The burden of mental health problems in detained persons is high. At the same time, mental health problems are discussed as possible predictors of criminal recidivism. During detention, mental health tends to improve. The aims of the study were twofold: First, to identify group-based trajectories of mental health problems over the course of detention; second, to test the association between trajectories and criminal recidivism. A prospective cohort of 1,904 adult males detained in Dutch pre-trial detention facilities was assessed at three time points after imprisonment . Mental health problems were measured using the Brief Symptom Inventory. Recidivism was defined as reconviction and re-incarceration up to 18 months post-release. We used group-based trajectory modeling and logistic regressions for the analyses. On average, self-reported mental health improved during incarceration. Two distinct groups of mental health trajectories were identified: The majority (81%) reported relatively low levels of mental health problems, remaining stable over time. A small group (19%) reported high distress after prison entry with improvements over time. Older age, pre-existing functional impairment due to alcohol or drug use, diagnosis of psychiatric disorders, debts, use of psychiatric care during detention, and a more severe experience of detention were associated with membership in the second group. Group membership did not predict reoffending. The study confirms prior findings illustrating a generally positive change in mental health symptoms during detention. The course of mental health was associated with pre-existing socio-demographic and psychological characteristics that seem worthy to be considered in correctional treatment plans. Changes in mental health did not result in better legal outcomes. An interesting avenue for future research would be to examine changes in specific mental health symptoms or disorders in relation to recidivism risk. Compared to the general population, detained persons are more affected by mental health problems. This pattern has been shown robustly across different countries and subgroups of individuals in custody –6. At thIn the literature, there is evidence of mental health problems as risk factors for criminal behavior including violent outcomes , 8. VariAt the same time, there is evidence that adequate treatment developed to meet the psychiatric and criminogenic needs of offenders with mental health problems can reduce the risk of recidivism. Even among high-risk offenders, appropriate interventions can reduce the recidivism rate to a risk level reported in general offender populations –21.A typical course of mental health problems seems to be a higher burden at the time of imprisonment that tends to improve during detention , 22–25. Supplementary material 1 and A number of factors can influence changes in the mental health status of detained persons. The method used to select relevant references as well as the flow diagram of resulting references can be found in It is a robust finding that older age, low level of education, and marginalized labor situation are associated with a number of adverse mental health outcomes in general populations , 31 as wBesides these standard demographic characteristics, debts are discussed as relevant factors for legal and mental health outcomes in detained individuals. Prisoners are affected by financial claims coming from different sources. Especially in the US, they include legal financial obligations like victim restitution, criminal fines and surcharges, court fees, incarceration charges, and fees for post-release supervision. The need for child support, the accumulation of preexisting debts that cannot be paid off while detained, as well as new debts incurred after release to cover living expenses represent common challenges that imprisoned individuals are faced with . ImportaLooking at specific disorders, psychosis at prison entry was associated with slight symptom improvement  or remaiafter release were associated with higher recidivism risk, better mental health in prison and especially an improvement in mental health after release were related to lower recidivism risk  could be approached and of these approached individuals, 67% agreed to participate in the interview, leading to a total response rate of 48% . Of the interviewed persons, 92% also filled out the written questionnaire . The sample size of persons providing information both in the interview and in the written questionnaire was n = 1,748 for T1, n = 838 for T2, and n = 265 for T3. At the 18-month follow-up, data for n = 1,641 individuals could be obtained. Detailed information on the sampling procedure and study design can be found in the description of the cohort profile , detained individuals were interviewed and asked to complete written questionnaires. Three months (T2) and 9 months (T3) after incarceration, they were again handed written questionnaires. Follow-up information on re-incarceration and re-conviction at three different time points after release  were gathered from official national registration systems. Of the total target population, 71%  , 50 totaBased on the variables known to be associated with change in mental health status of persons while they are detained, the following variables were included as possible predictors: Age at start of detention; level of education ; labor situation before detention: currently working or studying ; having debts ; type of index offense ; functional impairment due to alcohol or drug use before detention: 4-item scale of alcohol and drug functioning ; any psychiatric diagnosis in the previous 12 months before detention ; psychiatric care while detained ; subjective experience of detention .Criminal recidivism was defined as re-incarceration 18 months after release from custody, as recorded in official national registration systems. For the purpose of sensitivity analysis, we examined also re-conviction, and we used varying follow-up periods of 6 and 12 months after release.Group-based trajectory modeling (GBTM) is a kind of finite mixture modeling that identifies clusters of individuals following similar trajectories. GBTM assumes that there are distinct (unknown) developmental trajectories within the population, labeled as “groups.” It uses a multinomial strategy with maximum likelihood estimation to identify these groups. GBTM has been used in criminological research –60.We used a censored normal distribution (Tobit model) with linear and quadratic trends and included time-stable covariates that could influence the probability of group membership. The model generates group-membership probabilities based on these covariates. Parameters defining the trajectories and group membership probabilities were estimated jointly. The number of groups was selected using the Akaike information criterion (AIC), Bayesian information criterion (BIC), likelihood (LL), entropy, and the number of participants in each class (> 5%). Missing values were handled with full-information maximum likelihood to use all available information for the estimation. We first described groups (shape and size) and factors associated with group membership to answer our first research question. We then tested whether group membership affected recidivism using logistic regression models to answer our second research question. Odd-ratios (OR) are reported. The significance level was set at α = 0.05.SD = 10.75). About one-third  had at least a medium education level. Slightly less than half of the participants  were engaged in work before imprisonment. The majority  had debts. Almost half of the individuals  had committed a violent offense before imprisonment. One-third  had substance use problems.n = 634). While less than one in four received psychiatric care in prison just after incarceration , about half were in psychiatric treatment at month 3  and month 9 . The median BSI total score decreased from 0.47 shortly after incarceration to 0.42 in 3 months and 0.32 in 9 months after incarceration. The subjective experience of detention remained comparable over the three measurement points , so we chose the two-group model.GBTM allowed for a two- or three-group model. AIC, BIC, and LL were a little better for the three-group model , whereas the entropy was slightly higher for the two-group model (0.861 vs. 0.868). However, in the three-group model, there was a very small number of participants in one group  with a high initial level of mental health problems improving over time (significant linear and quadratic trends: p < 0.001), previous functional impairment due to alcohol or drug use functioning (p < 0.001), and debts (p = 0.004). They were more likely to access psychiatric care during detention (p = 0.001) and to have a more difficult experience of detention (p < 0.001). In addition, participants in group 2 were older than participants in group 1 (p = 0.004). There were no significant differences in the level of education, labor situation, and being incarcerated because of violent offending. Detailed parameter estimates are presented in Participants in group 2 were more likely to have psychiatric disorders diagnosed before detention  = 0.54, p = 0.464; OR = 1.12, 95% CI = , p = 0.461.Logistic regression was run with group membership as a predictor variable. Results indicated that group membership does not predict re-incarceration within 18 months after release: χAs predictors are important to define group trajectories, we calculated a model including predictors in our main GBTM analysis. Still, we calculated an additional model without predictors. This model also revealed two groups with slightly different proportions .OR = 1.19, p = 0.384; 12 months: OR = 1.25, p = 0.173), nor if re-conviction was used as outcome criterion.Since control variables were already included in the GBTM model as represented by the changes in group trajectories, the initial regression model to predict criminal recidivism was run with group membership as the only predictor. When running a regression model including the control variables, none of the variables proved significant neither. Results were neither significant for 6- and 12-months recidivism . Similar to the main analysis, a two-group model with comparable proportions  was preferred against a three-group model. Regarding possible predictors for group membership, fewer covariates proved significant, possibly due to a lack of power. Members of group 2 were more likely to have a diagnosis of any psychiatric disorder before detention (p = 0.004), have functional impairment due to alcohol or drug use (p = 0.032), and have a more difficult subjective experience of detention (p = 0.001). Logistic regression revealed no association between group membership and criminal recidivism in the reduced sample. Detailed information on the results of sensitivity analyses of the reduced sample is presented in the Finally, we ran the same models (GBTM and logistic regression) including only those participants who completed all three interviews . They reported very high distress at the start of detention with significant improvement over time, but still at a higher level compared to the other trajectory group. Several socio-demographic and psychological factors were associated with group membership: First, higher age increased the probability to belong to group 2. Thus, our results add to findings of the particularly high burden of somatic and mental healthcare needs in the group of elder persons in detention; a subject that will gain attention since the number and the portion of this special needs group is growing , 61, 62.despite their higher probability to judge detention as being more difficult—a factor that has been associated with adverse mental health outcomes  and time spans . Results may be interpreted in the way that psychiatric illness, or at least symptoms of specific disorders, are risk factors for criminal recidivism , 12, butAn effect of mental disorders manifested by symptoms that are highly apparent to the environment, including psychosis and externalizing disorders, on criminal recidivism has been robustly demonstrated , 66, 67.This study has several limitations. This applies first of all to the composition of the sample: Only males in pre-trial detention that were born in the Netherlands were included. Consequently, it remains unclear to what extent the findings can be generalized to females or to first-generation immigrants in detention.Second, the findings may be valid only for the Dutch correctional system with its relatively liberal and decent prison conditions and comparably low prison population rate. Moreover, short-term confinements of <6 months account for the majority of prison sentences served in the Netherlands. Consequently, a considerable portion of detained persons was already released at the follow-up measurements. The dropout, therefore, was not produced by non-response, but rather reflects the Dutch prison system with its relatively short sentence lengths. However, sentence length corresponds with offense severity, which could have led to an overproportioned representation of individuals with more severe index offenses.Third, mental health problems were only measured by a self-report instrument. The BSI total score reflects a number of different but rather mild symptoms that have been showing to be more resistant to changes. The instrument does not measure psychiatric diagnoses. Therefore, an exciting way for future research would be to assess distinct trajectories in symptoms of specific psychiatric disorders and their effect on recidivism.In this study, we identified different trajectories of mental health problems in a cohort of persons in pre-trial detention. The majority of participants displayed a low level of mental health problems remaining stable over time. By contrast, a smaller group of individuals reported high levels of mental distress that improved significantly during imprisonment. Group membership was associated with several sociodemographic and psychological characteristics indicating a high burden of pre-existing personal and mental health problems in the second group. These findings stress the need for correctional mental health services to improve detained persons' mental health. However, we could not find an association of membership in one of the two identified groups with criminal recidivism. An interesting avenue for future research would be to examine changes in specific mental health symptoms or disorders in relation to recidivism risk. Furthermore, research on the effectiveness of therapeutic interventions aiming at a positive effect on detained persons' mental health is needed.http://www.prisonproject.nl/eng/.The datasets presented in this article are not readily available but interested authors are welcome to request for collaboration from the principal investigators of the Prison Project. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by Ethical Committee for Legal and Criminological Research of the VU University Amsterdam. The patients/participants provided their written informed consent to participate in this study.MW, SB, and AD designed the study. AD and PN collected the data. SB analyzed the data with the involvement of LG, MW, and AD. MW took the lead in writing the manuscript in close collaboration with SB, LG, PN, and AD. All authors provided critical feedback and helped shape the design, analyses, interpretation, and manuscript.Data were collected as part of the Prison Project, which was financially supported by Leiden University, Netherlands Institute for the Study of Crime and Law Enforcement, the Netherlands Organization for Scientific Research (VICI grant 453-08-005), and Utrecht University.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Geographical indications of agricultural products are characterized by high quality and regional attributes, while they are more likely to be counterfeited by similar products from nearby regions. Accurate discrimination of origin on small geographical scales is extremely important for geographical indications of agricultural products to avoid food fraud. In this study, a widely targeted metabolomics based on ultra-high-performance liquid chromatography–tandem mass spectrometry combined with multivariate statistical analysis was used to distinguish the geographical origin of Pinggu Peach of Beijing and its two surrounding areas in Heibei province (China). Orthogonal partial least squares-discriminant analysis (OPLS-DA) based on 159 identified metabolites showed significant separation from Pinggu and the other adjacent regions. The number of the most important discriminant variables  was up to 62, which contributed to the differentiation model. The results demonstrated that the metabolic fingerprinting combined with OPLS-DA could be successfully implemented to differentiate the geographical origin of peach from small-scale origins, thus providing technical support to further ensure the authenticity of geographical indication products. The greenness of the developed method was assessed using the Analytical GREEnness Metric Approach and Software (ARGEE) tool. It was a relatively green analytical method with room for improvement. Food fraud, motivated by economic profit, which includes adulteration, misbranding, false geographical origin, untrue agricultural production, and so on, is a growing worldwide concern among consumers, government agencies, policymakers, industry, and scientists in recent years . Food auGeographical indication (GI) is a sign used on products that have a specific geographical origin and possess qualities or a reputation that are due to that origin, which is defined by the World Intellectual Property Organization . GI is nChina, as one of the origins of peach, is the largest peach production country in the world. Pinggu, one district of Beijing, is the largest peach-producing region in China, known as the “Homeland of Chinese peach.” Pinggu District has also received the honorary titles “China's High-Quality Peach Production Base” and “Nationally Advanced District for Standardized Peach Production.” Pinggu Peach is the Chinese famous GI product known for its quality and flavor. It has been exported to more than 20 countries in Asia, Europe, and America. In addition, Pinggu Peach is one of China's 10 native products with the European Union protection ; its braLycium ruthenicum Murray , and formic acid was supplied by Sigma–Aldrich . Ultrapure water (18.3 MΩ cm) was obtained from a Milli-Q purification system .“Okubao” peach samples, which are a widely cultivated and popular variety, were collected from three adjacent and different ecotype regions in the harvest season. The regions were Pinggu Beijing , Laoting Hebei province , and Shunping Hebei province . The geographical location map of peach samples is shown in v:v = 3:1) with vortexing for 30 s and then treated ultrasonically for 15 min in an ice bath. The samples were shaken overnight and centrifuged at 10 000 g for 15 min at 4°C. Then, 500 μL of the supernatants were dried under gentle nitrogen flow. The residue of each sample was re-dissolved in 250 μL of methanol/water mixture (v:v=1:1) with vortexing for 30 s and sonicated at maximum frequency (40 kHz) continuously for 15 min in the ice bath. Afterward, the samples were centrifuged at 10 000 g for 15 min at 4°C  coupled with a Thermo Q Exactive Focus mass spectrometer  and a SCIEX 6500 Qtrap mass spectrometer  to evaluate the differences in metabolites among the three regions. The chromatographic separation was achieved on a Waters UHPLC HSS T3 column  maintained at 40°C. The injection volume was 2 μL, and the flow rate was 300 μL/min. The mobile phase A was 0.1% formic acid in water, and the mobile phase B was acetonitrile. The solvent gradient was as follows: 0–2 min, 2% B; 2–11 min, 2–98% B; 11–13 min, 98% B; 13–15 min, 98%−2% B .The QE Focus mass spectrometer  was used to acquire high-resolution MS/MS spectrum data in an information-dependent acquisition mode. In this mode, the acquisition software  continuously evaluated the full scan survey MS data while collecting and triggering the acquisition of MS/MS spectra depending on preselected criteria. In each cycle, three precursor ions whose intensities were greater than 5000 were chosen for fragmentation at collision energy. Acquired mass range was divided into 70–300, 290–600, and 590–1100 with three injections. Elaectrospray Ionization source conditions were set as follows: spray voltage: +3500/−3500 V; capillary temperature: 350°C; sheath gas: 30; aux gas: 10; CE: 10, 30, and 50. A Qtrap 6500  mass spectrometer was applied for metabolite quantification in the MRM mode. The ion source parameters were as follows: ion spray voltage: +5000/−4500 V; curtain gas: 35 psi; temperature: 500°C; ion source gas I: 55 psi; ion source gas II: 60 psi; declustering potential: ±100 V .www.r-project.org/). KEGG pathway analysis was used to annotate and enrich differential metabolites  using MAPS software (version 3.2) . The metabolites .The accuracy and reproducibility of the analysis process were monitored using QC samples, which were inserted for every five test samples, to obtain high-quality mass spectrum data. The retention time and the peak area of QC samples in the total ion current graph overlapped well, indicating that the instrument was stable . As showIn the present study, 174 peaks were detected and 159 peaks were left after using the relative standard deviation de-noising and total ion current normalization method. The qualitative and quantitative analyses of metabolites in samples were performed based on the in-house MS2 database, KEGG database, HMDB database, and MRM. A total of 159 metabolites were detected and quantified with the widely targeted metabolite technique, which included 26 carbonyls, 20 organic acids and its derivatives, 18 amino acid and its derivatives, 14 glucosides, 12 alcohols and polyols, 11 flavonoids, 5 nucleotide and its derivatives, 5 glycerophospholipids and fatty acyls, three vitamins, 13 benzene and substituted derivatives, and 32 other metabolites including catechol derivatives, choline and derivatives, pyridine derivatives, tetrapyrroles derivatives, and others. The information and content of the identified metabolites is shown in 2Y or Q2 after replacement, and the two dotted lines represented the regression lines of R2Y or Q2. The value of R2Y was very close to one, and the value of Q2 was closer to one, which showed the established modules corresponding to the real situation of the samples. A relatively approximate distribution would be obtained if a new sample was added to the model. The result confirmed that the model was meaningful, and the original model could well explain the differences between the two groups of samples.The orthogonal partial least squares-discriminant analysis (OPLS-DA) decomposes the X matrix information into Y correlation and irrelevance by orthogonal signal correction and partial least squares-discriminant analysis (PLS-DA), which can filter out the variables not related to classification and can maximize group differentiation and help find differential metabolites . OPLS-DAThe number of the variable important in the projection  greater than one was up to 62 with further analysis of the metabolic profiles. The information of the 62 compounds is shown in t-test or analysis of variance, the multivariate data analysis pays more attention to the correlations between several variables simultaneously and analyzes the statistical rules of data sets under multiple objects and variables related to each other , such as the Student ch other . Student2S-cysteine cycle and methionine-associated ethylene synthesis induce the alternative oxidase pathway to scavenge reactive oxygen species by cooperating with antioxidant enzyme systems . GAC is the concept that makes analytical chemists consider the environmental, health, and safety issues during their activities . The greFood authenticity, including geographical origin, planting pattern , or animal origin, has become increasingly important, directly influencing people's consumption willingness and happiness indices. In particular, people have higher psychological expectations for high-end and regional characteristic products, which have a higher price and often more serious counterfeiting. Ensuring food authenticity is an important challenge faced by researchers, regulatory bodies, and industries. The accuracy of geographical origin is an important part of food authenticity, which has always been a hot research issue. At present, many researches are devoted to this area, and the related technologies are also diverse. However, great challenges in distinguishing agricultural products from adjacent origins remain. Researchers combined multiple techniques, such as stable isotopes, elements, and amino acids, to trace the origin of milk from different districts in Inner Mongolia . HoweverIn our study, peach samples were collected from Beijing Pinggu District, which is the major peach-producing area. The other two sampling sites were located in Hebei province, which are adjacent peach-producing areas to Pinggu District. The straight line distance among Pinggu District and the other two sampling sites was about 200 km. All the three sites belonged to the same cumulative temperature zone, but with some climatic differences. The UHPLC-MS/MS was applied to determine the geographical origin of peach samples from three adjacent origins. This technology had not only super-sensitivity but also adequate repeatability, and the experimental results were stable and reliable. Based on differential metabolite screening in combination with multivariate statistical analysis, this method achieved good performance in differentiating the peach samples from small-scale districts. Also, the prediction model was stable and reliable, and could be used to classify the origins of samples based on identified patterns.However, this study also had some aspects for further in-depth research and improvement. First, the differences in the metabolite expression profiles of peach samples from different geographical origins were confirmed by this study, but the reasons for the differences are still ambiguous. Besides, the agronomic measures or production management also affects the physiological metabolism of plants to some extent. Therefore, further studies specifically aimed at the effect of the environmental factors on the metabolic expression profile alone should be performed for ensuring the consistency of agronomic measures to further clarify the reasons for the differences in metabolite expression profiles. In addition, the high-resolution mass spectrometry was first used to establish the MRM mass spectrometry library, and then the high-sensitivity mass spectrometry was applied to quantify metabolites in this study. This technological process helped improve the accuracy of metabolite characterization and quantification. It also narrowed the number of metabolites obtained and lost some metabolite information to a certain extent, leaving some room for subsequent improvement to this method. Anyway, the widely targeted metabolomics results showed that the kind and number of identified metabolites were also satisfactory for the differentiation of samples from different origins.At present, metabolomic techniques based on different principles have been increasingly reported in the field of product origin traceability and authenticity identification. The unique advantages of this technology definitely provide more room for development in the future.The results of this study confirmed that the metabolites based on widely targeted metabolomics could be used as fingerprints to discriminate the geographical origin of peach samples from small-scale districts. In addition, the representative metabolites with VIP value >1 made larger contributions to the distinguishing model with OPLS-DA. In conclusion, the proposed method was a more effective method to combine the widely targeted metabolomics and OPLS-DA for the identification of the geographic origins of peach samples from small-scale origins. The method could help further protect the geographical indications, protected designation of origin, and the regional characteristic products.The datasets presented in this study can be found in online repositories. The names of the repository/repositories can be found in the article/JZ: investigation, methodology, formal analysis, visualization, and writing. AL, XJ, and GL: resources. LP: supervision and project administration. All authors contributed to the article and approved the submitted version.The National Natural Science Foundation of China (32102057) and the Beijing Natural Science Foundation (6194038) supported to the samples collection and metabonomics analysis. Besides, the China's Post-doctoral Science Fund (2019M650554) also provided fund support. The publication fees will be provided by our institution.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Bone-modifying agents (BMA) such as bisphosphonates and denosumab are frequently used for the treatment of bone metastases, osteoporosis, and multiple myeloma. BMA may lead to anti-resorptive agent-related osteonecrosis of the jaw (ARONJ). This study aimed to clarify the risk factors for and probabilities of developing ARONJ after tooth extraction in patients undergoing BMA therapy. In this study, the records of 505 target sites of 302 patients undergoing BMA who presented with mandibular fractures at the Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, from March 2014 to January 2022, were retrospectively analyzed for the onset of ARONJ after tooth extraction. The following variables were investigated as attributes: anatomy, health status, and dental treatment. The correlation coefficient was calculated for the success or failure of endodontic surgery for each variable, the odds ratio was calculated for the upper variable, and the factors related to the onset of ARONJ were identified. The incidence rate of ARONJ was found to be 3.2%. Hypoparathyroidism was an important factor associated with ARONJ development. Thus, systemic factors are more strongly related to the onset of ARONJ after tooth extraction than local factors. Bone-modifying agents (BMA) such as bisphosphonates (BP) and denosumab (DMAb) are used to prevent osteoporotic fractures, bone metastases, and bone-related events in multiple myeloma. However, since the first case of BP-related osteonecrosis of the jaw was described by Marx in 2003 , cases oIn Japan, a position paper was published in 2016 by six related academic societies , which identified several known risk factors for the onset of ARONJ . FactorsThe purpose of this study was to clarify the risk factors and probability of developing ARONJ after tooth extraction in patients undergoing BMA.A retrospective clinical study was conducted on the incidence and risk factors of osteonecrosis of the jaw in patients who underwent tooth extraction at the Oral and Maxillofacial Surgery Department of Kagawa Prefectural Central Hospital between March 2014 and January 2022.This study was approved by the Institutional Review Committee of Kagawa Prefectural Central Hospital . Informed consent was obtained from all patients in this study. All data were anonymized and analyzed.The following criteria were used to select target patient cases: among patients taking BMAs, including BP and DMAb, an antibody-targeting receptor activator of nuclear factor kappa-b ligand (RANKL) therapy, those who had “hopeless” teeth, a good general condition, and a sufficient prognosis for life were included. All tooth extractions were performed under local anesthesia with the consent of the patient.Exclusion criteria were patients who had consented to surgery other than tooth extraction, such as dental implant placement surgery and bone ridge resection, patients who could not be followed up for 1 month or more, and those who had a history or ongoing radiation treatment in the facial area.According to the above criteria, 302 patients (505 tooth extraction sites) with BMAs were treated during the study period.All tooth extraction procedures were performed under local anesthesia, with or without intravenous sedation. A single surgical team of seven, under the guidance of two professional oral and maxillofacial surgeons (YF and SS), performed tooth extractions. In all cases, 4–0 absorbent silk was used for sutures, and the sutures were removed 10–14 days after surgery  The postoperative clinical management was performed in routine care. Patients received antibiotics  for 2 days postoperatively, as well as non-steroidal anti-inflammatory drugs .The resulting variable was the incidence of ARONJ after tooth extraction. ARONJ was diagnosed according to the contents of the position paper  of the AThe predictor variables for this study consisted of sets of exposures considered to be convincingly related to ARONJ and were classified as attribute, anatomical, health status, and dental treatment variables. Attribute variables included age and sex. Health status variables included body mass index (BMI), height, weight, alcohol consumption, smoking, anemia, diabetes, hypocalcemia, hemodialysis, hypoparathyroidism, hyperthyroidism, rheumatoid arthritis, steroid intake, molecular-targeted drugs, hormone therapy, chemotherapy, radiotherapy, malignant tumor, breast cancer, lung cancer, prostate cancer, colorectal cancer, and multimyeloma. Anemia was defined as hemoglobin levels <12 g/dL for women and <13 g/dL for men, according to the World Health Organization guidelines . Diabetep-value < 0.05. Any association in bivariate analyses (p < 0.05) was included in a multiple logistic regression analysis, which was subsequently used to provide adjusted odds ratios (ORs) to control the simultaneous effects of multiple covariates. Statistical significance was set at p < 0.05.Data were recorded in an electronic database throughout the study using Microsoft Excel . For statistical analysis, the digital database used was JMP version 14.2.0 for Macintosh . Categorical variables are presented as numbers and percentages, while continuous variables are presented as mean and standard deviation (SD). For the two-group comparison, we used the Mann–Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Statistical significance was set at a two-tailed The correlation coefficient is a measure of the strength of the linear relationship between two data points or a random variable. In the range of 0 to 1, the onset rate of ARONJ increases with the increasing index. Conversely, in the range of 0 to −1, as the index decreases, the likelihood of ARONJ occurrence decreases. Thus, the correlation coefficient chart was plotted according to the variable data based on the number of occurrences of ARONJ. Further, an algorithm for calculating statistical properties was implemented in Python (version 3.7.13) using NumPy (version 1.21.5) and the Pandas library (version 1.3.5).p < 0.05) included age (p = 0.004) for demographic variables, hypoparathyroidism (p <0.001), hormone therapy (p = 0.002), chemotherapy (p <0.001), radiotherapy (p <0.001), and breast cancer (p = 0.01) for health status variables.When examining the correlation coefficient accounting for the prognosis of ONJ onset after tooth extraction, the top five factors were hypoparathyroidism, chemotherapy, radiotherapy, hormone therapy, and age . Among tFor further statistical exploration, we used a multivariate logistic regression model for the occurrence of ONJ after tooth extraction, using significant variables in the bivariate analysis and variables with higher correlation coefficients. The selected items were hypoparathyroidism, chemotherapy, radiotherapy, hormone therapy, and age .In multivariate logistic regression analysis, hypoparathyroidism was a significant factor in the onset of ONJ. Chemotherapy showed a high OR for the extracted variables (OR = 3.617). It was also suggested that hypoparathyroidism is most involved in the onset of ONJ. However, it was difficult to properly calculate the OR because ONJ occurred in almost all patients with hypoparathyroidism.This retrospective study investigated the prevalence of and risk factors for ARONJ. The incidence of ARONJ in the present study was 3.2%, while the reported incidence of ARONJ is 17.8%, which is higher than the estimated value of 0.001–0.01%  reportedThe risk of ARONJ onset in hypoparathyroidism has not yet been explored. Hypoparathyroidism is an endocrine disorder in which parathyroid hormone (PTH) production is abnormally low or absent . It is aIn addition, breast cancer had a high correlation with ARONJ; however, in patients with metastases, intravenous BPs or RANKL inhibitors were used, which reduced bone metabolism and turnover and resulted in ARONJ. The risk was therefore considered to be high in such cases. Moreover, radiation therapy to organs other than the jawbone is often administered to such cancer patients, and the risk factors are thus inevitably increased. Chemotherapy, such as BMA, suppresses bone metabolism and causes immune changes; hence, it is also considered a risk factor for ARONJ ,15,16. TRegarding the BMA drug holiday and administration period, the AAOMS position paper (2014) advocates a 2-month drug holiday given the risk of ARONJ in those treated with BP for 4 years or more . HoweverWe used the correlation coefficient as a statistical tool to identify the risk factors responsible for the onset of ARONJ due to tooth extraction. Although most ranks of the correlation coefficient were similar to those of odds ratios obtained by multivariate analysis, some ranks were distinct. The correlation coefficient is an ordinal scale, and it is not possible to compare the strengths of causality. Therefore, it is necessary to identify risk factors using odds ratios by multivariate analysis. The advantage of calculating the correlation coefficient is that one can quickly and visually evaluate the correlation between two factors . Our stuThis retrospective study has two limitations. The first limitation is that the sample composition is biased. Since there are many referrals of patients with ARONJ to our department, the incidence of bone resorption inhibitor-related osteonecrosis of the jaw is higher than the value estimated by the International Task Force on Osteonecrosis of the Jaw. Therefore, future studies with a larger number of cases are necessary. Second, we could not confirm the treatment for comorbidities without treatment at our hospital. Therefore, confirmation of the treatment of comorbidities may be necessary for more accurate estimates in future studies. Despite the above limitations, to the best of our knowledge, multifactorial factors such as comorbidities and associated treatments were detected as risk factors for ARONJ in this study. In the future, for patients with comorbid diseases that are risk factors, active dental intervention should be performed on teeth that are the source of infection before BMA administration.This retrospective study investigated the prevalence and risk factors for ARONJ after tooth extraction. The incidence of ARONJ was 3.2%, and we found that hypoparathyroidism was a strong risk factor for ARONJ after tooth extraction. Thus, systemic factors are more strongly related to the onset of ARONJ after tooth extraction than local factors.


Besides, these findings provide available references for colleges to conduct educational activities, and at the same time provide scientific suggestions for preventing IGD among undergraduates.As an increasingly serious social problem, Internet gaming disorder (IGD) of college students may be related to their social self-efficacy. However, the relationship and its internal mechanisms underlying are still unclear. The current study tested the mediating effect of alexithymia in the association between social self-efficacy and IGD, and whether this mediating process was moderated by empathy. Social Self-Efficacy Scale (PSSE), Chinese version of Internet Game Addiction Scale (IGAS-C), Toronto Alexithymia Scale (TAS-20) and Interpersonal Response Scale (IRI-C) were adopted to examine the model on 888 Chinese college students. The results indicated that social self-efficacy was significantly negatively associate with IGD. Mediation analysis illustrated that alexithymia mediated the association between social self-efficacy and IGD. Further, moderated mediation analysis manifested that the mediated effects was stronger for lower level of empathy. The conclusions corroborate and clarify the mechanisms that alexithymia mediated the association between social self-efficacy and IGD, and the mediation effects is moderated  With the rapid development of society and technology, the internet has become an imperative component of our daily life. According to the 48th Statistical Reports on Internet Development in China, as of June 2021, the number of internet users in China had reached 1.011 billion, while the number of online game users had reached 510 million, including more than 100 million young users . Along wAmong the many factors associated with IGD, self-efficacy has attracted much attention of researchers . As the It is important, therefore, to explore the potential mediators of social self-efficacy and their possible effects on IGD. From this perspective, alexithymia can be a useful frame for explaining the possible relationship between social self-efficacy and IGD. Alexithymia describes an inability to articulate and interpret internal feelings . Its cenAlexithymia can be related to IGD . Many reDespite social self-efficacy can affect alexithymia, not all individuals are influenced by social self-efficacy and suffer from alexithymia equally. The reason may be that there are some other individual internal factors that probably moderate the association between social self-efficacy and alexithymia, for example, empathy. Empathy entails the ability to perceive, understand and feel the emotional states of others . Two comThe effect of social self-efficacy on IGD, and the potential mediating mechanism  remain unclear. Furthermore, the function of moderating variables which probably touch upon the association is still unclear to a great extent . Taken together, the present study explored whether alexithymia would mediate the associations between social self-efficacy and IGD, and whether empathy would act as a moderator between social self-efficacy and alexithymia .M = 21.08, SD = 1.57). Among them were 399 males (44.9%), 489 females (55.1%); The participants included 100 freshmen (11.3%), 253, sophomores (28.5%), 214 juniors (24.1%), 304 seniors (34.2%), and 17 students in fifth college graders (1.9%). Furthermore, the average Internet age was 7.99 years (SD = 3.372), and time spending on online game per day was 2.53 h (SD = 2.369).The present study was approved by the Institutional Review Board of Yangtze University. Random sampling was adopted to conducted online testing on the students from various colleges and universities in Hubei province. After obtaining informed consent from the participants, the research was conducted by trained senior students majoring in psychology. All participants were told that their answers would be protected and that they were free to withdraw from the study at any time. A total of 1,000 students completed all the questionnaires, and 888 valid questionnaires remained after excluding invalid ones. The age of the subjects was between 17 and 25 years old  was revised by IGD was assessed by the Chinese version of Internet Game Addiction Scale for college students (IGAS-C) . The queToronto Alexithymia Scale-20 (TAS) was used to measure individual’s alexithymia level . Its ChiEmpathy was assessed using the Interpersonal Response Indicator Scale (IRI-C), which was developed by Davis and inspected with great reliability and validity . The scaIn the proposed model, gender, grade, and time spending on online game per day are regarded as the control variables, as they have been found to be closely associated with our main variables in existing researches .Before statistical analysis, responses with the missing data were excluded from the data processing since the proportions of missing data for all variables were low (<1%). Firstly, descriptive statistics, the analyses of variance and correlation were conducted with IBM SPSS 22.0. Secondly, Hayes’ PROCESS macro (Model 4)  was perfThe Harman one-factor test was used to test for common method bias. The results showed 12 factors with characteristic roots greater than 1, explaining the amount of variance explained by the first factor was 21.95%, when the critical criterion was under 40%, indicating no serious common method bias variance.The mean, standard deviation, and correlation coefficient matrices for all variables are presented in β = −0.33, p < 0.001). In addition, results simultaneously indicated social self-efficacy significantly negatively predicted alexithymia . As it can be seen in β = 0.41, p < 0.001). Further, the bias-corrected percentile bootstrap method indicated that the indirect effect social self-efficacy on IGD via alexithymia was significantly , ab = −0.11, 95%, CI = . In addition, the mediation effect accounted for 33.3% of the total effect. The above results provided compelling evidence that social self-efficacy was associated with the increase of IGD, moreover, the relation was mediated by alexithymia simultaneously. Consequently, Hypothesis 2 was fully verified.In accordance with the anticipation of Hypothesis 2, alexithymia played a mediating role in the relationship between social self-efficacy and IGD. Model 4 of PROCESS macro  was perfβ = −0.22, p < 0.001); and more importantly, the effect was moderated by empathy . Additionally, simple slope analyses were conducted to illustrate this significant interaction and explore whether slopes for the high-empathy group (1 SD above the mean) were different from slopes for the low-empathy group (1 SD below the mean) in the mediator variable model. The results were plotted in β simple = −0.25, p < 0.01) than those who high in empathy . Therefore, Hypothesis 3 was supported.Hypothesis 3 assumed that the association between social self-efficacy and alexithymia will vary with empathy. To examine the hypothesis, Model 7 of PROCESS macro  was perfvia increased alexithymia and whether this indirect association was moderated by empathy. These findings facilitate our understanding of “how” and “for whom” social self-efficacy impacts IGD, and they also provide insights into the intervention of behaviors of IGD among undergraduates.Based on social control theory , self-deThe current study showed that social self-efficacy was negatively associated with IGD. Prior studies have identified social anxiety as a potential influencing factor among IGD in undergraduates . The curThis study not only focuses on the direct impact of social self-efficacy on IGD, but also pays attention to the indirect impact of alexithymia on IGD. As stated in Hypothesis 2, the results demonstrate that social self-efficacy can directly and negatively predict IGD among undergraduates, and it can also indirectly predict IGD through alexithymia, which is consistent with the previous research results . In realAs envisaged in Hypothesis 3, this study indicated that empathy plays a moderating role between social self-efficacy and alexithymia. In particular, the social self-efficacy of individuals with low empathy has a greater negative impact on alexithymia than that of individuals with high empathy. These findings are congruent with the theoretical deduction from the self to other model of empathy (SOME) and also consistent with previous research . On the The following limitations need to be noted before interpreting the results of our study. Firstly, its cross-sectional and correlational nature does not allow for causal interpretations of the data. Therefore, longitudinal research may be a better option for future research. Secondly, our study employed the self-report approach, thus there might be more or less biases in participants’ respond, which probably impacts the authenticity of results and the verifiability of the data . BesidesIn spite of the above limitations in our study, there are still certain theoretical and practical implications. First of all, given that social self-efficacy is negatively associated with the IGD among undergraduates, universities should provide courses which taught college students to improve skills for recognizing maladaptive cognitions during social interactions and effective interpersonal communication, thereby enhancing the students’ self-confidence and reducing social anxiety. Secondly, our study found that alexithymia mediated the association between social self-efficacy and IGD, which indicates alexithymia plays a significant role in increasing undergraduates’ IGD. The above findings remind us it might have some benefits for college students to strengthen their ability of expressing inner thoughts to a certain extent. Additionally, at the theoretical aspect, our findings have certain significance for deepening the comprehending of the influencing factors of IGD among college students. Thirdly, the relation between social self-efficacy and alexithymia is stronger for undergraduates with a lower level of empathy. Due to the essential exacerbating role of empathy, increasing undergraduates’ empathy could serve as an indirect intervention strategy for decreasing IGD.To sum up, our study found that social self-efficacy was positive associated to IGD. Moreover, alexithymia was proved to mediate the association between social self-efficacy and IGD in the mediation analysis. Simultaneously, the moderated mediation analysis reveals that empathy would exacerbate the relation between social self-efficacy and alexithymia. Concretely, the association between social self-efficacy and alexithymia would be stronger for undergraduates with a lower level of empathy.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Research Ethics Committee of College of Education and Sports Sciences, Yangtze University. Written informed consent to participate in this study was provided by the participants or their legal guardian/next of kin.YZ, TL, XG, and XZ designed the work and were responsible for the overall development of this study, including the planning of sample collection, data analysis, writing, and polishing of the manuscript. TL, HL, and JZ were in charge of data collection and analysis of this study. YZ, TL, and XG were in charge of the main revision for this manuscript. YZ and TL were responsible for revising the manuscript and made a great contribution to the final acceptance of the manuscript. YZ provided the manuscript fee. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: To analyze the perception of physical fitness, screen time, and self-reported sleep hygiene in children and adolescents (CA) from the extreme south of Chile and its associations with waist-to-height ratio (WtHr). Material and methods: An observational cross-sectional study was conducted in a sample of 594 schoolchildren from 5th to 8th grade of primary education, belonging to municipal educational establishments in the Magallanes region, Chile. Cardiorespiratory fitness was assessed through the 20-m shuttle run test, muscle strength through handgrip and the standing broad jump test, physical fitness perception through the International Fitness Scale, and central obesity through the waist-to-height index. In addition, sleep hygiene and screen time were measured. Results: More than 92% of CA spent more than two hours a day watching or using screens. In addition, CA with excess central adiposity had a lower perception of physical fitness, and lower muscle strength and cardiorespiratory fitness compared to CA with normal values of adiposity. Conclusions: CA of the present study spent a high number of hours watching or using screens and had poor sleep quality. In addition, excessive central adiposity was associated with lower physical fitness. Reducing obesity in children and adolescents (CA) is a major challenge for public health worldwide. It is estimated that more than 330 million children aged 5–19 years suffer from excess malnutrition . Many auWithin this context, the most commonly used indicator for the diagnostic of overweight and obesity in CA is the body mass index (BMI). However, BMI has been questioned due to its limitations in detecting adiposity in CA . In contAlthough several studies associating lifestyle with obesity use BMI, other authors have incorporated the WtHr as a marker of central adiposity , showingOverweight/obesity is a multifactorial condition where lifestyle plays a key role in its development in CA . In thisFew studies have investigated the influence of extremely cold weather in controlling overweight/obesity in CA . In thisTo date, few studies have analyzed physical fitness and nutritional status in CA from territories with extremely cold climates. Furthermore, few have used WtHr as a marker of nutritional health and analyzed its association with lifestyle and physical fitness in CA. No research has been found studying the association between WtHr and physical fitness, screen time, and sleep habits in CA from territories with extremely cold climates. The present study is relevant because the Magallanes region has the highest prevalence of childhood overweight and obesity in Chile .Additionally, it is a region that, due to geographic, climatic, and light-dark cycle conditions, does not favor systematic programs for the control of overweight, obesity, and the practice of physical activity. This study could make it possible to generate a profile of lifestyles (screen time and sleep hygiene) and perception of physical fitness of CA in a region with an extremely cold climate, being the first study of this kind conducted in South America.This study aimed to analyze the perception of physical fitness, screen time, and self-reported sleep hygiene in CA from the extreme south of Chile and its associations with the WtHr.An observational, cross-sectional study was conducted using data from the health survey of CA from the extreme south of Chile (2019). The variables analyzed were screen time, physical fitness, sleep hygiene, and WtHr.CA from the second cycle of primary education (5th to 8th year) from three public educational establishments in Punta Arenas city  were invited to participate. A representative sample of 615 CA completed all the evaluations after acquiring the signed consent of the parents/legal guardians. A total of 14 CA were excluded for not having the signed informed consent, 4 CA did not participate due to inability to perform the physical tests, and 3 CA did not complete all the evaluations, so the final sample was 594 CA. The sample calculation was obtained considering 50% of heterogeneity, a margin of error of 5%, and a confidence level of 95%.The municipal corporation of Punta Arenas (CORMUPA) and the research team signed a collaboration agreement. Then, three educational establishments were randomly selected. The management team, the teachers, and the research team planned the study design and its execution together.The research team was in charge of hiring a kinesiologist, a nutritionist, a psychologist, and a physical education teacher. Then, they conducted a short training session on assessment instruments to reduce the risk of inter-rater bias. The data collection was carried out in the first semester of the year 2020 within the educational establishments in spaces adapted for each test and test. All the tests were carried out within the class schedule and on the same day. Families, directors, teachers, and students were informed about the purpose of the study and agreed to collaborate in it. All schoolchildren who participated in the study gave their consent and their parents and legal guardians signed their informed consent. The project was approved by the Ethics Committee of the south-central macro zone of the Universidad Santo Tomás de Chile, code number 96–20, and all procedures were carried out following the Declaration of Helsinki and Singapore.Waist-to-height ratio (WtHr): WtHr is a specific index highly correlated with visceral adiposity. Waist circumference was measured taking as reference the equidistant point between the last non-floating rib and the iliac crest. Height was measured in centimeters. Then, WtHr was calculated by dividing waist (in cm) by height (in cm). Pediatric reference values are ≤0.47 normal adiposity; 0.47–0.50 moderate adiposity; and >0.50 excess adiposity ,24.Cardio-respiratory fitness: The 20-m shuttle run test was used, measuring speed (m/s), and number of paliers, following the protocol and reference values given by Alpha Fitness for schoolchildren .Muscle strength: handgrip strength dominant hand  and the standing broad jump test were performed, using the reference values given by Alpha Fitness for schoolchildren .Physical fitness perception (IFIS): Evaluation of self-perception of the physical condition. This survey has five questions focused on knowing the self-perception of general physical fitness, cardio-respiratory fitness, muscle strength, flexibility, speed, and agility ,28.® brand digital scale , the waist circumference was measured while standing with a 1.5 m tape, and the height was measured with a SECA® brand portable stadiometer . These measures were performed according to the standardized procedures described by the International Society of Film anthropometry (ISAK) [Nutritional status: The bodyweight of the schoolchildren was measured with a SECAy (ISAK)  and accoy (ISAK) . Subsequy (ISAK) .Screen time: A self-reported survey was applied by adding the responses (hours) of three questions: “How many hours a day do you usually watch television?”; “How many hours a day do you usually play video games on a tablet, computer, or cell phone?”; and “How many hours a day do you usually use a tablet, computer, or cell phone for purposes other than gaming, for example, email, chats, social networks, internet, or doing homework?” ,33.Sleep hygiene: The questionnaire used to assess sleep habits was the Sleep Self-Report (SSR) in its Spanish version. Each item has a 3-point scale to indicate the frequency of each habit: usually (2 = 5 to 7 times a week), sometimes (1 = 2 to 4 times a week), and rarely (0 = never or once a week). The questionnaire consists of 19 questions , grouped into 7 for sleep quality, 6 for sleep-related anxiety, 4 for rejection of sleep, 3 for routines to go to sleep, and 16 for the score total ,34.In addition, sociodemographic values such as sex , age (9–12 years/13–15 years), school grade (fifth grade/six grade/seventh grade/eight grade), place of residence , and if they belong to the school integration program (yes/no) were measured.p < 0.05.Data were analyzed with the statistical software SPSS 25.0 . Continuous variables were presented as mean and standard deviation, and categorical as percentages. After performing the Kolmogorov–Smirnov test to assess normality and the Levene’s test to assess homogeneity, all the variables showed a normal distribution and homogeneity of variances, so parametric statistics were used. Then, to establish an association between categorical variables, the Chi-square test was used. To establish differences between the three groups  a one-factor ANOVA test was performed (level of adiposity). To determine differences between groups, a post hoc analysis (Bonferroni) was used. The association of adiposity and physical fitness were investigated using linear regression analyses. Data were presented as coefficient and its 95% CI. Multivariable models were adjusted for relevant confounding variables, selected from descriptive p < 0.001) and aerobic capacity (p < 0.001) than girls. In addition, children aged 13–15 years had better performance on tests of muscle strength (p < 0.001) and aerobic capacity (p < 0.01) than children aged 9–12 years. Furthermore, CA that belong to school integration programs had a lower standing broad jump test (p < 0.05) performance, compared with other CA. Moreover, CA with healthy adiposity had better performance in the standing broad jump test (p < 0.001) and the 20 m shuttle run test (p < 0.001) than children with overweight/obesity. Finally, children without sleeping problems had higher handgrip strength (p < 0.05) than children with sleeping problems.p < 0.001), cardiorespiratory fitness (p < 0.001), speed/agility (p < 0.001), and flexibility (p < 0.001).p < 0.001) and in the 20 m shuttle run test (speed and shuttle) (p < 0.001) between CA with normal adiposity and CCA with moderate or excess adiposity. CA with normal adiposity had a better physical performance in all the tests performed.p < 0.001) compared to those who had excessive adiposity. Along the same lines, CA with normal (p < 0.001) and moderate (p < 0.001) adiposity presented a better performance in the 20 m shuttle run test than children with excessive adiposity. The same association was found (as found  once theas found .This novel research suggests that a high percentage of CA of the south of Chile spend more than 2 h a day using or watching screens and have a low sleep quality. Children with excessive adiposity have a poor perception of physical fitness and poor cardiorespiratory fitness and muscle strength compared with children with normal adiposity.The participants of our study spent too much screen time and not enough hours sleeping, regardless of their adiposity. This differs from what was expected since the evidence shows that high amounts of screen time and insufficient sleep are associated with obesity . A studyOn the other hand, it was observed that children with excessive adiposity reported a poor perception of physical condition more frequently than children with normal fat mass. In this regard, the perception of physical fitness is part of the multidimensional construct of physical self-concept . In thisThe mediation model described above provides a plausible explanation for the findings of this study regarding the relationship between excessive fat mass and poor perception of physical fitness in children from the extreme south of Chile. These results evidence how environments with extreme cold weather favor excessive adiposity in CA ,44,45. TCA with normal adiposity showed a higher aerobic capacity and muscle strength compared to those with excessive adiposity. These results are in line with the extensive existing evidence, where an inverse relationship between BMI and physical fitness is described ,47,48. SIn this context, we have previously reported on differences in anthropometric indicators according to the physical fitness of CA who live in the extreme south of Chile . OverweiThis study has several strengths: a representative sample of CA belonging to educational centers in a city in the extreme south of Chile; the WtHr used as a grouping variable of the fat mass, which provides originality, relevance, and pertinence; and the context of childhood obesity within a territorial context of extreme cold weather. This study provides useful information about lifestyles and physical fitness of the CA for teachers and health professionals, particularly those who work in extremely cold territories.The present study is a pioneer in Chile and South America in characterizing lifestyles, physical fitness, and body composition in children from territories with extremely cold climates. In addition, according to the literature studied, it is the first study that analyzes WtHr and its association with physical fitness, screen time, and sleep hygiene in children from territories with extremely cold climates.However, this study has some limitations. For example, the variables of screen time and perception of physical fitness used self-reporting instruments so that the responses of the CA were subject to their mood, understanding, and even the maturity to understand the relevance of their responses. Nevertheless, the teachers who used the surveys answered all the doubts that the children had. This method of collecting information is widely used in the literature  and alloTo date, there is little evidence about childhood overweight/obesity in territories with extremely cold climates. In the present study, children who had excessive adiposity had a low physical fitness perception and poor physical fitness . In addiIn addition, this study shows the relevance of lifestyle and environmental factors such as sleep, screen time, physical activity, and extremely cold weather concerning overweight and obesity in children. These results can be used in educational centers and health centers to analyze how healthy lifestyles are being promoted and how weight control is being addressed in CA.Future studies should further investigate the consequences of childhood obesity on the physical, mental, and emotional health of children living in extremely cold regions. Moreover, future research should focus on the risk factors leading to childhood obesity and use the WtHr as an adiposity marker.As future lines of research, many studies use BMI, waist circumference, and WtHr as predictors of cardiovascular risk and physical fitness in children ,30,31. HIn the extreme south of Chile, children and adolescents spend a high number of hours watching or using screens and indicate having a low sleep quality. In addition, children with excessive central adiposity have a poor perception of their physical fitness and concordantly have worse cardio-respiratory fitness and muscle strength compared to those with normal central obesity. These results are independent of socio-educational and lifestyle variables such as age, sex, school grade, participation in a school integration program, BMI, and bedtime routine.


Schizophrenia is one of the most severe chronic mental disorders that is currently diagnosed and categorized through subjective clinical assessment of complex symptoms. At present, there is a recognized need for an objective, unbiased clinical test for schizophrenia diagnosis at an early stage and categorization of the disease. This can be achieved by assaying low-molecular-weight biomarkers of the disease. Here we give an overview of previously conducted research on the discovery of biomarkers of schizophrenia and focus on the studies implemented with the use of GC-MS and the least invasiveness of biological samples acquisition. The presented data demonstrate that GC-MS is a powerful instrumental platform for investigating dysregulated biochemical pathways implicated in schizophrenia pathogenesis. With this platform, different research groups suggested a number of low molecular weight biomarkers of schizophrenia. However, we recognize an inconsistency between the biomarkers or biomarkers patterns revealed by different groups even in the same matrix. Moreover, despite the importance of the problem, the number of relevant studies is limited. The intensification of the research, as well as the harmonization of the analytical procedures to overcome the observed inconsistencies, can be indicated as future directions in the schizophrenia bio-markers quest. Schizophrenia is one of the most severe chronic mental disorders with still undisclosed etiological mechanisms that usually develop slowly over months or years and requires lifelong treatment. The critical age of onset of schizophrenia is 15–25 years for men and 25–30 years for women ,5,6. HowThe NCBI PubMed, Google Scholar, ScienceDirect and Semantic scholar databases were searched for original experimental articles using the keywords schizophrenia or psychosis, GC-MS or gas chromatography–mass spectrometry or biological marker or biological signature. Three of the chosen machines supported the Boolean advanced search, so the keywords mentioned above were formulated accordingly to search machine rules. A semantic scholar has different mechanics for relevance search, so mentioned keywords were chosen, respectively, to logical operators. The work should be an original study (not a review) involving patients with schizophrenia (or its various forms) and a control group of individuals without mental illness. Biomarker studies of other psychiatric diseases to schizophrenia as a comparison group would also be of interest to differentiate these illnesses. The diagnosis of schizophrenia should be made based on DSM-III-R or DSM-IV (V).Biological samples should be represented by biomaterial available for minimally invasive acquisition and suitable for early diagnosis . Some works using cerebrospinal fluid were of interest as demonstrating the potential of GC-MS but, strictly speaking, did not meet the criteria of this review due to the invasiveness of the intervention and were referred to as background information. Post-mortem studies, animal brain tissue, and human cadaver studies were excluded due to possible post-mortem changes.The original articles were selected so that individuals preferably represented the group of patients with schizophrenia with a first episode or with suspected schizophrenia before receiving therapy . However, the treated cases were also of interest  as a comparison group. A control group of persons without psychiatric disorders should be present regardless of whether thT0 or Tn represents the patient group.The substances of endogenous origin/products of human metabolism should be the subject of the work; research on pharmaceuticals and narcotic substances is beyond the scope of this review.The main analytical method used in studies should be gas chromatography with mass spectrometric detection (GC-MS), irrespective of ionization types of mass spectrometers. Studies involving other methods  were considered as reference or complementary approaches.The age of the articles was not limited, but the study did not include papers whose data are presented only by title and in which at least an abstract is not available.Thus, processes of the studies identification were performed . In totaThe following criteria were defined for the inclusion of papers in this study:p = 0.0001) and humans (p = 0.005) [trans-3-methyl-2-hexenoic (TMHA) acid by gas chromatography, mass spectrometry and NMR [Specific smells of the body or body excretions  have been used for centuries by physicians to diagnose up to 40 diseases since Hippocrates, who pointed out the diagnostic value of body odors and described several disease-specific odors in patients’ exhaled air, urine and sputum . At pres= 0.005) . Later,  and NMR . In 1971 and NMR . In schitrans-3-methyl-2-hexenoaten-butyl. The authors failed to detect a free acid in the sweat of normal and schizophrenic subjects by the GC-MS methodology used. The main conclusion of the study is that there is no obvious correlation between TMHA and schizophrenia. At present, it is recognized that TMHA is the most dominant and characteristic component of human axillary odorants produced from an excreted precursor with the implication of the skin microbe Corynebacterium striatum [However, subsequent studies failed to confirm TMHA as a specific biomarker of schizophrenia. In 1970 Thomas L. Perry et al. did not detect TMHA in the sweat of 11 schizophrenic patients and 10 healthy controls . The parstriatum  may be tstriatum ,18, the Disease-specific odorants used for centuries for disease diagnosis are only a small fraction of volatile organic compounds excreted by the organism. The not odorous volatile compounds cannot be detected by human or animal olfactory systems, but they can be detected and quantified by instrumental methods. The GC-MS is a method of choice for the analysis of volatile organic compounds (VOCs) and, in particular, the volatile organic metabolites (VOM). The total of VOMs comprises the human volatolome that is considered to present the real-time snapshot of the organism’s physiological and biochemical status. At present, the investigation of VOM is at the forefront of the development of a non-invasive method for a plethora of disease diagnosis, treatment monitoring and preventive screening ,22. HoweOur search revealed only a few investigations of the schizophrenics’ volatolome for the detection of the disease and discrimination of the patients from healthy people or patients with other mental health disorders.2 was significantly increased in comparison with patients with other mental disordered. It has been suggested that the gut microbiota may be the source of CS2, a known neurotoxin that may be involved in the pathogenesis of schizophrenia. It is increasingly recognized that gut microbiota can promote the pathogenesis of schizophrenia via multiple pathways [In 1993 Philips et al. investigated exhaled VOC in 88 subjects, of whom 25 were schizophrenic patients with exacerbations of psychosis, 26 were with non-schizophrenic mental disorders other than schizophrenia, and 37 were healthy volunteers . The volpathways . AnotherTwo years later, the same research group  using thIn GC-MS is the best method for the analysis of volatile compounds; however, as mentioned above, it can be a method of choice for the analysis of non-volatile compounds after their chemical transformation to volatile derivatives. This is a well-developed procedure with a wide selection of derivatization reagents and reactions . After dAmino acids are substrates and, at the same time, regulators of many metabolic pathways ,30, inclIn 1991 Baruah et al. measured the plasma concentration of serine and glycine in the plasma of 15 drug-naïve schizophrenic (T0) patients and 15 healthy controls . After ap = 0.0232) and did not identify serine as a discriminatory biomarker for these two groups [However, 20 years later, Xuan et al. found glycine concentrations in schizophrenic patients’ serum significantly lower than that in healthy controls p = 0.02 and did 1H-NMR to identify additional metabolite markers for schizophrenia. The differentiating metabolites detected in urine differ from those found in serum, and this underlines the role of matrix selection in biomarkers discovery. A significantly different set of also 22 differential metabolites in the serum of unmedicated schizophrenics and healthy controls was found by Yang et al. , who useThe 2-piperidinec carboxylic acid was referred to by Al Awam et al. as a new distinctive serum biomarker of schizophrenia . The 2-pPlasma and serum were and still are the main matrices used in biomarker research, but hair can be considered as a new matrix for metabolomics research and disease biomarker detection . This maIn Glucose homeostasis is fundamental for the maintenance of normal brain function. Glucose is mainly metabolized through the glycolytic pathway and the tricarboxylic acid cycle (TCA) to provide energy and biosynthetic intermediates and through the pentose phosphate pathway, an important branch of glucose metabolism that is involved in NADPH formation for biosynthetic processes and cellular redox balance.n = 55 for each group). The authors divide samples and present results for training (35/group) and test (20/group) sets. However, specifying the test group, the authors did not inform about the specificity and sensitivity of the method. In the training set, seven metabolites were significantly increased in schizophrenia subjects relative to healthy controls, including glucose, glucose 6-phosphate, fructose, fructose 6-phosphate, glycerate 3-phosphate, succinic acid and ribose 5-phosphate. Moreover, four metabolites were significantly decreased in schizophrenia subjects relative to healthy controls, including glyceraldehyde-3-phosphate, dihydroxyacetone phosphate, glycerol 3-phosphate and citric acid. The other detected metabolites, pyruvate and lactic acid, did not differ between these two groups. On the contrary, Xuan J. et al. found that schizophrenic patients showed significantly higher serum levels of lactate compared to matched controls, whereas the two studies agree on the glucose increase [In the work of Liu M.L. et al. , GC-MS bincrease . Perhapsincrease , while ap < 0.001) of those in high PUFA patients and healthy control. Bimodality was mainly accounted for by docosahexaenoic acid and arachidonic acid. The authors conclude that these findings may define two distinct endophenotypes of disease [Impaired lipid metabolism has long been considered a cause of schizophrenia . Glen et disease . In a su disease . Clinican = 55), only after 5 years of treatment, during remission. The control group consisted of 51 healthy people. The results were reproduced almost exactly, with 29% of patients having reduced levels of long-chain PUFAs and 71% having increased levels. A limitation of this work is that there is no direct indication that patients with schizophrenia were initially untreated. It is likely that all patients have been in therapy for some time.The work of Dag K. Solberg et al.  was a loIn the aforementioned study by Xuan et al., the serum fatty acids composition was investigated, and they found lower levels of saturated , monounsaturated  and polyunsaturated  fatty acids in schizophrenic patients . Palmitistratum corneum, and the analysis of stratum corneum components by chromatography–mass spectrometry [It is interesting that impaired lipid metabolism can also be detected by examination of skin lipids by tape stripping of the skin’s very top layer, called trometry . Smesny trometry . The certrometry . Thus, tA GC-TOF/MS study by Yang J. et al.  found thIn a recent study, Rog et al.  did not p = 0.030). These authors found a positive association between this increase and the reduction in schizophrenia clinical symptoms . Later, the authors determined the levels of all main SCFA  and found significantly higher serum levels of total SCFAs, acetic in patients than healthy controls (p < 0.05) [From the above-reviewed studies, it can be concluded that in the investigation of lipid metabolism main attention was given to the status of PUFA. However, short-chain fatty acids (SCFA) play an important role in microbiota–gut–brain axis and brain function. They are produced by gut microbiota and are involved in lipid and glucose metabolism. Acetate, propionate and butyrate are the three most common SCFAs and together constitute 85–89% of the SCFAs in human serum. Li et al.  compared < 0.05) .In n = 10) with schizophrenia and individuals without schizophrenia . Endogenous cannabinoids were isolated from CSF by HPLC and quantified by isotope dilution GC-MS (IDMS). Cerebrospinal concentrations of two endogenous cannabinoids  were significantly higher in schizophrenic patients than in controls (p < 0.05). In contrast, levels of 2-arachidonylglycerol, the other endogenous cannabinoid lipid, were below detection in both groups. The findings were not related to gender, age or medication and appeared to reflect an imbalance in endogenous cannabinoid signaling contributing to the pathogenesis of schizophrenia. This work does not meet the criteria for an early diagnosis due to the invasiveness of biological sample obtaining but demonstrates one of the possibilities of the GC-MS method and also had a wide interest in the scientific community involved in schizophrenia research.The endogenous cannabinoid receptor activator system, the pharmacological target of cannabis-derived drugs, also appears to be dysfunctional in schizophrenia. In order to test this hypothesis, Leweke F.M. et al.  investig2-CH2-). All of them are derivatives of aromatic amino acids such as phenylalanine, tyrosine, and tryptophan and comprise catecholamines and indolamines. The levels of catecholamines  and 5-hydroxytryptamine and their metabolites were analyzed by HPLC with an electrochemical detector (HPLC-EC) and GC-MS in the CSF from age-matched elderly in-patients affected with senile dementia of Alzheimer type (SDAT) and chronic schizophrenia [p < 0.001) and 5-hydroxyindole-3-acetic acid (p < 0.02), were found in the SDAT group than in the schizophrenia group, while no significant differences were detected for other substances measured. These metabolites were measured by GC-MS and HPLC-EC concurrently, and significantly different levels (up to 15% for 3-methoxyphenylacetic acid) were found by two methods, despite the linear correlation between the results of two measurements with Spearman’s r > 0.9.Monoaminergic systems, which use monoamines to provide neurotransmission, are involved in the regulation of mental processes, emotions, cognitive functions, memory, attention, agitation, etc. Moreover, monoamine neurotransmitters play an important role in the production and secretion of neurotrophins, in particular, neurotrophin-3 by astrocytes, which is important for ensuring the integrity of neurons, their normal differentiation and development, trophic support and their resistance to apoptosis . The claophrenia . SignifiTrace amines are a group of endogenous compounds that are present at very low concentrations  in the central nervous system. They are structurally similar to the classical monoamine neurotransmitters and include primarily 2-phenylethylamine, m- and p-tyramine, tryptamine, m- and p-octopamine, and synephrine. The trace amines act as neuromodulators for monoamine neurotransmitters and are implicated in several psychiatric and neurological disorders, including schizophrenia . The reln = 41) and healthy control subjects (n = 34) [The levels of PEA were also analyzed by negative chemical ionization GC-MS in the plasma of patients with schizophrenia ((n = 34) . The stu(n = 34) ; additio(n = 34)  and coulBufotenin  is a serotonin metabolite and a potent serotonin agonist. Bufotenin was found to be present in urine samples of schizophrenic patients and autistic children but not in normal controls . ElevateThe functional analog of bufotenin is N,N-dimethyltryptamine, which also elevated concentrations in the group of patients with schizophrenia compared to controls, but there were no significant differences between patients with and without acute psychosis and between males and females .Liu M.L. et al., 2014 observed a significant decrease in aspartic acid and homoserine in patients with schizophrenia, with a concomitant increase in dopamine, which is involved in neurotransmitter metabolism .Summary of the discussed research data on neurotransmitters and their metabolites presented in Inflammation and associated oxidative stress are considered pathophysiological factors in schizophrenia and related disorders . Markersn = 22), major depression (n = 18), and controls (n = 43) [p = 0.004) and major depression (p = 0.037). Interestingly, 8-iso-PGF2a levels in urine were further increased in schizophrenic patients after 6 weeks of treatment, suggesting an accumulation of membrane lipid damage in psychosis. It is unlikely that this increase is related to the effect of treatment, as no correlation was found between antipsychotic dosage and changes in 8-iso-PGF2a levels.Urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) were analyzed by GC-MS in acutely ill drug-naïve first-episode patients with schizophrenia ((n = 43) . The 8-iIn GC-MS based metabolomics study , it was Another pattern of 22 deferential metabolites was found in serum  with difThe discussed reports on the markers on oxidative stress are summarized in Increasing evidence from animal, preclinical and clinical studies demonstrate that steroids and particularly neuroactive steroids are important modulators of brain functions and may play an essential role in the pathophysiology and symptomatology of schizophrenia (SZ) and other mental disorders . In thisp < 0.001) than that in 23 age and gender-matched healthy controls (24.0 ± 17.9 nmol/L) [One of the first GC-MS based study devoted to the investigation of steroid levels in schizophrenic patients demonstrated that dehydroepiandrosterone (DHEA) plasma mean concentration in 23 medicated patients (90.9 ± 61.4 nmol/L) is significantly higher ( nmol/L) . Derivatp = 0.043 and r = 0.72, p = 0.041, respectively. The authors underline that this is a preliminary result that suggests that 3α,5α-THP may affect aggression in humans [A similar GC-MS method was used for the quantification of 3α,5α-tetrahydroprogesterone  in plasma samples of eight outpatients with diagnosed schizophrenia in order to investigate a possible relation with aggressive and hostile behavior . The resn humans .There are multiple evidences that GABAergic signaling could play an important role in the pathophysiology of schizophrenia, and levels of 18 GABAergic steroids were quantified in the plasma of 13 adult men with diagnosed schizophrenia before (T0) and after 6-months therapy (T6) by atypical antipsychotics and compared with that in 19 aged-matched healthy controls . The 18 Subsequently, the same research group, Bicikova et al., extended the number of quantified serum steroids up to 39 aiming to cover the whole metabolome of neuroactive steroids . In contAs demonstrated above, schizophrenia is a complex disorder involving the dysregulation of different pathways, and one single cause of schizophrenia has not been identified. Dopaminergic, glutamatergic and GABAergic neurotransmitter systems can be affected in schizophrenia and lead to different clinical manifestations and different types of the disease. Thus, it is suggested that holistic metabolome profiling may reveal a set of metabolites, also called metabolites’ signatures, which may have better clinical validity and utility in diagnosing disease than biomarkers of a single metabolic pathway. Really, as demonstrated by Xuan et al., GC-quadrupole-MS-based metabolome profiling in the serum of 18 schizophrenic patients before and after 8-week risperidone therapy revealed 22 discriminating metabolites of different metabolic pathways . BiomarkLater, Yang et al. profiled serum metabolites using GC-TOF-MS and also identified 22 differential metabolites between unmedicated schizophrenia patients and normal control groups . Most ofn = 69) and healthy controls (n = 85) to identify and validate biomarkers for schizophrenia [Obviously, the matrix used for metabolite profiling can also affect the results of discriminating metabolites identification. Liu et al. used peripheral blood mononuclear cells (PBMCs) from schizophrenia subjects  from those without violence (NV.SC) . The GC-As mentioned above, schizophrenia is a complex psychiatric disorder that can be triggered by the dysregulation of various biochemical pathways and systems. Additionally, this review demonstrates that GC-MS is a powerful instrumental platform for investigating these pathways and systems dysregulation with the final goal of discovering specific metabolic biomarkers of the disorder for its early diagnosis. The specific metabolic biomarkers can also reveal the biochemical background of the disease and hint at the best effective treatment. However, despite the potential and importance of the problem, the number of relevant studies is limited, and our systematic search found only 34 publications published to date. Most of these were published before 2015 and have not been followed up. With the recent advances in instrumental analysis, untargeted metabolomics, and a recognized need for an objective, unbiased clinical test for schizophrenia diagnosis, this research can be and should be intensified. It is also important that there is an inconsistency between the biomarkers or biomarkers patterns revealed by different groups even in the same matrix see . This maFrom our review, it can also be concluded that there is no systematic approach to finding accurate, unbiased markers of schizophrenia and that there is ample opportunity and need to intensify this research. For example, there is practically absent research on volatile organic compounds in the exhaled breath of schizophrenia patients. Breath research is now at the forefront of the search for specific volatile markers for the diagnosis of a plethora of diseases . Breath Moreover, there are only a few studies on the holistic metabolite profiling in other biological matrices of schizophrenic patients, e.g., serum or sweat. Metabolite profiling is thought to be a useful tool for diagnosing disease and monitoring the effectiveness of its treatment. It is hoped that the information from metabolite profiling will make it possible to suggest personalized therapies for more effective treatment of the disease.Thus, our review can clarify future directions in schizophrenia biomarkers research. Due to the importance and complexity of the early schizophrenia diagnosis, the search for unbiased specific biomarkers should be intensified. The indicated in this review inconsistencies presented by different teams’ data should be resolved by coordinated research of different teams and the development of harmonized procedures of the analysis, e.g., sample treatment, instrumental analysis, data treatment and interpretation. At present, the wide spectrum of the applied sampling and sample treatment method obviously leads to discrepancies in the detected biomarkers. More attention should be given to the biomarkers distinguishing schizophrenia from other mental diseases.