Students (n = 1204) completed a survey on why they do not engage in contract cheating as well as measures of several individual differences, including self-control, grit and the Dark Triad traits. Morality and motivation for learning received the greatest endorsement for why students do not engage in contract cheating. Controlling for gender, individual differences predicted students’ reasons for not contract cheating. This study supports the use of criminological theories relating to rational choice, self-control and opportunity to explain why students do not engage in contract cheating. Practically, this study may inform academic policies and assessment design that may reduce contract cheating.Contract cheating refers to students paying a third party to complete university assessments for them. Although opportunities for commercial contract cheating are widely available in the form of essay mills, only about 3% of students engage in this behaviour. This study examined the reasons why most students do  Since this seminal work, contract cheating has gained notoriety as a problem facing tertiary institutions around the world  measure . Drawing on the relevant research findings outlined above, Stage Two of the data analysis tested the following hypotheses.Student engagement in contract cheating is low, despite available opportunities. The factors discussed above, including student motivation for learning, provide potential explanations for why students do H1. Self-control will negatively relate with a lack of opportunity as a reason for not engaging in contract cheating.H2. The psychological constructs of self-control, satisfaction of students’ need for competence, and grit will positively relate to students’ motivation for learning as reasons for not engaging in contract cheating.H3. The Dark Triad personality traits of Machiavellianism, narcissism, and psychopathy will be negatively related with morals and norms as reasons for not engaging in contract cheating.H4. The Dark Triad personality traits will positively relate with fear of detection and punishment as reasons for not engaging in contract cheating.1, SurveyCircle (an online survey sharing website), and social media – principally university student Facebook groups. Given the focus of this research on non-cheaters, any responses where past engagement in contract cheating was indicated (n = 27 [2%]) or not disclosed (n = 14) were removed from analysis. Other exclusions were made based on: failure to respond to any questions (n = 42), not being currently enrolled in a degree or course (n = 167), and responses that lacked variation . Participants under 18 years old were also excluded (n = 8). A further 342 cases were removed that had more than 10% missing data. This resulted in a total of 604 response exclusions.A sample of 1808 university students was recruited online through a Western Australian University’s Research Participation PortalM = 24.77, SD = 7.39, median = 22). The sample consisted predominantly of female students (87.5%), only 10.1% of participants identified as male, a further 32 (2.7%) students did not report their gender or selected the response option not specified. Just over 20% of participants reported completing a psychology major and 17.9% reported attending the Western Australian University.2The final sample of 1204 consisted of undergraduate and postgraduate students from around the world, including Australia and New Zealand, the United Kingdom, several African countries, the United States, Canada, and numerous South American, European, and Asian countries. Over 55% of participants were Australian. Participants were aged between 18 and 59 .Self-control was measured using the Brief Self-Control Scale . Particistrongly disagree and 7 = strongly agree. The measure included three competence frustration items, such as “I doubt whether I am able to carry out my tasks properly,” and three competence satisfaction items, such as “I feel I am very good at the things I do.” This scale demonstrated good fit in a CFA as a two-factor measure .The Need Satisfaction and Frustration competence subscales were used to measure how effective and capable students feel when completing tasks and mastering challenges . Particinot at all like me and 5 = very much like me.3 This scale demonstrated good fit in a CFA as a two-factor measure .Grit was measured using the Short Grit Scale . The meastrongly disagree and 9 = strongly agree. This scale demonstrated acceptable fit in a CFA as a three-factor measure .Personality was assessed using the Dark Triad Dirty Dozen, a 12-item measure of Machiavellianism, narcissism, and psychopathy . MachiavParticipants were asked to respond to a series of demographic questions, including: age, gender, institution, university major, and country.no responses were directed to the end of the survey. Yes respondents progressed to the next page where they were provided with the definition and asked if they had ever engaged in contract cheating  = 1573.76, p = 0.344; missing scores were imputed for analyses.Scale means were calculated for each of the psychological measures’ subscales, with items reversed where necessary. Means and standard deviations are presented in KMO = 0.84). A visual inspection of the correlation matrix, scree plot, and item loadings with oblimin rotation indicated that the items were factorable. The identified factors had inter-correlations less than 0.30, which support the use of a principal axis factor analysis with orthogonal rotation  rotation was conducted on the 21-items of the RNCC measure. This analysis was run to assess the assumptions of whether a factor analysis with orthogonal rotation was appropriate. The sample size exceeded 1000 participants, which is excellent . Sample rotation .A principal axis factor analysis with varimax  rotation was then conducted on the 21-items. This analysis returned five factors with eigenvalues exceeding 1, these factors accounted for 48.62% of the total variance. The five factors were labelled based upon the themes present in the loaded items, these are: (1) Fear of Detection and Punishment, (2) Self-Efficacy and Mistrust, (3) Morality and Norms, (4) Lack of Opportunity, and (5) Motivation for Learning. Item descriptives and rotated loadings can be seen in 2[179] = 1812.04, p < 0.001, GFI = 0.863, CFI = 0.827, TLI = 0.797, RMSEA = 0.087 ). Modification indices (MI) and standardised residuals were examined, and a model with reasonable fit was achieved by removing the three items with ambiguous factor loading and co-varying error terms on items within the same factor when MI’s > 15; χ2(116) = 653.99, p < 0.001, GFI = 0.935, CFI = 0.932, TLI = 0.921, RMSEA = 0.062 . Notably, as can be seen in As The mean of the items in each factor were calculated and are presented in F = 886.76, p < 0.001, A repeated measures ANOVA was conducted to examine whether students endorsed the reasons for not engaging in contract cheating differently, as represented by each factor. The overall ANOVA was significant, and all factor means were significantly different from each other  and females (n = 1053), gender was entered into the five regression analyses at the first step followed by the psychological individual differences variables at second step. Not specified and missing responses to the demographic question on gender were excluded from the analyses. The multicollinearity assumption for regression was satisfied . The results from the multiple regression analyses are presented in Five multiple linear regression analyses were conducted to determine which psychological individual differences predicted each factor of the RNCC scale. Due to the distinctly different sample sizes between males , and identified three significant predictors from the nine variables, these were: Machiavellianism, narcissism, and consistency of interest. These variables were all positive predictors of Fear of Detection and Punishment, suggesting that students who scored highly on Machiavellianism, narcissism, and consistency of interest are more likely to report fear of detection and punishment as a reason why they do not engage in contract cheating.The regression analysis for Fear of Detection and Punishment accounted for 5.5% of the variance in this factor , and identified narcissism, psychopathy, self-control, competence satisfaction, consistency of interest, and perseverance of effort as positive predictors of Self-Efficacy and Mistrust. This implies that students who scored highly on these psychological measures were more likely to report reasons relating to self-efficacy and mistrust as contributing to why they do not engage in contract cheating.The second regression analysis on Self-Efficacy and Mistrust accounted for 8.7% of the variance (p < 0.001) as well as step two (discussed below). Step two of the regression analysis accounted for 11.9% of the variance , and found gender and all the psychological variables, excluding both competence subscales, were significant predictors. Machiavellianism and psychopathy were both negative predictors of Morality and Norms, suggesting that students who scored highly on these personality traits were less likely to report morality and norms as contributing to why they do not engage in contract cheating. Narcissism, self-control and both grit subscales (consistency of interest and perseverance of effort) positively predicted Morality and Norms, implying that students who score highly in these traits are more likely to report morality and norms as a contributing reason to why they do not engage in contract cheating. Interestingly, the inclusion of gender in the regression resulted in narcissism being a significant predictor despite it not being a significant correlate.The regression analysis on Morality and Norms identified gender as a significant predictor at step one , and identified three significant predictors, these are: psychopathy, self-control, and consistency of interest. Self-control negatively predicted Lack of Opportunity, suggesting that students with high self-control were less likely to report a lack of available opportunity as a reason for not engaging in contract cheating. Psychopathy and consistency of interest were positive predictors of Lack of Opportunity. This implies students who scored highly on these measures were likely to report a lack of opportunity as a reason they do not engage in contract cheating.The regression analysis on Lack of Opportunity accounted for 7.9% of the variance (p = 0.002) at the first step, however, gender was not significant at the second step of the analysis. This regression accounted for 10.5% of the variance , and four significant predictors were identified at the second step, these were: Machiavellianism, self-control, competence satisfaction, and perseverance of effort. Machiavellianism was a negative predictor of Motivation for Learning, suggesting students who scored highly on this trait were less likely to report motivation for learning as a contributing reason for why they do not engage in contract cheating. Self-control, competence satisfaction, and perseverance of effort were all positive predictors of Motivation for Learning. This implies students with high self-control, satisfaction of the need for competence, and perseverance of effort were more likely to report not engaging in contract cheating due to reasons relating to their motivation for learning.The final regression analysis, conducted on Motivation for Learning, identified gender as a significant predictor . Just over 10% of the total sample identified as male, this gender imbalance may have influenced the findings of this study. Despite suggestions that males are more likely to engage in academic misconduct see , there ido students engage in contract cheating, using similar measures. This would enable a comparison of how reasoning differs between those who engage in this behaviour compared with those who refrain. Future research in this area may also benefit from the inclusion of other measures, such as: academic self-efficacy and autonomy. Academic self-efficacy refers to an individual’s confidence in their own ability to perform academic tasks  and how individual differences can influence these reasons and variation across assessment items. The results from this study supported the theoretical explanations offered by the criminological theories of self-control and opportunity, and suggested that the main reasons students refrain from engaging in contract cheating is due to their sense of morals, perception of norms, and their motivation to learn. The individual differences measured in this study, particularly self-control and the Dark Triad personality traits, were predictive of student reasoning. Tertiary institutions may be able to decrease student engagement in contract cheating by influencing these factors, such as by encouraging students to develop their self-control and by interrupting the opportunity structure that enables contract cheating. In addition, our findings suggest that emphasising learning goals, ethics, and the low normative endorsement of contract cheating may bolster students’ rationales for not cheating. By reducing engagement in this form of cheating, tertiary institutions can bolster the validity of assessments in higher education to evaluate student learning. Future research should aim to address the limitations discussed above and build upon the findings of this study.Contract cheating is a serious issue facing tertiary institutions, but happens at a relatively low frequency across students. This study sought to address a significant gap in the literature by examining the reasons why the majority of students do The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by the Murdoch University Human Research Ethics Committee. The patients/participants provided their informed consent to participate in this study.KR, GC, and JC contributed to the conception and design of the study. KR conducted the study under the supervision of GC and JC, and conducted the statistical analysis with the assistance of GC. KR wrote the first draft of the manuscript, with assistance provided by GC and JC. All authors contributed to the manuscript revision, and read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Metamizole is a medication with analgesic, antipyretic, spasmolytic, and weak anti-inflammatory effects. The aim of our study was to evaluate a six-year trend in the utilization and expenditure of metamizole in comparison to other group of licensed non-opioid analgesics in Serbia and Croatia, in order to rationalize its use and prescribing in these countries.Methods: The data of metamizole vs. all other non-opioid analgesics utilization and expenditure in Serbia and Croatia was analyzed according to the WHO methodology and expressed as defined daily doses per 1,000 inhabitants per day  and total costs, respectively, during the 6-year period from 2010 to 2015.Results: In the observed period, utilization of metamizole was 3.31 fold higher in Serbia than in Croatia . Expenditure of metamizole in the same period was 5.29-fold higher in Serbia than in Croatia .Conclusion: Utilization and expenditure of non-opioid analgesics, including metamizole, in Serbia was significantly higher comparing with Croatia.Further research is needed to determine whether the current analgesic consumption in Serbia meets the needs of the patient. The benefits of metamizole should be weighed against the risk of metamizole-induced adverse effects. Until then, its prescribing should be based on indications and the appropriate duration of therapy. Metamizole  is a nonsteroidal anti-inflammatory drug (NSAID), with analgesic, antipyretic, spasmolytic, and weak anti-inflammatory properties. Based on its chemical structure it belongs to the group of pyrazolones, along with phenazone, aminophenazone, propyphenazone, nifenazone , 2. MetaMetamizole was synthesized in 1920, and introduced into the clinical practice under brand name Novalgin® in Germany in 1922 . CentralThe review of the therapeutic benefits and risks of adverse drug reactions (ADRs) should always be assessed in order to achieve the proper balance between therapeutic efficacy and safety risks.Metamizole use was associated with abdominal discomfort, maculopapular rash, Stevens-Johnson syndrome, Lyell syndrome, agranulocytosis, hypotension, bronchospasm, arrhythmia and allergic reactions . Agranul9 L−1 (<500 μL−1)  . The ris00 μL−1) . Metamiz00 μL−1) , 16. In 00 μL−1) . Agranul00 μL−1) . Several00 μL−1) . Accordi00 μL−1) . On the It is important to note that the first bone marrow transplantation in the former Yugoslavia was performed in the patient with agranulocytosis as ADR of metamizole. Among other analgesics that could cause agranulocytosis are indomethacin, oxyfenbutazone, and phenylbutazone. All adverse reactions to pyrazolones are not dose-dependent .Therefore, there is a different policy regarding metamizole usage among countries. In many of them, including United States of America, United Kingdom and Japan, it is withdrawn from the market; in some of them, it is available only as a prescription drug for strictly defined indications, while in Mexico, Brazil and China it can be obtained as an OTC drug , 7, 20.Data concerning metamizole consumption and expenditure are scarce and not readily available. According to ATC/DDD classification system, metamizole utilization should be analyzed within the group N02B, “other analgesics and antipyretics” , 22.The aim of this study was to analyze and evaluate a six-year trend in utilization and expenditure of metamizole in Serbia, in relation to other registered non-opioid analgesics, and to compare those parameters in Croatia.https://www.alims.gov.rs/eng/) and the Agency for Medicinal Products and Medical Devices of Croatia (HALMED) . The data were compared between those two countries as the Croatia is one of the countries considered referral for our own, by the Republic Health Insurance Fund  in Serbia and Croatia were retrieved from editions of the publication “Marketing and consumption of medicinal products for use in human medicine,” issued on yearly bases by the “Medicines and Medical Devices Agency of Serbia” (ALIMS)  methodology , 13, 24.Results were calculated and presented for the following groups of non-opioid analgesics, according to the ATC codes: M01AB, Acetic acid derivatives and related substances ; M01AC, Oxicams ; M01AE, Propionic acid derivatives ; M01AH, Coxibs ; M01AX, Other antiinflammatory and antirheumatic agents, non-steroids ; N02BA, Salicylic acid and derivatives ; N02BB, Pyrazolones ; and N02BE, Anilides (paracetamol).http://www.nbs.rs/internet/english/scripts/ kl_prosecni.html) and Croatian National Bank average annual course HRK-€ (https://www.hnb.hr/en).The median (IQR- interquartile range: range between 25th and 75th percentile) of DDD/1,000 inhabitants/day for metamizole and other non-opioid analgesics in the above mentioned six-year period was calculated, as well as total expenditure (median and IQR) of observed drugs for both countries. Expenditure was calculated and expressed in euros (€) .Total non-opioid analgesics consumption was higher in Serbia compared to Croatia in the observed six-year period 2010-2015) expressed as DDD/1,000 inhabitans/day .The results presented in this study showed higher levels of all non-opioid analgesics consumption in Serbia than in Croatia. In Croatia, in 2007–2013, the ATC N02B group was the only one of the four analyzed groups of NSAIDs that showed an overall decrease in total consumption .The analysis of total consumption of metamizole in Serbia in the period from 2010 to 2015 based on the annual issues of the publication “Marketing and consumption of medicinal products for use in human medicine” published by ALIMS, expressed as DDD/1,000 inhabitants per day, indicates a gradual, but constant decline in metamizole consumption in the observed six-year period.Tends observed in Lithuania in the period from 2005 to 2007, showed 8.46% increase of medicines consumption which belongs to the ATC N02B group. Simultaneously, metamizole consumption decreased .In Serbia, metamizole is available as metamizole sodium formulations designed for oral, intravenous and intramuscular administration, registered under the trade names Novalgetol® and Analgin®. It is registered for short-term use in severe posttraumatic and postoperative pain, when therapy with other non-opioid analgesics is unsuccessful . TherapeIn both countries (Serbia and Croatia) paracetamol was the most prescribed analgesic and its consumption was increasing from 2010 to 2015, except in 2015 in Serbia, when an insignificant decrease in consumption was observed. The most likely reason for high utilization of paracetamol could be its favorable benefit/risk ratio at an acceptable price, which makes it one of the most common prescribed antipyretic and analgesic in children. According to the results from study conducted in Finland, as a representative country with high standards of pain therapy and pharmacovigilance as well, analgesics and antipyretics, including NSAIDs , were the most common used medications among OTC medicines in children .The lowest consumption within analgesic groups in Serbia was registered for coxibs. The possible limitations for prescribing this group of NSAIDs are narrow indications and higher prices in relation to other analgesics, whereas in Croatia increased consumption of coxibs was obeserved in the last two years.A constant decline in consumption of acetylsalicylic acid is evident in the both countries. Lower dose of this medication needed for the prevention of cardiovascular diseases than dose for analgesic treatment could explain such trend.Drugs within the ATC group M01AB  were more utilized in Serbia for pain treatment than medications within the M01AE group (propionic acid derivatives), regardless of the fact that ibuprofen is considered to be the safest conventional NSAID concerning the gastrointestinal side effects . In CroaThe total expenditure for non-opioid analgesics increased over a 6 year period both in Serbia and in Croatia. Highest costs were observed for paracetamol during the whole period.The higher consumption of metamizole in Serbia was accompanied with the higher expenditure, since it was found that 5.3 times more money was spent on this drug in comparison to Croatia. Moreover, the expenditure per inhabitant per year for metamizole in Serbia was 2.89 times higher than in Croatia , 33.Krnic et al. analyzed consumption of opioid and nonopioid analgesics in Croatia during period from 2007 to 2013 . The N02The trend of reduced utilization of metamizole could be explained by two reasons. Better quality of monitoring and registering of adverse reactions to metamizole resulted in increased number of adverse reaction reports, based on WHO VigiAccess database records and influenced medical practitioner's decision to opt for another analgesics. On the other hand, other non-opioid medications, like paracetamol and COX-2 selective inhibitors, were gaining more popularity, based on more favorable characteristics, including safety, or at least they appeared like safer drugs.The most common reported adverse reactions to metamizole, both according to WHO data, as well as ALIMS data, were the skin and subcutaneous tissue disorders. The constant increase in the number of reported adverse reactions to metamizole has been noticed since 2007.Moreover, skin reactions, like pemfigus vulgaris and mild forms of skin rash, including urticaria, were also recorded in VigiAccess base . Rarely,Moreover, extensive epidemiological investigations showed that short-term exposure to metamizole does not increase risk of agranulocytosis and it is lower than risk for aplastic anemia connected with application of indometacine or diclofenac .The number of reported ADRs regarding medicines belonging to the ATC groups M and N in Croatia is not very large. In 2010, ketoprofen for topical administration was the only one of all NSAIDs with a safety issue, mostly due to observed rare but serious photosensitivity adverse reactions . In 2015Metamizole has become more popular in Europe in last 10 years, as soon as an epidemiological study showed that the risk for adverse reactions to metamizole was similar to paracetamol and even lower than to acetyl salicylic acid .In spite of its utilization for more than 90 years, the efficacy of metamizole have neither been well documented nor there were enough large randomized clinical trials to show its benefits comparing with other NSAIDs.Consumption of all non-opioid drugs in Serbia was significantly higher than in Croatia. However, consumption of metamizole was decreasing in both countries in the observed period. Overall costs of metamizole in Croatia were steadily decreasing, except in the last observed year, 2015. In Serbia, overall costs of metamizole were slightly increasing and amounted a share of 4.85% of the total costs for all analyzed drugs in Serbia.The benefits of metamizole should be evaluated in the context of metamizole-induced agranulocytosis. For short-term use in the hospital settings, metamizole seems to be a safe choice when compared to other analgesics. However, its place in the contemporary pharmacotherapy needs to be reevaluated in the controlled, randomized clinical trials, both concerning efficacy and safety.NR, DS, and VD-S jointly designed the study and defined research questions. RN and MM did most of the data mining and extraction, purification of files for missing data and artifacts and statistical analysis. MM, TP-P, VD-S, DS, and RS contributed to the tables and figures creation and interpretation of data. MM, NR, AK, and VD-S drafted the working version manuscript but all authors contributed to the final version to the extent of important intellectual content.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.


A higher ICW/LM ratio was associated with greater muscle strength, better functional capacity, and a lower frailty risk, even when adjusted by age, sex, nº of co-morbidities, and LM. ICW content in LM (including the muscle) may influence muscle strength, functional capacity and frailty. However, further studies are needed to confirm this hypothesis.High intracellular water (ICW) content has been associated with better functional performance and a lower frailty risk in elderly people. However, it is not clear if the protective effect of high ICW is due to greater muscle mass or better muscle quality and cell hydration. We aimed to assess the relationship between ICW content in lean mass (LM) and muscle strength, functional performance, frailty, and other clinical characteristics in elderly people. In an observational cross-sectional study of community-dwelling subjects aged ≥75 years, ICW and LM were estimated by bioelectrical impedance, and the ICW/LM ratio (mL/kg) calculated. Muscle strength was measured as hand grip, frailty status was assessed according to Fried criteria, and functional status was assessed by Barthel score. For 324 recruited subjects (mean age 80 years), mean (SD) ICW/LM ratio was 408 (29.3) mL/kg. The ICW/LM ratio was negatively correlated with age (r Water is an essential nutrient with structural, metabolic, transport and temperature control functions in the body. Total body water (TBW), which represents approximately 55–60% of the body weight of adults, is distributed in intracellular water (ICW) and extracellular water (ECW) compartments, with the latter including plasma and interstitial fluid. Water exchange between intra- and extracellular compartments is regulated mainly by osmotic pressure, with water flowing across the cell membrane to balance osmolarity on each side . This trMuscle is the most extensive organ in the body, representing approximately 40% of total body weight and 50% of body lean mass (LM). Muscle function is associated with successful aging and reflects the integrated health status in aged population . Since 7The objective of this study was to explore the possible links between the ICW/LM ratio  and muscle strength, functional performance, frailty, and other clinical characteristics in elderly people.An observational cross-sectional study was designed, for a sample randomly selected from a population of community-dwelling subjects aged 75 years and older in the catchment area of 3 primary care centers in the city of Mataró  during the period January–July 2014. Subjects were excluded if they were institutionalized, had active malignancy, dementia or serious mental illness, or had a life expectancy of under 6 months. Details of the study methodology have been previously reported . The insThe ICW content in LM  was used as an indicator of muscle quality and cell hydration. ICW and LM were assessed by bioelectrical impedance analysis  , a non-invasive, reproducible and validated method of analysis that—on the basis of the body’s ability to conduct electrical current—accurately calculates fat mass, LM, and muscle mass (in kg and as a percentage of TBW), and ECW and ICW (in liters and as a percentage of TBW) . The mets) was used to assess correlations between the ICW/LM ratio and other continuous variables such as muscle strength, Barthel score and gait speed. For dichotomous variables such as sex or frailty, the mean ICW/LM ratios between categories were compared using the t-test or the Mann–Whitney U test, depending on the normal distribution of the ICW/LM ratio in the analyzed groups. Simple linear regression analyses were performed to assess the relationship between the ICW/LM ratio and the other study variables and beta (β) coefficients were calculated. Moreover, multiple linear regression analysis was used to assess the independent effect of ICW/LM ratio on hand grip strength and Barthel score, and simple and multiple logistic regression analyses were performed to estimate the crude and adjusted effect of the ICW/LM ratio on frailty. Variables included in multivariate models were those associated with ICW/LM ratio in the bivariate analysis . Medications were not included in the multivariate analyses because of multi-collinearity with number of co-morbidities. Statistical significance was set to p < 0.05 for all analyses. The program IBM SPSS 15.0 was used for the statistical analysis .Spearman’s correlation coefficient (rp < 0.001). The ICW/LM ratio was negatively correlated with age, with rs = −0.249 (p < 0.001) and a linear regression coefficient β = −2.07 (p < 0.001). The ICW/LM ratiowas associated with the number of co-morbidities  and also with the number of medications .Recruited were 324 individuals (170 men and 154 women), with a mean (SD) age of 80 (3.5) years. p < 0.001).All the studied functional capacity parameters were consistently associated with the ICW/LM ratio; thus, higher ICW/LM ratio was related to greater strength, better functional capacity and a lower frailty risk.The relationships between LN and indicators of muscle strength, functional capacity and frailty are shown as Our main results indicate that the ICW/LM ratio decreases with age in elderly people, is higher in older men than in older women, and that a higher ICW/LM ratio is independently associated with greater muscle strength, better functional capacity and a lower frailty risk. We propose the ICW/LM ratio as an indicator for intracellular space size in LM, which may reflect cell hydration or extracellular space expansion, both of which indicate LM quality and, indirectly, muscle mass quality. As expected, the ICW/LM ratio varied relatively little, oscillating as it did between fairly narrow values, and it was associated in a plausible and coherent way with some clinical characteristics such as age, sex or the number of co-morbidities. Therefore, we think that it could be a useful indicator of muscle quality in clinical research, although more studies are needed to confirm it.Regarding the observed negative correlation between ICW/LM ratio and age, our results are consistent with well-established evidence indicating a loss in TBW and an increased risk of dehydration with age . The risThe main results of our study point to a robust relationship between ICW/LM ratio and hand grip, different indicators of functional capacity , and frailty—even in the multivariate analysis after adjusting for age, sex, co-morbidities, and LM. The ICW/LM ratio showed an independent association with frailty with an adjusted OR = 0.98. In our opinion, this statistically significant effect is also of clinical relevance, as it indicates an approximately 2% reduction in the risk of frailty for each mL of ICW/kg LM increase. Thus, an increase of 1 SD of ICW/LM ratio 29 mL/kg) would correspond to an approximately 50% reduction in the risk of frailty. The independent effect of ICW/LM ratio on muscle strength is also statistically significant but of more moderate clinical relevance, with an increase of approximately 0.8kg of hand grip strength for 1 SD increases in ICW/LM ratio. We want to emphasize that the effect of ICW/LM ratio on muscle strength, functionality and frailty is independent of LM, indicating the importance of intracellular hydration in muscle functioning. These results, suggesting a relevant effect of low-grade chronic cell dehydration on muscle function, corroborate Yamada’s findings of a relative reduction in ICW compared to ECW in skeletal muscle in aging individuals , and als mL/kg woOn the other hand, Grazi has studied the interaction between water and muscle contractile proteins. The muscle cell contains thousands of myofibrils, formed by thin filaments (actin) and thick filaments (myosin), which interact to produce the shortening or contraction of the muscle. According to Grazi, the participation of water in muscle contraction is due to the hydrophilic nature of the proteins of the contractile apparatus and the non-ideal chemical property of such water solution . This prThis study has two main limitations. First, the cross-sectional design does not allow causal relationships to be established, as the directionality of the relationships is uncertain. Second, instructions for the correct realization of BIA were established, which include no intense physical exercise 24h before the test, no alcohol consumption 8h before the test, no water or fluid intake 2 h before the test or go to the toiled just before the test. Patients received these instructions when they were cited to the assessment visit, but the full compliance of these patient’s instructions cannot be guaranteed in all cases, which can influence BIA results. It remains to comment that, although BIA is not the gold standard for evaluating body composition, it is a validated, widely used, and well-accepted method for calculating accurate water distribution and body mass indicators .In summary, the ICW/LM ratio obtained by BIA points to a robust relationship with age, sex, number of co-morbidities, and number of chronic medications, as well as an independent association with muscle strength, functional capacity, and frailty. These results suggest an important role in muscle function and frailty onset for ICW content in LM. However, further research is needed to corroborate these preliminary findings.


Mortality in patients with chronic renal failure is high compared to the general population. The objective of our study is to evaluate the predictive factors related to mortality in hemodialysis.This is a retrospective study involving 126 hemodialysis patients in the Nephrology Department of Ibn Rochd Hospital, Casablanca. Data were collected between January 2012 and January 2016. For each of our patients, we analyzed demographic, clinical, biological and anthropometric data. The Kaplan-Meier method and the log-rank test were used to evaluate and compare survival curves. To evaluate the effect of predictors of mortality, we used the proportional Cox hazard model.The analysis of the results showed that the surviving patients were younger than the deceased patients . Also, the latter has a significantly lower albumin and prealbumin levels (p=0.01 and p=0.04 respectively). Overall survival was 80.2%. Cox regression analysis at age , inflammation , AIP> 0.24  and cardiovascular disease  were associated with global and cardiovascular mortality.Our study showed that the mortality rate is high in our cohort. In addition, cardiovascular diseases, under nutrition and inflammation are predictive factors for mortality. Treatment and early management of these factors are essential for reducing morbidity and mortality. Over the last two decades, advances in the treatment of chronic kidney disease (CKD) helped increase the survival of hemodialysis (HD) patients. There are currently about 2 million people on hemodialysis worldwide, representing only 10% of people who need it . In 2011This is a descriptive retrospective study, which took place over a period of 4 years from January 2012 to January 2016 in the Department of Nephrology-Transplantation and Hemodialysis of the University Hospital Centre of Casablanca, Morocco. In 2012, we included 126 hemodialysis patients (66 women and 60 men) in our study. During this period 22 patients died. Patients with chronic dialysis for less than 6 months, patients with cancer at the time of inclusion, pregnant women, amputee patients or patients with a pacemaker, since this makes impedance measurement impossible, have been excluded. The causes of death were identified by differentiating deaths directly related to CKD, from those caused by cardiovascular causes or other causes .For each of our patients, we analyzed the demographic, clinical, biological and anthropometric data. Clinical data were collected from patients records which include: sex, age, hemodialysis duration in months, initial nephropathy, and blood pressure. We also chosed to study as biological parameters: albumin, prebuminemia, serum calcium, phosphatemia, lipid profile , lipid ratios including the atherogenic index plasma (AIP), hemoglobin and C-reactive protein (CRP). In this study we defined the presence of under nutrition based on serum albumin (S.Albumin): presence of under nutrition if S.Albumin <38 g/L and no under nutrition if S.Albumin ≥38g/L.Statistical analyses: we analyzed the data using SPSS software version 21.0. First, we performed a descriptive analysis of the sample as a whole; the quantitative variables were expressed as mean ± standard deviation, and the qualitative variables as frequencies and percentages. The ANOVA test was chosen for the comparison of quantitative variables and the Chi 2 or Fisher exact test for the comparison of qualitative variables. The distribution of the delay in the occurrence of death was first described by the Kaplan-Meier estimator. All variables are studied in univariate (log-rank). To evaluate the effect of the different predictors of mortality for any cause, we used the proportional hazard Cox model to include the parameters most significantly associated with survival. The association between each of the explanatory variables and the time to death was tested with a univariate Cox model. The variables were then included in the multivariate Cox model if their p-value was less than 0.20 in univariate analysis. For all analyses, the significance threshold was set at 0.05.Presentation of the study population: in the present study, the mean age of participants was 44.81±14.01 years old. Of 126 subjects, 52.38% were females and 47.62% were males. We compared patients according to their “surviving” or “deceased” status. The demographic and clinical data of the two groups are listed in Predictors of mortality in hemodialysis patients: Cox regression analysis demonstrated that age, inflammation, elevated AIP (>0.24) and the presence of cardiovascular diseases are associated with global and cardiovascular mortality independently  and when they are associated . Moreover, analysis of Kaplan-Meier survival over a four-year period revealed that advanced age, increased CRP and AIP are associated with decreased survival. The multivariate Cox model was performed on a sample of 116 patients. The proportionality of risks in this model was verified for each covariate, with adjustment for other factors . Multivariate analysis identified five potential risk factors . Among tVariable age of patients: the survival of HD patients obviously depends on age . It is 8Cardiovascular diseases (CVD): the analysis of the survival curve showed that the presence of cardiovascular diseases is a factor favoring death in our population (p=0.0001). Survival at 48 months was 22% for patients with CVD and less than 90% for patients without CVD .Atherogenic Index of Plasma (AIP): from Protein-energy malnutrition: survival analysis, depending on nutritional status, by the log-rank method, showed a difference between malnourished and non-malnourished patients (p <0.02). From Inflammation: the dosage of CRP was performed in 116 patients, 57.75% of whom had a CRP ≥8mg/l. The prevalence of inflammation was 77.27% of deceased patients. The analysis of survival curves showed that the presence of inflammation represents a factor favoring death in our study population (p=0.03). Survival at 4 years was 76% for patients with inflammation and less than 91% for patients without inflammation .Hypertension (HTA): the prevalence of arterial hypertension was 78.44% (65.51% of survivors versus 12.93% of deceased patients). However, this difference was not statistically significant (p=0.15). According to the survival curve, hypertension was not a factor contributing to death in our population (p=0.13). In fact, the 4-year survival was 85% for non-hypertensive patients and 71% for hypertensive .For many years, the variability in mortality of HD patients between different countries has been widely documented. Our study provides a set of indicators on the survival and causes of death of patients on ESRD treated with hemodialysis. During our study, 22 patients died 17.46%), whose etiology of death was mainly cardiovascular disease (22.72%). Our results also revealed that advanced age, undernutrition or cardiovascular disease, and inflammation are predictive factors for overall mortality of HD patients independently or when associated, thereby decreasing their life expectancy. Worldwide, end-stage chronic kidney disease accounts for about 1% of all deaths. Between 1990 and 2010, the mortality rate from ESRD increased by 15% while the all-cause mortality rate decreased by 21% . The bur.46%, whoIn our study, they were diagnosed in 22.72% of our patients, this value is probably underestimated, and especially that the cause of death was undetermined for 54.54% of the subjects. This proportion appears to be much lower than many studies  and is aHowever, there are other factors associated with high mortality in HD patients, including malnutrition which is a formidable but not unavoidable complication in chronic hemodialysis and is a major public health problem as evidence of numerous studies . This prOne of the first markers studied is albumin with a standard adopted by international companies of 38g/l measured by an immunonephelemetry method . The expet al. showed for the first time that CRP was frequently elevated in dialysis patients, with a very strong negative correlation with markers of nutritional status [It is very likely that much of the influence of nutritional biochemical parameters, particularly albumin, on the morbidity and mortality of dialysis is explained by the relationship between inflammation and these parameters . It has l status . Other tl status .These data are similar to older studies that have shown a greater frequency of cardiovascular damage in cases of hypoalbuminemia , illustrAn early and repeated evaluation of nutritional status is therefore essential in the follow-up of the dialysis patient. Simple actions in the management of our patients such as optimizing the dialysis dose, biocompatibility of membranes, enhancement of the arteriovenous fistula, the use of different concentrations of dialysis bath potassium and calcium could improve nutritional parameters by decreasing chronic inflammation and thus reducing the risk of mortality.Mortality in the chronic renal deficient patient is high compared to the general population;Mortality is partly explained by the presence of important co-morbidities;Protein-energetic malnutrition of the dialysis patient is frequent.Mortality is high in our cohort;Cardiovascular disease, malnutrition and inflammation are predictive factors of mortality;Treatment and early management of these factors are essential to reduce mortality in our patients.The authors declare no competing interests.


The first population-based cohort study in Uppsala with the aim to study cardiovascular disease was initiated in 1970 (ULSAM). This cohort of 2300 middle-aged men has since then been followed in a longitudinal fashion for almost 50 years. This study has been followed by the PIVUS study, investigating 1000 men and women at ages 70, 75, and 80. A very detailed examination has also been performed in 500 subjects aged 50 years, the POEM study. In recent years, a high-throughput study conducted in 13000 subjects has also been performed, named EpiHealth. Uppsala also collects data in 5,000 subjects in the nationwide SCAPIS study. Taken together, these cardiovascular-oriented studies constitute a very rich source for cardiovascular epidemiological research in Uppsala. This review summarizes the design of these studies and highlights some of the important results published based on data from these studies. Framingham Heart Study (FHS) was initiated in 1948 to study the natural course of cardiovascular disease (CVD) and its risk factors. Since then this cohort study has been the leading epidemiological CVD study. Inspired by FHS, Gösta Tibblin and co-workers started the study of ‘Men born 1913’ in 1963 in Gothenburg. At that time, it was recognized that coronary heart disease mainly was a disease of men, and therefore only men were included.www.pubcare.uu.se/ulsam)  with insulin determinations was performed together with the hyperinsulinemic euglycemic clamp that allowed an evaluation of both insulin secretion and sensitivity. This is still the largest effort in a single study to characterize these two major determinants of diabetes development. Other unique features of the 70-year examination cycle were an echocardiographic examination including determinations of left ventricular geometry and function, as well as skeletal muscle biopsies to assess the fiber composition in half of the sample. Based on the ‘development origin of adult disease (DOAD)’ hypothesis also the birth weight was included, and a 24-h ambulatory blood pressure measurement was performed.At the 70-year examination, and even more in the following years, also diseases other than CVD have been studied, and data from dietary records, cognitive function tests, and measurements of bone mineral content by dual X-ray absorptiometry (DXA) and bone fractures have been studied .Major findings published over the years regarding CVD in ULSAM include the following: proinsulin is an important risk factor for CVD ; left veThe major strength of the ULSAM study is the many re-examinations performed, which allows for collection of longitudinal trends of measured variables as well as for collection of incident cases of a number of diseases, not only CVD, over more than 40 years. www.medsci.uu.se/pivus)  study was initiated in 2001 (e/pivus) .In this study, all 1,016 participants were 70 years old, and 50% of the sample were women. Apart from endothelial function the vasculature was characterized by arterial compliance and carotid artery ultrasound measurements to evaluate atherosclerosis, and total atherosclerotic burden by magnetic resonance angiography. The heart was examined by echocardiography and magnetic resonance imaging (MRI) with late enhancement.Fat distribution was characterized by DXA and abdominal MRI. Dietary data were recorded, and FA composition in cholesterol esters were determined.At age 75, the sample was reinvestigated, and at this time MRI of the brain and three cognitive function tests were performed. These investigations were also repeated at age 80  were published some 10 years ago, ULSAM and PIVUS have participated in a number of the big consortia trying to find the genetic architecture of obesity, diabetes, coronary heart disease, and stroke. There are two major conclusions from these studies. First, the top gene findings, the FTO gene, the TF gene, and the 9.21 loci, were largely unknown gene regions before the GWAS era and could therefore not be found by a candidate gene approach. Second, in none of these outcomes was a single or a handful of genes of major importance; rather, hundreds of genes have a small impact each.During the recent years, ULSAM and PIVUS have put a large effort into proteomics and metabolomics and published that low levels of lyophosphatidylcholine (18:2) are associated with a high risk of myocardial infarction , that ceThe PIVUS study has become famous in the field of environmental research in that we have measured >50 different environmental contaminants in plasma and found, amongst other things, that persistent organic pollutants, such as PCBs, perfluorinated compounds, and pesticides, are related to atherosclerosis ,27 and iThe major strength of the PIVUS study is the detailed characterization of the cardiovascular system at repeated examinations.The population-based Prospective investigation of Obesity, Energy and Metabolism (POEM) study was conducted in inhabitants of Uppsala, Sweden, all aged 50 years. Between October 2010 and October 2016, 502 individuals were investigated (50% women). The primary aim was to explore the links between obesity and CVD.2 determinations) were recoded. An OGTT with insulin determinations has been made. Whole-body MRI with determinations of visceral/subcutaneous adipose tissue and liver and pancreatic fat has been performed. Fat mass has been recorded by DXA. Also genomic, proteomic, and metabolomics measurements have been analyzed.A great number of markers of subclinical CV disease    . The stun = 2500). In spring 2017, incident CV diseases were updated by Swedish in-hospital care and mortality registers.By 31 December 2017, data on approximately 24,000 individuals have been collected . Traditional CV risk factors and fat mass (bioimpedance) have been recorded. Genomic, metabolomic, and proteomic data have been collected in a subsample (n = 100).In a substudy, atherosclerosis has been measured, and a whole-body PET/MRI scan with FDG-tracer has been performed with special reference to inflammation of atherosclerosis in the aorta and carotid arteries   with a planned ‘last subject in’ in Q4 2018  (apis.se) . The majIn addition to the traditional CV risk factors, an extensive imaging program is performed, including CT coronary angiography, CT scanning of lungs and abdomen for visceral/subcutaneous adipose tissue and liver fat (including ‘inflamed adipose tissue’ determinations), as well as ultrasound for carotid artery atherosclerosis (and MRI if carotid plaques are found). A detailed pulmonary function testing battery has been performed together with measurements of the ankle–brachial index to assess leg atherosclerosis. Genomic, proteomic, and metabolomics measurements are planned in a subsample of 5,000 during 2017 and 2018.The SCAPIS study is the largest academic collaborative project in Sweden in medicine with a budget of >40 million €for collection of data.Two extremes of epidemiological studies exist. First, studies with a limited number of subjects (some hundreds to a couple of thousands) that have been extensively phenotyped; ULSAM, PIVUS, and POEM are examples of such studies. Second, large high-throughput studies with less deep phenotyping; EpiHealth is one such example. The development of ‘omics’ technologies, especially GWAS, demands large-scale studies to deal with the multiple testing issue. On the other hand, to evaluate mechanisms involved in the development of CVD, the small-scale studies are needed with deep phenotyping of markers of subclinical CVD, such as endothelial function, atherosclerosis, and myocardial function. Thus, both large- and small-scale epidemiological studies are needed in order to move the knowledge of CVD forward. In the SCAPIS study, the features of both the large- and small-scale studies are merged into a large study with deep phenotyping. However, to accomplish that goal in a reasonable time-frame, this study has to be performed as a multi-center study and at a high cost.In conclusion, several CVD cohort studies with different characteristics exist in Uppsala which makes it possible to explore hypotheses demanding both a large number of participants, as well as a deep phenotyping of markers of subclinical CVD and long follow-up periods. In addition, having access to several cohorts makes it possible to replicate findings in one sample in another study, an important task to ascertain the validity of novel research findings.No potential conflict of interest was reported by the authors.


Background: Sarcopenia is frequently seen in patients with mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD). While appetite loss and physical inactivity, which are also frequently seen in dementia, appear to contribute to sarcopenia, to date, no study has investigated this association.Objective: The aim of this study was to examine factors associated with sarcopenia, including appetite and physical activity, in patients with MCI and early-stage AD.Methods: The study subjects comprised 205 outpatients  who were being treated at the Memory Clinic, National Center for Geriatrics, and Gerontology and had a Mini-Mental State Examination (MMSE) score of 21 or higher. All subjects were assessed for appetite by using the Council on Nutrition Appetite Questionnaire (CNAQ). Confounding variables assessed included physical activity, activities of daily living, mood, body mass index (BMI), nutritional status, and medications. Sarcopenia was defined as low muscle mass and low handgrip strength or slow gait speed. Multivariate logistic regression analyses were performed with adjustment for age, gender, education, and confounding variables to examine the association of sarcopenia with physical activity and appetite. Furthermore, sub-analyses were also conducted to clarify the relationship between CNAQ sub-items and sarcopenia.Results: The prevalence of sarcopenia among the subjects was 14.6% (n = 30). Patients with sarcopenia had lower CNAQ scores . Multivariate analysis showed that BMI , polypharmacy , and CNAQ  were shown to be associated with sarcopenia. Physical activity was not associated with sarcopenia. Of the sub-items of the CNAQ, appetite , feeling full , and food tastes compared to when younger  were shown to be associated with sarcopenia.Conclusions: These results suggest that appetite could be a modifiable risk factor for sarcopenia in patients with MCI and early-stage AD. A comprehensive approach to improving appetite may prove effective in preventing sarcopenia. Frailty is construed as a consequence of age-related decline in many physiological systems, resulting in vulnerability to sudden adverse changes in health status triggered by minor stressor events . FrailtyOf the three different domains of frailty, sarcopenia is attracting attention as a cause of physical frailty  and is dSarcopenia increases with age, but it is more prevalent in patients with dementia. It is also reported that the prevalence of sarcopenia is higher among patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) than among older people with normal cognition  and thatThe aim of this study was to examine factors associated with sarcopenia, including appetite and physical activity, in patients with MCI and early-stage AD. A previous study showed that sarcopenia is associated with impaired activities of daily living (ADL) in early-stage AD . TherefoThe subjects of this study were outpatients (aged 65–89 years) who presented to the Memory Clinic at the National Center for Geriatrics and Gerontology (NCGG) of Japan during the period from February 2015 to January 2017. For the present analysis, we included those with a Mini-Mental State Examination (MMSE) score of 21 or higher who were diagnosed with MCI, and AD, given that a MMSE score of 21 or higher may be used as a surrogate measure for the Clinical Dementia Rating for staging of questionable (0.5) to mild (1.0) dementia in AD . MCI andThe study included a total of 333 patients who had completed assessments for grip strength, gait speed, and skeletal muscle mass index (SMI). Finally, a total of 205 patients were available for analysis, after excluding 128 patients with missing data for any of the variables examined  that are reported to be associated with sarcopenia , 13–16. The study protocol was approved by the Ethics/Conflict of Interest Committee at the NCGG. Written informed consent was obtained from all patients before their study participation.All patients were assessed for appetite by using the Council on Nutrition Appetite Questionnaire (CNAQ) , which cWe evaluated physical activity using the following questions: (1) “Do you engage in moderate-level physical exercise or sports?” and (2) “Do you engage in low-level physical exercise?” Subjects were considered to be inactive if they answered “No” to both these questions .2)  using a Tanita body composition analyzer . Skeletal muscle mass index (SMI) was calculated as appendicular muscle mass divided by height squared (kg/m2) . Muscle 2) .Physical performance was measured by the gait speed. Gait speed was assessed during normal walking, with the participant instructed to walk at his or her preferred speed.2 for men and 5.7 kg/m2 for women as measured by BIA). The presence of sarcopenia was defined as low muscle mass and low handgrip strength or slow gait speed.Sarcopenia was defined according to the consensus of the Asian Working Group for Sarcopenia criteria , which iDemographic data on the subjects' age, years of education, marital status, smoking status, drinking status, living situation, and economic conditions were obtained from their clinical charts. The subjects were assessed for the presence of chronic disease  and the number of medications they were on. Polypharmacy was defined as five or more regularly prescribed drugs . NutritiU test for continuous variables, and the chi-squared test for categorical variables. In multivariate analyses, logistic regression analysis was performed incorporating physical activity, CNAQ, and all variables associated with P values < 0.10 in univariate analyses, with adjustment for the following confounding factors shown to be associated with sarcopenia in previous studies  and their 95% confidence intervals (CIs) were reported.Data are presented as mean ± standard deviation unless stated otherwise. A value of All analyses were carried out by using the Japanese version of SPSS for Windows version 23.0 .2, 23.3 ± 7.3 kg, and 1.0 ± 0.2 m/s, respectively.The clinical profile of the subjects with and without sarcopenia is shown in Table P < 0.001) and lower CNAQ sub-item scores  than those without sarcopenia. Patients with sarcopenia tended to be inactive . Moreover, compared to those without sarcopenia, patients with sarcopenia were associated with older age , lower performance in basic ADL , lower vitality , lower grip strength , and lower BMI values  and lower SMI . The frequency of polypharmacy was significantly high in those with sarcopenia , CNAQ total score , and polypharmacy  , gut- and neuro-peptides , and adipocytokines , which increase or decrease appetite. Ghrelin stimulates appetite in negative energy balance . On the Several studies have reported that serum ghrelin and leptin concentrations were associated with cognitive function , 48, whiAs for structural and functional changes in the hypothalamus among patients with MCI and AD, there are limited studies. Ahmed et al. reported that the hypothalamic volumes and appetite-related hormone levels were not different between those with AD and the healthy elderly . HoweverThere are several causes of appetite loss. Although there is no specific medicine against appetite loss, several medications, such as antipsychotic drugs, are expected to have an appetite-improving effect. It has been reported that ghrelin  and olanSome herbal medicines are also shown to improve appetite and mood. Of these, rikkunshito, hochuekkito, and ninjin'yoeito are often selected for elderly people, especially those with suspected frailty. Citrus unshiu peel and glycyrrhiza, which are crude drug components of herbal medicine, are included in both these drugs. Hesperidin, nobiletin (components of citrus unshiu peel), and isoliquiritigenin (composition of glycyrrhiza) are reported to increase and restore secretion of ghrelin . In addiPolypharmacy increases with aging and patients with dementia are more likely to have comorbidities and polypharmacy . It is rThis study has several limitations. First, because of the cross-sectional design of this study, the cause-effect relationship between sarcopenia and appetite remains unclear. Secondly, appetite and exercise habits were assessed by questionnaire, and actual dietary intake and physical activity were not evaluated. In patients with dementia, self-administered questionnaires are considered less reliable, given their memory dysfunction. However, it has been shown that CNAQ had the same level of validity and reproducibility in those with dementia as in local elderly residents . DespiteIn conclusion, our study demonstrated that sarcopenia was independently associated with low BMI, polypharmacy, and appetite loss in patients with MCI and early-stage AD. Appetite loss is a symptom that can be recognized by people around patients and be improved through pharmacological and non-pharmacological intervention. We believe that the study results offer important clues as to how to suppress the increase of sarcopenia as well as frailty.AK, TaiS, and TakS conceived the study. AK and TaiS contributed to the combined data analysis and presentation of data. SN contributed to the quality control of the clinical data. All authors contributed to the writing of the manuscript and revisions.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.


According to the Receiver Operating Characteristic (ROC) analyses conducted for the identification of MetS, defined in accordance with IDF, the largest areas under the curve (AUCs) in men were observed for WHtR and CUN-BAE indices, whereas in women, they were observed for WHtR and BRI. In the analysis carried out for the identification of MetS , the AUCs were larger for WHtR and BRI in women, while in men, they were larger for CUN-BAE, BMI, and WHtR. BMI was also characterized by a relatively strong discriminatory power in identifying individuals with MetS. An optimal cut-off point for MetS, in accordance with the conventional definition, for both sexes was the value of BMI = 27.2 kg/m2. The weakest predictor of the syndrome was the ABSI (a body shape index) indicator. The most useful anthropometric indicator for the identification of MetS, both in men and in women in the Polish population, was WHtR. The optimal cut-off points for WHtR equaled 0.56 in men and 0.54 in women. Despite several papers having been published on the association between adiposity and the risk of metabolic syndrome (MetS), it is still difficult to determine unambiguously which of the indices of nutritional status is the best to identify MetS. The aim of this study was to analyze the ability of six anthropometric indices to identify MetS in the Polish population. The highest odds ratios for the occurrence of MetS, according to International Diabetes Federation (IDF), were noted for the following indices: waist-to-height ratio  and Clínica Universidad de Navarra-body adiposity estimator  in men and WHtR (OR = 25.61) and body roundness index  in women. The highest odds ratios for the modified definition of MetS (without waist circumference) were found for the following indices: WHtR (OR = 7.32), BRI (OR = 6.57), and CUN-BAE (OR = 6.12) in women and CUN-BAE (OR = 5.83), WHtR (OR = 5.70), and body mass index  in men ( Obesity is a significant risk factor for the development of several diseases, such as type 2 diabetes , metabolMetS is defined as the accumulation of risk factors such as abdominal obesity, elevated blood pressure, dyslipidemia, and abnormal glycemia. It poses one of the main challenges for global and national public health institutions, as it is associated with a significantly higher risk of type 2 diabetes, cardiovascular diseases, some cancers, and all-cause mortality. Despite the fact that several papers have been published on the association between adiposity and the risk of MetS, it is still difficult to determine unambiguously which indicator of nutritional status is the best tool in order to identify individuals with MetS. To our knowledge, so far, there has been only one such study conducted in Poland, which involved the analysis of the relationships between ABSI and metabolic risk factors in a small group of 114 young men , whereasThe basis of our study involved data obtained from the POlish-Norwegian Study (PONS) project ,21. It wThe study was approved by the Ethics Committee from the Cancer Centre and Institute of Oncology in Warsaw, No. 69/2009/1/2011 (data collection), and by the Committee on Bioethics at the Faculty of Health Sciences, Jan Kochanowski University in Kielce, Poland, No. 45/2016 .Height was measured without shoes to the nearest 0.1 cm using a SECA stadiometer. Non-elastic tape was used to measure waist circumference (WC) at a point midway between the lowest rib and the iliac crest. Weight and %BF were measured using a body composition analyzer  with an accuracy of 0.1 kg and 0.1%. On the basis of the performed measurements, the following indicators were calculated:2;BMI = Weight (kg)/Height (m)WHtR = WC (cm)/Height (cm);2/3(kg/m2) Height1/2 (m)] [ABSI = WC (m)/[BMI1/2 (m)] ;eight)2] ;2) + (0.181 × BMI × sex) − (0.02 × BMI × age) − (0.005 × BMI2 × sex) + (0.00021 × BMI2 × age), where age is measured in years, and sex was codified as 0 for men and 1 for women [CUN-BAE was calculated using the equation %BF = − 44.988 + (0.503 × age) + (10.689 × sex) + (3.172 × BMI) − (0.026 × BMIBlood pressure (BP) was measured using an Omron blood pressure monitor . BP was measured on the artery of the right upper limb when the participant was seated. In the study, an average of two measurements were used for analysis. Fasting blood samples were obtained for measurements of glucose and lipids using standard techniques. Blood was centrifuged for 10 minutes at 3500 rpm at room temperature. The glucose concentration in the blood serum was measured using the enzyme method with hexokinase, while the concentration of triglycerides (TGs) was assessed using the phosphogliceride oxidaseperoxidase method. The concentration of HDL cholesterol was obtained using the colorimetric non-precipitation method. Laboratory tests were performed with Integra 800 . −1) [Socio-demographic data and information on the participants’ lifestyles were collected in face-to-face interviews using structured questionnaires. The socio-demographic variables included sex, age, and education . As an indicator of socioeconomic position, we chose education, which, in our opinion, reflects health awareness and health behavior patterns better than income. Moreover, education is comparatively easy to measure in self-administered questionnaires, garners a high response rate, and is relevant to people regardless of age or working circumstances, unlike many other indicators of socioeconomic position. For each participant, the daily intake of pure ethanol was calculated, with the consideration of the mean alcohol content in specific alcoholic beverages and the frequency of intake (g/week). Smoking was evaluated on the basis of the analysis of the prevalence of current, former, and never smoking behaviors. The respondents who smoked cigarettes during the study were classified as current smokers, and those who had not smoked for 6 months were classified as former smokers. The rest of the participants composed the group of nonsmokers. Physical activity (PA) was evaluated with the use of the International Physical Activity Questionnaire (IPAQ), long form. Total PA was calculated and expressed as metabolic equivalents (MET/min/week−1) . Following the criteria established by the International Diabetes Federation Task Force on Epidemiology and Prevention (joint interim statement in 2009) , MetS wap value <0.05 was assumed statistically significant for all calculations. All data were analyzed using Statistical Package Statistica software . All continuous variables were expressed as means and standard deviations (X ± SD) and medians (Me) and interquartile categories (Q1–Q3). All categorical variables were reported as frequency and percentage . Comparisons between the groups of men and women were conducted using U Mann–Whitney or Chi-squared tests depending on the distribution of each feature. Spearman’s rank correlation coefficients were calculated to test the association between anthropometric measures and indices. Multivariate logistic regression was used to evaluate the unadjusted and adjusted associations between anthropometric measures and MetS. Quintiles of anthropometric indices were created, and odds ratios (ORs) of MetS and 95% confidence intervals (CIs) were calculated in each quintile. For all six anthropometric indices, the lowest quintile was set as reference. Adjustments were made for age, education, physical activity, alcohol consumption (continuous variables), and smoking status . The analyses were performed separately for men and women. Receiver Operating Characteristic (ROC) analyses were used to compare the predictive ability and to determine the optimal cut-off values of the anthropometric indices. We estimated the area under the curve (AUC) with 95% CIs. The AUC represents a measure of accuracy of each anthropometric index to discriminate between subjects with or without MetS. The optimal cut-off point was the highest Youden index value (sensitivity + specificity − 1). A 2) and 30.0% of individuals with obesity (BMI ≥30.0 kg/m2). Men were characterized by higher values of all anthropometric features and indicators of nutritional status than women (p < 0.001). Among MetS components, only a lower HDL cholesterol concentration was found in women compared to men. No significant differences of physical activity depending on sex were noted  (p < 0.001) and BRI , whereas in the analysis performed separately for both sexes, BMI was most strongly correlated with CUN-BAE (p < 0.001). The correlation coefficient r between CUN-BAE and %BF equaled 0.873 for all subjects and was slightly higher in females (r = 0.888) compared to males (r = 0.808) . WHtR and BRI were the indicators most strongly correlated with waist circumference.For all subjects, CUN-BAE was the indicator most strongly and negatively correlated with height  . In the  CUN-BAE . Among oIn unadjusted models, the odds ratios for MetS grew along with quartiles for all six anthropometric indicators . Howeverp < 0.001) and CUN-BAE  in men and WHtR  and BRI  in women. The odds ratios for the modified MetS definition, including two out of four components, were significantly lower. In the fifth quintile, compared to the first one, the highest odds ratios in women were found for WHtR , BRI , and CUN-BAE . In men, the odds ratios in the fifth quintile were lower than in females for every analyzed indicator. The relatively highest values were noted for CUN-BAE , WHtR , and BMI . The risk of MetS was not significantly higher only in the second and third quartiles of the ABSI indicator in males.The odds ratios in models adjusted for age, level of education, smoking, alcohol consumption, and physical activity also grew along with quartiles for all analyzed anthropometric indices . HoweverAccording to the ROC analyses conducted for the MetS definition according to the IDF, the largest AUCs in men were observed for the WHtR and CUN-BAE indicators , whereas in women, the largest AUCs were for WHtR (0.758) and BRI (0.748) . The smaThe comparison of the odds ratios of MetS occurrence between the highest quintile (Q5) and the lowest (Q1) of every anthropometric index showed that the best MetS predictors, according to the standard MetS definition, were WHtR and CUN-BAE in men and WHtR and BRI in women. In the modified definition (without WC), the best MetS predictor in males was CUN-BAE followed by WHtR and BMI, whereas the best predictor of MetS in females was still WHtR, followed by BRI and CUN-BAE. The results obtained by the logistic regression analysis were also confirmed by the ROC curve analysis, showing that WHtR and CUN-BAE in the case of men and WHtR and BRI in the case of women should be considered the best anthropometric indices to identify MetS in the Polish population. Among these three indices, WHtR has the advantages of simplicity, low cost, similar usefulness both in men and in women, and a well-proven applicability in various populations. Ashwell et al. , on the The usefulness of four further indices  for the identification of individuals with MetS in the Polish population was also satisfactory and just slightly lower than that of WHtR. However, different discriminatory powers of particular indices were found depending on sex. In the analyses conducted for the modified definition of MetS among men, the largest AUC in ROC analyses was for CUN-BAE. Gomes-Marcos et al. also showed that, in a global analysis, the adiposity index that showed the highest odds ratio of MetS was CUN-BAE . The resThe results of the analyses performed by us also revealed the relatively high usefulness of BRI to identify individuals with MetS. It should be emphasized that this index has shown a relatively strong correlation with WHtR (r = 0.999) in the Dutch population . Its abi2. A similar cut-off point for MetS both in men and in women (BMI = 27 kg/m2) was obtained by Ofer et al. [The usefulness of BMI in the evaluation of the risk of MetS occurrence was not significantly different from the usefulness of other indices and was clearly higher than that of ABSI. An optimal cut-off point for MetS, based on the standard definition, in our population for both sexes was the value of BMI = 27.2 kg/mr et al. . Despiter et al. ,13,14, tr et al. ,36, suggThe discriminatory power of %BF was slightly lower not only than those of WHtR, CUN-BAE, and BRI but also than that of BMI. It may result from the fact that in MetS development, the distribution of adipose tissue is more important than its percentage in the body, as underlined by several authors ,38,39. MABSI was an exception among the analyzed parameters because, despite the fact that it turned out to be significant, in all analyses it was definitely the weakest predictor of MetS. This result is in compliance with the findings of most other authors, who concluded in their studies that the lowest AUC for MetS and other cardiometabolic risk factors belonged to ABSI ,40,41,42Several limitations of the present study should be considered. Firstly, it was a cross-sectional study; therefore, no conclusions can be drawn regarding the changes in the anthropometric measures over time. Secondly, the study was limited to participants coming from only one region of Poland; hence, the applicability of these results may be limited for other populations. It should be taken into account that, among representatives of different populations of Caucasian origin, there are differences in body height and proportions that can change the relationship between body fat indicators and MetS risk . In addiAn advantage of the study is, first and foremost, the large sample size. Moreover, the anthropometric indices of the participants were calculated on the basis of actual measurements and were not self-reported. Because the anthropometric cut-off points could be different for men and women, statistical analyses were performed separately for men and women. The analysis included numerous confounders related to MetS, such as physical activity, smoking, and alcohol consumption. 2, over 57% of the participants were healthy (without MetS). Therefore, it may suggest that in using the above indicators and the proposed cut-off points, a large percentage of individuals were diagnosed as false positive. However, studies with a follow-up period of at least 10 years showed that obese individuals who were metabolically healthy had an increased risk of cardiovascular events and all-cause mortality compared to metabolically healthy individuals with a normal body weight [2). In our analysis, we included the classic MetS definition  and a modified definition . To avoid late diagnosis of MetS, consideration should be given to setting cut-off points for the indicators in question that would allow people with only one MetS component to be diagnosed.An anthropometric index showing greatest usefulness in MetS identification in the Polish population is WHtR. Optimal cut-off points for WHtR equaled 0.56 in men and 0.54 in women. Indices recommended subsequently are CUN-BAE for men and BRI for women. The results of our study confirmed a satisfactory usefulness of BMI and %BF for identifying MetS, whereas ABSI was found to be the weakest predictor of the syndrome. Our results showed that in a population where the average BMI was 28 kg/my weight . Therefo


We thank Liu et al. for their letter and hope that the response will answer their concerns and will also be informative to others who are confused about these issues. Three points will be addressed.PRSS1) cause AP and RAP (primary phenotype), with a subset later developing CP, clarified the progressive relationship between these clinical syndromes (The clinicopathologic definitions of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are based on distinguishing clinical features of complex syndromes  with no reference to etiology. In the 1960s, attempts were made to distinguish RAP from CP , but thyndromes .vice versa, and they can occur in the same person at the same time.The etiology-based, progressive relationship between RAP and CP is specifically defined in the Mechanistic Definition of CP , a new dMCP-1, 1 in SPINK1, and 33 cystic fibrosis-causing variants in CFTR. Their limited data suggested that genetic variants cause RAP but not CP. More recent studies that are larger and/or that have deeper genotyping demonstrate that RAP and CP have common etiologies and that time and persistent injury or inflammation, or additional risk factors that are present within a subset of RAP patients, cause progression to CP   and did The sample selected for the study by Goodarzi et al.  includesLiu et al. also raised concerns about a selection bias for not having follow-up data on the patients for at least 2–5 years to exclude pancreatic cancer, referencing Kirkegard et al. . We are P = 0.93).Liu et al. suggest that we did not clearly highlight the heterogeneity within the group with CP and diabetes (CP-DM). On the contrary, we discussed at length the likelihood that the CP-DM group included people with diabetes caused by CP and people with classic T2DM. We even acknowledged that both etiologies may contribute to diabetes in some individuals. We explicitly stated that such heterogeneity could have reduced the ability for the genetic risk score (GRS) to distinguish the CP-DM group from the T2DM group. The potential heterogeneity is why we conducted additional analyses attempting to enrich the CP-DM group with pancreatogenic diabetes or deplete the group of T2DM. Regarding the latter, Liu et al. suggest we should have simultaneously excluded patients with multiple T2DM-related features in subanalysis. We had examined the strategy of stratifying on multiple features but found that it resulted in CP-DM subgroups of small size and generally did not add insight beyond considering single features. As an example, we provide the analysis requested by Liu et al. A CP-DM subgroup of 63 patients had diabetes occurring after pancreatitis, no family history of diabetes, and was not obese or overweight. Their mean GRS was 66.21, which was essentially identical to the mean GRS of 66.42 in the 423 patients with T2DM , U01-DK108314 (MOG), U01-DK108306 (DCW), P30-DK063491 (MOG), and the Eris M. Field Chair in Diabetes Research (MOG). The study sponsors had no role in the study design, collection, analysis or interpretation of data, in the writing of the report, or in the decision to submit the report for publication.Potential competing interests: D.C.W. is a consultant for AbbVie, Regeneron, and Ariel Precision Medicine and has equity in Ariel Precision Medicine. M.O.G. has no conflicts to disclose.


Supplemental Digital Content is available in the text To investigate the effectiveness and safety of Tai Chi for improving balance and reducing falls on people.The following databases will be searched: China Biology Medicine (CBM), China National Knowledge infrastructure (CNKI), Wan Fang Data, the Chinese Science and Technology Periodical Database (VIP), Medline, EMBASE, Web of Science, The Cochrane Library from inception to March 2019. All randomized controlled trials (RCTs) utilized Tai Chi to improve balance ability and reduce falls will be included. Primary outcomes are the fall-related indicators, including the number of falls, fall rate, and other fall-related outcomes. Additional outcomes include the Berg Balance Scale (BBS), standing-walk test, single-legged time, or other balance-related outcomes. Study selection, data extraction, and quality assessment will be performed independently by 2 reviewers. Assessment of risk of bias and data synthesis will be performed using Review Manager V5.3 software.The findings of this systematic review will be disseminated through peer-reviewed publication or conference presentations.Trial registration number PROSPERO CRD42019127810 Serious fall can also lead to disability or even death. China's annual medical expenses caused by falls exceed 5 billion yuan, resulting in a direct or indirect social cost of approximately 160 to 80 billion yuan. Apparently, falls not only cause damages among people's health but also bring economic burden to society. Therefore, many efforts were made to improve this public health problem.Falls, as a major public health problem, is affecting people around the world. Some injuries like soft tissue injury, joint dislocation, fracture, craniocerebral injury, and so on can occur on people due to falls.–7At present, methods like balance training, supplementation of vitamin D and calcium tablets, reduction of psychotropic medication, professional fall assessment, and education are commonly used for preventing falls.–10 Tai Chi can also improve the function of knee joint and alleviate pain in knee osteoarthritis patients. Meanwhile, Tai Chi can not only improve the ability of balance control, flexibility but also has a positive effect on the cardiovascular fitness. In recent years, Tai Chi gradually attracted attention of the public and has been used as a method to improve balance and prevent falls for both healthy and unhealthy people.–22As a Chinese traditional exercise, Tai Chi not only prevails in China but also has a large number of trainers in Korea, Japan, Europe, and the United States. Tai Chi can be seen as a way of balance training in which movements are soft and gentle. The training is not limited by venues and is easy to practice. Tai Chi needs mental concentration, physical balance and coordination, muscle relaxation, and relaxed breathing, which has been widely used as an adjuvant therapy in the medical and physical fitness fields. A large number of evidence have demonstrated that Tai Chi has a positive effect in improving the balance function and promoting limb function in stroke patients.–40 We used A Measurement Tool to Assess systematic Reviews 2.0 (AMSTAR 2.0) to evaluate the quality of 18 included meta-analyses. The results of AMSTAR 2.0 showed that 17 SRs were considered critically low methodological quality and 1 SR was considered low methodological quality, which suggested that a higher level of evidence is needed to clarify the effectiveness of Tai Chi for balance ability in both healthy and unhealthy people. Therefore, this SR aims to evaluate the effectiveness and safety of Tai Chi for improving balance and reducing falls. We will conduct this SR and meta-analysis strictly in accordance with the items in AMSTAR 2.0 and report in lines with the Preferred Reporting Item for Systematic Review and Meta-analysis (PRISMA).There were many randomized controlled trials (RCTs) using Tai Chi to improve balance function of people, and the results showed that Tai Chi did have a positive effect on it. So far, we did a search of related SRs and retrieved 18 published meta-analyses.22.1http://www.crd.york.ac.uk/PROSPERO). This SR will be performed in accordance with PRISMA statement guidelines.The protocol of this SR has been registered under number CRD42019127810 on PROSPERO  score, standing-walk test, single-legged time or other balance-related measurements.2.4① Non-RCTs, cross-over RCTs; cluster randomized trials, array studies, reviews, case-control studies; ② Tai Chi combined with other methods; ③ Duplicate or the data cannot be extracted; ④ Full text cannot be obtained through various approaches.2.5http://www.ClinicalTrial.gov and http://www.chictr.org.cn) will be searched for more related studies. A professional medical librarian will help us to design the terms to retrieve trials enrolling Tai Chi for improving balance and reducing falls. Ambiguous literature will be investigated manually to avoid missing eligible trials. Reference lists of identified publications will also be manually checked. No language or publication date restrictions will be set. The concrete search strategy is shown in appendix 1.The following databases will be searched from inception to March 2019: China Biology Medicine (CBM), China National Knowledge infrastructure (CNKI), Wan Fang Data, the Chinese Science and Technology Periodical Database (VIP), PubMed, EMBASE, Web of Science and The Cochrane Library, using the combination of key words of Tai Chi, fall, balance, randomized controlled trial and RCT. The RCT registration websites (2.6All the retrieved studies will be imported into Endnote (X8) and the duplicated studies will be filtered. Two reviewers will screen the studies by titles and abstracts independently according to the eligibility criteria. The full text of all possibly relevant studies will be downloaded after cross-checked by 2 reviewers. The downloaded studies will be further assessed independently and cross-checked by 2 reviewers. In case of disagreements, a third reviewer will be involved in.2.7Two reviewers will independently extract data with a pre-defined data extraction form, in which study characteristics , participant characteristics , methodological characteristics , results  will be included. The authors will be contacted immediately for more information when data reported in RCTs was missing. The data will be cross-checked by 2 reviewers in case of mistakes. As for discrepancy, it will be resolved through team discussion.2.8www.cochrane-handbook.org.) will be used independently by 2 authors to assess the risk of bias including the following items: random sequence generation, allocation concealment, blind subjects and therapists, blind assessors, incomplete outcome data, selective outcome reporting, and other bias. The risk of bias is categorized as low /unclear /high risk (meet none of the criteria) of bias. In case of disagreements, an agreement will be reached through discussion or a third reviewer will be involved in.The Cochrane risk of bias tool  will be used to analyze dichotomous outcomes. The mean difference (MD) will be used to analyze continuous outcomes with the same unit. Otherwise, the standardized mean difference (SMD) will be used. The uncertainty will be presented with 95% confidence intervals (95% CI).2 statistic. Fixed-effects model (FEM) will be used if acceptable heterogeneity is found. Random-effect model (REM) will be used where significant statistical heterogeneity exists. Heterogeneity will be further explored using meta-regression with backward elimination to analyze the associations between treatment effect and the participant characteristics. Results will be described qualitatively in the text when meta-analysis is not possibly carried out.We will assess heterogeneity using the I2.9.1If the extracted data is missing, the original authors will be contacted for more information. If there were no reply from the original authors, we will try to calculate the data through the available coefficients, the potential impact of these missing data on the results of this SR will be tested in the sensitivity analysis.2.9.2To investigate potential heterogeneity across studies, we will conduct subgroup analysis based on age, sex, different styles of Tai Chi, the health status of participants , different places where participants lived .2.9.3Sensitivity analysis of primary outcomes will be carried out to verify the robustness of the study conclusions by assessing the impact of methodological quality, study design, sample size, and the effect of missing data as well as the analysis methods on the result of this review.2.9.4For publication bias, each included study will be assessed according to the CONSORT criteria. The Egger test will be conducted to check whether there is a statistical significance. If the numbers of trials reporting the primary outcomes are over 10, funnel plot will be performed to assess the potential of publication bias of the included studies. If funnel plots are asymmetric, we will try to interpret funnel plot asymmetry.2.10 The quality of evidence will be graded as “high”, “moderate”, “low”, or “very low” in accordance with the GRADE rating standards. The results of GRADE including evidence profile (EP) and summary of finding table (SoF) will be generated using GRADE pro software.We will evaluate the quality of evidence of outcomes by using the GRADE system. The quality of the index will be evaluated from the following 5 aspects: limitations, inconsistency, indirectness, imprecision, and publication bias.3 Tai Chi needs mental concentration, physical balance and coordination, muscle relaxation, and relaxed breathing, which is regarded as an adjuvant therapy in rehabilitation.As a mind-body exercise, Tai Chi combines Chinese qigong and meditation and consists of a series of movements linked in a continuous sequence, flowing slowly and smoothly from one movement to another that emphasizes weight transfer and movement of the body.Recently, the beneficial role of Tai Chi for improving balance and reducing falls on healthy or unhealthy people becomes a research hotspot. We did an assessment on the methodological quality of the SRs on Tai Chi for improving balance and reducing falls by using AMSTAR 2.0. The results were shown in Table This study aims to investigate the effectiveness and safety of Tai Chi for improving balance and reducing falls on people. The results of this SR will provide more reliable evidence of Tai Chi for improving balance and reducing falls, which may broaden the clinical application of Tai Chi exercise. and recommendations described in PRISMA statement and the Cochrane Handbook for Intervention Reviews.The finding of this SR will be disseminated through publication in a peer-reviewed journal. The results of the completed study will be reported according to the Consolidation of Standards for Reporting Trials guidelines44.1This study will be performed and reported strictly according to the standards in the AMSTAR2.0 and PRISMA tools, to reach a high-methodological quality SR. The results of this SR will provide evidence of effectiveness and safety of Tai Chi for improving balance and reducing falls on healthy or unhealthy people. In order to ensure that all relevant studies are included without personal biases, study selection, data extraction, and quality assessment will be performed independently by 2 reviewers.4.2Different types of Tai Chi may cause considerable heterogeneity in this systematic review. A subgroup analysis will be performed based on the type of Tai Chi intervention.Conceptualization: Juan Li, Rongjiang Jin.Data curation: Yuxi Li, Jing Ye.Methodology: Hui Zheng.Project administration: Lina Xia.Writing – original draft: Dongling Zhong, Qiwei Xiao, Mingxing He.Writing – review & editing: Chi Zhang, Fanrong Liang.