Theory of mind (ToM) refers to the ability to understand others’ states of mind, desires, emotions, beliefs, and intentions to predict the content of their mental representations. Two major dimensions within ToM have been studied. The first is the type of inferred mental state, which can be cognitive or affective. The second comprises the types of processes involved according to their degree of complexity . ToM acquisition is fundamental—a key component in the development of everyday human social interactions. ToM deficits have been reported in various neurodevelopmental disorders through various tools assessing disparate facets of social cognition. Nevertheless, Tunisian practitioners and researchers lack a linguistically and culturally appropriate psychometric tool for ToM assessment among school-aged children.To assess the construct validity of a translated and adapted French ToM Battery for Arabic-speaking Tunisian school-aged children.The focal ToM Battery was designed with neuropsychological and neurodevelopmental theory and composed of 10 subtests distributed evenly in three parts: Pre-conceptual, cognitive, and affective ToM. Translated and adapted to the Tunisian sociocultural context, this ToM battery was individually administered to 179 neurotypical Tunisian children (90 girls and 89 boys) aged 7–12 years.via structural equation modeling (SEM) analysis, demonstrating that this solution has a good fit. The results confirmed that the age affected differentially the performance obtained on ToM tasks based on the two components of the battery.After controlling for the age effect, construct validity was empirically confirmed on two dimensions (cognitive and affective) Our findings confirm that the Tunisian version of the ToM Battery has robust construct validity for the assessment of cognitive and affective ToM in Tunisian school-aged children; hence, it could be adopted in clinical and research settings. These deficits manifest in the inability of children with ASD to distinguish physical from mental events, appearance, and reality . Therefore, it is crucial to develop and adapt tools for evaluating these processes in research and clinical activities, e.g., the psychological examination of the developmental aspects of these sociocognitive skills in children. In addition, in child clinics, psychiatric pathologies have recently garnered interest in the field of social cognitive neuroscience because they are characterized by both cognitive disorders and relational and affective disorders that can be linked to ToM dysfunction. One psychiatric pathology that has been the subject of extensive work in recent decades is autism spectrum disorder (ASD). Through the conjunction of affective and cognitive disorders it manifests, ASD functions as a privileged experimental paradigm for interrogating the relationship between affective and cognitive mechanisms and, specifically, their intricacies during development . Indeed, reality –4 or to  reality , 5–8. Co reality . This th reality .Theory of mind is a multidimensional construct that is typically defined as cognitive or affective ToM.Cognitive ToM refers to the ability of a subject to infer epistemic states  devoid of emotions. As children grow, their cognitive ToM evolves, allowing increasingly elaborate thought orders generally evaluated by false-belief tasks, based on their cognitive understanding of the knowledge of a given belief , 12. AutIn addition, work concerning school-aged children has focused on third-order, i.e., advanced, ToM , 17–20—tA believes that B feels., A believes that B believes that A feels.,  . These cManikin” . The mosManikin” , 29.Nevertheless, assessing the various components of ToM remains a thorny endeavor. For instance, Warnell and Redcay  underscoAlthough evaluating social cognition is recommended when assessing clinical conditions , 10, theWe have chosen to adapt the affective and cognitive evaluation battery for school-aged children by Lancelot  because 1.The first criterion is related to the representativeness of the ToM spanning the whole range of its dimensions. Indeed, Lancelot’s battery included a total of 10 subtests assessing pre-conceptual, affective, and cognitive aspects of ToM.2.The second criterion refers to the presence of a variety of tasks having different levels of complexity while reducing task-dependence bias. In addition, the focal battery offers various presentation modalities with illustrations that accompany the stories told verbally and in writing.3.The third criterion refers to various mental states that can facilitate the development of rehabilitation programs focusing on specific impaired aspects of the ToM.4.The fourth criterion concerns the presence of highly discriminant scoring method between age groups.Given the lack of ToM assessment tools for Arabic-speaking populations , 30, 34,ad hoc ethical committee involving human beings. The focal children’s parents provided their written informed consent for their participation in this study, and the children provided their oral informed consent.Our study involving underage participants was reviewed and approved by Pr. Ahmed Khouaja, vice president of the University of Tunis, and Pr. Abdelhamid Fenina, Dean of Tunis’s faculty of humanities and social sciences, who were part of an SD = 0.87) and 145.53 months (SD = 0.65) of age participated in the study. From each of the six primary education levels, 15 girls and 15 boys  were randomly selected, provided they were healthy and not suffering from any mental, sensory, or motor deficits. None of the participants had learning difficulties or neurological or psychiatric disorders. All the information was obtained in semi-structured interviews with parents, teachers, and educational staff, as well as from school records .A total of 179 Tunisian children between 83.52 months  = 1.17; p = 0.121; ηρ2 = 0.05] and the mother . The groups also demonstrate similarly fluid intelligence  among boys and girls in the same age group, with an improvement in average scores between 7 and 12 years . Similarly, we observed a non-significant effect of interaction between age and sex on variation in the level of fluid intelligence .As shown in The focal battery was constructed by Lancelot in the French language , 62. Lan1)A pre-conceptual component containing two subtests: (i) estimation of arousal and valence, and (ii) facial recognition of emotional expressions in drawings and photos.2)an affective component containing three subtests: (i) Attribution of emotions according to social context, (ii) distinction of apparent emotions/real appearances, and (iii) detection of a social misstep.3)A cognitive component containing two subtests: (i) First- and second-order false beliefs, and (ii) advanced cognitive ToM.The pre-conceptual part of the battery was conceived as a control stage prior to the assessment of mental states. It was not calculated in the analysis. Rather, it only allows certainty of the integrity of two basic aspects: (a) The capacity to detect the intensity  and valence of an emotional feeling; (b) the capacity to recognize facial emotional expressions in drawings and photos.The child is shown 30 photographs and is asked to indicate on the “Self-Assessment Manikin” cards  the valeThe test is carried out in two stages. In the first stage, we administer a task involving the recognition of drawings’ emotional facial expressions; we present 10 boards with hand-drawn faces, five of which correspond to boys’ faces and five to girls’, displaying a characteristic emotion of joy, fear, anger, sadness or, finally, surprise. The child is asked to identify the emotion on each face. In the second stage, we employ the task of recognizing photos’ emotional facial expressions ; we presThis part is composed of three tests: attribution of emotions according to social context; detection of social missteps (faux pas); and distinction between “apparent vs. real emotion.”This contains 10 different situation stories, presented in comic strips. Each relates to the adventures of the characters. At the end of each comic strip, the protagonist’s facial expression is deliberately absent. The child is thus asked to choose the most appropriate emotion for the feelings of the protagonist, confronted with the evoked social situation with pieces of cardboard representing faces with basic emotional expressions relating to joy, fear, sadness, anger, or surprise.These are eight verbally communicated stories in which an individual expresses social awkwardness about another character . In its This subtest includes two stories where the child is confronted with two vexing situations for the protagonist. To hide her or his vexation, the real emotional feelings are replaced by a so-called apparent emotion that contrasts with them. The child must discriminate the real emotional feeling of the character from her or his appearance by responding to four questions. The first question refers to the perception of the apparent emotion (perception question). The second refers to the child’s belief regarding the perception; the child must justify her or his answer. The third question entails the categorization of the felt emotion, followed by a fourth question where the child must justify her or his answer.This part includes two subtests evaluating 1st- and 2nd-order false-belief tasks taken from Perner and Wimmer  and ten via character and setting changes, ensures the child has mastered the tasks’ 1st-order false beliefs.These include adapted scenarios of “Sally and Ann”  and “MaxIn the 2nd-order false belief tasks, an absent character who is being tricked watches the action performed by the second character from a hidden location (looking out a window without the other character’s knowledge). These are so-called 2nd-order false-belief stories from the adapted version of Sally and Ann , supplem1This part of the battery comprises ten different tasks where various advanced ToM aspects are investigated. The intellectual work that the child must perform is based on the understanding of the mechanisms of empathy, imagination, language proficiency, and cultural and social knowledge. The humor detection task is based on eight short stories derived from experimental tests , 65; theThe parents of the children received a brief written presentation of the research and a consent form specifying that the information provided and the results of the testing would be confidential and anonymous, only be used for research purposes. After signing the consent form, they completed a demographic information sheet.All the tests were individually administered in a calm place without any distractions and had an average duration of 2 h, spanning two sessions. Breaks were granted as needed. The cognitive and affective ToM subtests were counterbalanced, i.e., two items from the same subtest were not presented successively. The stories told to the children could be accompanied by a visual medium  or performed using dolls and material specific to the focal situations .Notably, all the subtests and instructions were provided in the Tunisian dialect to promote better task understanding , 67.via this OSF link: https://mfr.osf.io/render?url=https://osf.io/nu6fx/?direct%26mode=render%26action=download%2358 6mode = render.Data can be accessed via Internet, browsing and video games, then movies and television. This is consistent with the degree of exposure to these contexts and channels of communication.All the children in our sample have mastered primarily the Tunisian dialect that was followed by standard Arabic, then French, and lastly some elements of English, both in terms of dominance and acquisition. The average exposure time of the dialect is 100 and 95% for Standard Arabic, 80% for French and 48% for English. When it comes to the possibility of reading a text, 83% prefer it to be in standard Arabic and 32% in French. No one searches preferentially in English when all language versions are available. In terms of the child’s proficiency in speaking and verbal comprehension, the parents stated that the proficiency follows this order: Tunisian dialect, standard Arabic, French, and finally English while in reading and writing the order is as follows: standard Arabic, French, and English. The parents think that their children are better in French than standard Arabic for 21% of the cases, and than English for 2% of the cases. In addition, the parents think that the factors with the most significant impact on their child’s linguistic status were ordered as follows: Interactions with family, interactions with friends, reading, self-learning It is crucial to note two important details: first, the fact that the choice of a French tool was strongly motivated by the geographical, historical, social proximity between France and Tunisia. In fact, previous studies on the validation of psychometric batteries from French to Tunisian culture, showed similar patterns of performance , 69. SecAs far as the translation and adaptation processes are concerned, we note that we adhered to the following steps recommended by the International Test Commission : (a) TheAt the end of the “translation–back-translation” procedure, the scores and percentages were calculated by comparing the original French version with the back-translated Arabic Tunisian version across all 10 subtests and all statements in the original version. We found that the terms are similar when they are synonyms. The similarity rate is estimated at 100%.post hoc analyses.The construct validity of the Tunisian version of the ToM battery was tested using structural equation modeling (SEM). The predictive validity was tested by examining the effects of age on the development of cognitive and affective ToM using mixed ANOVAs followed by Newman–Keuls attribution of emotions according to social context (attribution emotion), distinction between “apparent and real emotion” , and detection of a social misstep (affective misstep) for the affective dimension; 1st- and 2nd-order false-belief tasks ; and three dimensions of advanced ToM—substitution, disguise, and manipulation for the cognitive dimension. Due to a clear effect of age on ToM score, we adopted SEM with a correlation matrix based on standardized scores after controlling for the age variable, as shown in Construct validity was assessed using SEM. The two latent variables, cognitive and affective components, are reflected in the following ToM scores: Chi-square = 15.52, df = 19, p = 0.689). Moreover, the comparative fit index (CFI = 1.00) is higher than the cutoff value of 0.90, while the values of the standardized root mean square (SRMR = 0.041) and root mean square error of approximation (RMSEA = 0.000) are lower than the cutoff value of 0.08, entailing a good fit. Structural equation modeling was performed using the R package lavaan . AssuminF = 34.79; p < 0.001; ηρ2 = 0.50], suggesting that age significantly affects performance on ToM relative scores; a significant component effect , suggesting differential developmental trajectories between cognitive and affective components; and a significant interaction [F = 2.91; p < 0.05; ηρ2 = 0.08). The latter was subjected to a Newman–Keuls post-hoc test.To verify the two ToM components validated by SEM analysis support this prediction and to show the presence of differential developmental trajectories between cognitive and affective components, we performed mixed analysis of variance with age , 75–78 ap < 0.001). Concerning the developmental trajectory of each component (p < 0.01), between children aged 8 and 9 (p < 0.005), and among children aged 9 and 11 or higher (p < 0.005). No significant differences were observed among children aged 10, 11, and 12. For the cognitive component, the developmental trajectory is quite different from the affective one, with no significant difference in the total relative scores between children aged 7 and 8 (p = 0.227) but there were such differences among children aged 7 and 9 or higher (p < 0.005). There was no significant difference in the total relative scores between children aged 8 and 9 (p = 0.110) but there were such differences among children aged 8 and 10 or higher (p < 0.005). Unlike the affective component, the difference in the total relative scores between children aged 9 and 10 is significant (p < 0.05). However, similarity to the developmental trajectory of the cognitive and affective components was observed among children aged 10, 11, and 12, even though the cognitive relative scores were higher than the affective relative scores.These results show that across all the focal age groups, the children succeeded more in cognitive tasks than affective tasks  fit the data very well. Moreover, these results confirm the widely accepted assumption that ToM is a non-unitary construct for clinical . The social perceptual component shows specific growth, while the social-cognitive component is aligned with the development of language, reasoning, and inhibitory control. Our study validates this two-component model with SEM analysis while covarying age. Therefore, our results are in line with previous studies defending the two-component approach to ToM (Our results also align with developmental studies such as Meinhardt-Injac et al. , who valh to ToM , 81, 89.h to ToM  has idenh to ToM . These pFurthermore, our findings based on the analysis of the effect of age on different ToM components reaffirm validity of the two-component battery model by showing a significant component effect and distinct trajectories for the two components. This confirms previous studies that have revealed various behavioral expressions of ToM in different age groups , 91, reivia empathic behaviors while integrating the mechanisms necessary for carrying out cognitive mentalization. Some of these processes can only emerge from social interactions that peak only in adolescence, hence their stagnation during the school period. Conversely, advanced cognitive ToM is dependent on the recursive language processing capacities that develop significantly during the school period.Furthermore, our results show that in regard to the variation in the average success rates noted in the tasks evaluating affective ToM, these register performances significantly lower than those for cognitive ToM, with a plateau of performance from the age of 10 years. In other words, school-aged Tunisian children reach performance stability at an earlier age than for the cognitive dimension. On the other hand, affective ToM performance develops rapidly between 7 and 9 years and then slows. This is concordant with Dennis et al. , who havvia testing in Tunisia, integrates ten tasks selected from previous experiments (Some important issues need to be addressed. The first is the conceptualization of ToM, especially its advanced aspects. Across studies, the definition and operationalization of affective and cognitive ToM are fairly stable, but for advanced ToM, they are inconsistent, with important variability in the tasks adopted for studying it. For example, advanced ToM has been defined and measured as the ability to interpret emotional cues in pictures of eyes in some studies , 95 or aeriments , 65 and eriments . These deriments  is approeriments . Warnelleriments  point oueriments  find thaThe second issue is the status of the pre-conceptual ToM tasks in the ToM battery . As noteThird, we adopted only SEM and age predictive validity to test the construct validity of the translated adapted version of the ToM battery. Among the different methods for test validation, we did not select face validity due to its weakness . For theFourth, the cultural dimension of ToM processing was not analyzed, as this was not the main objective of this psychometric article. Our translation–adaptation procedure followed the best practices suggested by the recommendations of the International Test Commission  and signAlthough the assessment of social cognition is recommended in clinical situations , there ivia clinical and non-clinical samples are needed. Data on cognitive and affective ToM evaluation battery in children indicate a gradual and continuous improvement in the performance of children aged 7–12 years concerning the intentional decoding of affective and cognitive components of mentalization. Such variation during this developmental period reflects the literature and affirms the sensitivity of our tool to the Tunisian population (The aim of this study was to examine the construct validity of the focal battery, one of its major psychometric qualities, using SEM. Our results mirror the conceptual models supported in previous studies  and confpulation , 63, 67.Finally, our data, obtained from a sample of school-aged Tunisian children using a Tunisian version of the ToM battery, confirm its validity and allow its use in both clinical and developmental research, especially among children with neurodevelopmental disorders. The question regarding whether the instrument can be extended to all Arabic-speaking children is legitimate. Although the test is translated and administrated using the Tunisian Arabic dialect, this does not exclude the fact that it can be used in other Arabic countries with different dialects. Therefore, a follow up studies can alleviate such issue by providing a version with standard Arabic that can be understood univocally across all Arabic speaking countries.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Pr. Ahmed Khouaja, Vice-President of the University of Tunis, and Pr. Abdelhamid Fenina, Dean of Tunis’s Faculty of Humanities and Social Sciences, members of the ethics committee. Written informed consent was obtained from the participants’ legal guardian for the publication of any potentially identifiable images or data included in this article.IS: data collection, data analysis, statistical analyses, and manuscript writing. CL: study design, construction tools, and design the procedure for social recording. YM: statistical analyses and manuscript writing. WS and AB: data collection and manuscript writing. DL: manuscript writing. TB: data analysis, statistical analyses, and manuscript writing. All authors contributed to the article and approved the submitted version.


Intracerebral hemorrhage (ICH) is one of the most serious complications in patients with chronic kidney disease undergoing long-term hemodialysis. It has high mortality and disability rates and imposes a serious economic burden on the patient's family and society. An early prediction of ICH is essential for timely intervention and improving prognosis. This study aims to build an interpretable machine learning-based model to predict the risk of ICH in patients undergoing hemodialysis.The clinical data of 393 patients with end-stage kidney disease undergoing hemodialysis at three different centers between August 2014 and August 2022 were retrospectively analyzed. A total of 70% of the samples were randomly selected as the training set, and the remaining 30% were used as the validation set. Five machine learning (ML) algorithms, namely, support vector machine (SVM), extreme gradient boosting (XGB), complement Naïve Bayes (CNB), K-nearest neighbor (KNN), and logistic regression (LR), were used to develop a model to predict the risk of ICH in patients with uremia undergoing long-term hemodialysis. In addition, the area under the curve (AUC) values were evaluated to compare the performance of each algorithmic model. Global and individual interpretive analyses of the model were performed using importance ranking and Shapley additive explanations (SHAP) in the training set.A total of 73 patients undergoing hemodialysis developed spontaneous ICH among the 393 patients included in the study. The AUC of SVM, CNB, KNN, LR, and XGB models in the validation dataset were 0.725 (95% CI: 0.610 ~ 0.841), 0.797 (95% CI: 0.690 ~ 0.905), 0.675 (95% CI: 0.560 ~ 0.789), 0.922 (95% CI: 0.862 ~ 0.981), and 0.979 (95% CI: 0.953 ~ 1.000), respectively. Therefore, the XGBoost model had the best performance among the five algorithms. SHAP analysis revealed that the levels of LDL, HDL, CRP, and HGB and pre-hemodialysis blood pressure were the most important factors.The XGB model developed in this study can efficiently predict the risk of a cerebral hemorrhage in patients with uremia undergoing long-term hemodialysis and can help clinicians to make more individualized and rational clinical decisions. ICH events in patients undergoing maintenance hemodialysis (MHD) are associated with serum LDL, HDL, CRP, HGB, and pre-hemodialysis SBP levels. Maintenance hemodialysis (MHD) is the primary renal replacement therapy for patients with uremia . IntraceICH often has no identifiable warning signs or symptoms. Although optimal strategies for the medical and surgical management of ICH have been investigated, survival and functional outcomes have not been significantly improved . TherefoMachine learning (ML), an artificial intelligence method, uses computers to statistically learn from datasets and build corresponding models to identify relationships between various factors. In the field of medicine, ML is increasingly used through statistical learning methods to overcome possible obstacles in clinical practice , 7. In rTo analyze complex variables that may be related to a cerebral hemorrhage after regular hemodialysis, we integrated the demographic data, laboratory test results, hemodialysis indicators, and other information of patients to construct a model for predicting the risk of a cerebral hemorrhage. To make the model more applicable for the diagnosis of chronic kidney disease with intracerebral hemorrhage, overcome the “black box” nature of ML, and explore the relationship between each feature and its clinical significance, we used the extreme gradient boosting (XGBoost) algorithm to develop the model . SHAP waPatients with end-stage kidney disease undergoing hemodialysis from August 2014 to August 2022 at the Affiliated Hospital of Xuzhou Medical University, Xuzhou Central Hospital, and the Second Affiliated Hospital of Xuzhou Medical University were recruited for the study. According to the occurrence of ICH, the patients were divided into ICH and non-ICH groups.2) diagnosed with CKD stage 5, which is the uremia stage (via a CT examination of the head. The exclusion criteria were as follows: (a) patients with severe failure of the heart, lung, and other organs, blood system diseases, autoimmune diseases, and malignant tumors; (b) patients with primary subarachnoid hemorrhage, secondary cerebral hemorrhage, such as trauma, intracranial tumors, ICH caused by hemorrhage after an ischemic stroke, and severe coagulation dysfunction; (c) patients on antiplatelet drugs, hormones, immunosuppressants, and antibacterial agents in the past 1 month; and (d) patients with missing clinical data. Based on the diagnosis and inclusion and exclusion criteria, 393 patients with end-stage kidney disease complicated with cerebral hemorrhage owing to long-term hemodialysis were included. Of these 393 patients, 73 patients were included in the ICH group, whereas 320 patients were included in the non-ICH group. Because this study had a retrospective design, there was no security-related risk. The present study was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University.The inclusion criteria were as follows: (a) patients diagnosed with uremia according to chronic kidney disease (CKD) staging and recommendations or the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines formulated by the American Kidney Foundation, that is, patients with estimated glomerular filtration rate (eGFR) of < 15 ml/ demographic data (sex and age); (2) vascular risk factors ; (3) baseline blood pressure ; (4) treatment during hemodialysis ; and (5) laboratory tests .Before constructing ML models, the original clinical data were normalized. Normalization can improve the speed of gradient descent to find the optimal solution, and the algorithm for Euclidean distance can effectively improve the accuracy. In this study, the min–max normalization method was used to normalize the characteristic values of clinical data to the range of .D = {, i = 1, 2, …, N}, where xiis , which is a row vector with input variables (or features) of real value as its elements, and yi∈{0, 1} is a scalar with the output of an integer value as its element. The task in hand was a binary classification problem, that is, the generation of a model (y = f[x]) in the training set. The model was subsequently verified in the validation set to predict Approximately 70% of the samples in the dataset were randomly selected as the training set, whereas the remaining 30% of the samples were used as the validation set. The dataset is represented as We applied five ML algorithms to model the data: logistic regression (LR), support vector machine (SVM), K-nearest neighbor (KNN), complement Naive Bayes (CNB), and XGBoost. To be able to ensure that the training samples selected for multiple-model training were consistent, we generalized the performance of each model over multiple training sessions using a resampling training/validation mechanism. The XGBoost (version 1.2.1), lightGBM (version 3.2.1), and sklearn (version 0.22.1) packages were used for developing the ML models. For the RF algorithm, “ntree” was set to 100, and “mtree” was set to 3. To avoid overfitting and enhance interpretability, the maximum tree depth was set to eight nodes in the XGBoost algorithm. In addition, to evaluate the predictive accuracy of various ML models, accuracy, precision, sensitivity, specificity, F1 score, and the area under the receiver operating characteristic curve (ROC) were evaluated.SHAP is a “model interpretation” package developed based on Python. To understand the results of the model output, the SHAP package was used to interpret and sort the features of the trained model and examine the contribution of each element in the features to the model.t-test  was subsequently used for comparing the data, which were expressed as mean ± standard deviation. The Mann–Whitney U-test was used to compare data with non-normal distribution, which were expressed as the median (first and third quartiles). A P < 0.05 was considered statistically significant.The R software (version 4.02) was used for data processing and statistical analysis. Categorical variables were expressed in terms of quantity and percentage and were compared using Fisher's exact test or the chi-square test. For continuous variables, the Shapiro–Wilk test was initially used to determine whether the variables conformed to a normal distribution, and the independent sample A total of 393 patients were included in this study, and the baseline characteristics of the ICH and non-ICH groups are shown in Five ML algorithms were used to construct predictive models. The training set was used to create and train the models. All ML models were tested in the test set, and their accuracy, precision, sensitivity, specificity, and F1 score were compared. The XGBoost model had the highest accuracy, precision, sensitivity, specificity, and F1 score  . Figure XGboost was used to rank the importance of features. As shown in In addition, SHAP can be used to analyze the influencing factors of a cerebral hemorrhage in each patient. via multivariate logistic regression (Intracerebral hemorrhage is characterized by a high rate of disability and death, which greatly increases the economic burden on families and society, so it is essential to investigate the factors influencing the complications of ICH events in MHD patients. Many scholars have identified the risk factors of ICH and hematoma expansion in patients undergoing MHD and screened variables, such as serum calcium, serum creatinine, and serum antiplatelet agents, gression , 17. UnlXGBoost is a lifting algorithm based on tree models. Since its establishment in 2016, it has been used to deal with non-linear relationships and complex interactions between variables owing to its higher prediction accuracy and faster operation speed . The XGBIn addition, in this study, we used SHAP to interpret the results of ML models. Emphasis is placed on features that have the greatest impact on outcome measures, thus helping clinicians to realize the rationale behind predicted outcomes early enough to initiate prompt intervention. The results showed that changes in LDL, HDL, CRP, SBP, and HGB levels were the main predictors of ICH in patients undergoing MHD, which was consistent with clinical studies.Lipid is an indispensable neutral fat in the human body. To date, numerous studies have investigated the relationship between lipid metabolism and ICH. Lipid metabolism disorders in patients undergoing long-term hemodialysis are closely related to the occurrence of a cerebral hemorrhage , 20, whiCRP is an important part of the immune system and one of the signs of acute inflammation . In thisAccording to the model results of this study, the SBP before daily hemodialysis in the cerebral hemorrhage group was higher than that in the control group, which is consistent with the conclusion that hypertension is a risk factor for cerebral hemorrhage in MHD patients as reported in previous studies. Hypertension is a known traditional risk factor for ICH . In patiPatients undergoing MHD are predisposed to anemia owing to factors such as reduced erythropoietin synthesis . HGB is This study has some limitations. First, although this study had a multicenter design, it only includes patients from three hospitals in Xuzhou, China. In future studies, we will include datasets from different regions and hospitals for external testing to improve the generalization ability of the model. Second, the number of patients with and without ICH was not well-balanced, which may have led to impaired prediction. Considering that deep learning has been widely used in the medical community in recent years, we will use deep learning models to incorporate a wider range of data in future studies. Overall, compared with traditional models, the prediction model developed in this study contains more information and has better predictive accuracy. In addition, the visualization of results based on SHAP can, to a great extent, alleviate the “black box” problem.A predictive ML model was developed based on XGBoost, and SHAP was used to explain the clinical significance of each risk factor in predicting the occurrence of ICH in patients undergoing MHD. ICH events in patients undergoing MHD are associated with serum LDL, HDL, CRP, HGB, and pre-hemodialysis SBP levels. The combination of the XGBoost algorithm and SHAP can provide a clear explanation for risk prediction, which has great application value in future clinical research. This combination can help clinicians to implement early clinical interventions, provide more comprehensive information for the long-term management of patients undergoing MHD, and prevent and reduce the risk of ICH.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University. Written informed consent from the patients/participants or patients/participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.FL and AC conceptualized the study, outlined the study design, collected data, analyzed and interpreted results, and wrote the manuscript. ZL and QP preprocessed input data, built machine learning models, analyzed data, and wrote the manuscript. LG collected data and preprocessed input data. YF, JF, and PW helped to adjust the ideas of the manuscript, suggested changes, and revised the manuscript. All authors agreed to take responsibility for their contributions and read and approved the final manuscript.


Asphodelus bento-rainhae subsp. bento-rainhae (AbR) is an endangered endemic plant restricted to Serra da Gardunha , and knowledge of those changes will help to design conservation measures. MaxEnt was used to model AbR’s current distribution and project it into the future, 2050, using the Shared Socioeconomic Pathway SSP3-7. The Portuguese LULC maps from 1951–1980, 1995, 2007, and 2018 were used to assess and quantify LULC changes over time. The results showed that the AbR current predicted distribution matches its actual known distribution, which will not be affected by future predicted climate change. The significant LULC changes were observed during the study periods 1951–1980 to 2018, particularly between 1951–1980 and 1995. Scrubland and Agriculture decreased by 5% and 2.5%, respectively, and Forests increased by 4% in the study area. In the occurrence area, Agriculture increased, and Forests decreased between 1980 and 2018, due to Orchard expansion (34%) and declines in Chestnut (16.9%) and Pine (11%) areas, respectively. The use of species distribution models and the LULC change analysis contributed to understanding current and future species distribution. The LULC changes will have a significant impact on future species distribution. To prevent the extinction of this endemic species in the future, it is crucial to implement conservation measures, namely species monitoring, replantation, and germplasm conservation, in addition to guidelines for habitat conservation.Climate change and land use and land cover (LULC) change are impacting the species’ geographic distribution, causing range shifts and reducing suitable habitats.  Asphodelus bento-rainhae P. Silva (Asphodelaceae), an endemic species of the Iberian Peninsula, known in this region by abrótea, abrótega, gamão or bengala-de-são-josé, and first described in 1956 by the botanist and agronomist Pinto da Silva  anA. bento-rainhae P. Silva subsp. bento-rainhae (AbR)  and A. bento-rainhae P. Silva subsp. salmanticus Z. Díaz & Valdés . The habitats of the first subspecies are the understories of Galicio-Portuguese oak woods , Castanea sativa Mill. woods (9260), and Prunus avium L. orchards, those mainly on path slopes and edges without herbicide application and frequent soil mobilization . Th. Th44]. The presence dataset was obtained from two datasets: (1) 90 occurrences, resulting from the fieldwork conducted in 2005 by Esteves ; and (2)2) spatial resolution, were downloaded from WorldClim v2.1 . The species’ suitable and unsuitable habitats were assessed through binary presence-absence maps obtained by applying the 10th percentile training Cloglog presence threshold . The valTo assess LULC changes over time , both the study area and the species occurrence area were considered . The LULThe species’ occurrence area was defined considering the AbR occurrences and using the "Minimum Bounding Geometry" tool and the "Convex hull" geometry type of ArcGIS software. For the occurrence area, 14 classes were considered: four classes of the first level , Grasslands, and Shrublands), and 10 classes of the fourth level  OA, .The LULC change analysis was carried out in ArcGIS software, version 10.8.1.Acacia dealbata and of urban areas contribute to the reduction of suitable habitat for the species.AbR is an endemic plant that only exists in a narrow area of the Serra da Gardunha Regional Protected Landscape, located in mainland Portugal. Considering its endangered status and valuable medicinal properties, its conservation and increase in area, reducing the risk of extinction is of utmost importance. The main constraints to its conservation are its small occurrence area and the low numbers of individuals remaining. The increase in the area of cherry orchards and the expansion of invasive species like The SDM MaxEnt was used to model AbR’s current and future distribution. The results suggest that future climatic conditions (2050) will be favorable for the species’ development. Considering the LULC analysis between 1951–1980 and 2018, it was concluded that the observed changes in land use contributed to the decrease in suitable habitat for AbR. Assuming future changes in LULC, the area of cherry orchards will continue to increase due to cherry’s economic importance for the region, and the species’ occurrence area will be reduced, which will be more pronounced if conservation measures are not implemented.The current study has highlighted the importance of assessing climate change together with LULC changes. Thus, it is recommended that in future studies, the LULC variable be considered in the species distribution modeling to quantify which of the two direct drivers, climate and land use change, will be more relevant for the future distribution of the species, to provide decision-makers with the necessary information to adopt preservation and conservation measures to prevent the species’ extinction. In any case, conservation measures should be taken into consideration due to the species’ current conservation status, together with habitat management measures due to orchard expansion, herbicide use, declines in oak and chestnut areas, the probability of an increase in wildfires, the difficult control of invasive species, and the putative influence of N accumulation, which means the promotion of agricultural and forestry practices compatible with the species’ conservation and habitat restoration.


The review was registered in PROSPERO (CRD42020175020). The systematic search for clinical trials was performed in the databases PubMed, CINAHL, Cochrane Central Register of Controlled Trials, PEDro, Scopus, SciELO and Dialnet. Articles were selected according to the inclusion and exclusion criteria, regarding the effectiveness of physical therapy interventions on adult patients with TTH published in the last 11 years with a score ≥ 6 in the PEDro Scale (Physiotherapy Evidence Database). (4) Results: In total, 120 articles were identified, of which 15 randomized controlled trials were finally included in order to determine the inclusion criteria. Changes in pain intensity, headache frequency or headache duration of individual studies were described (5) Conclusions: This systematic review shows that there is no standardized physical therapy protocol for the approach to tension headache, although all the techniques studied to date address in one way or another the cranio-cervical-mandibular region. The approach to the cranio-cervical-mandibular region reports significant effects in terms of decreasing the intensity of pain and frequency of headache episodes in the short and medium term. More long-term longitudinal studies are needed. The most frequent type of headache, tension-type headache (TTH), is addressed frequently but there is no agreement on its pathogenesis, making adequate care difficult for medical professionals . AccordiBy age, between 20 and 64 years, TTH is the most prevalent of all headaches. The profile of a patient diagnosed with tension headache is female (80%), white (65%) and with an average age of 40 years . The IntDespite this, all subtypes of tension-type headaches share a common characteristic: bilateral non-pulsatile pain of oppressive nature and mild to moderate intensity does not worsen with movement or is associated with nausea or vomiting. Mild nausea exclusively appears in the Chronic Tension-type Headache .In addition, the patient who suffers from it may have discomfort when exposed to light or noise, but not both at the same time and bears at least 10 episodes per year witha duration ranging from 30 min to 7 days .The majority of migraine patients suffer episodes where it is combined with TTH and do not know it. The diagnosis of TTH is exclusively clinical because there are no biological indicators associated with this type of headache. Therefore, diary headaches, a detailed history and clinical examinations which rule out other associated pathologies are essential for its diagnosis .Regarding its etiology, the cranial and neck musculature, stress, and central sensitization are among the potential culprits . It is lOther studies found gender differences in the presence of Trigger Points (TrPs) in patients with TTH, especially in the temporal, suboccipital and splenius capitis muscles. Women with TTH exhibited a greater number of active TrPs, especially in temporal and suboccipital muscles, and a pressure threshold lower than men .Episodic TTH can evolve into the chronic form due to different aspects and several triggers may be involved at the same time. Components such as muscle stress, lack of relaxation and factors such as posture, sleep disturbances and medication abuse cause symptoms to be triggered more frequently and even TTH to become chronic .Currently, the most accepted model to explain the origin of pain in patients with chronic tension headache is based on sensitization . AccordiAt the European level, tension headache is a very high economic cost. This is due to the consumption of drugs, the performance of diagnostic tests and visits to the Emergency Room. To all the above, the high indirect cost represented by the days of sick leave and the decrease in performance at work .Among the therapeutic approaches for TTH is Physiotherapy , since iNon-pharmacological treatments may include counseling , biofeedback, manipulative therapy, muscle relaxation training, massage, therapeutic exercise and acupuncture, as part of the physiotherapy care process to help reduce TTH symptoms. In order to achieve a positive effect with these techniques, once the origin of the problem has been correctly diagnosed, an adequate and personalized muscular, postural and biomechanical evaluation must be initiated, which will allow the choice of the most appropriate therapeutic procedure for the patient’s condition .The aim of this study is to synthesize the effects of physical therapy on pain, frequency, or duration management in the short, medium, and long term in adult patients diagnosed with tension-type headache.The purpose of this study is to find and synthesize the results of the RCTs published in the last 11 years with a score of ≥6 in the PEDro Scale examining the effectiveness of physical techniques on adult patients with Tension-Type Headache (TTH).Our research question was established following recommendations from the PICO model . Patients included were both male and female adult subjects, clinically diagnosed of TTH. Intervention was any type of physical therapy modality compared with another intervention group, control or placebo. Outcome measures were pain intensity, headache frequency and headache duration.This systematic review of Randomized Controlled Trials (RCTs) was performed following PRISMA guidelines  . An elecStudy design. Randomized controlled trials;Population: Adults (19+ years) diagnosed with TTH;Intervention: Physical therapy. The intervention must be led by a physiotherapist and the procedure must be within their competence;Score ≥ 6/10 in the PEDro scale;Comparison: placebo, active intervention or no therapy.Language: English and SpanishThe inclusion criteria were:Studies with different style than RCT’s ;Not evaluating the effectiveness of physical therapy on intensity of pain or frequency of headache;Sample of patients with other types of headaches such as migraine or as side effect of another disease;Articles which were published prior to January 2011.The exclusion criteria were:Articles were selected by screening title and abstract, and duplicates were removed. After that, the analysis of selected full text studies was performed. Inclusion and exclusion criteria were then checked by two independent reviewers. When articles for this research were identified, quality assessment (risk of bias) was conducted independently by three investigators. Any disagreement on quality assessment was resolved by consensus.The data extraction process extracted the following information from each study: first author, publication year, sample size, population main characteristics, treatment methods and duration, comparison group characteristics, measurement tools and follow up period. Main outcomes were pain intensity and headache frequency. The secondary outcome was headache duration.The methodological quality of the RCTs was assessed according to the PEDro scale (Physiotherapy Evidence Database) . Althougp value > 0.05 was considered statistically significant.Main outcomes were pain intensity and headache frequency. The secondary outcome was headache duration. Results for primary and secondary outcome measures were thoroughly described. The database search in the cited databases produced a total of 120 articles identified as potentially eligible, 20 of which were excluded as duplicates. A screening of the 100 remaining articles was performed based on titles and abstracts. 10 studies were rejected for not belonging to the field of physical therapy, resulting in 90 articles potentially eligible that were excluded following the exclusion criteria: not RCT studies  ,48,49,50Likewise, having a score < 6/10 in the PEDro scale ,80,81,82Of the 15 RCTs included in the present review, 33% of them obtained a PEDro Scale score of 6/10, 47% a score of 7/10, 13% a score of 8/10 and 7% a score of 9/10. In all of them, outcome measures were obtained for at least one of the study variables . These data are grouped in The characteristics of all the studies included in this review are set out in p = 0.003) and the frequency of chronic tension headache (p < 0.001). The techniques do notoverlaps with the others.Castien et al.  reportedp = 0.027) and frequency of episodes (p < 0.001). The duration of headache episodes was significantly reduced in the medium term, 8 weeks post-intervention (p = 0.013). Ajimsha [p < 0.001).They also improved significantly in the long term, 26 weeks post-intervention, pain intensity ( Ajimsha  concludep = 0.035).Da Silva et al.  showed tp = 0.047).Berggreen et al.  demonstrp = 0.04). In addition, the manipulation of the upper cervical vertebrae decreases in the short term, after the intervention period, the intensity (p = 0.004) and the frequency of episodes of tension headache (p = 0.03). Finally, when the intervention combines suboccipital inhibition and manipulation of the upper cervical vertebrae, tension headache (p = 0.01) and the frequency of episodes (p = 0.02) also decrease significantly in the short term, after the intervention period.Espí-López et al.  concludep = 0.026).Moraska et al.  showed tp = 0.005).Chassot et al.  showed tp < 0.01).Espí-López et al.  concludep < 0.001) and frequency (p < 0.001) of short-term, post-intervention period and 1-month post-intervention tension headache episodes.Ferragut-Garcías et al.  concludep < 0.05).Georgoudis et al.  concludep = 0.18)Pérez-Llanes et al.  concludep = 0.012), as well as the values of maximum intensity (p = 0.014) and minimum (p = 0.03). The frequency of pain (days/month) did not reflect significant differences between the different groups. In all groups, the duration of painful episodes and medication was reduced, showing a response rate of more than 90%. They concluded that tension headaches with pericranial sensitivity responded better to separate medical training, and those without sensitivity to treatment with acupuncture or combined with medical training.Schiller et al.  revealedp < 0.05) and in the medium term, 3 months after intervention (p < 0.05) as well as the intensity of tension headache in the short term, post intervention period (p < 0.05) and medium term, 3 months after intervention (p < 0.05). They also concluded in their study that suboccipital inhibition significantly decreases the frequency of tension headache in the short term, post-intervention period, (p < 0.05) and in the medium term, 3 months post-intervention (p < 0.05). Finally, suboccipital inhibition decreases the intensity of tension headache in the short term, after the intervention period (p < 0.05) and in the medium term, 3 months after intervention (p < 0.05).Corum et al.  concludep < 0.001) and medium term, 8 weeks and 3 months post intervention (p < 0.001).Gopichandran et al.  concludep < 0.05), frequency (p < 0.05) and duration (p < 0.5) of tension headache in patients with anxiety in the short term, post intervention period. The summary of individual results of each study in this review are set out in Runa et al.  concludeThis systematic review focuses on analyzing the effectiveness of physical therapy in adult patients diagnosed with Tension-type headache (TTH). The guiding line when showing the results of the articles, follows an axis of effectiveness in time . In the short term: direct treatment of trigger points ,88, suboIn the medium term, between 8 weeks and 3 months after treatment, there are mobilization techniques accompanied by a postural re-education program , direct In the long term, beyond 36 weeks of intervention, only the mobilization techniques accompanied by a postural re-education program applied by Castien et al. .Most of the studies included in this review have reported results for the variables ‘headache intensity’ and ‘frequency of headache episodes’ ,94,95,97Four of the studies included in this systematic review have also reported results for the variable “duration of headache episodes” ,86,94,97In the last eleven years, different protocols of action have been studied, such as mobilization of the cervical and thoracic spine accompanied by a program of postural re-education of the head and neck , myofascAlthough the physical therapy protocols in the treatment of adult patients with tension headache are very varied. All of them, except the general electroacupuncture , addressGeneral electroacupuncture has only been reported to significantly reduce the intensity of tension headache in the short term . GeneralThe manipulation of upper cervicalspine did not report significant differences in the short term either for the intensity of pain or for the frequency of headache episodes when compared with massage of the cranio-cervical region . NeverthOnly the mobilization of the cervical and thoracic spine accompanied by a program of postural re-education of the head and neck in patients with chronic tension headache has reported significant long-term results, 26 weeks post-intervention, for frequency and intensity of headache episodes variables . In thisIn general, all studies reported significant improvement in some of the study variables.Acupuncture could have positive effects in terms of pain intensity and frequency.Supervized physical activity could have a positive effect on pain intensity at the end of treatment and frequency during follow-up, although the recommendation for use is weak.Manual joint mobilization techniques  could have a positive effect on frequency and quality of life during follow-up.A recent study related to our systematic review of Krøll et al. , concludThe evidence after the analysis of the results is very low, in fact the authors justify that solid conclusion cannot be drawn from this review . HoweverThis systematic review found that, to date, there is no consensus on a single physical therapy protocol in the treatment of adult patients diagnosed with tension headache.The techniques used to address this pathology are very diverse. So, there is no standardized physical therapy protocol for tension-type headache treatment, although all the techniques studied to date address in one way or another the cranio-cervical-mandibular region. The approach of the cranio-cervical-mandibular region reports significant effects in terms of decreasing the intensity of pain and frequency of headache episodes.The studies included in this systematic review are heterogeneous in methodology and only one of them performed long term follow-ups on the intervention, 26 weeks post-intervention, for two study variables, intensity and frequency of pain: mobilization of the cervical and thoracic spine accompanied by a postural reeducation program of the head and neck.From these results, it would be interesting for future studies to analyze in depth etiological factors such as the relationship between the appearance of chronic tension headaches and the position of the head and neck..Finally, this systematic review can serve as useful basis for promoting a consensus on non-pharmacological approaches to tension-type headache.The studies included in this systematic review are heterogeneous in methodology and only one of them performed long term follow-ups on the intervention, 26 weeks post-intervention.The effectiveness of physical therapy with respect to the duration of headache episodes has not been analyzed by almost any of the studies. For that reason, more studies are needed regarding the effects of long-term physical therapy, as well as its effects on the duration of headache episodes in people with tension headache.


Background: Gestational diabetes mellitus (GDM) is a serious health issue for both mother and child. As GDM is common worldwide, healthcare providers pay attention while screening and managing pregnant women to ensure good outcomes for both mother and child.Objective: This study aims to identify the risk factors associated with developing GDM in pregnant women attending antenatal care clinics in Prince Sultan Military Medical City (PSMMC) in Riyadh, Saudi Arabia.Methods: This is a case-control study that utilized patients' medical records for data collection. The study included 317 pregnant Saudi women who attended antenatal care clinics and antenatal diabetic clinics in PSMMC from May 2022 to May 2023. Cases were defined as women who met the inclusion and exclusion criteria and had a positive oral glucose tolerance test (OGTT) result, while controls were defined as women in the same age group and gravidity who had negative OGTT. Analysis was conducted using SPSS Statistics version 29.0 Results: The total number of cases was 132 out of 313 total samples, representing 42.2% of the total sample. Three factors were associated with an increased risk of developing GDM, including a family history of diabetes , a history of GDM , and macrosomia . The study also found higher BMI and advanced maternal age were risk factors for GDM , respectively. However, the study did not find a significant association between GDM and other factors, such as chronic disease prevalence, history of miscarriage, or history of fetal death.Conclusion: The study identified several risk factors associated with an increased risk of GDM including family history of diabetes, history of GDM, macrosomia, overweight/obesity, and advanced maternal age. It is recommended that antenatal care providers screen for GDM risk factors and closely monitor overweight, obese, or older women. Education and counseling on healthy lifestyle habits, such as maintaining a healthy weight and engaging in physical activity, may also be beneficial for preventing GDM. Further research is needed to confirm and identify additional risk factors for GDM. Gestational diabetes mellitus (GDM) is a type of diabetes mellitus (DM) that is defined as a different degree of carbohydrate intolerance that first manifests during pregnancy or begins during early pregnancy . DiabeteSeveral well-known risk factors have been reported as predictors of the progression of DM during pregnancy. These factors include obesity, physical inactivity , advanceGDM is a serious health issue for both mother and child. It can cause pre-eclampsia, preterm labor, and macrosomia. Women with a history of GDM are also at risk of developing T2DM later in life. As GDM is common worldwide, healthcare providers should be careful with screening and management to ensure good outcomes for both mother and child. Our study aimed to identify risk factors associated with developing GDM in pregnant women attending antenatal care clinics in Prince Sultan Military Medical City in Riyadh (PSMMC), Saudi Arabia.Study designThis is a case-control, record-based study.Study areaThe study took place in PSMMC in Riyadh, Saudi Arabia.Study populationThe study population consisted of pregnant Saudi women aged 20-45 years who attended antenatal care clinics and antenatal diabetic clinics in PSMMC from May 2022 to May 2023. Cases and controls were selected from antenatal clinics in the Al-Wizarat Healthcare Centers, a branch of PSMMC.Inclusion and exclusion criteriaThe inclusion criteria for this study were Saudi women between the ages of 20 and 45 who had a documented OGTT during pregnancy between May 2022 and May 2023. Exclusion criteria included pre-pregnancy diabetes (type 1 or type 2), as well as pregnant women with an estimated delivery date after May 2023.Cases were defined as women who met the inclusion and exclusion criteria and had a positive OGTT test result. Controls were defined by their negative OGTT results.Selection of case group and control groupThe total sample size was estimated to be 375 using the epi-info website . To achiWe obtained lists of patients who visited an antenatal care clinic and an antenatal diabetic clinic during their pregnancy from the hospital's registries after obtaining the necessary permissions. Control selection was based on age group and gravidity to match the cases.Data collectionData from the files of the selected patients were collected using a prepared data collection form.The study's variables can be categorized into three main sections: demographic information , pregnancy-related information , and medical information .Diagnostic criteriaIn the current study, the diagnosis of GDM was made according to the new criteria established by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) . All womStatistical analysisSPSS Statistics version 29.0  was used for data analysis. Descriptive statistics were used to summarize the study population's demographic and clinical characteristics. To test for normal distribution, we used the Shapiro-Wilk test. The results showed that all the variables were skewed, which is why we used the median and IQR to summarize continuous variables. Frequencies and percentages were calculated for categorical variables. The case and control groups were compared using the chi-square test or Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. A p-value less than 0.05 was considered statistically significant.Ethical considerationAs this is a case-control study, no explicit consent was obtained from participants. However, the study obtained ethical approval from the PSMMC Institutional Review Board (E-2089) and ensured that the rights, safety, and well-being of the participants were protected. The medical records of the participants were accessed only for research purposes and were kept confidential. The study did not offer any incentives or compensation to the participants.The study included 313 participants. The age ranged from 20 to 45 with a median of 31 years and an IQR of 28-35 years. The median BMI was 28 (IQR 24-32). The median gestational age at the time of recruitment was 26 weeks (IQR of 25-27 weeks). Cases had a significantly higher median age (32.5 vs. 30 years) and median BMI (28.5 vs. 27) compared to the control group. Demography results of the total sample with a comparison between cases and controls are shown in Table Of the participants, 42.2% were diagnosed with GDM based on plasma glucose levels and glucose tolerance tests. The median fasting glucose level was 4.4 mmol/L with an IQR of 4.2-4.8 mmol/L. The median one-hour glucose level was 4.5 mmol/L with an IQR of 7-9.8 mmol/L. However, the median two-hour glucose level was 7.3 mmol/L (IQR 6-8.7 mmol/L). Similarly, the median hemoglobin level was found to be 11.3 g/dL (IQR of 10.6-12.1 g/dL).Our analysis did not reveal significant differences in smoking status or chronic disease prevalence between the two groups. The demography, smoking status before pregnancy, and the presence of chronic diseases were compared between cases and controls in Table The past medical history showed the following percentages for each factor, from highest to lowest: history of fetal death (29.4%), history of miscarriage (28.1%), and history of GDM (9.9%). Further results are shown in Table The association between GDM and past medical history was analyzed to determine significant associations. The following factors were significantly associated with GDM: history of GDM , macrosomia , and family history of DM . Significant findings are demonstrated in Figure There was no significant association between GDM and a history of miscarriage, history of fetal death, history of congenital anomalies, multiple gestation, corticosteroid use before pregnancy, or chronic disease prevalence. All the results of the association are shown in Table Our study included 313 pregnant women with the purpose of investigating risk factors for developing GDM. The results showed that various factors were linked to an increased risk of GDM, such as a family history of diabetes , a history of GDM , and macrosomia . However, the study did not find a significant association between GDM and other factors, such as chronic disease prevalence, history of miscarriage, or history of fetal death. These findings suggest that antenatal care providers should screen pregnant women for GDM risk factors, including family history and previous GDM. Close monitoring is necessary for overweight, obese, or older women. Educating women on healthy habits, like maintaining a healthy weight and being active, can prevent GDM.GDM is a debilitating disease that affects maternal and prenatal health, and worldwide an alarming 537 million people suffer from T2DM ,17. GDM One study in a large cohort defined that macrosomia is not only known to cause GDM, but macrosomia in normal women can also lead to T2DM . AlthougIn a similar line of thought, a retrospective study by Han et al. of 15,668 Chinese women with no history of diabetes established a linear relationship between GDM risk and age. Age was an important factor, and the risk increased by 8% for every increase of one year of maternal age . This isOur study sheds light on a topic of relevance, as diabetes in pregnant women is detrimental to their overall health and may lead to chronic diabetes after birth. In brief, this study has broader applications and can be applied to a larger population. In our study, there is a chance of inaccuracies or inherent bias as the data was collected through pre-defined forms. Moreover, our study was only for one year, and long-term follow-up is required to decipher factors that cause GDM in mothers and children. Additionally, there may be other genetic and epigenetic factors that our study did not explore. Data collection was limited by time. For example, information on pre-pregnancy BMI, dietary intake, exercise during pregnancy, and long-term prognosis after childbirth could not be accurately obtained. Additionally, since the study is record-based information, missing data is found as previous miscarriages, smoking status, family history, occupation, and education level.The results of this study suggest that several factors are associated with an increased risk of developing GDM, including a family history of diabetes, a history of GDM, and macrosomia. The study also found that overweight/obesity and advanced maternal age were risk factors for GDM, which is consistent with previous research. However, the study did not find a significant association between GDM and other factors, such as chronic disease prevalence, history of miscarriage, or history of fetal death. It is recommended that healthcare providers in antenatal care clinics screen pregnant women for risk factors associated with GDM, such as a family history of diabetes and a history of GDM. Additionally, women who are overweight or obese or of advanced maternal age should be closely monitored for the development of GDM. Education and counseling on healthy lifestyle habits, such as maintaining a healthy weight and engaging in physical activity, may also be beneficial for preventing GDM.Further research is needed to explore and identify additional risk factors for GDM. Additionally, future studies may benefit from exploring interventions for managing GDM and its associated risks, such as early screening and treatment, patient education and counseling, and improved monitoring and follow-up care. Further research may also explore the effectiveness of lifestyle interventions, such as diet and exercise, in preventing and managing GDM.


Encapsulating peritoneal sclerosis (EPS), a condition with a high mortality rate, is a serious complication of peritoneal dialysis (PD). In Japan, EPS became a central issue in the clinical setting during the mid-90s and the beginning of this century. However, following the introduction of biocompatible neutral PD solutions containing lower levels of glucose degradation products, the incidence and clinical severity of EPS has been greatly lessened. During the past three decades, the etiology of EPS has been elucidated by findings obtained by peritoneal biopsy, laparoscopy, and surgical intervention. Accumulating findings suggest the need for a paradigm change on the nature of EPS pathophysiology; notably, EPS appears not to reflect peritoneal sclerosis per se, but rather the formation of a neo-membrane as a biological reaction to peritoneal injury. This narrative review looks back on the history of EPS in Japan, and discusses EPS pathophysiology, the impact of neutral PD solution on peritoneal protection, and a future novel diagnostic approach, ultra-fine endoscope, for the identification of patients at high risk of EPS. Encapsulating peritoneal sclerosis (EPS) is the most serious complication in peritoneal dialysis (PD) therapy, but this condition is about to become a disease of the past in Japan. The present narrative review discusses the pathophysiology of EPS, based on the findings in the past three decades in Japan, an interval that spanned the start and end of era of EPS. This discussion includes the role of neutral PD solution for peritoneal protection, and the use of a novel diagnostic approach employing PD-specific laparoscopy.EPS is characterized by peritoneal encapsulation due to fibrosis, resulting in gastrointestinal obstruction , 2. The The impact of EPS was large, reflecting the concomitant rising number of PD population in Japan. The penetration of PD increased rapidly during 80s and 90s until 1997); however, it subsequently stagnated due to the EPS shock to medical personnel until recently , leading to PS –30. AGEsIn response to the above findings, PD solutions with lower levels of GDPs  were developed in the expectation that such reagents would reduce toxicity compared to conventional (acidic) PD solutions.At present, three kinds of neutral low-GDP PD solutions are available commercially around the world, including a lactate-based neutral solution, a bicarbonate-based solution, and a solution that incorporates both lactate and bicarbonate. In Japan, the lactate-type glucose-based neutral PD solution has been available from the start of this century, and since 2004, neutral PD solution has completely replaced the conventional acidic lactate PD solution. Furthermore, the mixed-type (bicarbonate and lactate) PD solution became available in the clinical setting since 2014.The use of neutral PD solutions has been reported to result in increased levels of cancer antigen-125 (CA 125) and procollagen peptide, and decreased levels of interleukin (IL)-6 and hyaluronic acid in dialysate effluents . These cRegarding the morphological changes of the peritoneum, direct observation by laparoscopy, and histologic examinations by peritoneal biopsy, have been reported in Japan –48. LapaThese observations were validated histologically by comparing biopsies of parietal peritoneal samples obtained from patients undergoing PD using conventional solution or neutral solution from the initiation of PD . PeritonBased on the findings obtained from the patients using neutral PD solution, it appears that a lactate-based low-GDP neutral PD solution prevents the development of PS that was associated with the duration of PD treatment in the patients treated using conventional PD solutions –49. To iCan the use of neutral PD solution actually suppress the development of EPS? To date (to our knowledge), no such well-controlled randomized study (RCT) has been conducted. Such a study would be impractical, because the incidence of EPS is very low, and the development of EPS takes a long time. In addition, from the perspective of experimental ethics, it would be difficult to justify such an RCT study. Instead, we conducted a prospective observational study (the NEXT-PD study) among patients who had been treated using a neutral solution since their initiation on PD . A totalInterestingly, increased EPS incidence by PD duration was not observed in this cohort Table . In addin = 3713), 8.3% in patients maintained primarily on HD (n = 5269), and 1.1% in patients maintained on combination therapy . With regards to the duration of PD among these patients, the prevalences of EPS were as follows: 0.4% in cases with less than 1 year of PD, 0.6% in cases with 1–2 years of PD, 0.7% in cases with 2–4 years of PD, 1.1% in cases with 4–8 years of PD, and 1.5% in cases with more than 8 years of PD. The relatively high prevalence of EPS among patients undergoing HD may reflect the improved survival of patients with EPS, and be a result of the use of corticosteroid therapy [n = 28,730) for which a cause of death was reported, only 12 deaths were attributed to EPS; thus, the rate of death attributable to EPS was 0.04% in 2011 in Japan.According to data collected as part of the annual survey conducted by the Japanese Society for Dialysis Therapy (JSDT)  , the pre therapy  in assoc therapy . Among 6In the 2019 PD guidelines of the JSDT, the regular use of the peritoneal equilibration test (PET) is recommended; PD needs to be stopped in cases with a long-standing high-transport state , given tDespite this progress, there remains the question of how to identify patients undergoing PD who are at elevated risk of EPS; this issue will continue to be a challenge for the practice of PD in Japan. The most reliable technique to confirm early-stage EPS is to inspect the peritoneal cavity by laparoscopy. However, current laparoscopic examination remain invasive, and cannot be performed repeatedly in patients undergoing PD.To address this challenge, an ultra-fine endoscope designed specifically for use in patients with PD was developed . This enBased on the clinical experiences in Japan, conventional acidic PD solutions were hypothesized to be primary drivers of peritoneal membrane damage in patients undergoing PD therapy. The presence of GDPs in such PD solutions, and the associated production of AGEs in the peritoneal membrane, are thought to play a major role in the etiology of peritoneal damage (PS) in such cases. Empirical results, epidemiology, and histological analysis all indicate that low-GDP neutral PD solutions help to preserve peritoneal membrane integrity during PD, thereby lessening the risk of development of EPS.One hypothesis has been considered that EPS represents a more severe form of PS. However, laparoscopic and histological findings suggested the need for a paradigm change regarding the pathophysiology of EPS. We conjecture that EPS is not, in fact, a form of PS, but is, instead a physiological wound-healing reaction to peritoneal injury. Endoscopic examination using an ultra-fine endoscope designed for the use in PD patients is expected to reveal temporal changes in the peritoneum during the course of PD therapy. This technique also may provide further insights into the pathophysiology of the peritoneum, including EPS, in patients undergoing PD.


Psychosocial factors frequently occur in kidney transplant recipients (KTRs), leading to behavioral alterations and reduced therapeutic adherence. However, the burden of psychosocial disorders on costs for KTRs is unknown. The aim of the study is to identify predictors of healthcare costs due to hospital admissions and emergency department access in KTRs.This is a longitudinal observational study conducted on KTRs aged >18 years, excluding patients with an insufficient level of autonomy and cognitive disorder. KTRs underwent psychosocial assessment via two interviews, namely the Mini-International Neuropsychiatric Interview 6.0 (MINI 6.0) and the Diagnostic Criteria for Psychosomatic Research Interview (DCPR) and via the Edmonton Symptom Assessment System Revised (ESAS-R) scale, a self-administrated questionnaire. Sociodemographic data and healthcare costs for hospital admissions and emergency department access were collected in the 2016–2021 period. Psychosocial determinants were as follows: (1) ESAS-R psychological and physical score; (2) symptomatic clusters determined by DCPR ; and (3) ICD diagnosis of adjustment disorder, anxiety disorder, and mood disorder. A multivariate regression model was used to test the association between psychosocial determinants and total healthcare costs.p < 0.001). Somatization clusters (p = 0.020) and mood disorder (p < 0.001) were positively associated with costs due to total healthcare costs.A total of 134 KTRs were enrolled, of whom 90 (67%) were men with a mean age of 56 years. A preliminary analysis of healthcare costs highlighted that higher healthcare costs are correlated with worse outcomes and death (This study showed somatization and mood disorders could predict costs for hospital admissions and emergency department access and be possible risk factors for poor outcomes, including death, in KTRs. Kidney transplantation (KT) is the most desired therapy for stage 5 chronic kidney disease as for these patients it represents the most cost-effective treatment, improving quality of life and prolonging survival , 2. In sKT is often accompanied by high patient expectations, but it is indeed a stressful condition both physically and mentally that requires special adaptations encompassing changes in a patient's personal and financial life, meeting possibly unrealistic expectations, the possibility of rehospitalizations, infections, graft rejections, and the necessity of long-term immunosuppression therapy , 14. IndWhile many studies have highlighted the detrimental effects of psychosocial conditions on KTRs, this is the first study with the intent to directly investigate the contribution of psychiatric and psychosocial diagnoses as identified by both ICD and DCPR systems on healthcare use costs in KTRs. Specifically, using linear regression models, we aimed to identify predictors of total healthcare costs due to hospital admissions and emergency department access.A monocenter prospective observational longitudinal study was performed at the kidney transplant center of the Ferrara University Hospital from 2016 to 2021. The study was conducted according to the 1995 Declaration of Helsinki and its revisions . The EthInclusion criteria were age ≥ 18 years and being a recipient of a kidney from a cadaveric or living donor. Exclusion criteria were an insufficient level of autonomy  and the presence of cognitive disorders . Two individual interviews, namely the Mini-International Neuropsychiatric Interview (MINI6.0)  and the The ESAS-R is a pragmatic patient-centered symptom assessment tool with a visual analog scale, designed to assist in the assessment of six physical  and four psychological  symptoms. In particular, the physical symptoms are assessed objectively . The items can be summed in order to create subscales of psychological, physical, and total distress, which can be used to monitor symptoms and screen for mental and psychological disorders. It has been validated in dialysis patients  and kidnAll data, including clinical characteristics and routine biochemistry, were collected from digital patients' archives.The following variables were used as a measure of outcome: total healthcare costs due to hospital admissions in the 2016–2021 period; and total healthcare costs due to emergency department access in the 2016–2021 period. Costs, covered by Italy's National Health Service, were expressed in euros (€), the Italian currency, and were extracted from a hospital software database, searching for each patient record both the type of medical service delivered and the related amount charged across the period from 2016 to 2021.2), time under dialysis before the transplant (months), transplant vintage (months), estimated glomerular filtration rate (eGFR) (ml/min), blood creatinine (mg/dl), blood albumin (g/dl), blood hemoglobin (g/dl), blood phosphate (mg/dl), blood calcium (mmol/l), blood inactive vitamin D (ng/ml), and past psychopathology (positive history versus no history) were entered as covariates in the analysis to control for variables that can affect healthcare use or somatic outcomes of the kidney transplant.As predictors of healthcare costs, we used the following psychosocial determinants, all measured before the outcome: ESAS, as a severity measure of physical and physiological symptoms; symptomatic clusters as measured by the DCPR; and clinical diagnosis according to MINI6.0 within the mood, anxiety, and adjustment disorder spectrum. Age (years), sex (men versus women), body mass index  version 28. All tests were two-tailed, with alpha set at p < 0.10. In the model, discrete variables were entered as continuous values while nominal variables were entered as dichotomous  were more likely than women (n = 15 (34%)] to have a personological cluster . Above all, kidney transplant patients were Caucasians, coming from local districts.Overall, 134 kidney transplant recipients, of whom only 10 were from living donors, were included in the longitudinal study, of which 90 (67%) were men and 44 (33%) were women. Nine patients declined to participate . Men and women did not differ in demographic characteristics, biochemical values, and healthcare costs except for eGFR, blood creatinine, and personological cluster . In factAt the end of the 2016–2021 observational period, the sample included 28 participants (21%) who had died. In preliminary investigations, increasing costs were related to an increased chance of a worse outcome, such as death . Hence, The results of the univariate linear regression model are reported in We then proceeded to apply the stepwise multivariable model to evaluate the independent contribution of each predictor taking into account the covariates and the impact of the other predictors.The model, concerning total healthcare costs due to hospital admissions and emergency department visits in the 2016-2021 period, extracted four variables as predictors of the outcome according to the predefined threshold for removal, with the other variables excluded for their negligible contribution .F = 7.88; p < 0.001; R2 = 19.6%; adjusted R2 = 17.1%; f2 = 0.244). Effect size, according to Cohen's f2, was estimated as medium to large. None of the variables in the model had a VIF higher than the suggested cutoff for multicollinearity.In this model, the presence of a mood disorder diagnosis, the presence of the somatization cluster, transplant vintage, and blood creatinine were associated with higher healthcare costs due to hospital use [p = 0.037. Just one point (case 19) was identified as influential based on Cook's distance  = 3.06; p = 0.019; R2 = 8.7%; adjusted R2 = 5.9%; f2 = 0.095. According to the diagnostic plots, the model had a good fit, there was no influential point according to Cook's distance, and there was no more deviation from the homoscedasticity .Some diagnostic plots were used for testing the assumptions underlying the linear regression model by taking into account residual errors and fitted values. The model, which focused on total healthcare costs due to hospital use, showed a reasonable adaptation. In the residual vs. fitted plot, the residuals were spread equally around a horizontal line without distinct patterns , indicating a linear relationship. In the Q-Q plot, the majority of the residuals follow the straight dashed line. In the Scale-Location plot, there was a minor deviation from the homoscedasticity, confirmed by the Breusch–Pagan test : BP = 10distance . We repedistance . In the In this study, we found that some psychosocial variables and clinical dimensions influenced total healthcare costs, hence total healthcare use, in kidney transplant recipients. In particular, a propensity to somatization and the presence of a mood disorder increased healthcare use costs for emergency department visits and hospital admissions. Furthermore, greater access to the emergency department and a higher chance of admission to the hospital were related to a greater risk of death in KTRs. These findings underline the need to assess psychosocial dimensions, such as somatization and mood disorder as predictors of healthcare use in kidney transplant recipients and possible risk factors for poor outcomes until death, using the DCPR semi-structured interview and MINI6.0 structured interview, respectively.Mood disorders were also shown to increase total healthcare costs due to emergency department access and hospital admission. Regarding the former, this is in line with the literature, as approximately 50% of frequent emergency department users have a mental health diagnosis  and patiRegarding somatization, it was found to be a predictor of higher costs. Compared with the general population, this tendency to experience and communicate somatic distress in response to psychosocial stress  has been associated with a higher hospital length of stay, higher inpatient costs, and more specialist visits . PatientFurthermore, some limitations of our study should be also mentioned. First, the lack of data regarding the costs of ambulatory care and their changes on the basis of psychosocial clinically significant conditions in KTRs. However, it is complex to quantify the economic burden of this activity as it requires the systematic quantification of the additional costs, which is not always comparable, due to the multiple medical and surgical procedures. Second, the absence of a control group with chronic kidney disease in other settings. Third, some demographics, such as the socioeconomic status  a combi, 70, andThis study demonstrated that higher healthcare costs for hospital admissions and emergency department access were strongly predicted by the DCPR diagnosis of somatization cluster and the ICD diagnosis of mood disorder, respectively. In addition, these healthcare costs were associated with a higher risk of poor outcomes until death in kidney transplant recipients. Further studies of cost analysis, cost-effectiveness, cost-benefit, and cost minimization analysis should be conducted to estimate the economic advantages of early diagnosis and treatment of psychosocial syndromes in kidney transplant recipients. Indeed, the healthcare allocation strategy, a pressing question in the transplantation community, should be rethought to invest accurately the resources that are even more limited; therefore, a comprehensive systematic economic analysis of the physical, physiological, and social aspects is needed.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethical Committee AVEC. The patients/participants provided their written informed consent to participate in this study.Conceptualization: YB. Investigation: LZ and YB. Formal analysis: AP. Data curation: NN and FG. Writing and editing—original draft: YB and LZ. Writing—review and editing: PE and FB. Supervision: RC and AS. Validation: LG. All authors have read and agreed to the published version of the manuscript.


Since the release of the last meta-analysis on the association between fish intake and prostate cancer risk, several cohort studies have been published. Moreover, none of the previous meta-analyzes examined the dose–response association between fish intake and prostate cancer. Therefore, the current dose–response meta-analysis was conducted to summarize available findings on the associations of fish intake with the risk of prostate cancer in men. Online databases of PubMed, Scopus, and Web of Science were systematically searched up to September 2022. We included prospective cohort studies that examined the associations of fish intake with the risk of prostate cancer , its mortality, and cancer progression. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated for the highest versus lowest categories of fish intake using random-effects models. Also, linear and non-linear dose–response analyzes were conducted. In total, 25 prospective cohort studies, recruiting 1,216,474 men, were included in the systematic review, and 22 studies were included in the meta-analysis. During the follow-up periods, ranging from 6 to 33 years, a total of 44,722 cases of prostate cancer were recorded. The comparison between the highest and lowest intakes of total fish revealed the summary RRs of 0.97 (95% CI: 0.86–1.10) for total, 1.01 (95% CI: 0.91–1.13) for advanced, and 0.90 (95% CI: 0.72–1.12) for localized prostate cancer, indicating no significant association. Moreover, the summary RR was 0.55 (95% CI: 0.33–0.92) for prostate cancer mortality and 0.84 (95% CI: 0.65–1.10) for prostate cancer progression, indicating an inverse association between fish intake and prostate cancer mortality. Also, in the dose–response analyzes, each 20 gram/day increase in total fish intake was associated with a 12% lower risk of prostate cancer mortality. Our findings support the protective association between total fish intake and the risk of prostate cancer mortality. Prostate cancer is the most prevalent cancer in men and the fifth cause of cancer-related death among this population . Based oSeveral risk factors including age, ethnicity (African and black ethnic), family history, genetics, smoking, alcohol consumption, and obesity have been identified for prostate cancer . Among mTwo meta-analyzes , 41 summThe current systematic review and meta-analysis were conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) . This meWe performed a comprehensive literature search in the online databases of PubMed, Scopus, and Web of Science up to September 12, 2022, to identify prospective cohort studies that examined the association between fish consumption and prostate cancer risk. We included prospective cohort studies that considered the intakes of fish or its products as an exposure variable and the risk of prostate cancer , its mortality, and cancer progression as an outcome variable. All types of fish and its products  were considered in the search strategy and study selection. Other inclusion criteria were reporting relative risk estimates including odds ratio (OR), risk ratio (RR), hazard ratio (HR), incidence rate ratio (IRR), or mortality rate ratio (MRR) along with 95% confidence interval (CI) for the association between fish consumption and risk of prostate cancer or presenting required data for the calculation of these effect sizes. If findings from one dataset were published in >1 article, we selected the most recent version meaning the one with the greatest number of cases or longer follow-up period.In the current meta-analysis, we excluded letters, comments, short communications, reviews, meta-analyzes, cross-sectional, case–control, ecological and animal studies, book chapters, and those studies with insufficient data. Moreover, studies that assessed a dietary pattern containing a high amount of fish in relation to prostate cancer were excluded. Studies that assessed the combined effects of fish and other food groups with prostate cancer were excluded as well.Required data were extracted from each eligible study by two independent researchers (NE and OS), and any disagreement between them was resolved by discussion with a third researcher. We designed an Excel-based form for data extraction, in which the following information, from each eligible study, was imported to it: the name of the first author, year of publication, cohort name, study location, age range, or the average age of participants, number of participants and cases of prostate cancer, duration of follow-up, methods used to assess dietary intakes and prostate cancer diagnosis, relative risk estimates reported for the link between fish consumption and prostate cancer, and confounding variables adjusted in the statistical analysis. If a study reported stratified relative risks based on a specific variable, we first combined the relative risks using a fixed-effects model, and then, the combined relative risk was included in the main analysis .We used the Newcastle-Ottawa scale (NOS), designed for prospective studies, to determine the quality of the studies included in the current meta-analysis . Based o2 values to assess heterogeneity among the included studies. I2 values greater than 50% were considered significant between-study heterogeneity  of prostate cancer, reported for the comparison between the highest and lowest intakes of fish, in the meta-analysis. None of the included studies reported OR for the association between fish intake and prostate cancer risk. In addition, since the prevalence of prostate cancer was rare (<10%) in the population of cohorts included in the current meta-analysis, we did not convert the HRs to RRs. To calculate the summary relative risk, a random-effects model was used to take between-study heterogeneity into account. Also, we used both Q-statistic and Iogeneity . In caseogeneity . To detep < 0.05 was considered statistically significant for all tests except for Cochran’s Q test which was considered significant at p < 0.10 , BMI (n = 12), smoking (n = 12), alcohol consumption (n = 7), physical activity (n = 11), energy intake (n = 12), other dietary variables (n = 15), and family history of prostate cancer (n = 6). The NOS scores of the included studies were between 5 and 8. Looking at the variation of NOS scores and considering the score of 7 as a median, 17 articles had a score of ≥7, defined as high-quality studies , indicating no significant association between total fish intake and prostate cancer . In the subgroup analysis, between-study heterogeneity reduced in the subgroups of studies performed in the US, those studies with <10 years’ duration of follow-up, and studies that controlled their analyzes for total energy intake. Findings from the meta-regression revealed that our findings on the association between fish intake and prostate cancer risk were not different in the subgroups of studies . In the subgroup analyzes, heterogeneity among the studies was low among all subgroups. In addition, based on the meta-regression, we found no significant difference among the subgroups of studies in terms of the association between fish intake and the risk of advanced prostate cancer  so the significant inverse association between fish intake and risk of prostate cancer mortality was stronger among low-quality studies compared with those with high quality  and each 20 gram/day increase in total fish intake was associated with a 12%  lower risk of death due to prostate cancer. In terms of the non-linear dose–response analysis, we found no evidence of non-linearity . For other associations, due to a limited number of studies, we did not assess the publication bias.Sensitivity analyzes based on a random-effects model showed that excluding any single study from the analyzes did not alter the pooled relative risks. We conducted the Egger’s test for the association between total fish intake and risk of overall prostate cancer with ≥10 effect sizes and found no substantial publication bias for this association . Therefore, the lack of significant inverse association at the dosages of >100 gram/day fish intake is misleading and further studies should be done to assess the associations of these dosages with the risk of prostate cancer mortality.In the current meta-analysis, no significant association was found between total fish intake and the risk of total and advanced prostate cancer in men. Similar to our findings, two previous meta-analyzes reported such findings for total fish intake , 41. In via the down-regulation of cyclooxygenase and lipoxygenase  should investigate the effect of fish intake on prostate cancer outcomes in affected patients.NH-E and NE contributed to the literature search. NE and OS contributed to data extraction and data analysis and drafted the manuscript which was critically revised for important intellectual content by all authors. HA contributed to the manuscript editing and obtained funding. GA contributed to the manuscript editing. OS supervised the study. All authors have read and approved the final manuscript.The meta-analysis was financially supported by the Gerash University of Medical Sciences, Gerash, Iran. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.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.