H = 20.14; p < 0.01). Differences between elements from different levels of PA were found for the autonomy , competence , and relatedness  psychological needs, suggesting that those who feel their BPN as more satisfied have higher levels of PA. The study found statistically significant correlations between anxiety-state and the satisfaction of the needs for autonomy , competence , and relatedness . These findings support the importance that PA has in the anxiety levels during social isolation, emphasizing the importance of multidisciplinary teams in an individual-based approach.This study explored the associations between physical activity (PA) anxiety levels, and the perception of satisfaction of basic psychological needs (BPN), during Coronavirus Disease 2019 (COVID-19) lockdown. Thus, 1,404 participants  ranging from 18 to 89 years old (36.4 ± 11.7 year-old) completed a questionnaire in the period between 1st and 15th April 2021. The survey included sociodemographic data and the following validated instruments: the International Physical Activity Questionnaire (IPAQ), the Basic Need General Satisfaction Scale and the State-Trait Anxiety Inventory. The Kruskal-Wallis test was performed to examine variation in anxiety levels and BPN satisfaction according to PA category . Spearman’s Rho correlations coefficients were used to determine the association between anxiety levels and psychological needs. Individuals presenting a higher level of PA revealed lower levels of anxiety-state ( On the 30th January 2020, the WHO  declaredThe state of emergency was declared in Portugal on March 18th by the President (Decree of the President of the Republic no. 14-A/2020). Thereafter, the Portuguese Government dictated a set of mandatory rules promoting social isolation. For example, gyms, health clubs, and sports centers were closed and all forms of collective exercise were also prohibited. Nevertheless, it was possible, during this time (during the first lockdown), to make short trips with the purpose to practice physical activity (PA).These social isolation measures, as well as quarantine measures, may have a positive effect in protecting peoples’ physical health. However, while preventing and mitigating the virus transmission, the application of these restraint initiatives can have a long-lasting and wide-ranging negative psychosocial impact. Indeed, they may induce the separation of significant relatives, and the perception of isolation, the loss of freedom and the demanding restructure of a new lifestyle .Literature acknowledged several psychological effects of social isolation such as high levels of anxiety , stress,Considering the possible negative consequences of this period, particularly by increasing the levels of stress and anxiety, the WHO emitted a set of deliberations . These aThe aim of this study was to examine if subjects with different levels of PA [determined by resorting to the International Physical Activity Questionnaire (IPAQ) physical activity categories], reported different anxiety levels and different perceptions of satisfaction of BPN, during the isolation period due to COVID-19. Thus, the association between PA, anxiety, and psychological needs were explored, using self-reported measures in a non-representative sample of Portuguese volunteers during the first COVID-19 lockdown. It was hypothesized that individuals who reported higher levels of physical activity would report lower levels of anxiety and higher perceptions of satisfaction of three BPN. It also expected that physical activity was associated with BPN and anxiety. It was also hypothesized that gender moderated the relationship between anxiety state and anxiety trait.This is a cross-sectional design conducted in the period between April 1st and 15th, 2020, during which a state of emergency was decreed in Portugal. Social media (Facebook and Instagram) and regional newspapers  were primary vehicles to advertise and recruit volunteers to take part in this study. Participants completed a questionnaire through google forms, which included four domains: sociodemographic data, PA levels, anxiety, and BPN satisfaction. There was no compensation or reimbursement involved for study participants.Procedures followed standards for research in sports medicine and were performed according to the Declaration of Helsinki. Participants were fully informed about the nature of the study and the procedures involving data recording. Participants were voluntary, could withdraw from the study at any time and provided informed consent before the questionnaire’s completion. Anonymity was guaranteed.Subjects were recruited by convenience sample method and were only eligible if they were aged over 18 years old and had Portuguese nationality. A total of 1,404 respondents participated (36.4 ± 11.7 years of age), ranging from 18 to 89 years old. The sample comprised 977 women (69.6%) aged 35.7 ± 11.6 years, 426 men (30.3%) aged 38.1 ± 11.6 years, and one respondent preferred not to answer . This survey, involving community adults, intended to embrace several domains of an individual’s behavior and feelings toward the confinement period of COVID-19. The survey sociodemographic questions were developed and reviewed by four experts in the areas of Exercise, Sports, and Psychology. The remain domains assessment comprised validated instruments.Participants were required to self-report age, gender, marital status, living status during the COVID-19 and academic level.α = 0.93; trait α = 0.93).The Portuguese version  of the Sα = 0.65; competence α = 0.78; and relatedness α = 0.66).The Portuguese validated version of the Basic Need General Satisfaction Scale BNSG-S;  was usedThe Portuguese validated version of The International Physical Activity Questionnaire (IPAQ-short form) was used to assess PA . This quCategory 1 (Low) – The lowest physical activity level, which corresponds to individuals who do not fulfill the criteria for categories 2 and 3, who are considered to be inactive; Category 2 (Moderate) – Individuals who meet one of the following criteria: (a) 3 or more days of vigorous physical activity for at least 20 min a day; (b) 5 or more days of any combination of walking, or moderate or vigorous physical activity, which reaches a total minimum of physical activity of at least 600 MET-min/week; Category 3 (High) – Individuals who meet one of the following criteria: (a) vigorous activity for at least 5 days, reaching a total minimum of physical activity of 1,500 MET-min/week; (b) 7 or more days of any combination of walking, or moderate or vigorous activities, which reach a total minimum of physical activity of at least 3,000 MET-min/week.Counts (and proportions), means, SD 95% CI (95% CI), and medians  were computed to describe both categorical and continuous variables for the total sample. Normality was checked using the Shapiro-Wilk test and by visual inspection of normality plots. The assumptions of normal distribution were violated for all variables.Participants were grouped according to PA level . The Kruskal-Wallis test was used to compare groups for anxiety levels and the perception of satisfaction of BPN. When the results for the dependent variables were significant, appropriated procedures for multiple comparisons between groups were executed.r < 0.1), small (0.1 < r < 0.3), moderate (0.3 < r < 0.5), large (0.5 < r < 0.7), very large (0.7 < r < 0.9), and nearly perfect (r > 0.9). Significance was set at 5%.The reported estimate of effect size measures following the recommendations for non-parametric tests . Those eSpearman’s Rho correlations coefficients were used to determine the association between the selected variables. Data analysis was performed using the IBM Statistical Package for Social Science software for Windows .The moderation was performed using Model 1 of PROCESS , an SPSSThe sample characteristics are presented in Variation associated with PA level showed significant differences among groups in both anxiety-state and anxiety-trait, and in all BPN . The resResults for the association between anxiety levels and BPN are summarized in To test the moderating effect of gender on the associations between PA and state-anxiety path analysis-based moderation was performed. Next, using ModGraph  this sigThis study explored the associations between PA, assessed by the IPAQ questionnaire, anxiety levels, and perception of satisfaction of basic psychological needs, during COVID-19 lockdown. Our main findings suggest that people with higher levels of PA present higher values of satisfaction of autonomy, competence, and relatedness, and lower levels of anxiety, both when we analyze PA category-related variation, and when testing the moderating effect of gender on the associations between PA and state-anxiety.H = 20.14; p =< 0.01; Regarding the anxiety-state, we verified significant differences between the three levels of PA , competence , and relatedness . These results are in line with previous investigations, stating that the higher the satisfaction’s perception of their basic psychologic needs the more self-determined (more autonomous) is the behavior  may integrate relatedness in addition to PA. Nowadays, with the massive use of social networks and technological devices such as the smartphone, computer, or tablets, this contact can be established even if the person is in social isolation. In fact, online training is considered number one in fitness trends for 2021 . To promIt is imperative that exercise physiologists are able to provide the satisfaction of BPN, in this context of social confinement. That will lead to internalizing behaviors, to more self-determined levels, in order to create conditions for the subjects to maintain this type of regulation of motivation that is usually associated with greater maintenance of behavior, commitment, persistence, and fun in the activity performed .The media and the Public Health Portugal have been advocating PA as crucial to individuals physical and mental health. It is thus important that future studies on COVID-19 or on social isolation and/or quarantine should try to understand if there were visible changes in PA practice and possible consequence on anxiety levels and/or mental health in general. It will be interesting to understand if someone starts practicing physical activities during the isolation period and if this habit is kept afterward. Looking for related differences could also be interesting. Future studies should consider the potential effect that PA could have on anxiety, which might be enhanced by an environment that promotes the satisfaction of BPN.p = 0.01; r = −0.46), competence , and relatedness , which in line with literature that refers that BPN negatively predicts anxiety (Regarding the analysis correlations, there were statistically significant correlations between state-anxiety and the satisfaction of the needs for autonomy ( anxiety . Further anxiety . Rather,Some limitations should be noted: the cross-sectional design of the study, which does not allow causal inferences to be made and the convenience sample enrolled with the recruitment being online and which does not allow the generalization of results Thus, results should be interpreted with caution. However, the present study presents several strengths. When studying individual concepts such as anxiety or satisfaction with psychological needs, self-reports are vital and the ideal strategy. Moreover, the sample size is notable, especially considering it was difficult to conduct any objective measurements during the COVID-19 pandemic.These findings may help develop ways to support people psychologically and socially during this outbreak, in case of future pandemics and/or future waves or purely in case of social isolation and/or quarantine. Understanding how to help fight the psychological consequences of social isolation and quarantine is important to advise policymakers and healthcare practitioners. It would be vital to enhance the practice of PA in contexts of social isolation and/or pandemic crises, in association with a climate that promotes the satisfaction of the BPN, which could buffer and reduce anxiety levels.Our findings support previous studies regarding the importance that PA may have in the anxiety level. Thus, in the case of future intervention programs aiming to help individuals dealing with social isolation, PA may be an important component, along with a motivational and psychological work regarding the satisfaction of BPN. In fact, our results underline the importance that the promotion of BPN may have in reducing anxiety.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.RA was the leader of the research group that conducted the study. RF, RA, RR-G, NA, RS, RM, and PM contributed to the conception and design of the study. RF, RA, and RR-G organized the database. RF and RA performed the statistical analysis and wrote the first draft of the manuscript. NA, RS, RM, PM, and RR-G reviewed and edited the first draft. 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.


Background: Recent studies reported, during the COVID-19 pandemic, increased mental distress among the general population and among women around the childbirth period. COVID-19 pandemic may undermine the vulnerable well-being of parents in Neonatal Intensive Care Units (NICUs).Objective: Our study aimed to explore whether parental stress, depression, and participation in care in an Italian NICU changed significantly over three periods: pre-pandemic (T0), low (T1), and high COVID-19 incidence (T2).Methods: Enrolled parents were assessed with the Parental Stressor Scale in the NICU (PSS:NICU), Edinburgh Postnatal Depression Scale (EPDS), and Index of Parental Participation (IPP). Stress was the study primary outcome. A sample of 108 parents, 34 for each time period, was estimated to be adequate to detect a difference in PSS:NICU stress occurrence level score (SOL) of 1.25 points between time periods. To estimate score differences among the three study periods a non-parametric analysis was performed. Correlation among scores was assessed with Spearman rank coefficient.Results: Overall, 152 parents were included in the study . No significant differences in the median PSS:NICU, EPDS, and IPP scores were observed over the three periods, except for a slight increase in the PSS:NICU parental role sub-score in T2 . In particular, the question regarding the separation from the infant resulted the most stressful aspect during T2 . The correlation between participation and stress scores (r = 0.19–022), and between participation and depression scores (r = 0.27) were weak, while among depression and stress, a moderate positive correlation was found (r = 0.45–0.48).Conclusions: This study suggests that parental stress and depression may be contained during the COVID-19 pandemic, while participation may be ensured. Research has indicated that, in ordinary times, the experience of a neonatal intensive care unit (NICU) hospitalization is a distressing and potentially traumatic event for parents . During So far, no study has explored how the COVID-19 pandemic affected parental stress, depression, and participation in care of their neonates admitted to the NICU. This study aimed at exploring whether, in an Italian NICU, parental stress, depression, and participation in care changed significantly over three time periods: before the pandemic and during periods of low and high COVID-19 incidence. Secondary aim was to assess the correlation between parental stress, depression and participation. This preliminary study is the first publication of the baseline assessment of an ongoing multicentre project called “Empowering Parents in the NICU” (EPINICU) exploring models to increase participation in NICU care in four different settings . The EPINICU study was approved by the Ethical Committee of Friuli Venezia Giulia Region, Italy .This was a descriptive cross-sectional study, and the Strengthening the Reporting of Observational Studies (STROBE) in Epidemiology guidelines were applied .It was conducted in the NICU of a referral pediatric hospital in the North-East of Italy. Since the 1980s, our NICU has been a 24/7 open ward for both parents. It is a small Open Bay NICU with 24 cots . In the last 2 years, it handled an average of 260 NICU admissions/year. During the whole study period, a total of nine neonatologists, 24 nurses, two unit psychologists were in service.Mothers and fathers of newborns who have been hospitalized in the NICU or semi-intensive care for at least 48 h, with an age of at least 18 years, and fluent in Italian were enrolled prospectively. Parents with previously diagnosed mental disorders, parents of newborns dead at birth or during hospitalization, not fluent in Italian or not providing consent were excluded.All participants provided a written consent before responding to questionnaires.0); summertime just after the first Italian wave characterized by low incidence of COVID-19 cases ; autumn with high COVID-19 incidence  as documented by the official statics from the Italian National Institute of Health . Three self-administrated questionnaires were used. Stress was measured with the Parental Stressor Scale (PSS) for NICU , validatParental depression was measured with the Edinburgh Postnatal Depression Scale (EPDS), which has been validated for use in several countries, including Italy . The scaParental participation was measured with the Index of Parental Participation (IPP), modified to describe activities related to newborn care. The adaptation was approved and back translated by Dr. Melnik, the author of the instrument . The IPPStress was the study primary outcome. A sample of 108 parents, 34 for each time period, was estimated to be adequate to detect a difference in PSS:NICU stress occurrence level score  of 1.25 points between time periods, deemed to be clinically relevant and assuming an overall type I error of 0.05, 99% power and a conservative standard deviation of 1  using a Wilcoxon-Mann Whitney test. Correlation between scores was analyzed using Spearman rank correlation coefficients. All tests performed were two tailed and a p-value of <0.05 was considered statistically significant. Statistical analyses were performed using Stata version 14 and R version 3.6.1.Summary statistics are presented as absolute frequencies and percentages, and as medians and interquartile ranges (IQR) for continuous non-normally distributed data. Due to deviation from parametric model assumptions, to estimate score differences among periods a non-parametric analysis was performed using the Kruskal-Wallis test. Bonferroni adjusted N = 99) did not differ from those whose parents were not enrolled (N = 64) except for having a lower birthweight , a longer length of stay  and higher frequency of ventilation at birth  , 96 (37%) were excluded as they did not meet the inclusion criteria. Parents of 64 (25%) newborns refused to participate (3/64) or were not approached for enrolment (61/64). Overall, we included 152 parents  . Newborn= 0.003) .0 50%, T1 46.2%, T2 80%, p = 0.034), and of infants admitted to the NICU compared to the semi-intensive unit in T2   .2, when the score was calculated as SOL    were observed in our population, with 34% of parents scoring ≥12 at EPDS . No sign= 0.038) . Differe= 0.008) .2 for two specific aspects regarding the change of clothes and diapers .r = 0.19–022), and between participation and depression scores (r = 0.27) were weak, while among depression and stress, a moderate positive correlation was found (r = 0.45–0.48) (The correlation between participation and stress score (45–0.48) .In our study, we found that parental stress, an EPDS value ≥12, and participation in care in an Italian NICU did not change significantly during the COVID-19 pandemic when compared with the period immediately before.It is well-documented that NICU parents are at increased risk of stress and depression . StudiesThere are no data in the literature to compare our findings on parental participation in care in the NICU. According to the IPP scoring system, parental participation resulted to be medium-to-high in our study, and it was higher for activities related to daily living, comfort provision and advocacy rather than technical tasks, which in our NICU setting are usually carried out by nurses .In our study we did not find changes in parental stress, depression, or participation in care during the COVID-19 pandemic. A lot of concern has been raised recently because the added burden of the COVID-19 pandemic may negatively impact the already vulnerable psychosocial health of NICU families , 5. A cr1, universal SARSCoV-2 testing with nasopharyngeal swabs and quantitative polymerase chain reaction tests was introduced for parents every 2 weeks and, since September 2020, every week. Despite visits were restricted to one parent per baby at the time, parents were allowed to enter as frequently and as long as they liked for a maximum of 2 per room in the semi-intensive unit. There was neither a decrease in the psychological support (two psychologists) nor in the medical and nursing staff. Psychologists were present in our NICU from Monday to Saturday and offered parental support also outside the unit by phone, as they did before COVID pandemic. During T1 and T2, all NICU staff had to wear a facial mask , environmental cleaning procedures were intensified but no other major changes in care occurred. When parents were not present, daily updates on the baby's clinical condition were provided through video-calls by unit psychologists or the director. Recently telehealth has been advocated as a potential low-cost strategy in order to keep patients and providers safe, while emphasizing family-centered care (During the study period, visiting restrictions were applied but other organizational changes were enacted to mitigate the impact of these restrictions on families. Starting from Tred care .All these aspects may have contributed in our NICU to ensure constant parental participation in care and stabilize stress and depressive symptoms, although our study was not designed as an intervention study to test this hypothesis.2, with separation from the baby deemed as the most stressful aspect. The higher percentage of babies in the NICU in T2 did not account for this difference. This result may well reflect a real difficulty related to the pandemic. As suggested by other authors (We did observe higher SOL stress scores during T authors , 19, the authors .2, when Parental Role SOL was significantly higher, there was a significant increase in changing clothes and diapers when compared to T0. However, the IPP questionnaire may not capture some aspects of the quality of parental participation in care, although it contains several items on relationship with staff and advocacy (When exploring the correlation between scores, we found weak to moderate positive correlations between them. Evidence from RCTs showed that increased parental participation in care can reduce parental distress , 21. Howadvocacy . Finally2, as it was a period characterized by a higher COVID-19 incidence.Limitations of this study include that it was not designed to test any specific intervention, nor to look specifically at the associations between parental characteristics, participation in care, stress, and depression. Gender differences in stress and depression in NICU parents are reported , 15 but Findings of our study cannot be directly generalized to other NICUs. More investigations on parental participation in care, in parallel with parental stress, anxiety and depression in different settings and over time shall further contribute to generate evidence on this often-neglected topic.Further studies are also needed to evaluate specific interventions to mitigate the additional psychological burden of COVID-19, such as telematic approaches including telephone helplines, video calls, video tutorials and conferencing to see the hospitalized baby and to communicate with NICU staff , 19.Compared to other existing evidence, our study suggests that stress and depression levels of parents with infants admitted to NICU may remain unchanged even during peaks of the COVID-19 pandemic, and that parental participation in care can be maintained in these settings.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 Institutional Review Board of Friuli Venezia Giulia Region. The patients/participants provided their written informed consent to participate in this study.ML: conception of the EPINICU study. ML, JB, IM, and MG: conception of this paper. JB, MG, MT, and AT: collection of data. MT and MG: data entry. IM, JB, MG, and ML: analysis and interpretation of the data. JB and ML: drafting of the article. JB, MG, IM, AT, MT, LT, and ML: critical revision of the article for important intellectual content and final approval of the article. All authors contributed to the article and approved the submitted version.The study was supported by Chiesi Foundation research grant 2019 in Neonatology to our Institute of Research. As per the contract undersigned among parties, The Grant does not constitute, directly or indirectly, a fee for services provided or to be provided in favor of the Foundation. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


The effects of RIPC on levels of oxidative stress, and liver and heart damage markers were investigated at rest after 10 consecutive days of training and after the marathon run. The 10-day RIPC training decreased the serum resting levels of C-reactive protein (CRP), alanine transaminase (ALT), γ-glutamyl transpeptidase (GGT), and malondialdehyde (MDA). After the marathon run, creatinine kinase MB (CK-MB), lactate dehydrogenase (LDH), cardiac troponin level (cTn), aspartate aminotransferase (AST), alkaline phosphatase (ALP), ALT, total bilirubin (BIL-T), and MDA levels were increased and arterial ketone body ratio (AKBR) levels were decreased in all participants. The changes were significantly diminished in the RIPC group compared with the control group. The GGT activity remained constant in the RIPC group but significantly increased in the control group after the marathon run. In conclusion, the study provides evidence for a protective effect of RIPC against liver and heart damage induced by strenuous exercise, such as the marathon.Clinical studies continue to provide evidence of organ protection by remote ischemic preconditioning (RIPC). However, there is lack of insight into impact of RIPC on exercise-induce changes in human organs’ function. We here aimed to elucidate the effects of 10-day RIPC training on marathon-induced changes in the levels of serum markers of oxidative stress, and liver and heart damage. The study involved 18 male amateur runners taking part in a marathon. RIPC training was performed in the course of four cycles, by inflating and deflating a blood pressure cuff at 5-min intervals (RIPC group,  Prolonged strenuous running, e.g., a marathon run, induces a rise in the concentrations and/or activity of biomarkers that reflect physiological stress of the skeletal muscle, liver, heart, and some other tissues . OxidatiMultiple studies aim to identify the optimal approach of reducing the impact of strenuous exercise on markers of tissue damage  and was conducted in accordance with the declaration of Helsinki. Written informed consent was obtained from all participants before inclusion in the study. The participants were informed about the possibility of withdrawing their consent at any time and for any reason, and were informed about the study procedures, but not about the rationale and study aim, so as to keep them naive as to the potential effects of RIPC.In the study, the effects of 10-day RIPC training on marathon-induced changes in the markers of oxidative stress, and liver and heart damage were evaluated. All participants were randomly assigned to two study groups undergoing either RIPC or sham-controlled intervention (RIPC vs. SHAM) for 10 consecutive days. During the first visit (pre-intervention) to laboratory, set early in the morning, basic anthropometric characteristics were measured  and venous blood samples were drawn. On the following and subsequent days, either RIPC or SHAM procedure took place. Early in the morning 1day after the last RIPC or SHAM training, blood samples were collected; the runners performed a marathon race on the same day. Blood samples were also collected immediately after, 24h after, and 7days after finishing the race.Twenty-four male amateur runners were enrolled in the study: 12 in the RIPC group and 12 in the SHAM group. Each runner had an experience of a minimum five full marathon runs, with the completion time between 2h 50min and 3h 20min. For the study, each participant ran the 46th Dębno Marathon . The starting temperature on the day was 12.1°C, and the starting (and finishing) line was in the town of Dębno (40m above sea level). The course is flat and allows the runners to achieve high running speed.n=10; SHAM, n=8). The basic anthropometric characteristics of the groups and their performance are shown in Two runners from the RIPC group and four from the SHAM group did not finish the race. Consequently, data for only 18 amateur runners were analyzed  each day and under the control of color flow Doppler ultrasound  to ensure the full closure of the arterial inflow. All ultrasound procedures were performed according to the standards of the Polish Ultrasound Society, by a physician who had completed a training in ultrasound imaging. The participants had no knowledge of the group allocation and differences in the procedures.The blood was collected five times: before and 24h after the RIPC/SHAM training period , immediately after, and 24h and 7days after the marathon race. Venous blood samples were collected into Sarstedt S-Monovette tubes  containing a coagulant for blood analysis; into tubes without anticoagulant for serum separation (with coagulation accelerator); or in tubes containing EDTA for plasma isolation. Samples were centrifuged using standard laboratory methods, aliquoted, and frozen at −80°C until further analysis. The selected markers were analyzed according to the medical diagnostic procedures referenced by European Federation of Clinical Chemistry and Laboratory Medicine. EFLM by Synevo Labolatory at an accredited laboratory  using a hematological analyzer, and immunoenzymatic and conductometric methods, as appropriate .The following were analyzed: (1) cardiovascular and cardiac muscle markers: creatinine kinase (CK), creatinine kinase MB (CK-MB), C-reactive protein (CRP), hemoglobin (HGB), LDH activity, myoglobin (MB), red blood cells (RBC), troponin T (TnT), and urea; (2) liver markers: albumin (ALB), alkaline phosphatase (ALP) activity, alanine transaminase (ALT) activity, AST activity, direct bilirubin (BIL-D), total bilirubin (BIL-T), GGT activity, globulin (GLB), and total protein (TP); and (3) oxidative stress markers: malondialdehyde (MDA), arterial ketone body ratio (AKBR), and conjugated dienes (CD).group: RIPC, SHAM×training: before, after) was used to investigate the difference between the effects of 10-day RIPC and SHAM training on the selected cardiac muscle, liver, and oxidative stress markers. Another two-way ANOVA with repeated measures  was performed to investigate the impact of marathon running on the selected marker levels in relation to the preceding 10days of RIPC training. In case of a significant interaction, Tukey’s post hoc test was performed to assess differences in particular subgroups. In addition, the effect size was estimated by eta-squared statistics (ƞ2). Values equal to or greater than 0.01, 0.06, and 0.14 indicated a small, moderate, and large effect, respectively. All calculations and graphics were done in Statistica 12 software . Differences were considered statistically significant at p≤0.05. The required sample size was estimated by using GPower ver. 3.19.4 software (Descriptive statistics (the mean±SD) were used for all measured variables. Two-way ANOVA with repeated measures . The patients/participants provided their written informed consent to participate in this study.JM and JA contributed to the conceptualization. JA, JM, AK, BS, BN, AB, LD-S, PB, and KS contributed to the methodology, the writing of the original draft preparation, and writing – review and editing. JM, AB, AK, BS, and BN contributed to the investigation. JM contributed to the project administration. JA contributed to the funding acquisition. All authors contributed to the article and approved the submitted version.The sponsor had no role in the design of the study; in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the article for publication. The study was registered as a clinical trial NCT03417700.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.


In 945 LURIC participants both markers were high (UHGH), in 935 both were low (ULGL), in 589 only eGFR (UHGL), and in 582 only sUmod (ULGH) was low. After balancing the groups for cardiovascular risk factors, hazard ratios (95%CI) for all-cause mortality as compared to UHGH were 2.03 (1.63–2.52), 1.43 (1.13–1.81), and 1.32 (1.03–1.69) for ULGL, UHGL, and ULGH, respectively. In VIVIT, HRs were 3.12 (1.38–7.08), 2.38 (1.01–5.61), and 2.06 (0.81–5.22). Adding uromodulin to risk prediction models that already included eGFR as a covariate slightly increased the Harrell's C and significantly improved the AUC in LURIC. In UHGL patients, hypertension, heart failure and upregulation of the renin-angiotensin-aldosterone-system seem to be the driving forces of disease development, whereas in ULGH patients metabolic disturbances might be key drivers of increased mortality. In conclusion, SUmod/eGFR subgroups mirror distinct metabolic and clinical patterns. Assessing sUmod additionally to creatinine or cystatin C has the potential to allow a more precise risk modeling and might improve risk stratification.Serum uromodulin (sUmod) shows a strong direct correlation with eGFR in patients with impaired kidney function and an inverse association with mortality. However, there are patients in whom only one of both markers is decreased. Therefore, we aimed to investigate the effect of marker discordance on mortality risk. sUmod and eGFR were available in 3,057 participants of the Ludwigshafen Risk and Cardiovascular Health study and 529 participants of the VIVIT study. Both studies are monocentric prospective studies of patients that had been referred for coronary angiography. Participants were categorized into four groups according to the median values of sUmod  and eGFR (LURIC: 84 ml/min/1.73 m UMOD locus with estimated glomerular filtration rate (eGFR) . Results from genome-wide association studies linking genetic variation at the e (eGFR) , chronice (eGFR) –3, artere (eGFR)  and diabe (eGFR) , as wells so far . Expresss so far . Studiess so far . In siliand KLF4 .In the case of pathophysiological conditions they act together to rapidly modulate Umod concentration. Due to its immunomodulatory and anti-inflammatory properties, sUmod concentrations might be actively increased in the setting of systemic illnesses to reduce systemic inflammation , 10. Thi2, independently from eGFR and albuminuria . In LURIC, also clinical cutoff criteria were applied to create the groups using cutpoints of 150 ng/ml for sUmod and 60 ml/min/1.73 m2 for eGFR. Continuous data are presented as the mean and standard deviation (SD) when normally distributed or as the median and 25th and 75th percentile for non-normally distributed variables. Categorical data are presented as percentages. Statistical differences between groups and continuous variables were determined using ANOVA. Non-normally distributed variables were log-transformed before entering analysis. Tukey's honest significant difference test was used to investigate differences between individual groups using family-wise correction for multiple testing. The chi-square test was used for categorical variables and differences between individual groups were examined using the “chisq.post.hoc” function implemented in the R package “fifer” v1.1 using the false-discovery-rate method for multiple testing correction.Study participants were categorized into tertiles of sUmod/eGFR or into four groups according to the median values of sUmod (146 ng/ml in LURIC and 156 ng/ml in VIVIT) and eGFR .All tests were two-sided and a  v4.0.3 .Regarding the survival advantage of the ULGH group compared to the ULGL group, the main cause probably is renal function, that is on average at an eGFR of 62 mL/min/1.73 mImportantly, rates of hypertension and heart failure are higher in UHGL than in ULGH in LURIC, suggesting that sodium and fluid overload occur that relate to high sUmod and cannot be balanced by a largely preserved renal function such as in the ULGH patient group.In VIVIT, there was no significant difference in the rates of hypertension between both groups. Information on heart failure was not available in this cohort but the concentration of NT-proBNP was almost three times higher in the ULGH group.2 in favor of the UHGL patient group.Conversely, when analyzing the higher mortality in UHGL vs. UHGH patients groups, a difference in mortality that is exceeding the difference between ULGH vs. UHGH by far, the obvious culprit is impaired renal function, that associates with higher rates of arterial hypertension, heart failure, and DM. The survival advantage when comparing UHGL with ULGL may be explained by protective, i.e., antiinflammatory and immunomodulatory effects of normal sUmod levels and by a somewhat better renal function. The difference in eGFR between both groups was 10 ml/min/1.73 m2 for eGFR in LURIC, we found significant differences between UHGL and ULGH regarding a number of vasoactive biomarkers that were not apparent in the analyses using the median groups  or to the Principal Investigator of the LURIC Study, Winfried März (winfried.maerz@luric-online.de) who are in charge of supervising ethical and legal aspects of the LURIC study. Finally, the authors confirm that they accessed these data upon approval by LURIC and that all other researchers can access the data upon approval in the same manner the authors did. Similarly, the data from VIVIT cannot be released to the public domain due to Austrian Data Protection Act, but access is also made available to researchers upon request and approval . Requests to access these datasets should be directed to Heinz Drexel; vivit@lkhf.at, winfried.maerz@luric-online.de.The data analyzed in this study is subject to the following licenses/restrictions: Due to the articles of Ludwigshafen Risk and Cardiovascular Health (LURIC) Study gGmbH, which needs to acknowledge the German Data Protection Act and the consent given by the study participants, data cannot be released to the public domain. The exploitation of the (LURIC) Study database is governed by the articles of the LURIC Study GmbH (non-profit LLC), registered under number HRB 7668 at the commercial registry of Freiburg in Breisgau, Germany. According to the articles of the organization, data access is made available to researchers upon request and approval. This procedure makes sure that rules of good scientific practice are followed and that credit is given to the people who have been in charge of the design and the organization of the study. Interested researchers are invited to address their request or proposal to Kai Grunwald ] and of Vorarlberg . The patients/participants provided their written informed consent to participate in this study.GD, MK, BY, and AL designed and performed research, made statistical analyses, and drafted the manuscript. BK, WM, and HD designed research and corrected the manuscript. JS drafted the manuscript. HS measured serum uromodulin and corrected the manuscript. All authors contributed to the article and approved the submitted version.LURIC was supported by the 7th Framework Program RiskyCAD (grant agreement number 305739) of the European Union and the H2020 Program TO_AITION (grant agreement number 848146) of the European Union. The work of WM and MK was supported as part of the Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD) which was funded by the German Federal Ministry of Education and Research. The work of GD was supported by the European Union's Horizon 2020 research and innovation programme under the ERA-Net Cofund action N° 727565 (OCTOPUS project) and the German Ministry of Education and Research (grant number 01EA1801A). The funding sources were not involved in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.WM reports grants and personal fees from AMGEN, BASF, Sanofi, Siemens Diagnostics, Aegerion Pharmaceuticals, Astrazeneca, Danone Research, Numares, Pfizer, Hoffmann LaRoche: personal fees from MSD, Alexion; grants from Abbott Diagnostics, all outside the submitted work. WM and MK are employed with Synlab Holding Deutschland GmbH. JS declares a patent at the University Charite, Berlin pending, and no other conflict of interest. BK reports travel support a/o lecture fees a/o advisory board memberships from Astellas, Bayer, BMS, Boehringer Ingelheim, Chiesi, Hexal, Pfizer, Sanofi, Servier, Vifor all outside the submitted work. MK reports lecture fees from Bayer outside the submitted work. The remaining 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.


IntroductionThis study aims to develop and validate a questionnaire to assess workplace violence (WPV) domains in the healthcare setting.Methods The study used a mixed-method design. In Phase 1, qualitative methods for developing the questionnaire were employed, including literature review, focus-group discussion, expert evaluation, and pre-testing. During Phase 2, quantitative methods were employed for establishing the construct validity of the questionnaire. In Phase 1, experts from departments like emergency medicine, medicine, obstetrics and gynecology, psychiatry, trauma, anesthesia, and critical care unit participated. For Phase 2, data were collected from 213 participants; mean age (30.48±5.95) in metropolitan cities.ResultsThe questionnaire consists of 37 items in five domains: (A) Forms of violence, (B) Impact of violent incidences, (C) Reporting of incidence, (D) Mitigation strategies, and (E) Risk factors. The Cronbach’s alpha value of the questionnaire is 0.86, suggesting an excellent internal consistency.ConclusionA reliable and valid tool for gathering information regarding WPV in the healthcare system from around the world has been developed. The tool can be used to study the elements that may contribute to violence and its consequences, which will help policymakers curate various mitigation methods to safeguard WPV victims. Workplace violence (WPV) in the healthcare sector is a global concern and has become unfortunate in different parts of the world . SeveralResearches conducted in different parts of the world have studied different aspects of the WPV in healthcare settings. Most of them have used non-validated semi-structured interview techniques, making it challenging to compare different studies . Most ofThis study was conducted to develop and validate a comprehensive, easy-to-administered tool that could assess all relevant domains of WPV in a healthcare setting  that would help in a comprehensive evaluation.This questionnaire was developed and validated using a standard scientific approach -13. ThisStep 1: Literature Review An in-depth literature review was done by using search string (violence OR aggression) AND AND (workplace) AND (determinants OR predictor) AND (intervention* OR strategy* OR prevent*) in PubMed and Wiley from looking for relevant studies done over the past ten years, in the English language. Five hundred fifty-three articles were screened, from which 27 relevant articles were selected. This helped identify various domains for the questionnaire like types/ forms of violence, reporting of violence, risk factors of violence, the impact of violence, and mitigation strategies under which 45 items were generated. Step 2: Focus group discussions (FGDs) and in-depth interviewsThe investigators performed five FGDs, each session having 6-8 participants. The sessions were organized over an online platform with the doctors and other healthcare workers. As per the literature review and collaboration with an expert , the FGD guide was developed, which included open-ended questions to help participants explore their viewpoints, practices, and issues. Active involvement was encouraged, and the discussion included topics such as types/forms of violence, reporting of violence, risk factors of violence, the impact of violence, and different mitigation strategies which can be used to reduce workplace violence. Later on, five in-depth interviews were also conducted to gain more information on this issue. The resulting data were qualitatively evaluated, and new items were added to the tool as a result. The focus groups and in-depth interviews resulted in the addition of 12 items.Step 3: Generation of itemsA set of 57 questions was created based on the literature review, focus group discussions, and in-depth interviews. The survey items were prepared in an easy-to-understand format, eliminating the double negatives.Step 4: Expert ValidationA team of eight specialists from various areas  validated the developed tool for critical review, content, and face validity. All elements were assessed based on their need, clarity, and relevance. The feedback made necessary adjustments to the questionnaire: 11 items were eliminated at this stage.Step 5: Pilot TestingFollowing the approach mentioned above, a questionnaire draft was created and pre-tested on 12 doctors and other health care workers. The participants remarked on the items’ need, relevance, and clarity. Six items were eliminated based on feedback and expert consultation, and necessary adjustments were made in four items to reduce ambiguity.Validation of the questionnaireDuring expert validation, the questionnaire’s content validity was examined using qualitative and quantitative approaches. An expert panel of eight participants was invited to examine the questionnaire and comment on the necessity, relevance, and clarity of items in the qualitative validity. The items were changed in response to the input. A three-point scale  was used to grade the usefulness of items. Lawshe scores were used to compute appropriate Content Validity Ratio (CVR) values. To determine the relevance, clarity and simplicity of each item, a four-point Likert scale was used. Items with a 0.7 or less Content Validity Index (CVI) were eliminated, and those between 0.7-0.79 were altered as per the expert’s opinion . Expert Cross-sectional surveyA cross-sectional survey was conducted to validate the questionnaire. Participants, including doctors and other healthcare staff from various departments like emergency medicine, medicine, psychiatry, nursing, obstetrics, and gynecology, were recruited during August 2021; a convenience sampling method was used to recruit the participants. After receiving written informed consent, the investigators administered the questionnaire in online and offline mode, and responses were recorded on Google forms simultaneously. Statistical analysisThe demographic information of the participants was analyzed using descriptive statistics. The Kaiser-Mayer-Olkin (KMO) measure determines the adequacy of the sample and values greater than 0.5 suggest that the data is suitable for factor analysis. To discover domains of the questionnaire and establish construct validity, exploratory factor analysis with principal component extraction and varimax rotation with Kaiser normalization were employed. The internal consistency was measured using Cronbach’s alpha. Its score of greater than 0.7 suggests that it has high internal consistency. IBM® SPSS® Statistics version 24.0 was used to analyze the data.The questionnaire has 37 items, comprising of five sections viz., forms of violence, the impact of violent episodes, reporting of incidence, mitigation strategies, and risk factors related to the health care workers in the various departments and settings. The questionnaire is available in Table Socio-demographic profile of the participantsTwo hundred thirteen doctors and other healthcare staff working in different departments  participated in this survey. The participants were aged 18-65 years  with a slight male predominance . 92% of the participants were practicing in government hospitals, out of which 79% were residents of metropolitan cities. The socio-demographic details of the participants are given in Table Descriptive statistics of the survey resultIt was observed that approximately 35% of the HCWs experience verbal altercations at their workplace daily, and 61% have never had any experience of physical violence. Due to episodes of violence at the workplace, 47% of the HCWS did not feel like working, which had a significant negative impact on their mental and psychological well-being. 33% of the participants did not feel comfortable reporting the incidence of violence to their authorities due to a lack of organizational support and believed no action would be taken. Validity of the questionnaire The questionnaire has good internal consistency (Cronbach’s Alpha =0.86) . MulticoThe developed questionnaire is a comprehensive and user-friendly tool with 37 items encompassing the problems related to WPV in the healthcare sector. It has five sections to assess the burden of the problem, the associated risk factors, and provide mitigation strategies to overcome it. The tool is developed on a Likert scale, which is beneficial in conducting comparative studies and can be used in different socio-cultural settings.Section A comprises two items to assess the frequency of different types of violence experienced within healthcare settings. Apart from the prevalence, the spectrum of the various forms  can also be assessed in this Section. Section B, comprising eight items, tries to analyze the impact of the episodes of WPV on the sufferers. The various components of an individual’s life such as personal , family , social (friends/colleagues’/ religious practice), and psychological well-being  are found be to significantly impacted due to such incidences. It is found that despite the significant impact of these incidents on the physical and psychological well-being of the victim, such occurrences go unreported. Section C, comprising 11 items, tries to assess the reasons for not reporting these violent episodes. Mitigation strategies that can be used to mitigate the episodes of violence at the workplace are assessed in Section D, which consists of 12 items. Lastly, Section E comprises five items to highlight the various risk factors that contribute to violence in healthcare settings.The most commonly available validated tool is made by WHO . It has The developed tool has certain strengths. Firstly, it is brief and simple and may be utilized in a resource-limited setting. Secondly, it will help assess various forms of WPV, associated risk factors, and their impact. Lastly, the result of the developed tool will give government officials and healthcare practitioners in-depth knowledge regarding WPV. It will also help in devising various mitigation strategies to reduce WPV. However, there are three limitations: the semi-quantitative nature of the study, the lack of assessment of the predictive validity, and the lack of confirmatory factor analysis, which could alter the number of significant items in a construct and the total number of factors in the questionnaire.A credible and validated tool for obtaining information about workplace violence in the health sector from numerous geographic regions of the world has been established. The study is specifically looking into variables that may lead to violence and its impact, which would assist policymakers in curating various mitigation strategies to protect the victims of WPV.


Background: The latest guidelines recommend the use of proton pump inhibitors (PPIs) to minimize gastrointestinal bleeding (GIB) in patients receiving dual antiplatelet therapy (DAPT), even though this co-administration may increase the risk of ischemia due to drug interactions. We have noticed that there are few studies conducted on patients with a lower risk of GIB. Therefore, we investigated the clinical effect of co-administration of PPI on DAPT patients with low GIB risk.Methods and Results: From January 2013 to September 2014, a total of 17,274 consecutive patients on DAPT from 108 hospitals with low risk for GIB in the China Acute Myocardial Infarction (CAMI) registry were analyzed. The primary endpoints were GIB and major adverse cardiovascular and cerebrovascular events (MACCE). Multivariate logistic regression analysis and Cox proportional hazard models were used to assess the effect of PPIs use. Of the analyzed patients, 66.6%  were treated with PPIs. PPI use did not show an extra gastrointestinal protective effect in patients with low risk for GIB who were hospitalized and on follow-up after 2 years. Moreover, it was associated with an increased risk of stroke during the 2-year follow-up  and an increased risk of MI after 6 months . We found the same results after propensity score matching.Conclusion: PPI use is prevalent in DAPT patients with low GIB risk. PPIs did not show an extra gastrointestinal protective effect, while an increased risk of stroke was observed during the 2-year follow-up.Clinical Trial Registration:www.clinicaltrials.gov, identifier NCT01874691. Althougidelines , especiafection] , a potenfection] . We notifection] , and thefection] , 10. TheAll patients analyzed in our research were from the China Acute Myocardial Infarction (CAMI) registry, which is a prospective, nationwide, multicenter observational study of patients with AMI. The registry includes three levels of hospitals  covering all provinces and municipalities across mainland China. The CAMI registry was registered with ClinicalTrials.gov (NCT01874691), and this project was approved by the institutional review board central committee at Fuwai Hospital, NCCD of China. All patient data were protected at all times. Detailed descriptions about data management and quality control can be found in the methodological article about the CAMI registry published previously .http://www.CAMIRegistry.org) by the local investigators at each participating site. Trained clinical investigators were employed to ensure the accuracy and reliability of data. Element definitions are accessible to investigators automatically at the point of data entry. The front page of the electronic case report form (eCRF) must be filled out and submitted online within 24 h from patient admission who meet the inclusion criteria.Simply, all elements  are collected, validated, and submitted through a secure, password-protected, web-based electronic data capture system (n = 370), no DAPT , and missing baseline data . We further excluded 449 patients treated with H2 receptor antagonists for gastrointestinal prophylaxis. A total of 4,709 patients were identified as a high-risk group for GIB  according to the guideline . GIB was defined as clinically evident GIB . MACCE was a composite endpoint of all-cause death, MI, and stroke. Secondary endpoints were all-cause death, MI, and stroke. All the information is collected using the standardized set of variables and standard definitions that were validated by trained investigators. All variables were coded with CDISC, ICD-10, MedDra, and WHO-DD to make them standardized.via centralized telephone interviews by trained personnel at 30 days, 6 months, 1 year, and 2 years. The clinical events were validated by source documents. PPI use was identified at the study baseline and each study follow-up. Patients were excluded if they had quit their PPI use during the follow-up.Post-discharge study follow-up was conducted p < 0.05 was considered statistically significant.Continuous variables are expressed as mean ± standard deviation or median (25th and 75th percentiles), and categorical variables are presented as percentages. Differences in baseline characteristics and outcomes in patients with and without PPIs were assessed using the chi-square test, Fisher's exact test for categorical variables and analysis of variance test, or the Wilcoxon rank test for continuous variables. Multivariate logistic regression analyses were conducted to evaluate the adjusted effect of PPI use on clinical outcomes. The 2-year follow-up endpoints were modeled using the Cox proportional hazard regression. Clinical characteristics that were imbalanced at a nominal 5% significance level between the two groups, treated or not treated with PPIs, were identified and included in the final adjusted model; other important factors that can affect the clinical endpoints were also included in the final model, although their differences were not significant between the two groups in the univariate analysis (such as the history of diabetes and congestive heart failure). These included age, clinical presentation, and medical therapy (detailed variables included are presented below the relevant tables). Odds ratio (OR) and hazard ratio (HR) were presented with the 95% confidence intervals (CIs). All statistical analyses were performed using SAS version 9.4, and a two-tailed We also performed propensity score matching (PSM) to select two comparable patients with balanced observed variables. A propensity score was estimated for each patient using a logistic regression model. Patients were matched on estimated propensity scores, with replacement, using the nearest neighbor approach. The detailed information about the propensity score model can be found in the n = 11,487) were treated with PPIs. Patients on PPIs tended to be older , female , and with a higher Killip class  and hematocrit  at admission with a history of hypertension , MI , stroke , and malignancy . On hospitalization, they were often treated with a GPIIb/IIIa receptor inhibitor  and heparin . Detailed information on demographic and clinical characteristics is presented in Among 17,247 DAPT patients with low risk for GIB, 66.6% (p = 0.7189) (p = 0.0062)  was similar between patients with PPIs and without PPI use  . Results 0.0062) .Patients were followed up throughout a period of 2 years, and event rates at 30 days, 6 months, 1 year, and 2 years are presented in After PSM, 5,014 patients with PPIs had an estimated propensity score that matched to 5,014 patients without PPI use. PPIs did not show an extra gastrointestinal protective effect, while an increased risk for stroke was seen during the 2-year follow-up .The main findings of our research were as follows: (1) among the DAPT population, 66% of patients with low GIB risk were treated with PPIs. (2) We did not find an extra protective effect of PPIs on the gastrointestinal tract among DAPT patients with low GIB risk. (3) PPI use was associated with an increased risk of stroke in hospital and during the 2-year follow-up and an increased risk of MI after 6 months. PSM did not change the final results.In our study, PPI use was common in patients with low risk for GIB. We noticed that PPI over-prescription was becoming a new concern in the field of AMI patient management , 10. And12 receptor inhibitors, which could decrease the effect of DAPT. Both clopidogrel and PPIs require bio-transformation into active metabolite via cytochrome P-450 (CYP) enzymes in the liver  The CAMI project was launched in 2016, and clopidogrel was prevalent in that period because limited research and guidelines recommended other P2Y12. Further sub-analysis and studies evaluating the effect of PPIs on other P2Y12 inhibitors are warranted. (4) The inclusion of only the Chinese population might limit its applicability to other populations.There are some limitations in our manuscript: (1) Although CAMI is a large-scale and multicenter registry, our research is a retrospective study. Therefore, the two groups were not comparable to some extent. This would affect the assessment of the effect of PPIs on clinical outcomes. We have used statistical approaches (PSM or multiple regression) to diminish the bias. (2) CAMI could not evaluate the individual effect of PPIs on endpoints; we admitted that drug interaction between different PPIs and P2YThe original contributions presented in the study are included in the article/The original study on which this paper is based was reviewed and approved by Ethics Committee of Fuwai Hospital. Reference Number: 2012-398. The patients/participants provided their written informed consent to participate in the original study.WS was responsible for literature search, study design, data management, data interpretation, and writing. XF and LN was responsible for data analysis, data interpretation, and writing. JY, MeiY, and HY was involved in study design, statistical analysis plan, and data interpretation. MenY and YY were involved in data interpretation and writing of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-009), Twelfth Five-Year Planning Project of the Scientific and Technological Department of China (2011BAI11B02), and National Natural Science Foundation of China (No. 81670415).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.


Multifunctional biomedical materials capable of integrating optical functions are highly desirable for many applications, such as advanced intra-ocular lens (IOL) implants. Therefore, poly(ethylene glycol)-diacrylate (PEG-DA) hydrogels are used with different photoinitiators (PI). In addition to standard UV PI Irgacure, Erythrosin B and Eosin Y are used as PI with high sensitivity in the optical range of the spectrum. The minimum PI concentrations for producing new hydrogels with PEG-DA and different PIs were determined. Hydrogel films were obtained, which were applicable for light-based patterning and, hence, the functionalization of surface and volume. Cytotoxicity tests confirm cytocompatibility of hydrogels and compositions. Exploiting the correlation of structure and function allows biomedical materials with multifunctionality. In tissue engineering and medical science, hydrogels are particularly suitable as tissue scaffolds due to their tunable properties including water content, swellability, diffusivity and stiffness ,2. In faCataract, the irreversible turbidity of the natural lens of the eye, is one of the most common causes for global blindness and can only be treated by replacing the clouded lens with an artificial IOL implant. Among the state-of-the-art IOLs are modern foldable hydrogel lenses . PersistThis is where the idea of volume holographic structuring comes into play. Prospective IOLs, based on multifunctional biomedical material with integrated optical functionality, could fulfill their function—i.e., to focus the light onto the retina—with an optically structured volume . As a reVolume holography is a very interesting field of application for photo-responsive polymers, where diffractive structures are induced by a spatially modulated holographic exposure . HolograPoly(ethylene glycol) (PEG)-based hydrogels are generally promising as tissue-engineering scaffolds due to their biocompatibility and intrinsic resistance to protein adsorption and cell adhesion . FurtherAdditionally, the micropatterning of PEG-based hydrogels with gold nanoparticles allows for the fabrication of functionalized PEG-based hydrogel films ,15. The In all this, the type of photoinitiator (PI) used is key for the specific photo-response of a certain material. The properties of the PI has strong influence on holographic grating formation in the respective material . It alsoPEG-DA was mixed with PI . Films were prepared by photopolymerization with 366 nm for 1 h. In terms of optical transparency, mechanical integrity, flexibility, and stability, the new gels compare well with other gels based on PEG-DA ,22,23.For PEG-DA with Irgacure, EB and EY as PI, a minimum concentration of PI was needed to make gel. With less PI concentration, no hydrogel was formed. The minimum concentration for the different PIs is shown in While Irgacure, which is an often employed and suitable photoinitiator for biomaterials research, has an absorption maximum in the UV/Vis-spectrum around 300 nm , the nova shoulder at 514 nm. After crosslinking, the absorption peak can be observed at 550 nm with a shoulder at 512 nm. The typical color for the hydrogel with EB as PI is pink, as shown in With EB as PI, the absorption maximum before crosslinking was around 552 nm with With EY as PI, the absorption maximum before crosslinking was around 542 nm with a shoulder at 507 nm. After crosslinking, the absorption peak can be observed at 543 nm with a shoulder at 506 nm. The typical color for the hydrogel with EY as PI is orange, as shown in The major advantage of the new PIs (EB and EY) over the standard Irgacure is their high sensitivity in the optical range of the spectrum, which enables optical patterning—e.g., by volume holography. To counter the disadvantage of strong coloring, the composition could be optimized, e.g., by use of a crosslinker so that the concentrations of EB and EY can be reduced, respectively.In the next step, the respective optical response must be determined depending on the composition. In some cases (such as with an organic cationic ring-opening polymerization system), competing effects regarding the contribution to the optical grating formation can be observed . It is aA live/dead staining assay has been used to study the cell viability after incubation with PI EB and EY and also EB 0.1% with PEG-DA before and after crosslinking for 24 h. In the live/dead staining assay, dead cells turn up red, while living cells turn up green when observed with a fluorescence microscope. As shown in In addition to the standard photoinitiator Irgacure, Erythrosin B (EB) and Eosin Y (EY) were used as photoinitiators (PI) in PEG-DA hydrogel. We have determined the minimum PI concentration for producing new hydrogels with PEG-DA for the different PIs respectively. All the PIs are cytocompatible and suitable as substrates for studying the behaviour of L929 cells at the biointerface.The new PIs (EB and EY) feature good spectroscopic properties, allowing for their application with light sources in the visible range and, thus, for applications in volume holography. Cytotoxicity test with cell line L929 were performed to confirm cytocompatibility of hydrogels and PIs. This opens up many options for PEG-DA hydrogels with PIs as multifunctional biomedical applications.The strategy to combine optical structuring of the volume and specific modification of the surface is particularly interesting for the design of advanced intraocular lens (IOL) implants: based on a multifunctional biomedical material with integrated optical functionality and operating by the principle ‘function by structure’, such a new type of IOL is expected to attain enhanced functionality . The optBeyond an enhanced functionality, the transfer of the optical functionality from the surface into the volume of the IOL implant brings further benefits such as the free interface for specific interaction with the biological environment. As the existing problems with conventional IOLs, such as postoperative clouding, emerge in vivo from interactions with the biological environment, they could be better addressed with free-surface IOLs.The next step towards such a multifunctional optical material is to better understand the processes that underlay optical structuring, such as the interplay of polymerization and diffusion in the case of holographic gratings. Here, the general approach is to understand holographic grating formation as a consequence of photopolymerization and mass transport processes: local polymerization is induced by a light pattern projected into the photosensitive medium. Polymerization proportional to the light intensity results in the induction of a chemical gradient, followed by monomer diffusion and subsequent polymerization. The final grating is formed as a periodic modulation of optical properties, according to the recording light pattern .It now remains to be clarified what role the individual components play in the formation of optical structures in cases of PEG-DA hydrogels with EB and EY. Furthermore, it remains to be examined if other additives—such as crosslinker or dopant, e.g., in the form of azobenzene-functionalized acrylates or gold nanoparticles—have a positive effect on the formation of optical patterns.Poly(ethylene glycol) diacrylate  and 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone (photoinitiator (PI)—Irgacure 2959), Erythrosin B and Eosin Y were from Sigma-Aldrich Chemie GmbH . The chemical structures of the hydrogel components are shown in PEG-DA was used as precursor. It was mixed with PI . PI concentration varied between 1% and 6 ppm. The chemical structures of different PIs are shown in Mouse fibroblast L929 cells were provided by Dr. Lehmann, Fraunhofer Institute for Cell Therapy and Immunology, IZI, Leipzig, Germany. RPMI 1640 medium, Trypsin, Fetal Bovine Serum (FBS) and Penicillin/Streptomycin (PS) were provided by PAA Laboratories GmbH, Austria, and cell culture plates are from SPL Live Sciences Inc., Seoul, Korea. The Incubator CB150 Series was from Binder GmbH, Germany. Phosphate Buffered Saline solution (Dulbecco’s PBS) was purchased from Sigma-Aldrich Chemie, GmbH, Germany. The counter chamber was from Marienfeld Superior .The mouse fibroblasts L929 cells were cultured in the tissue culture plate in RPMI 1640 medium with the addition of 10% Fetal Bovine Serum (FBS) and 1% Penicillin/Streptomycin (PS) in a cell culture plate in an incubator at controlled temperature (37 °C) and CO2 atmosphere (5%). The cells were grown in a cell culture plate and cell culture experiments were performed when a confluency of 75% to 95% was reached.2 atmosphere in a TCPS.The hydrogel samples were prior washed with water and kept in a PBS solution for around 30 min before cell culture experiments. As soon as a confluency of at least 75% was reached, the cells were washed with PBS, detached by using trypsin and, after the centrifugation process, a new medium was added on the cells and mixed properly. An amount of 10 μL of this cell medium solution was placed on a cell counter chamber in order to count the cell number by using an optical microscope and to achieve a concentration of 40,000 cells/mL. Depending on the counted cell number, the cell solution was mixed with a defined amount of new medium. The samples were placed in a TCPS plate or on the washed and precut hydrogel. The samples were then cultured within these cells for 24 h, at 37 °C in a 5% COThe live dead cytotoxicity assay is a fluorescence-based method for checking the viability of cells. Hereby, the cells are stained with fluoresceindiacetete (FBS) and propidiumiodid (PI) molecules. FBS is dissociated in the cytoplasma of live cells into green fluorescence molecules and, due to the size and charge of the PI molecules, they only can enter into the cell cytoplasm when the cell membranes are damaged and are bound to nucleic acids, which appear then as red fluorescence color. In this manner, the live cells appear as green-stained cells and dead cells appear as red-stained cells in a fluorescent microscope image.v/v solution of PI and FBS in PBS was prepared and added into the cell culture solution in a dark environment. Immediately after the mixtures are prepared, fluorescence images are taken.For the live dead assay, a 1:1 UV-Vis spectra were obtained with Cary 4000 UV-Vis Spectrometer . The spectral range from 300 to 900 nm was measured at room temperature. Liquid samples (before crosslinking) were converted in a cuvette for measurement. The flat, thin standalone hydrogel films (after crosslinking) were placed on a thin glass cover slip for measurement with a UV-Vis spectrometer.The results from cell culture experiments were observed via the optical microscope from Carl Zeiss, Germany, and analyses were performed with the AxioVision V4.8.2 software .


N = 2.1 million), we replicated the increase in uniqueness of Chinese names from 1920 to 2005, especially since the 1970s, with multiple uniqueness indices based on name-character frequency and name-length deviation. Over the years, Chinese characters that are rare in daily life or naming practice were more often used in given names, and the length of given names became more deviant from typical practice . Taken together, these findings not only reconfirmed the increasing prevalence of unique names but also demonstrated the validity of various indices in assessing name uniqueness in China.In this study, we aimed to address three comments proposed by Ogihara on a recent study where we found that unique names in China have become increasingly popular from 1950 to 2009. Using a large representative sample of Chinese names ( Over the past decades, massive sociocultural changes have occurred around the world. As a special case, shifts in naming practices have received much attention. The selection of unique names for children has become increasingly popular and represents a widely observed phenomenon. For instance, research has revealed that the tendency of giving children a unique name has increased in the United States from 1880 to 2015 , 2016, iRelevant to our current paper, Recently, however, this study was challenged . In a codaily life to indicate the uniqueness of Chinese name characters was appropriate. A character that is rare in daily use may not be equally rare in naming practices . Moreover, the popularity of name characters may vary with the cohort  has changed over time. A Chinese given name may consist of one, two, or even three characters. Compared with a single-character given name, a given name with multiple characters is more likely to be distinct from other names . That is, name length is also a potential index of name uniqueness in China, with a longer name indicating higher name uniqueness . Hence, Third, he wondered how the pronunciation of Chinese names has changed. In examining the change of name uniqueness in Japanese names, Ogihara found that it was the pronunciations, rather than characters or character combinations, of Japanese names that have become increasingly unique . AccordiIn this study, we addressed these questions except for the one related to pronunciation of name characters. We did not think pronunciation of name characters is as meaningful in China as in Japan, because Chinese characters used in Chinese language differ substantially from those used in Japanese, especially in pronunciation. A Chinese character in Chinese usually has a single fixed pronunciation, whereas most Chinese characters in Japanese carry multiple pronunciations based on context or usage , 2021b. name-character frequency: one was identical as we had used in our previous study . First, we tested two indices of name uniqueness based on name-length deviation. Besides the absolute (average) length of given name as suggested by Then, we tested four indices based on In summary, we would test whether unique names in China have been on the rise with a large representative sample of Chinese names and six potential indices of name uniqueness. In doing this, we hope to clarify the concerns proposed by N = 2,585,481) drawn by the NBS, which had been widely used in previous economic and population research.To obtain a nationally representative sample of Chinese names covering a long period, we accessed data from the 2005 China’s 1% Population Census . The 200Median = 26,514).The 2005 China Census collected respondents’ surname, given name, gender, birth year, ethnicity, and several other demographic and household variables. Because 89.1% of Chinese are Han Chinese and the naming norms are quite different between Han Chinese and ethnic minorities, we restricted our sample to Han Chinese only. Moreover, because the sample sizes for birth years < 1920 were not sufficient, we limited the range of birth years to 1920∼2005. Finally, we scrutinized the dataset and excluded those who did not have formal names . The final sample consisted of 2,144,025 individuals . The sample size of each year ranged from 2,178 to 48,152 .1 . The previous study used such “character-corpus uniqueness” (CCU) to indicate name uniqueness (–6 was added to adjust for its positive skewness) and reversed:Since most characters used in Chinese given names can be used in daily contexts, the uniqueness of a character can be estimated according to a contemporary Chinese corpusiqueness , Study 2iqueness . The perCCU ranges from 1.3 to 6. For example, CCU = 2 and 3 mean that the frequency of a character in the Chinese corpus equals to 1/100 and 1/1,000, respectively.To compute name-character uniqueness in naming practice for each individual in the 2005 China Census, we accessed a Chinese name database from the National Citizen Identity Information Center (NCIIC) of China. This database is publicly available in the R package “ChineseNames” , which cPcharacter)—an approximate estimate for a birth year using the weighted character frequencies of the nearest two birth cohorts  proportion of one-character given name, (2) proportion of three-character given name, (3) absolute (average) length of given name, and (4) standard deviation of name length. To note, in the 2005 China Census sample we used here, 82.82% of Han Chinese possessed two-character given names, whereas only 17.14 and 0.04% held one-character and three-character given names, respectively.yearb) in different periods. The two indices based on name-character frequency manifested similar changing patterns. Before 1970, the annual changes of character-corpus uniqueness  and name-character uniqueness  were trivial. However, since 1970, both character-corpus uniqueness  and name-character uniqueness  have linearly and continuously increased at a steady speed  and from 1960 (0.02%) to 1989 (0.02%)  but increased sharply from 1990 (0.04%) to 2005 (0.19%)  (SD = 0.27) to 1959 (SD = 0.26) , increased largely from 1960 (SD = 0.27) to 1989 (SD = 0.47) , and decreased negligibly to a moderately high level from 1990 (SD = 0.47) to 2005 (SD = 0.45)   to 1959 (0.03%) (< 0.001) ; the sta< 0.001) .Notably, the other two of four indices based on name length—the percentage of one-character given name  and the In summary, the name-uniqueness indices based on name-character frequency and name-length deviation produced similar findings: an increasing trend of name uniqueness in China over the past decades, especially since the 1970s.Research has demonstrated increasing prevalence of unique names in many countries. In a widely cited study, Taken together, we have replicated our previous finding, the rising trend of unique names in China, with two indices based on name-character frequency and four indices based on name-length deviation. Thus, we have reconfirmed the rising trend of name uniqueness in China and clarified the concerns proposed by name-character uniqueness in naming practice is preferred. This index is easy to understand and to be computed using the R package “ChineseNames” (Our research also contributes to the existing literature in several other ways. To our knowledge, this is the first study that uses multiple indices of name uniqueness in studying the temporal change of Chinese names. The convergent findings suggest that all six indices are valid to some extent and therefore applicable in future relevant studies. What we need to be aware is that each of these indices approaches the uniqueness of name in different ways, capturing either a specific kind of infrequency of name character or a specific kind of deviation from typical naming practice. To some extent, they are complementary to each other because all of them have captured some unique aspects of name uniqueness. If only one index is needed in a study, however, we would not recommend the absolute name length because its implication is unclear, depending on the relative importance of one-character names over three-character names or vice versa. Instead, seNames” . More imincreasing trend of individualism in China over the past decades (for reviews, see decreasing trend of individualist values in China from 1990 to 2007 (Moreover, our research advances a better understanding of cultural changes in China. A vast literature has used cultural products such as word usage in Google Books to reflect individualist values, revealing an  to 2007 . Since u to 2007 , the fin to 2007  and our 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 Institute of Psychology, Chinese Academy of Sciences. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.HC proposed, designed the research, and revised the manuscript. H-W-SB and JW collected the data. H-W-SB analyzed the data and drafted the manuscript. YJ provided critical feedback. All authors approved the submitted version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Systemic lupus erythematosus (SLE) is a refractory immune disease, which is often complicated with osteonecrosis of the femoral head (ONFH). Curcumin, the most active ingredient of Curcuma longa with a variety of biological activities, has wide effects on the body system. The study is aimed at exploring the potential therapeutic targets underlying the effect of curcumin on SLE-ONFH by utilizing a network pharmacology approach and molecular docking strategy.  Curcumin and its drug targets were identified using network analysis. First, the Swiss target prediction, GeneCards, and OMIM databases were mined for information relevant to the prediction of curcumin targets and SLE-ONFH-related targets. Second, the curcumin target gene, SLE-ONFH shared gene, and curcumin-SLE-ONFH target gene networks were created in Cytoscape software followed by collecting the candidate targets of each component by R software. Third, the targets and enriched pathways were examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Eventually, a gene-pathway network was constructed and visualized by Cytoscape software; key potential central targets were verified and checked by molecular docking and literature review. P value ≤ 0.05. 20 related signaling pathways were identified by KEGG analysis, when corrected according to a Bonferroni P value ≤ 0.05. Molecular docking showed that the top three genes  have good binding force with curcumin; combined with literature review, some other genes such as TNF, CCND1, CASP3, and MMP9 were also identified.  201 potential targets of curcumin and 170 related targets involved in SLE-ONFH were subjected to network analysis, and the 36 intersection targets indicated the potential targets of curcumin for the treatment of SLE-ONFH. Additionally, for getting more comprehensive and accurate candidate genes, the 36 potential targets were determined to be analyzed by network topology and 285 candidate genes were obtained finally. The top 20 biological processes, cellular components, and molecular functions were identified, when corrected by a  The present study explored the potential targets and signaling pathways of curcumin against SLE-ONFH, which could provide a better understanding of its effects in terms of regulating cell cycle, angiogenesis, immunosuppression, inflammation, and bone destruction. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, which prevalence ranges from 20 to 150 cases per 100,000 population and appears to be increasing as the disease is recognized more readily and survival increases –9. The phttp://pubchem.ncbi.nlm.nih.gov), which is an open chemical database that provides information on compound structures and descriptive data.The 2D chemical structure of curcumin  was obtahttp://www.swisstargetprediction.ch/) is a web-based tool, on-line since 2014, to perform ligand-based target prediction for any bioactive small molecule [http://herb.ac.cn/) was used to get curcumin targets for a comprehensive collection of drug targets, which is a high-throughput experiment- and reference-guided database of traditional Chinese medicine [http://www.megabionet.org/tcmid/) and TCMSP (https://tcmspw.com/tcmsp.php) databases [https://www.uniprot.org/) for screening. In order to increase credibility, we only need human targets which have been annotated and reviewed, and the potential targets of curcumin were identified by eliminating duplicate and nonstandard targets.The Swiss target prediction database  using the phrase “Systemic lupus erythematosus”, “SLE”, “Osteonecrosis of Femoral Head”, and “ONFH” as the keyword. The targets were also supplemented with the OMIM database (https://omim.org/) [The SLE and ONFH-related targets were identified in the GeneCards database (im.org/) . A Venn https://string-db.org/), which is including direct and indirect interactions between proteins and calculates a confidence score for all protein interactions [The curcumin target network and SLE-ONFH network were constructed and visualized using Cytoscape 3.8.0 software –33; theyractions , 35. Theractions , 37.Shared targets of curcumin, SLE, and ONFH were obtained by running the Venn script as described above, which was installed in the R 4.0.2 software. They were uploaded to Cytoscape software. The PPI data were obtained from the Database of Interacting Proteins (DIP™), Biological General Repository for Interaction Datasets (Bio GRID), Human Protein Reference Database (HPRD), IntAct Molecular Interaction Database (IntAct), Molecular INTeraction database (MINT), and biomolecular interaction network database (BIND) using the plugin BisoGenet of Cytoscape software .After uploading the common gene above, the nodes with topological importance in the interaction network were screened by calculating Degree Centrality (DC), betweenness centrality (BC), closeness centrality (CC), Eigenvector Centrality (EC), local average connectivity-based method (LAC), and Network Centrality (NC) with the Cytoscape plugin CytoNCA. At the heart of Cytoscape is a network. A simple network diagram consists of nodes and edges. Each node represents a gene. The node-node connection represents the interaction between these nodes. DC believes that the greater the number of neighbors of a node, the greater its impact. CC was used to calculate the importance of nodes. BC is a kind of centrality measure. EC is an indicator in ranking the importance of nodes in the network. The closer the EC of a node is to the network radius, the closer the node is to the network center. LAC is often used to determine the importance of proteins by assessing the relationship between proteins and their neighbors. NC is a method based on the edge clustering coefficient, which considers not only the centrality of nodes but also the relationship between nodes and adjacent nodes –41. ThesP value ≤ 0.05 was set as the default option. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis method is similar to the GO analysis above.GO analysis with the biological process, cellular component, and molecular function was carried out by R software. The result is obtained by running the script installed on R software including “colorspace,” “stringi,” “ggplot2,” “BiocManager,” “clusterProfiler,” and “enrichplot.” The top 20 items were selected and visualized; a Bonferroni-corrected The gene-pathway network was constructed based on the significantly enriched pathways with genes that regulated these pathways. The topological analysis of 20 pathways and 285 genes was carried out with BC. The squares represented target genes, and the V-shapes represented pathways in the network.Molecular docking simulations were used to explore the potential interaction between the top 3 genes of the network above. The SDF format of curcumin was downloaded from the PubChem database; Chem 3D software was used to convert the SDF format into mol2 format file; then, the RESB database was used to get the PDB format structure of the top 3 target proteins. After that, solvent molecules and ligands were removed by Pymol software and saved as pdbqt format. Docking simulations were performed in Autodock1.1.2 software, and Discovery Studio 2020 was used to visually analyze the docking conformation at last , 44.100, 152, and 11 target genes of curcumin were identified by searching the Swiss, HERB, and STITCH databases, respectively, and 240 genes were selected as curcumin target candidate genes through running R software to remove duplicate genes. In order to ensure credibility, the 240 target genes were inputted into the STRING database; by setting the highest confidence (0.9000) and selecting the condition “Homo sapiens,” 201 targets were finally identified after hiding disconnected nodes in the network. The PPI network of them was saved as “tsv” file and visualized by Cytoscape software according to the degree . This neAfter removing the duplication, we obtained 4338 SLE-related targets and 300 ONFH-related targets from the GeneCards and OMIM databases, respectively. In order to improve the comprehensiveness and credibility of the data, these targets were all included in the current study. Finally, 170 intersection genes related to SLE-ONFH were obtained by running the Venn map script installed in R software, and 36 genes related to SLE, ONFH, and curcumin were also received, as shown in According to the network pharmacology analysis method, 36 overlapping genes for curcumin, SLE, and ONFH were defined as potential genes  for curcTo reveal the mechanisms underlying curcumin's effects on SLE-ONFH and obtain candidate genes more comprehensively and accurately, topological analysis of 36 potential genes was performed through the plugin BisoGenet and CytoNCA of Cytoscape; a network consisting of 3653 nodes and 87728 edges is presented in P value < 0.05). The results demonstrated many targets involved in multiple BPs associated with mRNA catabolic process, regulation of DNA-binding transcription factor activity, and regulation of cell cycle phase transition, which confirmed the correlation with the gene transcriptional activity in SLE-ONFH. The CC results suggested that most targets are localized to the focal adhesion, cell-substrate junction, and nuclear chromatin. The MF results showed that many targets are associated with ubiquitin protein ligase binding and DNA-binding transcription factor binding.GO analysis of 285 candidate targets was analyzed based on biological process (BP), cellular component (CC), and molecular function (MF). 2,364 GO terms were finally enriched, 1,973 in biological process, 200 in cellular component, and 191 in molecular function. The top 20 terms are shown in P value < 0.05) are identified and shown in The pathways that are significantly influenced by curcumin in the process of treating SLE-ONFH were identified by KEGG pathway analysis; the analysis method is similar to the GO analysis by running the corresponding script in R software. The top 20 significant pathways , according to the network analysis. The results revealed that they can interact with curcumin; the combination of curcumin with them is shown in SLE is an autoimmune disease with multiple organ involvement and multiple antibodies. It is an urgent problem in the field of medicine. High disease activity of SLE is closely related to osteonecrosis especially ONFH, which has become the main cause of disability in SLE patients. In the whole process of disease development, immunity, inflammation, apoptosis, and angiogenesis are important factors –54. Becaβ, is associated with angiogenesis and vascularization and facilitates inflammation and joint damage [Curcumin has been found to be useful in the treatment of SLE and ONFH, but the central genes and significant pathways of curcumin against SLE-ONFH are not clear. Through the target interaction network, we found 36 potential targets as described in Results; there were 16 targets  with connectivity greater than the median degree. The TP53 gene is at the core of the whole network, which means that it is a central target. p53 protein is a tumor suppressor that inhibits the growth of aberrant cells; functional p53 is believed to sense DNA damage and, subsequently, to induce DNA repair, growth arrest, or apoptosis of the aberrant cell , 57. On t damage . CXCL8 it damage . FGF2 ist damage . SERPINEt damage .At present, the treatment of SLE depends on the organ involved in the disease. Patients with mild symptoms can use low-dose corticosteroids; however, moderate and severe SLE may require higher doses of corticosteroids or other immunosuppressive agents. The adverse effects and limitations of hormones and immunosuppressive agents make TCM become a candidate therapeutic drug because of their unique advantages. The characteristic of SLE is that the complement system is activated; curcumin could inhibit the complement cascade. Studies have found that curcumin inhibits the increase of matrix protein, glial fibrillary acidic protein, and vimentin in the hippocampus of lupus mice . As ment