Major depressive disorder (MDD) is characterized by impairments in mood and cognitive functioning, and it is a prominent source of global disability and stress. A functional magnetic resonance imaging (fMRI) can aid clinicians in their assessments of individuals for the identification of MDD. Herein, we employ a deep learning approach to the issue of MDD classification. Resting-state fMRI data from 821 individuals with MDD and 765 healthy controls (HCs) is employed for investigation. An ensemble model based on graph neural network (GNN) has been created with the goal of identifying patients with MDD among HCs as well as differentiation between first-episode and recurrent MDDs. The graph convolutional network (GCN), graph attention network (GAT), and GraphSAGE models serve as a base models for the ensemble model that was developed with individual whole-brain functional networks. The ensemble's performance is evaluated using upsampling and downsampling, along with 10-fold cross-validation. The ensemble model achieved an upsampling accuracy of 71.18% and a downsampling accuracy of 70.24% for MDD and HC classification. While comparing first-episode patients with recurrent patients, the upsampling accuracy is 77.78% and the downsampling accuracy is 71.96%. According to the findings of this study, the proposed GNN-based ensemble model achieves a higher level of accuracy and suggests that our model produces can assist healthcare professionals in identifying MDD. Depression is a major source of disability and disease burden worldwide, affecting about 264 million people. Major depressive disorder (MDD) is a serious psychological problem that can cause people to feel sad, lose interest, become listless, and have trouble thinking . IndividIn recent years, research on MDD has focused on brain structure and function using morphological or neurobiological features. Functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), electroencephalography (EEG), and positron emission tomography (PET) are the common physiological methods employed in comparing people with MDD to healthy controls (HCs) . ResearcMachine learning (ML) methods are of increasing interest for the medical industry at present, and it has emerged as an essential part of the diagnosis and treatment of conditions pertaining to oncology, neurology, and cardiology. The process involved in a typical deep learning pipeline for the identification of MDD can be highlighted as follows: region of interest (ROI) extraction from R-fMRI, functional connectivity matrix generation, graph construction, deep learning model training, and classification . Figure This study presents a high-performance graph neural network (GNN)-based deep learning method for classifying individuals with MDD using R-fMRI data. In recent years, graph neural network (GNN) has become increasingly popular in graph-based learning. GNN become the optimal deep learning approach for analyzing graph-structured information. GNN algorithm combines node attributes, edge attributes, and graph topology by embedding node characteristics in a neural network and transferring data through the graph's edges. GNN can work well on non-euclidean domains and this is in contrast to traditional convolutional neural networks, which are limited to accepting only euclidean inputs . GNN hasvia different static and dynamic connection metrics retrieved from R-fMRI , logistic regression, and neural networks, to differentiate between MDD and HCs using fMRI data. Especially, resting-state functional connectivity characteristics of the entire brain were studied in MDD. In order to distinguish individuals with MDD from controls, several studies –16 emplom R-fMRI . In thism R-fMRI . The dynm R-fMRI  allows tSome other studies have used different ML methods, such as regression and neural networks, to differentiate between individuals with MDD and HCs. Using partial least squares regression on R-fMRI data, researchers developed a low-dimensional representation that links symptoms to brain activity and predicts clinical measures . R-fMRI via a group sparse representation and a structured equation modeling approach . Instead of using a single unified GNN model to learn representations for all of the nodes in a large graph, it is better to use ensemble learning methods  to improThis study provides a methodology for MDD analysis and classification using brain functional networks derived from R-fMRI data. Since the brain is a complex network system, the present study analyses the R-fMRI as the whole brain functional structure rather than individual FCs. In this research, our main aim is to employ an ensemble- based GNN framework to perform the primary classification. Our main scientific contributions are as follows:Developing a robust ensemble-based GNN model that takes R-fMRI data for the detection of MDD. A created novel ensemble model is used for identifying individuals with MDD from HCs as well as to perform analysis between two sub groups of MDD patients, namely first episode drug nive (FEDN) and recurrent (REC) MDD patients.GCN, GAT, and GraphSAGE models are created as the base line models for the ensemble model, for improving classification accuracy. A developed ensemble model is trained using individual whole-brain functional networks.Methods of upsampling and downsampling are employed to achieve balanced sample size. A 10-fold enumeration is used to refine the classification process. Empirical investigations with a large sample size showed that our model is more accurate and beneficial for classification of MDD compared to other models that are currently available.R-fMRI data from the REST-meta-MDD collaboration , which cData from R-fMRI and structural MRI were acquired and the DPARSF toolkit  was usedG, where N and E are collections of nodes and edges. Nodes are the 160 brain regions identified by the ROIs, and their characteristics are the matrix representation of the functional connection between them. The link between nodes are represented by a weighted adjacency matrix (A). Each node is linked to its nearest neighbors using a k-nearest neighbors (KNN) technique to establish edges  as a base model. The dimensions of the node embeddings are the same as the size of the hidden units that are used in each GraphSAGE layer, which is 64. The ReLU activation function and a dropout rate of 0.3 are used in each of the GraphSAGE layers. Also, Every model has a weight decay value of 5 x 10−4 and a learning rate of 0.01. Each model in GNN, such as GCN, GAT, and GraphSAGE, is trained with the same set of node features, edge features, weights, and learning rate. First, the FC matrix was represented as a graph structure, along with an adjacency matrix and node characteristics. The GAT model uses a graph attention layer to learn the node representation, followed by an attention pooling layer and a classification layer to retrieve the node representation and perform the task of learning. We began by stacking three GAT layers with exponential linear unit (eLU) activation functions, then moved on to a global mean pooling layer, then a dropout layer, and finally fed that information into a classification layer. The head size is 8 and the dropout rate is 0.5 in the GAT model. Input layer, graph convolutional hidden layer, fully connected layer, and global average pooling layer are the components that make up GCN model. After each hidden layer, there is a rectified linear unit (ReLU) activation function. The dropout rate is 0.3 in the GCN model. We also use GraphSAGE with three layers , specificity (SPE), sensitivity (SEN), and area under the curve (AUC). The diagnostic accuracy of a classifier can be measured with the use of receiver operating characteristic, which is a curve that is generated by graphing the true positive rate against the false positive rate. The process of determining classification ACC, SPE, and SEN is denoted as,In this case, TP indicates a successful classification of positive samples, TN indicates a successful classification of negative samples, and FP indicates incorrect classification of negative samples as positive, and FN indicates incorrect negative classification.In this section, we validate the efficiency of the suggested MDD identification approach by analyzing the following scenarios: (a) using FC as features; (b) using GCN, GAT, and GraphSAGE as base learners; (c) using an ensemble classification model. We used a 10-fold cross-validation, and in that cross-training, we split the samples of all MDD and HCs into 10 groups. Each time the method is modified, one unit is chosen as the testing dataset for assessing the performance of the model, while the remaining 9 units are used as the training dataset. By stratifying the 10-fold cross-validation, we are able to keep the percentage of samples from each class in every fold equal across the entire sample. In this case, the samples are not balanced, so in order to create samples that are balanced, random upsampling is performed on the majority classes, and random downsampling is performed on the minority classes. For the primary analysis, there were a total of 1,586 participants included in our method (821 patients with MDD and 765 HCs). Based on the clinical data for the patients who are included, 243 were FEDN patients, and 203 are REC patients.The ensemble model attained an accuracy of 71.8% for upsampling and 70.4% for downsampling when it came to classifying MDD and HC. When using upsampling, the ensemble model achieves an AUC of 76.53%, while using downsampling, it achieves an AUC of 71.27%. Specificity and sensitivity values for upsampling are 74.96 and 68.23%, respectively, whereas the values for downsampling are 67.27 and 72.88%. The findings for upsampling and downsampling based on a 10-fold cross validation for MDD and HC classification are given in FEDN could be distinguished from HCs with a classification accuracy of 88.93% for upsampling and 64.17% for downsampling. Classification of FEDN patients with HC achieved an upsampling AUC of 85.75% and a downsampling AUC of 62.25%. Upsampling has a specificity and sensitivity of 89% and 85.79%, whereas downsampling has a specificity and sensitivity of 60.31 and 61.36%. The findings from classifying FEDN and HCs are shown in Classification accuracy for upsampling REC with HC is 91.6%, whereas classification accuracy for downsampling REC patients with HC is 68.78%. Using upsampling, we are able to classify REC patients as distinct from HC with an AUC of 88.24%, while using downsampling, we are only able to reach an AUC of 67.11 %. The respective results for specificity and sensitivity while upsampling are 93.15 and 87.20%, while they are 60.96 and 66.92% when downsampling. The FEDN and the REC are discriminated from each other by the use of a subgroup analysis. There is a 77.78% accuracy rate when upsampling FEDN against REC and a 71.96% rate when downsampling. When we compared the existing approach  to the sWe proposed an ensemble-based GNN method for automatic MDD identification using whole brain functional network features. Using a large open source dataset, the current study employed an ensemble based GNN to classify MDD as well as to classify FEDN with REC, and the resulting upsampling classification performance outperformed typical machine learning approaches by around, 71.18% and 77.78%, respectively. In the analysis process, initially, separate base models are created, and then the classification performance of each model is examined. Models such as GCN, GAT, and GraphSAGE are employed as base line models. The GAT approach is utilized during the training of the model, which resulted in an upsampling accuracy of 66.24% when comparing MDD to HC and 71.67% when comparing FEDN to REC. The GCN technique is also separately applied during the training process of the model, which led to an upsampling accuracy of 64.72% while correlating MDD to HC and 73.58% while comparing FEDN to REC. Also, the GraphSAGE model alone was employed when training the model, which produced in an upsampling accuracy of 64.47 % for MDD among HC classification and 72.78% for FEDN with REC classification. In addition to this, we used an all-individual model to analyze subgroups such as FEDN with HC and REC with HC. The results of the individual base models such as GCN, GAT, and GraphSAGE are listed in In the majority of the earlier investigations, the ML algorithm was employed to differentiate between all MDD and HCs , 41–43. Some limitations should be taken into account when evaluating the present findings. We were not able to reach the classification performance in the case of MDD with HC categorization when compared with the previous approach . HoweverIn this study, we effectively created an ensemble model based on GNN for classifying MDD by utilizing R-fMRI data. In particular, we investigated a sub-group analysis between FEDN with REC. The proposed model that employs whole brain functional connectivity classifies MDD patients and healthy individuals with high accuracy. In order to improve the overall performance of the ensemble model, we used three different GNN base models under 10-fold cross-validation. Based on large dataset and a number of different of validation techniques, an ensemble model could classify MDD and HCs with a feasible accuracy of 71.18% for upsampling and 70.14% for downsampling. When compared to earlier approaches, the findings that these methods yield in the subgroup analysis are higher. This method achieves an accuracy of 77.78% for upsampling and 71.96% for downsampling when applied to an analysis of FEDN and REC. The findings of this validation suggest that our model produces a feasible application to assist healthcare professionals in identifying MDD.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Institutional Review Board of Kunsan National University. Written informed consent from the was not required to participate in this study in accordance with the national legislation and the institutional requirements.SV, MV, LW, SK, ML, UH, I-HR, and H-GJ contributed to conception and implementation of the study. SV wrote the first draft. All authors contributed to review, editing, and approved the submitted version.


The main aim of the study was to assess the psychometric properties of the Polish version of the Sports Anxiety scale-2 (SAS-2). The study covered 396 athletes, ages ranging from 18 years to 35 years. The task and ego orientation in sport questionnaire (TEOSQ) and State and Trait Anxiety Inventory (STAI) were used for validation of the scale. Cronbach’s alpha for the somatic anxiety subscale was 0.88, for the worry subscale was 0.95, and for the concentration disruption was 0.86, respectively. The three-factor model and hierarchical model fits perfectly as CFI > 0.95, TLI > 0.95, and RMSEA < 0.08. Satisfactory results in measurement invariance show the use of the tool for any gender or athlete  group. The internal consistency (α = 0.86–0.95) and the test–retest reliability (ICC = 0.87–0.90) were satisfactory. There was a statistically significant negative correlation between task orientation and total anxiety along with its three subscales, and a weak positive correlation between ego orientation and worry subscale. Meanwhile, a weak to moderate positive correlation was exhibited between total anxiety and its subscales with the STAI-T and STAI-S. Additionally, female, recreational, and female recreational athletes’ groups had weak negative associations between worry and concentration disruption trait anxiety and task orientation, and a weak positive association between somatic anxiety and ego orientation.  Sports is a context in which an athlete intensively develops himself, competes, strives to win, and improves his skills. This process of self-growth exposes him to experiencing anxiety. The importance of sports anxiety is documented by a large number of studies conducted ,2,3. AthThe multidimensional anxiety theory has been the foundation for the development of two questionnaires. The Sport Anxiety Scale-2 (SAS-2) focuses on sport-specific trait anxiety, which was originally defined by Martens, while the Competitive State Anxiety Inventory-2  focusesSAS-2 adaptations in various languages or countries, including Spain , Brazil To make personalized interventions for athletes, research on competitive anxiety has focused on finding out how anxiety symptoms vary by gender, age, type of sport, and other psychological factors. With regard to gender, female athletes typically reported higher levels of precompetitive state anxiety, factors associated with worries, and global competitive trait anxiety ,24. CorrIn Poland, the cross-cultural adaptation of SAS-2 was conducted independently by two research teams: Tomczak et al.  and oursOverall, this study aims to investigate the psychometric properties of construct validity and reliability of SAS-2 in a Polish context. It also aims to fill a gap in previous research by testing criterion validity and expanding research on relationships between the SAS-2 and other scales, such as STAI and TEOSQ, which will broaden research on the scale’s validity.This study comprised 396 Polish athletes, ; aged from 18 to 35 years old  who participate in various sports, including football, hockey, volleyball, handball, gymnastic, athletics, judo, MMA, karate, tennis, table tennis, badminton, and cycling. High-professional athletes were either playing for professional sports clubs or national teams, while recreational athletes reported playing in sports clubs or the university’s sports club, and they also reported their participation in sports competitions from time to time. Participants responded to demographic questions . In addition to the Polish version of the Sports Anxiety Scale-2, the study employed the following instruments to assess convergent, divergent, and discriminant validity.A Polish translation of the SAS-2 was used in this study. The adaptation procedure is given below. The original SAS-2 scale was developed in the English language by Smith et al. , which cThe SAS-2 was translated into the Polish language by three linguistic experts. The translation was compared and reviewed by authors and a sports psychologist. The final version was then back-translated by two other psychologists who were fluent in English. The translations were reviewed by the authors and discussions were held for minor changes. The final version of the scale was checked for the readability of items and instructions, along with an analysis of factor structure among a sample of (N = 150) participants. Later, a sample of (N = 246) participants completed the anonymous paper-and-pencil mode of the Polish version of SAS-2 along with measures used for validation purposes. To select the sample, the following inclusion criteria were used: recreational and high-professional athletes of any of a variety of sports modalities and either sex, age 18–35 years and participation in sports competitions at least once per month. This study was approved by the ethical committee of Kazimierz Wielki University. All subjects voluntarily participated in the study and signed the informed consent form.We used the Polish version of this scale, adapted by Tomczak et al. . It consState and trait anxiety was measured with STAI developed by Spielberger et al. . The PolTIBCO Statistica and R version 4.2.2 were used for analyzing this study. Due to the significant multivariate non-normality of the data, analyses were performed using the robust maximum likelihood estimator (MLR). The first stage of the analysis consists of construct validity which was evaluated using confirmatory factor analysis. Based on theories, a hierarchical model with total anxiety and its three subscales: somatic anxiety, worry, and attention disruption was estimated. The 3-factor model with only three subscales without total anxiety was then estimated. Then, the 1-factor model  was estimated and compared with the other two models, to assess the validity of the tool. The postulated models were assumed to have a satisfactory fit to the data if CFI and TLI were greater than 0.90, and RMSEA and SRMR were less than 0.08 . The SatNext, the measurement invariance of SAS-2 was examined across gender and sports participation level . Configural, metric, scalar, and strict invariance was estimated. A significant difference between groups will be seen if there is a decline in CFI below 0.01, a rise in RMSEA above 0.015, an increase of 0.01 for strict and scalar invariance, and 0.03 for metric invariance for SRMR .Item reliability was evaluated by looking at the values of factor loadings and their squared values (the proportion of variance in an item due to a given construct), which led to the analysis of convergent validity indices of the SAS-2 scale. For minimum standardized loading values, criteria ranging from 0.40 (the most flexible) to 0.70 (nearly 50% of the variance in the item explained by the factor) are commonly used. The average extracted variance (AVE) and composite reliability (CR) values for each subscale were then determined .When AVE is less than 0.5 but the CR requirement is met, we can say that the construct satisfied the convergent validity requirement. On the other hand, discriminant validity was assessed by comparing the maximum shared variance (MSV), which is the highest value of the square of the correlation between a given latent variable and another construct-latent variable, with the AVE of a particular latent variable. The discriminant validity of the construct is proven when the AVE value surpasses the MSV .Additionally, Cronbach’s alpha (N = 396) as well as the interclass correlations  were used to investigate the reliability of the scale. The discriminatory power of a particular test item was calculated by its correlation with the total subscale score.A Mann–Whitney U-test was performed to compare participants’ mean anxiety and subscale scores across gender and their level of sport participation. In order to examine the relationship between anxiety and goal orientation and state or trait anxiety, the Spearman correlation method was applied to a sample of (N = 246) participants.The descriptive statistics results  show thaThe overall fit test results of the CFA models are presented in p < 0.001) and ranged from 0.685 to 0.94. We assumed discriminant validity since the average variance explained (AVE) was more than the maximum shared variance (MSV) for each of the subscales, with the exception of the concentration disruption scale, where the AVE value of 0.303 was just slightly higher than the MSV value of 0.30.The Cronbach alpha coefficient for the whole scale was 0.93. For all subscales of SAS-2, Cronbach’s alpha coefficients ranged from 0.86 to 0.95  which inThe results of invariance analysis for the Polish version of SAS-2 are shown in Looking at the differences between gender, the data were almost identical; therefore, no significant differences were found. Only for somatic anxiety, a statistically significant effect of gender was found . Men hadThrough Spearman correlation, statistically significant, negative weak associations were found between anxiety  and task orientation  in the whole group of the examined athletes. Correlations between anxiety and goal orientation were reported in Utilizing confirmatory factor analysis, this study modified and examined the precision of the Sport Anxiety Scale-2 (SAS-2) instrument in Polish. CFA supported the hierarchical and the three-factor model. Performance anxiety is viewed as a global construct with three associated somatic and cognitive subcomponents in the theoretical model behind the SAS . SAS-2 iFactor loading values of all items in this Polish adaptation were fairly high (≥0.50), which shows that all the items were acceptable ,35,36. TThis Polish version of SAS-2 has a high level of internal consistency. Cronbach’s alpha coefficient for each subscale ranges from 0.86 to 0.95. These findings are consistent with the reliability test of the original version  and the Additionally, it was demonstrated that the measurement was independent of sport participation levels  and gender . In both cases, one of the four basic types of measurement invariance was shown: configural, metric, scalar, or strict see . Every gThe average level of anxiety by gender and level of sport participation were also compared in this Polish SAS-2 scale validation study. According to research, general anxiety and its components are more prevalent among women than men . We obtaOur findings largely agree with those of studies conducted with participants aged 18 or older, such as those by Tomczak et al.  and MartIn our attempt to find a correlation between competitive anxiety and task and ego orientation see , there wRegarding SAS-2 subscales’ correlation with STAI, it shows a weak to moderate correlation for STAI-T and moderate correlation for STAI-S which suggests that to some extent these two measures are measuring the same underlying construct. Previous studies support these findings to an extent, as some studies had a strong correlation with both state and trait anxiety of STAI with SAS-2  while otAlthough the study is in line with previous research and shows good psychometric properties, it has several limitations, as the sample size was not that large, and dividing them into groups (according to gender and level of sports participation), further made the groups smaller, which could possibly lead to identical fit indices in hierarchical and three-factor models. To add to the enrichment and reliability of the data, future research may also make use of more sophisticated diagnostic tools for psychiatric disorders, which was previously attempted by the Brazilian adaptation . It woulThis study aimed to prove the reliability and validity of the Sports Anxiety Scale-2 in the Polish population and to overcome the limitations suggested by the previous Polish adaptation of SAS-2. We were successful in having similar, rather better results, than the study by Tomczak et al.  and alsoThis study tested the accuracy of the Polish version of the Sport Anxiety Scale-2 (SAS-2) instrument model using confirmatory factor analysis. The Polish version of SAS-2 has a high level of internal consistency and convergent and divergent validity. A statistically significant, negative correlation between task orientation and total anxiety along with its three subscales and a weak positive correlation between the ego orientation and worry subscale was obtained. In addition, the SAS-2 subscales and total anxiety showed a weak to moderate correlation with the STAI-T and STAI-S, and the measurement was independent of sport participation levels and gender. Competitive anxiety, task and ego orientation, and state–trait anxiety are all correlated; the female, recreational, and female-recreational athletes’ group had weak negative associations between worry and concentration disruption trait anxiety and task orientation, and weak positive associations between somatic anxiety and ego orientation. This study aimed to prove the reliability and validity of the Sports Anxiety Scale-2 in the Polish population but had a few limitations. Future research may use more sophisticated diagnostic tools and improve the validity of the scale.


Routine anticoagulation therapy in acute pancreatitis (AP) is not recommended by the guidelines in the field, although it is frequently used in clinical practice.We aimed to analyze the efficacy and safety of adding anticoagulants therapy to AP management.The systematic search was performed in three databases on the 14th of October 2022 without restrictions. Randomized controlled trials (RCTs) and observational studies that reported the differences in the outcomes of AP for patients receiving anticoagulants (intervention group) in addition to the standard of care (SOC), compared to patients managed by SOC alone (control group), were eligible. A random-effects model was used to calculate the pooled odds ratios (OR) and mean differences (MD) with the corresponding 95%-confidence intervals (CI). We performed subgroup analysis for study design and disease severity, among other criteria.Of the 8,223 screened records, we included eight in the meta-analysis. Except one, all studies reported on low-molecular-weight heparin (LMWH). Both RCTs and observational studies reported results in favor of the LMWH group. Subgroup RCTs’ analysis revealed significantly decreased odds of mortality  and multiple organ failure  in the intervention group. Moreover, the need for endoscopic or surgical interventions  were significantly reduced by LMWH. The subgroup analyzes for moderate and severe cases, respectively, yielded similar results. Due to limited data, we could no perform subgroup analysis for mild cases.LMWH therapy reduces major complication rates in moderate and severe AP. Across all identified RCTs, LMWH were initiated early after AP diagnosis and improved its prognosis. Summarize the established knowledge on this subjectThere is a need in pancreatology for novel treatment approaches to decrease the severity and mortality of acute pancreatitis (AP).The existing AP guidelines do not provide any guidance about Anticoagulant therapy in AP.What are the significant and/or new findings of this study?LMWH can significantly decrease mortality, multiple organ failure, and the need for endoscopic or surgical intervention rates in AP.The prophylactic and therapeutic doses of low molecular weight heparin are both effective.Data about mild AP are scarce.Acute pancreatitis (AP) has an increasing incidence globally that has risen by 30% in recent decades , 2. MoreAnticoagulants therapy for the management of AP is based on the expertise of the attending physicians, and there are no recommendations despite it being frequently utilized in clinical practice . HoweverA few randomized controlled trials (RCTs) revealed decreased major complication rates after adding anticoagulants therapy to the standard of care (SOC) for the management of acute AP , 9. MoreOur systematic review and meta-analysis aimed to investigate the efficacy and safety of adding anticoagulants to the SOC for managing AP across all disease severity stages. We analyzed moderately severe and severe cases, the anticoagulant dose, the duration of therapy, and pooled separately the results of the RCTs.This systematic review and meta-analysis was performed according to Cochrane recommendations  and is iPICO) framework. Our investigated population (P) consisted of patients diagnosed with AP. Eligible studies compared the outcomes of AP in patients who received anticoagulant treatment in addition to the standard of care for disease management (I) to patients who did not receive anticoagulant treatment (C). Our primary outcome (O) was the in-hospital mortality rate. Our secondary outcomes were: length of hospital stay (LOH), local and systemic complications occurrence (multiple organ failure (MOF), acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), pancreatic necrosis, pseudocysts), the need for endoscopic or surgical interventions, progression of AP severity, thrombotic or bleeding events.To formulate our clinical question and identify the eligible studies, we used the population-intervention-control-outcome (The systematic search covered three databases: MEDLINE (via PubMed), EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), from inception until the 14th of October 2022.Our search strategy is detailed in the in extenso published papers and conference abstracts were considered for analysis, without language restrictions. The pool of articles provided by the advanced search was downloaded to Endnote X . Duplicates were removed first automatically and then manually. The selection was made by 2 independent review authors (CP and AÉ), based first on the title and abstract, and subsequently on full-text contents Cohen’s Kappa coefficient was calculated to evaluate inter-rater agreement during each selection step and  datasheet . For dichotomous outcomes, we calculated odds ratios (OR) with corresponding 95% confidence intervals (CI) to investigate the differences between the two groups   and dmetThe quality assessment of the eligible reports was carried out by two independent reviewers (CP and LF), and disagreements were solved by third-party arbitration. We used the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) to assess RCTs . The RisTo evaluate the level of evidence for our findings, we used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework with the GRADEpro tool  Detaile.Our search strategy yielded 8,285 studies after removing duplicates, and after selection, 57 articles were eligible for full-text review. In total, nine studies fulfilled the eligibility criteria for the qualitative synthesis , 23–29 aOf the nine eligible studies, five were RCTs , 24, 29,Duration of anticoagulant administration ranged from 1 to 14 days. In almost all studies, LMWH was used in the intervention group, except for the study of Kroner et al.  in whichI2 = 53%; 95%CI 0–79%]  , X2 = 0.12 p = 0.73   : five RCTs , 24, 29  97–99%] . The RCTificance .Due to insufficient data, we could not perform meta-analytical calculations for the rates of bleeding, thrombosis, local complications, or for the effect of anticoagulants on AP severity progression  (p < 0.05) with no hemorrhagic complications. In this RCT, pancreatic necrosis were present in one patient in the LMWH group compared with 2 patients in the standard care group. Lu Xin et al. in their RCT randomized 265 patients into conventional therapy group  and, LMWH group (n = 135). In the CT group, out of 130 patients, 6 had ARDS, 3 had AKI and 6 had MOFs while in the LT group, 11 patients had ARDS, 9 patients had AKI and 7 patients had MOFs. The results were statistically insignificant (p > 0.05).Timing of LMWH initiation: only 5 out of 9 eligible studies reported the timing of the initiation of anticoagulants. Only in one RCT comprising of 134 patients with severe AP, the LMWH was started after admission, although the exact time was not specified. The rate of in-hospital mortality was 2.9% in the intervention group compared to 5% in the control group ( < 0.05) . In the  < 0.05) , 24, in  < 0.05)  I which  < 0.05) , 9. RegaThe only study in which type of anticoagulants was not mentioned is that of Kroner et al. who explored the association of systemic anticoagulation before AP onset with in-patient outocomes through a retrospective propensitive score matched cohort analysis. Overall they were able to include in the study 5,776 pairs  and patients on anticoagulants although having loinger hospital stay and increased care costs, tended to have better prognosis with lower rates of ICU admission organ failure development, and in-hospital mortality–therefore their results were similar to those of the studies assessing LMWH specifically.In our meta-analysis based on the included studies, the LMWH treatment was associated with a lower rate of MOF but without statistically significance. The detailed data analysis from the articles are shown in the Overall, the risk of bias across the eligible studies for our systematic review was moderate or serious, mainly due to bias in the selection of the reported results. The results of the risk of bias assessment for observational studies based on ROBINS-I are summarized in Publication bias could be assessed for all outcomes using funnel plots, which are available in Also, influential analysis was performed for all outcomes and identified possible outliers .Based on the GRADE assessment, the quality of evidence for every outcome was low or very low when analyzing RCTs and observational studies together, and moderate when performing meta-analysis only on the RCTs .In this systematic review and meta-analysis, we summarized the current evidence on the efficacy and safety of anticoagulant treatment in AP. Currently, there is no consensus regarding the use of anticoagulants in AP regardless of its severity , 35–38, AP mortality rate strongly depends on disease severity and ranges from 3% in mild cases to 30% in severe ones . MortaliThe thrombotic complications were only scarcely reported across the identified studies. In contrast with the findings of Tozlu et al.  and Patip < 0.01], lower mortality , lower incidences of multiple organ failure , pancreatic pseudocyst , and operation rate  in patients with severe acute pancreatitis . The level of evidence for some of our results is high, since we could perform subgroup analysis for RCTs. Moreover, this is the first quantitative synthesis that assesses the effect of anticoagulants in moderate cases of AP.There are several limitations to this study as well. The analysis included a low number of studies, especially for the moderately-severe subgroup. Many of our results have substantial heterogeneity  resultinFirst and foremost, there is a paucity of data in the literature regarding the use of anticoagulants in mild AP cases. We found no study that reports specifically on this subgroup. Further RCTs assessing this category of patients will be necessary. Another important implication for research is that studies should report the safety outcomes related to anticoagulants, such as bleeding or thrombocytopenia.Regarding implications for practice, adding anticoagulant treatment is beneficial for moderately severe and severe cases of AP and may be used earlier in the course of the disease.Anticoagulants decrease major complication rates in moderately severe and severe AP. Prophylactic and therapeutic doses of LMWH might have similar effects. Administration of anticoagulant therapy in moderately severe AP cases leads to lower complication rates than in severe cases. Further studies are necessary to assess the effects of anticoagulants in mild AP and to confirm their safety profile.The original contributions presented in the study are included in the article/CP: conceptualization, project administration, investigation, formal analysis, writing–original draft, and visualization. DV: formal analysis, visualization, and writing–review and editing. SB: conceptualization, supervision, writing–review and editing, and methodology. DP: writing–review and editing. BE: conceptualization, supervision, and writing–review and editing. FD: methodology and writing–review and editing. LF: formal analysis and writing–review and editing. AÉ: investigation and writing–review and editing. PJH: conceptualization, methodology, supervision, and writing–original draft. PH: conceptualization, funding acquisition, and writing–review and editing. All authors certify that they have participated sufficiently in this work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. All authors contributed to the article and approved the submitted version.


Background and Objectives: Urosepsis is a significant cause of maternal and fetal mortality. While certain risk factors for urinary tract infections (UTIs) in pregnant women are well established, those associated with an elevated risk of urosepsis in pregnant women with upper UTIs remain less defined. This study aims to identify factors linked to an increased risk of urosepsis and examine urologic treatment outcomes in such cases. Materials and Methods: We conducted a retrospective analysis on 66 pregnant women diagnosed with urosepsis over a nine-year period. A control group included 164 pregnant women with upper UTIs, excluding urosepsis, admitted during the same timeframe. This study highlights factors potentially contributing to urosepsis risk, including comorbidities like anemia, pregnancy-related hydronephrosis or secondary to reno-ureteral lithiasis, prior UTIs, coexisting urological conditions, and urologic procedures. Outcomes of urologic treatments, hospitalization duration, obstetric transfers due to fetal distress, and complications associated with double-J catheters were analyzed. Results: Pregnant women with urosepsis exhibited a higher prevalence of anemia , 2nd–3rd grade hydronephrosis , and fever over 38 °C . They also had a more intense inflammatory syndrome  142.70 ± 83.50 vs. 72.76 ± 66.37 mg/dL, p = 0.001) and higher creatinine levels . On multivariate analysis, factors associated with increased risk for urosepsis were anemia (Odds Ratio (OR) 2.622, 95% CI 1.220–5.634), 2nd–3rd grade hydronephrosis , and fever over 38 °C . Regarding outcomes, the urosepsis group had a higher rate of urological maneuvers , a higher rate of obstetric transfers due to fetal distress , and migration of double-J catheters , but no maternal fatality was encountered. However, they experienced the same rate of total complications related to double-J catheters . The pregnant women in both groups had the infection more frequently on the right kidney, were in the second trimester and were nulliparous. Conclusions: Pregnant women at increased risk for urosepsis include those with anemia, hydronephrosis due to gestational, or reno-ureteral lithiasis, and fever over 38 °C. While the prognosis for pregnant women with urosepsis is generally favorable, urological intervention may not prevent a higher incidence of fetal distress and the need for obstetric transfers compared to pregnant women with uncomplicated upper UTIs. Sepsis is a major cause of morbidity and mortality during pregnancy, both for the pregnant woman and the fetus . Within Certain factors associated with an increased risk of UTI in pregnancy, including febrile infections, such as renal pelvis dilatation due to increased progesterone secretion, a history of UTIs, diabetes, anemia, socio-economic status, multiparity, and urologic disease associated with pregnancy, are known ,12,13,14In addition, studies looking at the efficacy and safety of the upper urinary drainage during pregnancy  ,17,18,19The aim of our study was to highlight the involvement of known risk factors for UTI in the occurrence of upper UTIs and their progression to urosepsis. We sought to profile pregnant women with upper UTIs who are at risk of developing urosepsis and evaluate the immediate impact of urologic treatments for urosepsis, such as double-J catheter insertion and percutaneous nephrostomy, on both the mother and child. As a secondary objective, we compared clinical and laboratory data, as well as the etiologic agents associated with urosepsis, in patients with febrile UTIs.We conducted a retrospective case–control study on pregnant patients hospitalized for upper UTIs at the urology clinic of Parhon University Hospital in Iasi between 1 January 2014 and 31 December 2022. The study received approval from the Hospital Ethics Committee and was registered under number 5424 on 7 July 2023. Patients data were extracted from the hospital’s electronic records, utilizing ICD-10 coding from the International Classification of Diseases, 10th edition. All pregnant women admitted to the urology clinic were included in the study. We excluded pregnant women without UTIs and patients with lower UTIs from the study.5 CFU/mL bacterial growth; antimicrobial susceptibility testing was performed by the disk diffusion method, using EUCAST clinical breakpoint tables for the interpretation of minimal inhibitory concentrations and zone diameters.Initially, we identified all pregnant patients with the O09 code (supervision of high-risk pregnancy) who were hospitalized during the 9-year study period, totaling 274 pregnant women. We excluded 37 patients who had been hospitalized for reno-ureteral lithiasis or pregnancy-related hydronephrosis and did not provide a urine sample showing signs of infection (such as leukocyturia or nitrites) and/or a positive urine culture. Additionally, we excluded 7 patients diagnosed with cystitis and positive urine cultures but lacking clinical and paraclinical signs of upper UTI . We defined a positive urine culture in samples with ≥10The remaining 230 patients with upper UTIs were divided into two groups: the study group consisted of 73 patients with urosepsis, and the control group included 157 patients with upper UTIs without urosepsis. Since our clinic adopted the new definition of sepsis, sepsis-3 , in 2018From the electronic records, we analyzed the demographic characteristics of the patients upon admission. This analysis included site of the infection , their age, trimester of pregnancy, place of origin, parity, and comorbidities such as anemia and diabetes mellitus.Regarding the factors associated with the risk of upper UTIs and urosepsis, we examined the presence and degree of hydronephrosis during pregnancy, secondary to gestational or reno-ureteral lithiasis, other urological conditions of the mothers, as well as the history of UTIs in pregnant women both during and outside of pregnancy, and previous endourological maneuvers during pregnancy.To assess the grade of hydronephrosis, we utilized a four-grade ultrasound classification system developed by Onen . We utilWe also compared clinical and paraclinical characteristics between the two groups, including the degree of fever, the presence of fever exceeding 38 °C, qSOFA elements, leukocyte count, creatinine levels, C-reactive protein (CRP) levels, and the presence of septic shock upon admission among pregnant women with urosepsis. Additionally, we compared the causative pathogens responsible for UTIs in the two groups.Concerning treatment, this study evaluated the rate of urological procedures, the insertion of a double-J catheter, percutaneous nephrostomy placement, and their localization . We performed percutaneous nephrostomy, only when we could not succeed to insert a double J catheter. Antibiotherapy for pregnant patients with complicated or uncomplicated UTIs was conducted according to the local protocol that followed the American College of Obstetricians and Gynecologists guidelines . Blood cWe also examined the immediate treatment outcomes for both the mother and fetus, considering factors such as the incidence of fetal distress necessitating transfer to the obstetrics clinic, length of hospital stay, and the occurrence of urological complications during pregnancy in the operated pregnant women from both groups.We defined reflux pyelonephritis as any pyelonephritis occurring in patients with a double J catheter in place, with the calcification of the double-J catheter being confirmed either by ultrasound or intraoperatively when changing the double J catheter.All pregnant women were examined by a gynecologist during their hospitalization. In cases of fetal distress, the gynecologist decided on the patient’s transfer to the obstetrics clinic for specialized treatment. The underaged patients were also monitored by a pediatrician.t-test for quantitative data and the chi-square test for qualitative data. Quantitative data were described using the mean and standard deviation. The analysis of factors associated with the risk of urosepsis was performed using multivariate analyses, utilizing the SPSS version 22 software .The comparison of the two groups was conducted using the Student’s During the nine years of the study, a total of 230 pregnant women with upper UTIs were admitted to the urology clinic. Out of these, 66 were pregnant with upper UTIs and urosepsis, while 164 were pregnant with upper UTIs without urosepsis. The characteristics and demographic data of the two groups are presented in There were no statistically significant differences between the two groups in terms of the site of the infection, mean age, trimester of pregnancy, place of origin, parity, or the incidence of diabetes. The majority of pregnant women in both groups were under 30 years of age, nulliparous, in the second trimester of pregnancy, from rural areas, and had a lower incidence of diabetes. In the study group, pregnant women had a higher rate of anemia, mainly moderate, compared with the control group. We did not encounter severe anemia in the two groups. The factors associated with the risk of urosepsis are presented in Patients with urosepsis had a higher incidence of hydronephrosis secondary to gestational, and a higher incidence of 2nd–3rd grade hydronephrosis for both gestational and secondary to reno-ureteral lithiasis. Also, the group with sepsis had a lower incidence of gestational 1st grade hydronephrosis compared with the non-sepsis group. Patients with urosepsis had the same rate of reno-ureteral lithiasis, the presence of other urological illnesses , a history of previous UTIs, and previous urological maneuvers during pregnancy. The characteristics of the two groups in terms of clinical and paraclinical data are detailed in The multivariate analysis of risk factors showed a statistically significant difference for 2nd–3rd grade hydronephrosis secondary to gestational and reno-ureteral lithiasis , anemia , and fever > 38 °C . Patients with urosepsis had a higher fever, a higher rate of fever over 38 °C, higher qSOFA scores, higher leukocytes, C-reactive protein (CRP), and creatinine levels. Also, 12 (18.2%) of the urosepsis patients had septic shock on admission. There was a statistically significant differences between the two groups, in favor of the urosepsis group, concerning the positivation of urine cultures.E. coli was the primary pathogen responsible for the etiology of pyelonephritis in both groups, with similar incidence rates. In addition, there were no statistically significant differences in the incidence of other pathogens. Antibiotic treatment was initiated in both groups with ceftriaxone 1 g/12 h i.v.; in the case of multidrug resistance (MDR) risk , treatment with meropenem 1 g/8 h i.v. was initiated; and in the case of septic shock, treatment with meropenem 1 g/12 h and vancomycin 1 g/12 h i.v. was initiated.Enterococcus spp. and Staphylococcus aureus, treatment was initiated with amoxicillin + clavulanic acid 1.2 g/12 h i.v. for 7–10 days or in the case of resistance, vancomycin 1 g/12 h i.v. for 7–10 days; and for Candida spp., treatment was initiated with fluconazole 200 mg/12 h i.v. for 7–10 days. In the sepsis group, there were eight cases with infections with MDR pathogens (12.12%), including two with Klebsiella spp., five with E. coli, and one with Serratia marcescens. In the non-sepsis group, there were five (3.05%) cases with MDR infections, three with S. aureus, one with Klebsiella spp., and one case with E. coli. There was a statistically significant difference (p < 0.05) in favor of the urosepsis group regarding the frequency of MDR infections. Blood cultures were positive in 13 patients (19.7%) with urosepsis, and the results corresponded to the bacterial spectrum outlined by the urinary culture. After the urine culture was positive, the pathogen was identified, and the antibiogram was performed, the treatment was adjusted as follows: For Gram-negative bacilli, cephalosporins were continued; for In There was a higher rate of surgical intervention in the urosepsis group, mainly due to the double-J catheter insertions, predominantly on the right side in both groups. Treatment outcomes for both groups are shown in The mortality rates were not included in the table due to the fact that we did not identify any fatality during the studied period.Hospitalization was longer in the urosepsis group, with a higher rate of long hospitalization (over 7 days), and fetal disturbances requiring transfer to a maternity hospital occurred more frequently. Patients in the urosepsis group had a higher rate of migrated double-J catheters, and the development of a new urosepsis, secondary to reflux pyelonephritis. Both groups had the same rate of urological complications, such as reflux pyelonephritis, calcification of double-J catheters, septic shock during double-J catheter insertion, and failure to succeed double-J catheter insertion.The factors associated with an increased risk for pregnant women with upper UTIs to develop urosepsis are hydronephrosis during pregnancy or secondary to reno-ureteral lithiasis of at least 2nd grade, moderate anemia, and fever over 38 °C.E. coli is the most commonly implicated microorganism, as indicated in other local studies [Among enteric pathogens,  studies ,28,29. UTo our knowledge, this is the first study that has analyzed the risk factors for the development of urosepsis in pregnant women with upper UTIs in a large number of patients over a significant period of time. One of the main limitations of our study is its retrospective nature, due to the small number of cases occurring each year. This required a longer study period to create a patient group suitable for statistical analysis. In addition, the urosepsis group included both patients without septic shock and those with septic shock, suggesting more severe disease. This could potentially affect treatment outcomes for both mothers and infants. However, further subdivision of the urosepsis group would have resulted in a smaller sample size, making statistical comparisons impossible. In both the urosepsis group and the control group, the primary source of infection was predominantly in the right kidney, because hydronephrosis during pregnancy was more pronounced on the right side than on the left . UrinaryWhen analyzing the differences between the two groups, we observed a higher incidence of urosepsis in patients from rural areas and in those with a higher degree of anemia. The predominance of rural residence may be explained by the lower level of education and limited access to healthcare, despite public health insurance being available in our country . It is wA significant proportion of urosepsis patients had septic shock, which may be attributed to the increased vascular risk in pregnancy due to specific physiological and immunological changes . RegardiRegarding the risk factors analyzed, in contrast to other studies that identify acute pyelonephritis without obstruction as the main cause of sepsis ,13,14,33Pre-existing urologic conditions were present in a low percentage in both groups, and there was no significant difference in their incidence between pregnant women with urosepsis and those without urosepsis. Therefore, these diseases do not seem to influence the occurrence of urosepsis and are not considered significant risk factors for it. Also, we observed no statistically significant difference in relation to a history of UTIs and urologic procedures. This suggests that these factors do not play a significant role in the development of urosepsis in pregnant women with febrile UTIs.Although both groups had clinical and paraclinical signs of inflammation, they were significantly increased in favor of the group with urosepsis. For both the presence of fever above 38˚C and leukocytosis, CRP and qSOFA were more elevated in the group with urosepsis. Although some studies give little importance to the presence of fever or CRP level in the detection of sepsis , we founE. coli, in a similar percentage as in the reports of other studies in pregnancy [Proteus spp., Klebsiella spp., Enterococcus spp., Serratia spp., germs of the gut microbiota, S. aureus, and Candida spp. Regarding MDR infections, we found a lower percentage of them compared with other studies, which is probably explained by the lower incidence of possible risk factors . Although the group with sepsis had a higher statistically significant percentage of MDR UTIs compared with the non-sepsis group, this incidence is lower than in other reports [The main microorganisms detected in urine cultures were regnancy ,14,21,33 reports . The facAn important aspect of our study was the fact that the overwhelming majority of patients with urosepsis had 2nd or 3rd grade hydronephrosis, in a higher percentage than in the group without urosepsis, which required surgical treatment. In our study, we had only nine cases with pyelonephritis without obstruction that developed urosepsis, five of whom had a double-J catheter in situ inserted during pregnancy for infected hydronephrosis. Thus, in the absence of hydronephrosis, the risk of progression of pyelonephritis to sepsis was low, except for the presence of double-J catheters. In all other cases, drainage was required, namely the insertion of double-J catheter or, failing that, the insertion of a percutaneous nephrostomy. A higher percentage of urologic drainage interventions was required in the group with urosepsis, due to the higher frequency of hydronephrosis with a higher grade compared to the group of pregnant women without urosepsis.Unlike other types of sepsis in pregnant women, for which a mortality rate of 7.7% has been reported , our stuOur study is important for obstetricians who supervise the pregnancy and for urologists who evaluate pregnant women with UTIs. They must actively look for pregnancy hydronephrosis or reno-ureteral lithiasis, initiate antibiotic treatment as early as possible at the first sign of cystitis  or febriThere is debate among obstetricians as to whether urine culture performed monthly during pregnancy is useful for the early detection of patients with UTIs or significant bacteriuria. We believe that this screening should be limited only to the category of high-risk patients, namely those with gestational hydronephrosis. If a renal ultrasound is also performed during the obstetric ultrasound examination at 14 weeks of gestation, which objectifies hydronephrosis, a monthly urine culture must be performed, thus reducing the unnecessary high number of urine tests during pregnancy. Further studies are needed to validate these findings.The patients with upper UTIs who had 2nd and 3rd grade hydronephrosis had moderate anemia and fever over 38 °C, which are factors associated with an increased risk of developing urosepsis for pregnant women. E. coli is the main germ involved in the etiology of urosepsis, similar to the group of patients without urosepsis. Pregnant patients with urosepsis have a more severe inflammatory syndrome at admission than those with upper UTIs without urosepsis. The prognosis of pregnant women with urosepsis is good, but with a higher incidence of fetal distress and subsequent transfer to maternity hospital, and the need for urologic surgery.


Placenta accreta spectrum (PAS) disorders have been reported with an increasing frequency of up to 3%. The increase in the incidence can be explained by the rising rate of Caesarean section (CS), assisted reproductive technology (ART) and previous uterine surgeries. PAS disorders are usually associated with postpartum haemorrhage (PPH). In our study, we investigated the risk factors for increased blood loss in women with histologically verified PAS disorders independent of delivery mode.In a retrospective single-centre cross-sectional study, 2,223 pregnant women with histologically verified PAS disorders were included. Risk factors for PPH in women with PAS disorders were examined and compared between women with PPH  and women with normal blood loss , independent of delivery mode. PAS disorders were diagnosed histologically from the following specimens: placenta, placental-bed specimens, uterine curettage, uterine resection and/or total/partial hysterectomy. Medical data were extracted from clinical records of pregnant women with PAS disorders delivering at the University Hospital Basel between 1986 and 2019. The placenta data of women with PAS disorders were obtained and identified through a search from the database of the Department of Pathology, University Hospital Basel.Between 1986 and 2019, there were 64,472 deliveries at the University Hospital Basel. PAS disorders were histologically verified in 2,223 women , and the prevalence of PAS disorders was 3.45%. A total of 879 women with PAS disorders showed PPH, independent of delivery mode (43.3%). Due to missing data for 194 women, the final analysis was conducted with the remaining 2,029 women. Placenta praevia , previous endometritis , previous manual placenta removal , ART  and vaginal operative birth  can be considered important risk factors, and previous CS  can be considered a moderate potential risk factor of PPH in women with PAS disorders.Placenta praevia, previous endometritis, previous placenta removal, ART and vaginal operative birth can be considered important risk factors of PPH in women with PAS disorders.http://www.ClinicalTrials.gov (NCT05542043) on 15 September 2022.The study was registered under The online version contains supplementary material available at 10.1186/s12884-023-06103-5. Placenta accreta spectrum (PAS) disorders, formerly known as morbidly adherent placenta, refers to a range of pathologic adherence of the placenta, including placenta accreta, increta and percreta , 2. VariPAS disorders have become more common in recent years due to increased maternal age at delivery and increasing rates of uterine surgery , 3, 5–7.PAS disorders are associated with increased maternal mortality and morbidity but do not contribute to adverse neonatal outcomes . The maiTo our knowledge, there is no study about risk factors for PPH independent of delivery mode in women with PAS disorders. In the present study, we examined risk factors for PPH independent of delivery mode in pregnant women with histologically verified PAS disorders.A retrospective single-centre cross-sectional study was conducted at the Department of Obstetrics and Antenatal Care, University Hospital Basel, Switzerland. A total of 2,223 pregnant women with histologically verified PAS disorders delivering at the University Hospital Basel between 1986 and 2019 were included in this study.http://www.ClinicalTrials.gov on 15 September 2022 (NCT05542043). If the person concerned provided a written or documented verbal refusal or was a pregnant woman under the age of 18, their health-related personal data or biological material were not used for this study.The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee for Northwest and Central Switzerland in Basel (EKNZ ID 2020 − 01047). It was registered under The medical data were extracted from the patient’s clinical records. The placenta data of women with PAS disorders were obtained and identified through a search in the database of the Department of Pathology, University Hospital Basel.The primary outcome was PPH (yes/no), as defined by the amount of blood loss during delivery. PPH was defined as blood loss of ≥ 500 ml following vaginal delivery or ≥ 1000 ml following CS , 16, 24.n = 879) and women with normal blood loss , independent of delivery mode. Regardless of the delivery mode, placentas were sent for histologic examination in the following cases: antenatal bleeding, manual placenta removal or uterine curettage, PPH, chorioamnionitis, intrauterine growth restriction, poor neonatal outcome, multiples, preeclampsia/eclampsia, preterm birth, placenta praevia, neonatal death, abortion beyond the 14th week of pregnancy and stillbirth.During a CS, blood loss has been measured by the amount of blood in the suction bag and in the pads. Pregnant women with histologically verified PAS disorders were divided into two groups: women with PPH , blood loss, gestational age, preterm birth, stillbirth, neonatal birth, delivery mode, tobacco use, placenta praevia, hypertension/preeclampsia, gestational diabetes (GDM), infection, bleeding during pregnancy, placental abruption, previous abortion curettage , previous hysteroscopic surgery or uterine curettage, previous CS, previous manual placenta removal, myomectomy, Asherman syndrome, ART, previous endometritis, ultrasound markers for PAS disorders, manual placenta removal or curettage during delivery.2); placenta praevia; previous uterine surgery ; previous abortion; Asherman syndrome; delivery mode; hypertensive disorders and preeclampsia [Our primary objective was to examine whether and how the following potential risk factors were associated with PPH (the definitions used for each objective are provided in the cited references): increased maternal age at delivery (≥ 35 years); high gravidity (≥ 5); high parity (≥ 4); obesity .For the primary analysis, a multivariable generalized linear model with binomial distribution of the error and a logit link function (logistic regression) was fitted to the data using PPH (yes/no) as the response variable and all the potential risk factors listed above as the explanatory variables. Starting with a full model including all the risk factors, a stepwise, bidirectional selection procedure based on the Akaike information criterion (AIC) was applied to select the potential risk factors that explained most of the probability of the occurrence of PPH. The AIC of the most parsimonious reduced model was then compared to the AIC of the full model and to the AIC of the null model . The best reduced model has the smallest AIC and hence the largest difference in AIC compared to the null and the full models. Only the odds ratios (O.R.) associated with the risk factors selected in the best reduced model are interpreted.2, 30 kg/m2-39.9 kg/m2, ≥ 40 kg/m2); placenta praevia (binary: yes/no); tobacco use (binary: yes/no); multiples (binary: yes/no); hypertension/preeclampsia (binary: yes/no); GDM (binary: yes/no); infection (binary: yes/no); abortion curettage < 12 weeks, 12–18 weeks, > 18 weeks (binary: yes/no); previous hysteroscopic surgery or uterine curettage (binary: yes/no); previous CS (binary: yes/no); previous manual placenta removal (binary: yes/no); myomectomy (binary: yes/no); Asherman syndrome (binary: yes/no); ART (binary: yes/no); previous endometritis (binary: yes/no); and mode of delivery .The following potential risk factors were investigated for possible association with the probability of occurrence of postpartum haemorrhage: maternal age ; gravidity ; parity ; BMI  associated with the estimate. The narrower the 95% CI, the stronger the conclusion about the association. A large O.R. with a large range in the 95% CI may be regarded as inconclusive regarding the existence of a true association.Between 1986 and 2019, there were 64,472 deliveries at the University Hospital Basel. PAS disorders were histologically verified in 2,223 women . The prevalence of PAS disorders was 3.45%; specifically, the prevalence was 1.4%  between 1986 and 2014 and 11.5%  between 2014 and 2019. Due to missing data for 194 pregnant women , the final analysis included 2,029 women.Table Table The differences in AIC between the best reduced model and the full and null models are large and indicate that the best model better explains the variation in the probability of occurrence of PPH than the null and full models. Table All factors in the best model help explain the overall variation in the occurrence of PPH although some factors contribute only very modestly whereas others are stronger risk factors. Some odds ratios have a large value and a large range in the 95% CI, making it difficult to conclude that there is an association between the risk factor and the occurrence of PPH.Based on the estimated O.R. and associated 95% CI, the following factors can be considered risk factors with strong evidence of a moderate (O.R. > 1.5) to strong association (O.R. > 2) with the probability of occurrence of PPH: placenta praevia , previous endometritis , manual placenta removal in the previous pregnancy , ART  and vaginal operative delivery . There were more women with concomitant placenta praevia and previous CS in the group with PPH (24//879 vs. 9/1150) .Based on the O.R. and the range of the associated 95% CI, CS in the previous pregnancy  can be considered a potentially moderate risk factor. However, due to uncertainty in the point estimates, the strength of the association with the probability of occurrence of PPH remains unknown in both cases and needs to be confirmed with further investigations.The following factors are associated with a decrease in the probability of occurrence of PPH: infection in pregnancy  (a large uncertainty remains regarding the true strength of the association) and CS in the current pregnancy .The best model using age and BMI as continuous variables completely aligns with the best model using age and BMI as categorical variables. The supplementary The prevalence of PAS disorders in our study was 3.45% and aligns with the prevalence reported in the literature , 6, 7. HOur study was an examination of the risk factors for PPH independent of delivery mode in women with histologically verified PAS disorders. Wright et al. investigated the predictors of massive blood loss ≥ 5000 ml) in women with PAS disorders who had undergone a hysterectomy . There w000 ml inPlacenta praevia is the most important risk factor for PAS disorders and PPH , 15, 36.In the present study, we found more PPH in women with PAS disorders who gave birth vaginally, particularly through vaginal operative delivery. First, this reflects the varying severity of placental disease and hence the related varying antenatal recognition. We suspect there are two clinically diverse groups of women with PAS disorders. The first group consists of women with significant amounts of placental tissue that invades the uterine wall. These women are recognised antenatally and get scheduled delivery with many benefits and minor blood loss. The second group consists of women with focal placenta accreta, which is mostly not recognised antenatally. These women often give birth vaginally, are unrecognised until the time of delivery and show more PPH. On the other hand, vaginal operative delivery per se is a risk factor for PPH in women without PAS disorders, and manual placenta removal per se is also an intervention associated with increased blood loss , 20–22. ART was first linked to PAS disorders in 2011 , and thiPrevious endometritis was associated with 3.011 times greater probability and previous manual placenta removal with 2.530 times greater probability of PPH in the study group. Our results are consistent with those of previous studies . HoweverWe cannot logically explain the decrease in blood loss in Asherman syndrome. Asherman syndrome occurs when trauma to or removal of the basal layer of the endometrium occurs in opposing areas in the uterine cavity. Histologically, Asherman syndrome is a fibrosis of the endometrium, and one of the typical symptoms is hypomenorrhea. The possible cause of decreased bleeding in pregnancy may be a smaller “active surface of the uterus” and thus the smaller adhesion surface for the placenta. Although, on the other hand, there is a little information about changes in the uterine myometrium in Asherman syndrome. Hypothetically, chronic inflammation of the uterine myometrium with excessive accumulation of extracellular matrix components produced by fibroblasts could lead to the development of diffuse fibrosis, in which connective tissue replaces normal parenchymal tissue and impairs uterine vascularization. This could secondarily cause a reduction of blood loss in PAS. Unlike chronic inflammation, acute endometritis is treated with antibiotics and is characterized by an accumulation of pathogens and white blood cells in the connective tissue by increasing blood circulation and thus improving the removal of damaged cells. Therefore, acute endometritis does not progress normally to chronic inflammation with fibrosis formation. Although previous endometritis is known as a risk factor for PAS, little is known about its effect on bleeding. Based on the O.R. in our study, previous endometritis can be considered a potentially strong risk factor for PPH. However, further prospective studies are needed to investigate the relationship between PPH and acute/chronic uterine inflammation in women with PAS.Our study has some weaknesses. First, it employs a retrospective design, which is also why many important data are missing or were not investigated. Examples are the lack of information on prenatal suspicion of PAS by ultrasound; the lack of objective measurement of blood loss because objective measurement of blood loss using a blood loss bag has been used for the last few years; the lack of investigation of known risk factors for PPH, such as macrosomia, induction of labour, severe anaemia, uterine fibroma, prolonged third stage of delivery, non-use of oxytocin in the third stage of delivery, recurrence of uterine surgery and polyhydramnios; and the lack of exact management of PPH in older data. The steadily improving prenatal diagnosis of PAS, the routine implementation of the DACH guidelines and the involvement of a multidisciplinary team improve the management of PPH with reduced blood loss and maternal morbidity and mortality in the last years. The second disadvantage is the long period over which the study was conducted. Risk factors for PPH, such as a CS, placenta praevia, curettage and manual removal of the placenta, were less common 15–20 years ago than in the last 10 years. On the other hand, not all placentas from women who gave birth in this period were examined, so a certain portion of PAS disorders has been undiagnosed. Because of these weaknesses - retrospective data of a single-centre over 30 years - this must be considered when we present these data, and the results must be used with care.In conclusion, this study provides strong evidence that placenta praevia, previous manual placenta removal, ART, previous endometritis and vaginal operative delivery can be considered risk factors for PPH in women with PAS disorders. However, further studies are needed to investigate the impact of risk factors for PPH in PAS disorders in a time-dependent manner, the impact of repeated uterine surgery, the use of ART, the role of ultrasound in the prenatal detection of PAS and the impact of other variables on blood loss in women with PAS disorders. Our results could initiate the planning and conducting of prospective powered studies to verify the potential risk factors for PPH in this high-risk group of women.Placenta praevia, previous endometritis, previous placenta removal, assisted reproductive technology and vaginal operative birth can be considered important risk factors of PPH in women with PAS disorders.Below is the link to the electronic supplementary material.Supplementary Material 1


Pancreatic cancer (PC) is infamous for its silent and lethal nature, making it one of the leading causes of cancer-related deaths worldwide. The early detection of PC is critical to achieve a favorable prognosis, as it typically goes unnoticed until advanced stages. Fatty pancreas (FP) is often associated with PC, but the causal relationship has not been clearly defined. With this systematic review and meta-analysis, we aim to strengthen the connection and emphasize the potential risks of FP to the development of PC. Based on our analysis, our findings exhibit a clear risk of PC in the presence of FP, advocating for future prospective studies to be performed in order to solidify the relationship.Pancreatic cancer (PC) is one of the most lethal cancers worldwide. Recently, fatty pancreas (FP) has been studied thoroughly, and although its relationship to PC is not fully understood, FP is suspected to contribute to the development of PC. We aimed to assess the association between PC and FP by conducting a systematic review and meta-analysis. We systematically searched three databases, MEDLINE, Embase, and CENTRAL, on 21 October 2022. Case–control and cross-sectional studies reporting on patients where the intra-pancreatic fat deposition was determined by modern radiology or histology were included. As main outcome parameters, FP in patients with and without PC and PC in patients with and without FP were measured. Proportion and odds ratio (OR) with a 95% confidence interval (CI) were used for effect size measure. PC among patients with FP was 32% . However, the probability of having FP among patients with PC was more than six times higher  than in patients without PC, whereas the proportion of FP among patients with PC was 0.62 (95% CI 0.42–0.79). Patients identified with FP are at risk of developing PC. Proper screening and follow-up of patients with FP may be recommended. Fatty pancreas (FP) is referred to as the Pandora’s box of pancreatology , as thisThe mortality rate of PC can be attributed to its late presentation and resistance to chemotherapy . Hur et Several risk factors have been identified to play a role in the development of PC. Among these, genetic mutations are responsible for 10–15% of all PC cases, for which there are screening protocols for high-risk individuals . AdditioAt the time of diagnosis, only 10–20% of patients with PC were found in resectable or localized stages . It is cDue to the high mortality rate as a result of the late diagnosis of PC, non-genetic factors should be determined for early PC detection. FP is a possible option as it can be detected earlier than icterus, which is one of the most common initial features of PC. Fatty pancreas is defined as a significant fatty infiltration of the pancreatic parenchyma and has been associated with increasing age, obesity, metabolic syndrome, non-alcoholic fatty liver disease, and PC ,13,14,15The lack of guidelines for reporting intra-pancreatic fat deposition and the need for early predictors of PC necessitated our analysis. We hypothesized that FP contributes to the development of PC. We aimed to determine the importance of FP as an early risk factor for the development of PC.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline  see Tab and CochStudies were included in which the pancreas of an adult human population was assessed using modern radiology (endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and computed tomography (CT)) or histology to determine the presence of intra-pancreatic fat deposition in PC and/or control patients. Population, Exposure, Comparator, and Outcome(s) (PECO) and Condition, Context, and Population (CoCoPop) frameworks were used to identify the articles eligible for this study. We approached the research question from two directions. In analysis A, FP was defined by modern radiology or histology (P). Articles were eligible if they reported whether patients had PC (E) or not (C) and assessed the outcome of the ratio of PC (O). In analysis B, patients with PC were examined (P) for the presence (E) or absence of FP (C), and the ratio of FP (O) was determined. Moreover, we ascertained the prevalence of FP (Co), where FP was defined by modern radiology or histology (Co) in patients with PC (Pop) in analysis B. All case reports, conference abstracts, reviews, narrative summaries, systematic reviews, and meta-analyses were excluded. No language filter was used.The search key for this review can be found in Document S1. The systematic search was performed in three electronic databases: MEDLINE (via PubMed), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) without any filters on 21 October 2022. After full-text selection, citation chasing was performed  to identArticles collected from the systematic search were processed using the Rayyan web software  and EndNFrom the eligible articles, two independent investigators (ML and DT) extracted the following data into a purpose-designed Excel sheet : overall demographic data ; characteristics of individuals with PC and without PC ). When available, odds ratio (OR) and their 95% confidence interval (CI) were recorded. The senior review author (AM) resolved all disagreements between the two reviewers. When necessary, the authors of the respective studies were contacted via email to request additional information to support our study.Two authors (ML and DT) independently assessed the risk of bias using tools developed by the Joanna Briggs Institute (JBI) and the Quality of Prognostic Studies tool (QUIPS) ,26. The 2 statistics [The detailed statistical analysis can be found in Document S2. As we assumed considerable between-study heterogeneity in all cases, we used a random effects model to pool effect sizes. Proportions and ORs with 95% CI were used for effect size measures. To determine the prevalence or OR, the total number of patients and those with the event of interest (in each group separately for OR) were extracted from every study. We reported the results as the odds of an event of interest in the experimental group versus the odds of an event of interest in the control group. OR results were considered statistically significant if the pooled CI did not contain the null value (OR = 1). We summarized the findings of the meta-analysis on forest plots. Where applicable—when the study number was large enough and not too heterogeneous—we also reported the prediction intervals  of results. Additionally, between-study heterogeneity was described by Higgins and Thompson’s Iatistics . Small satistics  for propatistics  for OR eatistics .All statistical analyses were performed with R v4.2.2  using thGrading of Recommendations Assessment, Development, and Evaluation (GRADE) workgroup recommendation  and the A total of 7077 studies were identified during the initial search. Studies were selected according to eligibility criteria, resulting in 17 eligible articles with 2956 patients ,50,51,52The main characteristics of the included studies are listed in 2 = 0.28 (95% CI: 0–0.93).We found three studies ,34,35 th2 = 0.67 (95% CI: 0.34–0.84).We investigated the presence of FP among patients with PC . Data fo2 = 0.89 (95% CI: 0.84–0.93).The prevalence of FP among patients with PC was also investigated, and data were collected from 14 articles ,47,48,49The risk of bias assessment for each outcome is presented in Small study bias was not assessed for analysis A as there were only three studies. In the assessment of publication bias for studies of patients with PC where the presence of FP was examined , a smallThe certainty assessment of the three investigated outcomes shows very low to moderate certainty of the evidence, as presented in Our meta-analysis found a sixfold higher probability of FP among patients with PC than in the control group. Furthermore, there is a high correlation between the prevalence of FP and the PC in the PC population; however, there was no significant relationship between the FP patient population and PC.A fatty pancreas is described as a fatty-infiltrated pancreas where adipocytes infiltrate the intralobular and/or interlobular space . The nomFP has different possible pathomechanisms. Among these, cellular mechanisms, such as proinflammatory environments, and molecular mechanisms, such as changes in core circadian genes, can be identified . CurrentBi et al. reported in their meta-analysis that FP was associated with an increased risk of metabolic syndrome and its components . Stamm eOur findings suggest that FP is a risk factor for PC. The probability of having FP among patients with PC was higher than in the control group. Additionally, evidence suggests an association between the presence of BMI, chronic pancreatitis, diabetes, pancreas exocrine insufficiency, and FP. All studies included showed a higher number of FP individuals in the case group. Kawamura et al.  demonstrp = 0.42). Previous data from animal studies and reviews suggest that FP contributes to the development of PC [In the proportion analysis, we found FP in more than half of the patients with PC. Kobashi et al. applied strict inclusion criteria that could result in fewer events . In a lont of PC ,14,52,67During our selection process, we chose high-evidence articles and intentionally used cross-sectional and case–control studies, offering advantages in assessing prevalence, associations, and risk factors. Yet, we must recognize the limitations inherent in these designs, including their inability to establish causality and their susceptibility to bias, which should be kept in mind when interpreting and applying our findings.Data on diagnostic methods were heterogeneous in most studies using EUS. Histological examination is the gold standard for FP diagnosis, but it is not routinely performed due to its invasive nature. The advantages and disadvantages of different methods were summarized by Truong et al. . Due to Our analysis revealed that the included articles employed a variety of exclusion criteria. Establishing study designs that can effectively determine the connection between fatty pancreas (FP) and pancreatic cancer (PC) is of utmost importance. Such designs necessitate stringent exclusion criteria to account for potential confounding factors, including, but not limited to, diabetes, obesity, family history of PC, chronic pancreatitis, genetic predisposition, alcohol intake, and smoking. In two of the articles, patients with alcohol consumption were excluded ,45. HoweThis is the most comprehensive systematic review and meta-analysis conducted with a rigorous methodology that has analyzed and confirmed the relationship between FP and PC. We followed our pre-registered protocol. In contrast to the previous meta-analysis by Sreedhar et al. in 2019, we applied a more thorough analysis to the topic of PC.We faced the following limitations: there was considerable statistical heterogeneity due to the clinical heterogeneity of the studies. For instance, different diagnostic methods were used to assess FP. Some studies examined patients who underwent EUS for hepatobiliary indications, whereas other studies selected PC patients who underwent pancreaticoduodenectomy. Cross-sectional and case–control studies are valuable research designs, but they come with several limitations; they cannot establish causality, and selection bias can occur. Additionally, there is no universal definition of FP, which may further complicate the analysis and comparison of the studies. Lastly, there was a moderate and high risk of bias in some of the domains.The utilization of scientific data for community benefits is of paramount importance ,70. Our Further prospective longitudinal data collection is necessary to assess the causality relationship between FP and PC in more depth. It is imperative to provide a clear description of whether metabolic syndrome and its components, age, alcohol consumption, smoking, and pancreatitis can influence the development of FP and PC. This would further support the necessity of detecting FP and the importance of follow-up in patients presenting with FP.Fatty pancreas is a risk factor for pancreatic cancer.