < 0.5, could lead to the conclusion of practically monodisperse samples ,62. A paextracts , it can extracts , the dimX-ray diffraction analysis is commonly used to study the crystalline nature of different types of samples, including phytosynthesized NPs, as previously demonstrated ,39,42. FBy evaluating the obtained results, it can be observed that the samples show three diffraction maxima, at 38°, 64°, and 77° ) of 2.39 nm , compared with the crystallite sizes of 3.31, 3.40, respectively 3.15 for the NPs using the same E. purpurea extracts concentration and extraction methods [By comparison with the results obtained for An attempt to evaluate the correlations between the total phenolics content and the NPs crystallite size was performed using NCSS 2023 Data Analysis and Graphics software v.23.0.1 . The Pearson coefficients (scatter graphs not shown)  reveal aIn order to obtain information regarding the morphologies of the samples, as well as for the visual observation of the NPs dimensions, two samples were selected for each set of NPs  for TEM analysis, after the stability evaluation period (9 months). A drop of NPs solution, dispersed in water (1:10 ratio), was placed on the TEM copper grid and dried. The results are presented in TEM images present spherical/semi-spherical morphologies, with particle dimensions under 15 nm, as well as the tendency to form nanoparticles with smaller sizes for lower extracts concentration. Additionally, at the highest concentrations, the obtained dimensions are lower for the LT5, compared with LM5, while for lower concentrations, the NPs dimensions are smaller for LM2, compared with LT2 (in very good concordance with the XRD data). The EDX spectra confirm in all cases the synthesis of silver nanoparticles, the additional elements present in the spectra being due either to the TEM analysis grids (in the case of copper) or to the elements present in the extracts (in the case of the other identified elements). L. japonicus extract [Following the analytical results, a comparison of the obtained results can also be made with literature data presenting synthesis of AgNPs using  extract . Thus, IThe results regarding the determination of antioxidant activity are presented in From the results of the antioxidant assay, a statistically significant increase in the antioxidant potential upon phytosynthesis can be observed, compared with the parent extract, as also observed in our previous works ,39,42. BL. cardiaca extracts [L. cardiaca extracts with the same geographical origin as in our study [When dealing with antioxidant potential, several authors found a direct correlation between the total phenolics  content and the antioxidant potential ,64,65,66extracts ,67. Howeextracts , some evur study . In the The results of the antimicrobial properties evaluation are presented in Results presented in Unlike the previously presented results , no signLeonurus cardiaca L. aerial parts extracts. The work also presents the influence of the extraction methods  and of the extract concentration on the morphological and biological properties of the NPs . The present work reports, for the first time in the literature, the phytosynthesis of silver nanoparticles using L. cardiaca extracts, the lowest nanoparticles dimensions being obtained using the extract developed using a microwave-assisted method at a concentration of 1 mg/mL . The results obtained support the phytosynthesis of silver nanoparticles using The AgNPs solutions possesses an enhanced antioxidant potential compared with the parent extracts, determined by the DPPH assay; all tested experimental variants had significant antimicrobial properties (against both Gram-negative and Gram-positive lines). At the same time, the differences between the dimensions of the nanoparticles did not strongly influence the final antimicrobial properties . The antioxidant potential of the NPs was statistically influenced by the extract concentration used, being also influenced, in a smaller extent, by the NPs sizes.The study demonstrates that the motherwort extracts are able to phytosynthesize silver nanoparticles with significant biological activities, thus allowing the proposal of nanotechnological approaches for future biomedical applications.


Two researchers conducted independent searches on five different electronic databases: PubMed/MEDLINE, Embase, SciELO, LiLACS and Web of Science. Studies were selected that covered cross-cultural adaptation methodology and validation in Brazil with type 1 and type 2 diabetes patients of any age. After reading the full-text articles, data related to psychometric characteristics were extracted from each study selected. Reliability was assessed with Cronbach’s α (Cα). The initial searches identified 2,211 studies. After exclusions, 26 were included, covering a total of 31 questionnaires. Questionnaires were grouped into 11 domains based on their main focus of interest: adherence (n = 8), quality of life (n = 7), diabetes knowledge (n = 3), hypoglycemia (n = 3), self-efficacy (n = 3), satisfaction with pharmaceutical services (n = 1), emotional stress (n = 2), hope (n = 1), attitude towards diabetes (n = 1), perception of disease severity (n=1), and risk of developing diabetes (n = 1). This study identified and reviewed all of the diabetes-specific questionnaires that have been validated for Brazilian Portuguese, which should facilitate selection of the most appropriate instrument for each domain of interest in future research and clinical settings. Recent data show that the global prevalence of diabetes increased from 108 million in 1980 to 425 million in 2017 .The special and rigorous care that is necessary for good glycemic control affects several spheres of patients’ lives, such as eating, physical activity, quality of life, and mental health, among others. This characteristic of the disease requires frequent monitoring by health professionals, preferably with a multidisciplinary approach . AdditioQuestionnaires can be classified as general questionnaires, which evaluate health variables and allow comparison between patients and healthy persons, or specific questionnaires, which evaluate characteristics related to a specific disease . DiabeteThe number of questionnaires cross-culturally adapted and validated for the Brazilian culture is still insufficient for the high diabetes demands in Brazil . There aInternational Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42017073407. This protocol is fully available on the National Institute of Health Research – Health Technology Assessment Database (NIHR HTA) website. This systematic review follows the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (This systematic review protocol was registered on the (PRISMA) .rd, 2017.The literature search was conducted independently by two reviewers on five electronic databases  in order to identify diabetes-related questionnaires, scales, and other instruments that have been translated, adapted, and validated for the Brazilian culture. Other mechanisms such as Google Scholar were also used in order to reduce publication bias and include unpublished data or publications not indexed in the databases listed above. Manual searches were also conducted in the references of the articles selected and in the annals of major Brazilian and international conferences related to diabetes held during the last three years. Where studies were identified, but the full text was unavailable, the authors were contacted in order to request the full article. The most recent search was performed on October 3Descriptors “Diabetes”, “Questionnaires”, and “Brazil” and related terms and keywords were used in the search strategy, in English and Portuguese. The search strategy run on PubMed is described in Studies were selected based on the following criteria: translation to Brazilian Portuguese, cross-cultural adaptation, or validation of questionnaires, scales, and other instruments related to diabetes. Only patient-reported outcome measures were included. A decision was taken to exclude articles in which the instrument validated required additional information, such as the results of laboratory procedures, imaging examinations, or careful professional evaluation, thereby ruling out inclusion of risk scores. No date or language restrictions were applied.Duplicates were identified and excluded. Two researchers (L.G.B. and M.M.M.) independently evaluated titles and abstracts against the inclusion and exclusion criteria. Publications for which the information needed could not be extracted from the title or abstract were selected for full article reading. All studies selected in the first evaluation were referred for analysis of the full text. Disagreements were resolved by arriving at a consensus in discussions or by a third researcher (G.H.T). Agreement between the two researchers was analyzed using the kappa coefficient and a value > 0.80 was defined as almost perfect agreement . EndNoteTM spreadsheet.Two researchers (L.G.B. and M.M.M.) separately extracted the following data from each study: title in Portuguese and English, publication date, authors, instrument name in English and Portuguese, population used for validation, target age, cross-cultural adaptation process, reliability data, type of validation, instrument application time, mode of administration (self-report or administered by an interviewer), instrument accessibility, number of items and domains, scores and cut-off points. Disagreements were resolved by discussion and, if unresolved on this basis, a third researcher (G.H.T.) was consulted. When two studies validated the same questionnaire in a similar population but with different sample sizes, only the most accurate was included. Data were inputted to a pretested Microsoft Office ExcelThe quality of studies was evaluated using the Cochrane tool . CertainReliability was measured with Cronbach’s α. In general, the minimum acceptable value for the reliability of a questionnaire is 0.70; below this value, the internal consistency of the scale is considered low. In contrast, the expected maximum value is 0.90; above this value, one might consider redundancy or duplication, which means that several items would be measuring exactly the same element of a construct; therefore, redundant items should have been eliminated. Usually, Cronbach’s α values between 0.80 and 0.90 are preferred . We usedThe initial searches identified 2,211 articles; 128 were duplicates and were excluded; 2,083 articles were analyzed by title and abstract, and 43 were selected for full-text reading. Two papers were found only in abstract form. Since their validation studies were not found, the authors were contacted and requested to provide them. Both ,17 had uThe total number of instruments adapted/validated was 31, because some articles used more than one questionnaire. Some of these validations were conducted for the same questionnaire, but in different populations, such as type 1 and type 2 diabetes [the Self-Care Inventory-revised questionnaire ,20 and tWith regard to the populations used to validate the instruments, one study stated that the questionnaire had been validated for patients with both types of diabetes type  diabetesIn order to facilitate understanding and enable comparisons between the instruments selected, the researchers grouped the studies into domains based on the main subject addressed. This resulted in 11 large domains representing the primary focus of each questionnaire: treatment adherence ; quality of life ; diabetes knowledge ; hypoglycemia ; self-efficacy ; satisfaction with pharmaceutical services ; emotional stress ; hope ; attitude towards diabetes ; perception of disease severity ; and risk of developing diabetes . Half of the studies reporting overall reliability had instruments with Cronbach’s α between 0.7 and 0.9. More details on the studies included in this systematic review and the instruments validated are presented in Analyses of the risk of bias within studies found that most studies presented a low risk of bias in the methodological steps and psychometric data evaluated . HoweverDue to the increasing number of diabetes cases in Brazil, it has been necessary to develop specific instruments to assist health professionals to follow-up these patients. The present study analyzed diabetes-specific questionnaires available and validated in Brazilian Portuguese with the purpose of facilitating the process of choosing the best surveys to use in clinical settings and research. A total of 26 studies were found that validated one or more instruments, totalling 31 different questionnaires validated in different populations (children/adolescents or adults with type 1 diabetes or type 2 diabetes).There is a discussion in the literature about using disease-specific questionnaires rather than general questionnaires ,44. It iAdherence to treatment was the area with the greatest number of questionnaires. This is defined as behavior of accepting and following recommendations  provided by a health care professional . The impRegarding quality of life assessment, a considerable number of questionnaires assess global quality of life or quality of life in relation to a specific complication, such as diabetic neuropathy . Health-Another essential subject to be measured in patients with diabetes is their knowledge about their disease, since it is directly associated with adherence to treatment . The DiaHypoglycemia plays an important role in management of patients with diabetes, especially those with type 1 diabetes undergoing intensive treatment . QuestioThe remaining concepts measured are also of great importance in the research and clinical follow-up of patients with diabetes: attitude towards diabetes, emotional distress, hope, perception of disease severity. However, some common barriers faced by patients with diabetes, such as beliefs, relationship with health care professionals, lifestyle changes , physicaThis study has some limitations. First, it is limited to the evaluation of specific questionnaires in the population with diabetes, which may limit comparisons to other populations. Also, when analyzing the time taken to administer the instruments, it appears likely that some studies reported the total duration of the interviews conducted for validation of the instrument , rather than only the time needed to administer the instrument itself. Because of this, we believe that the administration times for some of the instruments shown in In conclusion, this systematic review identified and analyzed all the diabetes-specific questionnaires that have been validated in Brazilian Portuguese in order to assist health professionals in follow-up and treatment of patients with diabetes, in both clinical and research settings.


Dietary supplements (DS) and their purchase is often based on a consumer's personal choice and advertisements. The associated DS regulations, particularly in manufacturing and marketing, are far more flexible and permissive than that of the well-regulated prescription pharmaceuticals. However, the adverse health effects associated with the inadvertent use of mega-doses of DS are not well understood. The demand for DS, nutraceuticals, and herbal remedies has experienced an upswing during the past two to three decades, and global product sales have thrived. More so, the prevention of cardiometabolic syndrome (CMS) and related disorders like diabetes mellitus, obesity, hypertension, and serum lipid abnormalities, as well as of other noncommunicable diseases (NCDs), is of highest health care priority globally, since these disorders impose very high economic burdens on health care systems and society. In this review, we argue why DS could prevent cardiometabolic syndrome, by providing the potential benefits and risks associated with them, especially self-medication considering their intake by the public at large. Good manufacturing practices and quality control are absolutely necessary for the manufacture of DS products, and proper labeling is needed regarding the optimal dose schedules of various DS and bioactive ingredients. Specific examples are used to underscore the indications and dosage recommendations made for the marketing and promotion of fish oil, coenzyme Q10, and Mg-containing products for the prevention of cardiometabolic syndrome. Cardiometabolic syndrome (CMS) represents a cluster of events associated with distortion of carbohydrate and fat metabolism as well as macro- and micro-vascular complications. Basically, CMS is characterized by hypertension, hyperlipidemia, atherosclerosis, increased risk of coronary heart disease and stroke, hyperglycemia, insulin resistance, and some cancers. In the majority of cases, an increase of abdominal fat, diabetes mellitus, and unhealthy dietary habits promote this syndrome. The leading diagnostic signal is abdominal obesity, which serves as a warning of an elevated risk of CMS and the need to search for any hidden CMS parameters. Dietary supplements (DS), which include food supplements and nutraceuticals have gained much popularity for the management of weight and the detrimental sequelae associated with obesity and diabetes. More so, DS are widely used all over the world by teenagers and adults, especially by elderly individuals and particular groups of people such as athletes and body-builders. In 2021, global DS sales were estimated to be 151.9 billion USD , 4. In tThe earliest signs of increased risk of cardiometabolic syndrome are overweight or obesity. This means 48.7% and 68.3% of overweight BMI > 25 to  < 30) and obese (BMI > 30) subjects, respectively, are metabolically abnormal  to  < 30. Even inThe primary question arises regarding taking DS: for what purpose should one take DS? For instance, the good health promotion effects of DS can be expected if they are used according to recommendations. In case of DS, a wide variety of medical indications must not be declared on the package labels. However, many ingredients containing DS list the main active pharmaceutical component as well and therefore the indication is indirectly validated. Pharmaceuticals often serve as beacons of light for DS users. Wrongly interpreted indications can counteract the health benefit expectations. The main ingredients of fish oil (EPA and DHA) also exist as ingredients of approved pharmaceuticals, indicating fish oil is a reliable tool for the prevention and management of CMS , 35. ButThe predominantly non-pharmaceutical DS containing coenzyme Q10 on the market are promoted as if prospective randomized controlled multicenter clinical trials are a trustworthy indication of its effects , 39. TheIn many places around the globe, the assortment of ingredients (the composition) of DS during the development process are not restricted; however, there are some national restrictions. The United States FDA and EU EMA regulate ingredients which are prohibited in DS; however, product samples are not submitted to any safety assessment prior to commercialization. Therefore, qualitative and quantitative errors and non-conformities emerge only after public announcements regarding quality defects or other problems , 49. ForThe chemical representation is a key factor in this respect, e.g., in Q10 products, ubiquinone, the oxidized form of Q10, is a more common ingredient in commercial supplements; however, reduced ubiquinol  appears to be a better form to promote the patients' Q10 status . The salIn the European Union, nutrition declaration for vitamins and minerals is regulated by regulations 1924/2006/EC and 1925/2006/EC . AccordiResearch has shown that in a part of the population, serum magnesium-level is too low, lower than 1.4 mg/dl (ca. 0.65 mmol/L), the cut-off for normal value. Hypomagnesemia develops secondary to decreased intake  or following medications . 2% of the general population, 30%–80% of alcohol-use disorders, and 25% of diabetes patients are prone to hypomagnesemia. The dietary magnesium intake is negatively correlated with development of CMS . For asyIn case of fish oil, sometimes only n-3 PUFA content is emphasized for health promotion on labels or in advertisements. However, alpha-linolenic acid (ALA) is basically different from eicosapentaenic acid (EPA) and docosahexaenic acid (DHA). ALA is mainly from plant origin, whereas EPA and DHA are from fish-origin n-3-PUFAs . ALA is Among the key basic questions of medical therapy is “dosage”. For food supplements, there appears to be no pharmacological dosage recommendation. Despite this, national authorities continue to provide the recommended daily allowance (RDA). Even on labels, many manufacturers provide recommendations for daily dose. It should be noted that the RDA data are usually age- and condition-dependent. And in order to minimize customers expenditure and gain an advantage over rivals, the manufacturers often indicate lower daily dosages on the label. For example, for fish oil, the pharmacologically recommended therapeutic dosage for hypertriglyceridemia, part of CMS, is 2 g per day or more with a minimum-content of 1,600 mg of eicosapentaenic + docosahexaenic acids. In contrast, many commercial fish oil capsules contain less than 500 mg of this combination and the recommended dose is 1–2 capsules daily. A study in 2018 explored that, in New Zealand, 74% of fish-oil consumers do not take the minimally recommended 400–600 mg EPA + DHA or more per day . ObviousThe therapeutic dose of coenzyme Q10 is recommended to be between 100 and 200 mg/day. This substance is very safe as it is an endogenous molecule, therefore, it is quite difficult to overdose. In case of low coenzyme Q10 levels, for prevention, lower doses (100 mg/day) are also adequate. For comparison: from a healthy diet, only 2–10 mg/day can be obtained, which is enough only in the presence of redox balance . MagnesiMost consumers only look for the bioactive ingredients and the amounts of bioactive substances. As the LADME (liberation-absorption-distribution-metabolism-excretion) process is similar for pharmaceuticals and dietary supplements, the formulation that determines the liberation of the main ingredient from the dosage form (tablet-capsule-suspension-etc.) plays a critical role from a utility point of view. The bioavailability, i.e., the proportion of active substance reaching the systemic circulation is crucial from an effectiveness point of view. As a DS is not usually subject to a bioavailability test, relevant differences may arise in this respect as well. Fine et al. observed that the enteric coating of the magnesium tablet impairs the bioavailability of magnesium . InadverIn case of Q10, there is a significant difference among the various formulations , 78 as wDS manufacturers tend to produce and market safe and reliable products, as it is their clear interest and intention to do so in the long-term. Nowadays, however, there are inconformity issues with DSs. Microbial contamination, heavy metal contamination, prescription drug adulteration, substitution of active plant varieties, or fraudulently underdelivering ingredients are among the major challenges –85, some


Brazil has the largest public and universal healthcare system in the world,but little is known about the outcomes of patients on hemodialysis (HD) inthe country according to the source of funding for the treatment.To compare the profile and survival of patients under HD treatment funded bythe Public Healthcare System (SUS) to those with private insurance.Retrospective analysis of adults undergoing HD between 2012 and 2017 in 21dialysis centers in Brazil that provided both by the SUS and private healthinsurance. Participants, regardless of the paying source, received similardialysis treatment. Data were censored after 60 months of follow-up or atthe end of 2019.4,945 patients were included, 59.7% of which were financed by the SUS.Patients financed by SUS, compared to those with private insurance, wereyounger  and with a lower prevalence ofdiabetes . The 60-month survival rates inthese groups were 51.1% and 52.1%, respectively (p = 0.85). In the analysisof the subdistribution proportional hazard ratio by the Fine-Gray model,including adjustment for concurrent outcomes, a significant increase in therisk ratio for death was found in patients with treatment funded by the SUS.Patients on HD with treatment funded by the SUS have a higher adjusted riskof death when compared to those with private insurance, despite similardialysis treatment. Factors not directly related to dialysis therapy couldexplain this difference. This is probably due to the lack of access totreatment in lower-income countries. Public funding for all aspects of renalreplacement therapy is available from 75% of high-income countries, 43% ofupper-middle-income countries, 19% of lower-middle-income countries, and nolow-income countries. It is estimated that Brazil currently has more than 140,000 patients on adialysis program, around 93% on hemodialysis and 7% on peritoneal dialysis. Morethan 80% of dialysis patients in the country are financed by the SUS, most of thetime in private clinics with contracts. The rest of the patients have theirtreatments covered by private healthcare insurance, and generally undergo dialysisin the same clinics that treat patients funded by the SUS. The mortality rate among HD patients is extremely high. However, little is known about the survival of HD patients in Brazilaccording to the source paying for the treatment.Brazil, an upper-middle-income country, has one of the largest dialysis populations,with an estimated prevalence of 684 pmp, and has the largest universal publichealthcare system in the world, the Unified Health System (SUS). SUS was createdafter the enactment of the 1988 Constitution and has faced the challenge ofproviding all treatments, including the most complex and with highest financialimpact, such as renal replacement therapyThus, the objective of the present study was to compare the profile and survival ofpatients who have HD treatment funded by the SUS with those with privateinsurance.®.This is a retrospective database analysis of 23 dialysis clinics in Brazil . Of these, patients from 2 clinics, one in the FederalDistrict and the other in São Paulo, which exclusively treated patients throughprivate health insurance, were excluded. The remaining 21 clinics treated both SUSand private health insurance patients and were included in the study. Allparticipating clinics used the same electronic medical record, EuCliDAll patients aged 18 years or older undergoing outpatient hemodialysis atparticipating clinics in the period between July 1, 2012 and June 30, 2017 wereincluded. Patients transferred from other dialysis centers, those who migrated fromperitoneal dialysis and those who had previously undergone kidney transplantationwere considered prevalent in renal replacement therapy and excluded from theanalysis.® in the form of spreadsheets in which the patients wereidentified only by registration number. Data regarding body composition analyzed byspectroscopic bioimpedance on admission to the clinic were also extracted. Anincrease in pre-HD extracellular volume above 15% in men or 13% in women wasclassified as fluid overload.The date of the first HD session at the clinic was considered as the start offollow-up. Demographic, clinical and laboratory data on admission were extractedfrom the EuCliD. The standardized dialyzers were high flux polysulfone or high flux helixonemembranes. Automated reuse of dialyzers and blood lines was allowed, except forpatients with hepatitis B and C or HIV. All were dialyzed with ultrapure dialysissolution, with glucose 100 mg/dL, potassium 2.0 mEq/L, acetic acid 4 mEq/L andcalcium 3.0 mEq/L, but with the option of calcium 2.5 mEq/L at medical discretion.The standard dialysis prescription was sodium 136 mEq/L, bicarbonate 31.5 mEq/L, but with changes in these parameters at the discretion ofthe attending physician. The standard dialysis solution flow rate was 500 mL/min,temperature 36°C. For patients with arteriovenous fistula, the standard needle was15G, the blood flow, regardless of the vascular access, was as high as possible,respecting the pressure limits in the arterial and venous lines. The frequency of 3sessions per week lasting 4 hours was also standardized. Regardless of the payingsource, at the discretion of the attending physician, patients with difficultycontrolling blood volume could receive a fourth dialysis session in the week forbetter blood volume control. The only exception was the daily short HD option , which was basically limited topatients with private insurance, due to lack of coverage by the SUS.All the patients received similar dialysis treatment, regardless of the payingsource, and in accordance with the country’s legislationDeath from any cause was the main outcome, while kidney transplantation, transfer toperitoneal dialysis and recovery of renal function were considered as concurrentoutcomes. The hospitalization rate was also analyzed according to the type ofinsurance and expressed in number of hospitalizations/patient-year. The data werecensored with 5 years of follow-up or on December 31, 2019, to avoid the impact ofthe covid-19 pandemic on the analysis, and also due to the introduction of onlinehemodiafiltration from 2020, restricted to patients with private insurance, at oneof the participating clinics.This study was carried out in accordance with the Declaration of Helsinki and wasapproved by the Research Ethics Committee of the Medical School of the FederalUniversity of Rio de Janeiro, under number CAAE 76623317.1.0000.5243. As it is aretrospective study, using only aggregated data, obtaining the Free and InformedConsent Form was waived by the Ethics Committee.The Kolmogorov-Smirnov test was used to test the distribution of variables.Continuous variables with normal distribution were expressed as mean ± standarddeviation or as median and interquartile range, otherwise. Categorical variableswere presented as frequencies. Comparisons between means in different groups ofpatients were performed using the unpaired t-test or the Mann-Whitney test.Comparisons between frequencies were performed using the chi-square test.Survival rates were calculated using the Kaplan-Meier method and comparisonbetween the curves was performed using the Log Rank test., with adjustment for concurrent outcomes . Initially,univariate analysis was performed for each variable. Next, only the payingsource (SUS) was included in the multivariate analysis as the variable ofprimary interest and the variables that presented p values < 0.10 in theunivariate analysis. Subsequently, the same analysis was performed, butincluding adjustment for daily HD treatment. Any patient who underwent 20 ormore monthly sessions for at least one month during the observation period wasconsidered to have been treated with daily HD. At the end, p values < 0.05were considered statistically significant. All analyzes were performed usingSPSS version 21.0 for Windows , except for thesubdistribution hazard ratio analysis using the Fine-Gray method, which wasperformed using the freely available R software version 4.0.2.The risk ratios for death were estimated using the subdistribution proportionalhazards model described by Fine and GrayInitially there were 5,129 patients undergoing HD in the period, but after excluding136 patients from the two clinics not affiliated with the SUS and 48 aged under 18years, a total of 4,945 patients were included in the analysis . The characteristics ofthe patients upon admission, as well as the comparisons between those with treatmentfunded by the SUS or by private health plans, are shown in Almost 60% of the patients were financed by the SUS and the rest by privateinsurance. Patients with private insurance, compared to those financed by the SUS,were older , with a higher prevalence of diabetes asa cause of renal failure  and, more frequently, hadbeen followed up by a nephrologist before starting dialysis , although a higher percentage of them had unplanned HD started in hospital. Patients whose treatment was funded by the SUSmore frequently started HD through AVF , had moretemporary catheters and less tunneled catheters  asinitial vascular access. Of the 3,682 patients assessed by bioimpedance onadmission, 45.2% had fluid overload, but with no difference between groups. Theseand other comparisons between the two groups are shown in During the study period, 1,605 patients died, 1,037 were transferred to othercenters, 511 underwent kidney transplantation, 243 migrated to peritoneal dialysis,238 recovered kidney function and 49 lost follow-up. The mean follow-up time was26.7 months. HD exits due to kidney transplantation  andrecovery of renal function  were more frequent amongpatients with private insurance, but not switching to peritoneal dialysis .Over the follow-up period, the hospitalization rate was higher among patients withprivate insurance than among those with SUS-funded treatment  .During the follow-up period, 355 patients with private insurance (17.8%) and 8 withtreatment funded by the SUS (0.3%) were treated with daily short HD for at least onemonth. The median and interquartile range of time that patients were on daily HD was9 (5 to 19) months.Survival rates, by Kaplan-Meier curves, at 60 months among patients with privateinsurance or with treatment funded by SUS were 52.1% and 51.1%, respectively (p =0.85), Other variables associated with increased risk of death in the adjusted model wereage (p < 0.0001), diabetes (p < 0.0001), initiation of HD in hospital (p =0.0057), preoperative fluid overload -dialysis by bioimpedance (p < 0.0001) andhigher levels of alkaline phosphatase (p = 0.0083), while the body mass index (p =0.014), hemoglobin levels (p = 0.0074), serum albumin (p = 0.0001), and highertransferrin saturation index (p = 0.0063) were associated with a lower risk ofdeath. The associations between gender, previous follow-up with a nephrologist, thebeginning of HD via catheter, serum levels of phosphorus, calcium, parathyroidhormone, lean mass index and pre-HD diastolic blood pressure with the risk of death,found in the analyzes univariate, disappeared in the adjusted model .The present study made it possible to compare the profile of patients who entered anHD program with treatment funded by the SUS, with that of patients using privatehealthcare insurance treated at the same clinics. It was possible to study thesurvival of these patients over a period of up to 5 years and define the associationbetween the type of coverage of dialysis treatment costs and the risk of death. Asfar as we know, this is the first study of this nature in the country and itsfindings could contribute to the development of healthcare policies aimed atimproving medical care and survival of patients on HD with treatment funded by theSUS.The 5-year survival rates were similar. However, as patients with treatment funded bythe SUS, among other differences, were younger and had a lower prevalence ofdiabetes than patients with private insurance, a 22% increase in the adjusted riskof death.The reasons for this increase in the risk of death among patients using the SUS areopen to debate. All adjustments in the risk of death analysis were initially madefor the characteristics of the patients upon admission, but not for how they weretreated over the follow-up period. However, it is unlikely that differences in thedialysis treatment provided to patients, according to the paying source, can explainthe difference in outcomes, since, regardless of the paying source, all receivedvery similar treatments, including dialysis machines, dialyzers, dialysis solution,prescription dialysis, and were assisted by the same nephrologists. The onlydifference in treatment may have been the availability of the daily short HD optionfor privately insured patients. However, the vast majority of patients, even withprivate insurance, spent the entire follow-up period on the traditional HD scheme,with 3 weekly sessions. In any case, seeking to adjust for an effect of thisconcerning dialysis on survival, an additional analysis was performed, includingadjustment for daily short HD exposure. Even after this adjustment, the risk ofdeath among patients whose treatment was funded by the SUS changed little, remainingsignificantly higher..The most plausible justification for the difference in the risk of death according tothe source of payment for the treatment would be that patients with privateinsurance had easier access to diagnostic tests, follow-up and treatment by otherspecialties, as well as extra dialytic medications, although these variables werenot evaluated in the present study. The hospitalization rate among patients withprivate insurance, which was more than twice that observed among patients assistedby the SUS, may reflect the difference in access to medical care in general. Despiteuniversal access to the public healthcare system in Brazil, there is stillinefficiency in hospital care, with inequalities in access and in the adequacybetween demand and supply of vacancies, heterogeneity in the quality of services anddeficiency in the integration of hospitals in the care network. More recently, after the inclusion of online hemodiafiltration in the listof therapies authorized by the National Agency for Supplementary Health, an increasing number of patients with private healthcare insurance have beentreated by this modality of dialysis and with a single use of dialyzers, wideningthe difference in the way they are cared for depending on the funding source of thetreatment.As demonstrated in the present study, patients dependent on the SUS have adisadvantage in the risk of death even when receiving similar dialysis treatment. Itis possible that this situation will get worse as a result of insufficient fundingof renal replacement therapy by the SUS over the years, which may provide conditionsfor widening the gap in the quality of dialysis and, even, in access to dialysistreatment in the country. The lag in reimbursement values has inhibited theexpansion of SUS-accredited places in private dialysis clinics in the country andled to the opening of new dialysis centers aimed exclusively at patients withprivate insurance, mainly in the country’s large cities. In 2018, the averageestimated reimbursement value per HD session by private healthcare insurance wasapproximately double than that reimbursed by the SUS  and are not the focus of the present study, as we have already analyzed anddiscussed such associations in more detail in a previous study with the same cohort.The other admission variables associated with the risk of death found in the presentstudy were age, diabetes, initiation of HD in a hospital, body mass index,transferrin saturation index, hemoglobin, albumin and alkaline phosphatase levelsand fluid overload . The ass, patients with private insurance also had some tests not covered by the SUS,such as bicarbonate dosage, hemoglobin A1c, β2- microglobulin and C-reactiveprotein. On the other hand, the study also has its strengths, such as the largesample size and the long follow-up period.The present study has several limitations, including the retrospective nature of theanalysis, the very high number of clinics in the state of Rio de Janeiro, thesignificant number of patients without bioimpedance evaluation, and some differencesin the list of routine laboratory tests performed. While all patients had a list oflaboratory tests and the periodicity of their performance in accordance with legal requirementsIn conclusion, patients on HD with treatment funded by the SUS have a higher adjustedrisk of death than those with private insurance, despite similar dialysis treatment.Factors not directly related to dialysis, such as greater access to diagnostictests, procedures and hospitalization among patients with private insurance couldexplain this difference. The identification of these factors, as well as theplanning and implementation of public policies aimed at improving and enhancing thispopulation’s access to medical care more broadly in the SUS network, going wellbeyond the right to dialysis treatment, could have an effect favorable in reducingmortality.