It remains controversial whether radiotherapy (RT) improves survival in patients with stage IIB/III PDAC. A growing number of studies have found that patients’ age at diagnosis and tumor site not only affect prognosis, but also may lead to different treatment responses. Therefore, the purpose of this study was to verify whether the survival effect of radiotherapy in patients with stage IIB/III PDAC varies across age and tumor site groups.The target population was selected from PDAC patients undergone surgery in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016. This study performed the Pearson’s chi-square test, Cox regression analysis, Kaplan-Meier (K-M) method, and focused on propensity frequency matching analysis.Neither neoadjuvant radiotherapy (nRT) nor adjuvant radiotherapy (aRT) patient group had probably improved survival among early-onset patients. For middle-aged patients, nRT seemed to fail to extend overall survival (OS), while aRT might improve the OS. Plus, both nRT and aRT were associated with improved survival in elderly patients. The aRT might be related with survival benefits in patients with pancreatic head cancer, while nRT was not. And RT in patients with PDAC at other sites did not appear to provide a survival benefit.Carefully selected data from the SEER database suggested that age and tumor location may be the reference factors to guide the selection of RT for patients with stage IIB/III PDAC. These findings are likely to contribute to the development of personalized treatment for patients with stage IIB/III PDAC. Pancreatic ductal adenocarcinoma (PDAC) is considered to be one of the most common gastrointestinal malignancies in the world, with an estimated incidence of 60,430 cases in 2021 .Radiotherapy (RT) is also one of the important weapons against PDAC, including neoadjuvant radiotherapy (nRT), adjuvant radiotherapy (aRT) and palliative treatment. It works by delivering ionizing radiation directly to the primary tumor and regional lymph nodes, which may cause genetic damage and ultimately apoptosis of cancer cells . HoweverIn recent years, many studies have confirmed that the survival outcome and treatment effect of PDAC patients vary with age . YoungerGiven the above questions, we used the Surveillance, Epidemiology, and End Results (SEER) database, which collects cancer case data from every state in the United States, to verify whether the survival effect of RT for stage IIB/III PDAC patients was different among different age and tumor site groups.Data for this retrospective study was collected from the SEER database (from 1973 to 2016), which includes 18 population-based cancer registries covering approximately 30% of the US population. The target population was limited to PDAC patients pathologically confirmed by post-operative specimens between 2004 and 2016. Other important information extracted included: general basic information, TNM stage, treatment information ) and follow-up. In addition, the T and N stage were recorded according to the 8th edition TNM stage system by combining tumor size. Exclusion criteria were as follows: not confirmed by postoperative pathology , non-PDAC patients , non-stage IIB/III patients , non-surgical patients  and survival months is 0 (n = 571). Ultimately, enrolled patients were divided into three groups  by the age at diagnosis and two cohorts (pancreatic head and other site groups) by the site of the primary tumor Figure 1The endpoint of this study was overall survival (OS). Pearson’s chi-square test was used to analyze differences between groups. Multivariate Cox proportional risk regression model was performed to analysis the hazard ratio (HR) and 95% confidence interval (CI). The survival analysis was carried out by the Log-rank test, and the survival curve was drawn by Kaplan-Meier (K-M) method. We performed propensity score matching (PSM) to eliminate the influence of other variables. All statistical analyses in this study were conducted by software SPSS 25.0. All p values less than 0.05 generated in the study were considered statistically significant.The total population consisted of 11,865 PDAC patients with stage IIB/III, including 3,336 early-onset patients (age<60), 3,966 middle-aged patients (age: 60-69), and 4,563 elderly patients (age≥70). As shown in In addition, 74.13% of primary tumors were located in the head of pancreas  and 25.87% in other sites  of the target population. Although the proportion of T3/T4 stages in patients with pancreatic head cancer is lower than tumors in other parts of the pancreas, more patients develop lymph node metastases. Similarly, patients with pancreatic head cancer tend to undergo RT (36.21%) and chemotherapy (70.86%) as well as surgery with RNE≥15 (57.24%) compared to patients with tumors in other sites of the pancreas .The results of univariate and multivariate cox proportional risk regression model Table 2 According to the multivariate Cox regression model, neither nRT (p=0.531) nor aRT (p=0.106) improved OS in early-onset patients with stage IIB/III PDAC Table 3.; p=0.065), while aRT might improve the OS of patients , while the OS of aRT patients was significantly better than that of non-RT patients  in the pancreatic anatomic region . FurtherIn addition, the effect of tumor anatomical site on the prognosis and treatment of pancreatic cancer has gradually become a research hotspot in recent years. A retrospective study of 128 patients with pancreatic cancer from Japan showed that tumor location was not a prognostic factor for overall survival of locally advanced pancreatic cancer, although the clinical presentation of PDAC at different sites may differ . HoweverTo date, our study was the first to specifically investigate the impact of RT on survival in PDAC patients with stage IIB/III at different ages and tumor sites. As a retrospective, non-randomized study, selection bias and confounding factors inevitably interfered. Although we use PSM to try to compensate for these defects, there are still some confounding factors that cannot be identified and some known confounding factors that cannot be controlled. The degree of tumor invasion, health status (comorbidities and frailty), surgical complications and recovery are all important factors affecting the decision of radiotherapy. These variables cannot be obtained and coded directly in the SEER database, so they can only be controlled indirectly. Furthermore, the data was sourced from a public database (SEER) rather than a separate queue, and the available information was limited. For example, the SEER database does not provide ECOG performance status, resectability status, surgical margin status, radiotherapy target design, technique, and dose, which undoubtedly weakens the reliability of the conclusions of this study. In addition, the data only provided whether the patients underwent chemotherapy, so it was not possible to determine whether the patients underwent 5-fluorouracil-based regimen. Finally, genomic data from tumor samples also have great clinical reference value to guide prognosis and treatment, but this is also not recorded in the SEER database. These missing variables are critical to prognosis and need to be discussed in future studies.In summary, this study was based on a stratified analysis of age and tumor location, highlighting the difference in the efficacy of RT in different subgroups of patients. Of course, the results of this study need to be further confirmed by prospective cohorts in patients with stage IIB/III PDAC.Carefully selected data from the SEER database suggested that age and tumor location may be the reference factors to guide the selection of RT for patients with stage IIB/III PDAC. These findings may contribute to the development of individualized treatment for patients with stage IIB/III PDAC.https://seer.cancer.gov/.Publicly available datasets were analyzed in this study. This data can be found here: The studies involving human participants were reviewed and approved by Ethics Committee of Xiangya Hospital of Central South University. Written informed consent from the participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.Conceptualization: DW, CL, and CG. Data curation: HG, MT, and CLL. Formal analysis: DW, LZ, QP, and FT. Methodology: DW, YL, QP, and FT. Writing-original draft: DW. Writing review & editing: CL. Revise & proofread: DW, YL, CG, and CL. All the authors read and approved the final manuscript.The first author, DW, received funding from the China Scholarship Council. The corresponding author, CL, received a grant from the Nature Scientific Foundation of China, contract grant number: 8217131506.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: In contrast to the drug situation in the rest of the world, synthetic drugs, rather than traditional drugs, have been the dominant abused drugs in China since 2019. However, the public misconception that synthetic drugs are not as addictive as traditional drugs, such as opioids and the scarcity of specific measurement instruments, have hindered the clinical diagnosis and treatment of synthetic drug abusers, thus the development of a localized instrument to evaluate dependence on synthetic drugs is in urgently needed.Method: Using a sample of 618 Chinese synthetic drug abusers , the present study developed and examined the psychometric properties of a self-reporting instrument, the Synthetic Drug Dependence Scale (SDDS), which consists of four subscales: physical dependence, psychological dependence, health injury, and social function injury.Results: The SDDS revealed a three-factor model structure  = 0.876, comparative fit index (CFI) = 0.965, Tucker–Lewis index (TLI) = 0.953, and Root mean square error of approximation (RMSEA) = 0.070), with good internal consistency  and convergent validity. Elevated scores on the SDDS were associated with a higher level of reward sensitivity, punishment sensitivity, and stronger impulsivity. Interestingly, psychological dependence was the only significant predictor (p < 0.05) of criterion variables compared with the other three subscales, implying the important role of psychological factors in synthetic drugs dependence. Adequate measurement equivalence across sex, age (18–30 and 31–57 years old), and employment group (employed and unemployed) was also established.Conclusion: The SDDS appears to be an effective and reliable instrument that could be used to further investigate the characteristics of synthetic and traditional drug dependence, promoting a deeper understanding of the physical and psychological roles in drug dependence. Synthetic drugs, compared with traditional drugs derived from natural plants, are artificially synthesized from chemical substances , which is widely used for Chinese opiate abusers, for application in the dependence rating of synthetic drugs.The OASI is a self-report instrument used to measure the severity of opiate dependence, with good reliability and validity for both the community-based drug users and rehabilitation drug users  and then examine the psychometric properties of the scale, consisting of the following procedures: (a) item revision. Several items are specific for opioid abusers needed to be modified for their generalizing to synthetic drugs. (b) Factor structure confirmation. (c) Internal consistency and convergent validity evaluation. Item reliability, composite reliability, and Cronbach's alfa jointly acted as indicators of internal consistency, and drug craving, reinforcement sensitivity, and impulsivity were chosen as the validation variables to evaluate the convergent validity. Reinforcement sensitivity and impulsivity are closely associated personality traits with drug abuse. Those with high reward sensitivity are more attentive to the euphoric effects of drug taking . The education level of most people was under high school (66.18%); 369 had jobs (59.71%) and 240 were unemployed (38.83%). As for their marital status, 187 (30.26%) were single, 149 (24.11%) were married, and 198 (32.04%) had a broken relationship, such as separation or divorce. Among them, 374 participants also completed the correlated validity scales and 370 validity samples were gained. Lastly, 100 participants were chosen at random for retesting 1 month later. Ethical approval was obtained from the Institutional Review Board of the Second Xiangya Hospital of Central South University.Overall, 650 participants joined in the survey and 618 valid SDDS questionnaires were left after deleting the incomplete and problematic questionnaires, such as those with identical responses for all items. In terms of the demographic details, the mean age of the sample was 34.69 years  and 44.17% were female   Lynam,  measuresThe item revision was completed by the expert group consisted of five professors working within the psychometrics and drug dependence fields. Three experts revised the item wording and expression, and the remaining experts evaluated the content validity of all the items. Based on the OASI scale, 10 items kept the same wording except for the deletion of “heroin.” Besides, given the difference in specific behavior characteristics between traditional drugs and synthetic drugs, the two remaining items were refined to make them more suitable for synthetic drug users in the expert group meeting. The second item “amount of daily heroin use” was transformed to “amount of daily synthetic drugs use,” and the dosage range varied in methamphetamine, ketamine, and ecstasy according to their dosage features. The choice of these three synthetic drugs lies in the fact that they are the top three abused synthetic drugs in China  and were placed in the low group if they scored in the bottom 27% on the SDDS score . Lastly, internal consistency was evaluated using the corrected item-total correlation, and a value higher than 0.30 was acceptable , for which a low value indicated higher stability and less variability of data. Then skewness and kurtosis were inspected to examine the distributional properties that influence the choice of subsequent estimation methods , and the validation sample had 292 participants for confirmatory factor analysis (CFA). SPSS 19.0  which was developed for ordinal data when categorical data are analyzed  should be lower than the composite reliability, whose values >0.60 are desirable , medium (r = 0.30), and large effect size (r = 0.50) were adopted  was conducted separately to test measurement invariance between males and females, young and middle age, and employed and unemployed people in the final model. Testing measurement invariance consists of three procedures from the least restrictive level to the most restrictive level: (a) configural invariance  is the base model that must be established to make subsequent tests meaningful. (b) Metric invariance  is the prerequisite for unambiguous cross-group comparison Bollen, . (c) Sca2 difference between models is the normal index and the Satorra–Bentler chi-square (ΔSB-χ2) can be used in place of the standard Δχ2 value in analyses of ordinal data  and participants in the high-synthetic drug dependence group scored significantly higher than those in the low-synthetic drug dependence group on the SDDS total score (p < 0.001). The internal consistency was evaluated using the corrected item-total correlation, and item 5 was identified as unacceptable based on the criterion of 0.30  indicated the adequacy of the current sample for factor analysis. This initial analysis produced a two-factor structure accounting for 47.33% of the observed total variance. Given the four-factor model proposed by the original scale author  and Bartlett's Test of Sphericity  of related variables, with standardized coefficient estimates from 0.149 (impulsiveness) to 0.259 (SR), implying the importance of psychological factors in synthetic drugs dependence.Correlations between the SDDS and related variables can be found in 2 and subtle change in CFI, TLI, and RMSEA scores, but not for the scalar invariance model. Then partial invariance test was conducted by releasing the second threshold of item 2 to be freely estimated  with a smaller change in CFI (−0.004) and TLI (0.002) and continued to release the third threshold of item 2, the ΔSB-χ2 was insignificant  with acceptable change in CFI (−0.002) and TLI (0.005), hence the partial invariance was established.The results of measurement invariance are shown in 2 was non-significant, ΔCFI and ΔTLI were < 0.01, and ΔRMSEA was < 0.015), the metric invariance was supported. Similarly, the non-significant Δχ2 and small change in other indices of the scalar invariance model supported the scalar invariance. In terms of the employment group, metric invariance was established . Although the Δχ2 was significant (p = 0.002) of the scalar invariance model, the change of other fit indices indicated nuanced differences between the models. Therefore, the scalar invariance was established. Overall, the SDDS exhibited favorable measurement invariance across the sex, age, and employment group.The change-in-model fit indices across age group suggested that the fit of metric invariance model was slightly better relative to the configural invariance model  is consistent with the study of Gu et al. , indicatThe results of CFA supported the three-factor structure. Compared with the two-factor model, the three-factor model provides a more detailed classification and allows further exploration. Specifically, given that physical dependence and psychological dependence might play different roles in the mechanism of synthetic drug dependence  of the first two options (lower dosage of drug use) in females and caused a bigger difference between options than males. A possible explanation could be that women have a stronger episodic memory ability than men  can be found in the article/The studies involving human participants were reviewed and approved by Institutional Review Board of the Second Xiangya Hospital of Central South University. The patients/participants provided their written informed consent to participate in this study.M-TL sorted data and wrote all the manuscript and files. JZ made a lot of efforts in sampling communication and arrangement. D-CZ and X-WL provided many suggestions on statistical analysis and design. Q-QC and P-WY helped collect the data. Z-LL provided many helpful suggestions and instructions during the interactive reviewing. T-SC designed the whole study and followed up all the procedures. All authors contributed to the article and approved the submitted version.This work was supported by the National Key Research and Development Program for Science and Technology under Grant (Number 2016YFC0800908).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.


Diabetes mellitus is considered to be a global epidemic. The combination of genetic susceptibility and an unhealthy lifestyle is considered to be the main trigger of this metabolic disorder. Recently, there has been increased interest in the roles of gut microbiota as a new potential contributor to this epidemic. Research, in recent years, has contributed to an in-depth characterization of the human microbiome and its associations with various diseases, including metabolic diseases and diabetes mellitus. It is known that diet can change the composition of gut microbiota, but it is unclear how this, in turn, may influence metabolism. The main objective of this review is to evaluate the pathogenetic association between microbiota and diabetes and to explore any new therapeutic agents, including nutraceuticals that may modulate the microbiota. We also look at several mechanisms involved in this process. There is a clear, bidirectional relationship between microbiota and diabetes. Current treatments for diabetes influence microbiota in various ways, some beneficial, but others with still unclear effects. Microbiota-aimed treatments have seen no real-world significant effects on the progression of diabetes and its complications, with more studies needed in order to find a really beneficial agent. Diabetes mellitus (DM) is a major health issue around the world. The International Diabetes Federation (IDF) Diabetes Atlas Ninth Edition  estimateOut of the total number of DM, around 90% of the cases are type 2 DM (T2DM), 5–10% are type 1 DM (T1DM), and 1–2% are other forms of DM. In 2019, 20.4 million (15.8%) live births occurred from mothers with some form of hyperglycemia  [The world’s economic burden related to DM was estimated to be around 760 billion USD in 2019, with an expected increase up to 825 billion USD by 2045 [To have a better understanding of the global impact of diabetes, it is important to consider that the rising number of people living with DM might be driven by the increased number of new cases , but also by an increased life expectancy  .Firmicutes and Bacteroidetes with the genera Lactobacillus, Bacillus, Clostridium, Enterococcus, and Ruminococcus (of the first phylum) and Bacteroides and Prevotella (of the second phylum) [It was 2000 years ago that Hippocrates, the “father of medicine”, said “all diseases begin in the gut” and, today, we experience the same feeling. There are many microbes in the human body and, collectively, they form the microbiota . Most of phylum) ,5.Lactobacillus and Bifidobacterium in breast milk decreases if a mother has been treated with antibiotics during pregnancy or breastfeeding [Colonization of the body by microorganisms begins at birth and changes in the first year of life, affecting human health during its entire lifespan . Microbitfeeding .Various factors can influence the microbiota, not only in infants but in early childhood. Changes in the composition and function of the microbiota can also develop in adults under the action of environmental factors, medical conditions , or living conditions  .Human microbiota play an important role in the homeostasis of the body. Changes in the composition and diversity of the microbiota can contribute to various diseases, ranging from gastrointestinal disorders, such as irritable bowel syndrome, and inflammatory bowel disease, to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and cancer ,10,11,12Changes in the composition of the gut microbiota in patients with DM have been studied in recent years. The results have shown that the Firmicutes/Bacteroidetes ratio is higher in patients with diabetes as compared with healthy individuals. Moreover, certain bacterial species are increased or decreased in patients suffering from DM .Gut microbiota are involved in health and disease through: the synthesis of amino acids, the production of short chain fatty acids (SCFA), the absorption of nutrients, the prevention of colonization with pathological bacteria, the influence on the composition of bile acid, and the production of several pattern recognition molecules .Clostridium, with a role in the fermentation of amino acids; Peptostreptococcus, with an impact on the use of glutamate and tryptophan; and bacteria from genera such as Fusobacterium, Bacteroides and Veillonella [Amino acids play important roles in protein synthesis and metabolism and in signaling pathways. Among the bacteria with a high impact on amino acids are: the genus llonella .Firmicutes phylum, the family Ruminococcaceae , and the family Lachnospiraceae  [Bacteroidetes phylum, i.e., acetate by Bifidobacterium spp., Lactobacillus spp., Akkermansia muciniphila, Bacteroides spp., Ruminococcus spp., Prevotella spp., and Streptococcus spp. and propionate by Bacteroides spp., Ruminococcus obeum and Salmonella spp. [Dietary fibers, transformed into monosaccharides, colon proteins, together with amino acids resulting from intestinal fermentation of proteins in the large intestine are the main substrates for producing SCFA. Acetate, propionate, and butyrate are the main and most abundant SCFA ,26. Butyia spp.) . Acetatella spp. . SCFA halla spp. ,30. All lla spp. .Bacteroides, Clostridium, Lactobacillus, Bifidobacterium, and Listeria. Intestinal bacteria have the ability to convert primary bile acids to secondary bile acids by eliminating the hydroxyl group. The dehydroxylation process is performed under the action of Clostridium and Eubacterium [Regarding the microbiota and bile acids, there is a two-way relationship. On the one hand, the microbiota can influence the composition of bile acids; on the other hand, bile acids have antimicrobial properties and can inhibit the overgrowth of bacteria. There are two types of bile acids: primary bile acids such as colic and chenodeoxycholic acids and secondary bile acids such as deoxycholic and lithocholic acids . Primaryacterium ,34. Freeacterium ,36,37.It is known that DM is correlated with inflammation, a process with an important role in T1DM, T2DM pathophysiology, and their complications. Cellular and humoral immunity are involved in the pathogenesis of T1DM. It is believed that there are various factors that occur early in life, such as infections, nutrition, or the composition of the intestinal microbiota, and have the ability to contribute to the development of T1DM by activating immune cascades ,39. ProiProteobacteria and Clostridiaceae, increased Bacteroidetes spp., and decreased Roseburia spp.; IL-6 level with increased Bacteroidetes spp. and decreased Roseburia spp.; IL-1β level with an increase in Bacteroides spp. and Veillonella spp. and a decrease in Bifidobacterium spp., Faecalibacterium spp., and Roseburia spp. [Correlations between proinflammatory cytokines and certain bacteria in the gut microbiota have been demonstrated: high TNF-α levels with decreased ria spp. . TNF-α cria spp. ,46.In healthy patients with healthy intestinal epithelium, LPS does not cross the intestinal barrier. Therefore, the maximum concentration of LPS occurs in the intestinal lumen and it is almost undetectable in the circulating plasma . This efThe most important SCFA in preventing increased intestinal permeability is butyrate. It plays an important role in mucin synthesis (increases mucin expression) and maintains tight junction integrity  ,52.An accurate quantitative and qualitative measurement of gut microbiota related metabolites in biological samples is needed, in order to understand the relationships between these metabolites and the development of metabolic disorders.Feces are a useful biological matrix that reflect the health of the lower gastrointestinal tract. The easiest and most straightforward approach appears to be the culture of fecal microbiota in selective, differential media. However, this method has proven to be unreliable since certain bacteria cannot be cultured. A large number of bacteria found in feces are strict anaerobes, with many of them being oxygen sensitive. As a result, during processing and culture, strict reducing conditions are required.Mass spectrometry is a technique that is commonly used together with other techniques (gas or liquid chromatography) to assess metabolites such as fatty acids or bile acid products. However, there are some limitations in using these methods, i.e., many enzyme activities are not limited to a given microorganism or bacterial community .Therefore, in recent years there has been rapid growth and improvement of analytical methods by using a derivatization step . The aimA novel approach to bacterial enumeration using rRNA-molecule-targeting RT-qPCR seems to be very helpful in quantifying the dynamic changes occurring in the gut microbiota during host aging .Therefore, feces are a dynamic and diverse matrix. Despite all the research, there is still a lot of work to be done on this subject, both in the analytical field to develop an optimal method to determine GM-related metabolites, and in the biological field to look for a link between gut bacteria and health or disease status.The management of DM has the potential to be modulated by interaction with gut microbiota. Lifestyle interventions  and pharmacotherapy  used to control hyperglycemia can influence or be influenced by the microbiome constellation. In human studies performed in T2DM patients, it has been difficult to disentangle gut signature of the DM from those of a specific diet or medication . Diet asMetformin is prescribed as first line pharmacotherapy in T2DM according to the guidelines recommendations, due to its good safety profile, good antihyperglycemic efficacy, pleiotropic effects and low cost . RegardiA. muciniphilla  [Escherichia and to lower Intestinibacter abundance [Metformin can act as a growth factor for some gut bacteria, such as of diet) ,61, and bundance . Metformbundance . There ibundance ,63. Othebundance ,60.A. muciniphila and a decrease in Clostridium orbiscindens. Furthermore, A. muciniphila has been shown to be negatively correlated with serum glucose, while Clostridium orbiscindens has been negatively correlated with PPARα and GLUT2 and has been positively correlated with TNF-α, MUC2, and MUC5 [Blautia, Bacteroides, Butyricoccus, or Phascolarctobacterium [In experimental studies on rats fed a high-fat diet, metformin has been shown to decrease the bacterial diversity . Metformand MUC5 . An animand MUC5 . Metformacterium .A clinical study realized on Japanese patients with T2DM showed that small changes in gut microbiota composition were observed after taking metformin for four weeks; a reduction in the Firmicutes/Bacteroidetes ratio was observed. This decrease was based on a reduced level of the Firmicutes phylum, and an increased level of the Bacteroidetes phylum .The effect of metformin on gut microbiota, especially regarding the genus Lactobacillus, are not consistent between animal and human studies . The expThese drugs have hypoglycemic effects by closing ATP-sensitive K-channels in the pancreatic beta cell membrane, followed by insulin release in the blood stream .Bifidobacterium lactis, Lactobacillus acidophilus, and Lactobacillus rhamnosus, in a study with alloxan-induced diabetes in rats, showed an elevated bioavailability of gliclazide [In experimental studies, probiotic pretreatment with a mixture of iclazide .In a recently published study using the parallel artificial membrane permeability assay (PAMPA) method, it was observed that probiotic bacteria and bile acids had important roles in bioavailability and patients’ responses to gliclazide, i.e., probiotic bacteria increasing the permeability of the drug .On the one hand, in the urine of patients with T2DM treated with sulfonylureas, increased levels of hippurate and aromatic amino acids  were observed, providing indirect evidence of the potential effect of sulfonylureas on the gut microbiota and its ability to process plant phenols and aromatic amino acids .On the other hand, a recently published study showed that 12 weeks of treatment with gliclazide in T2DM patients had no impact on diversity and the composition of gut microbiota, and there were no significant associations between microbiome composition and clinical parameters .Thiazolidinediones (TZDs) or ”glitazones” improve glycemic control in patients with T2DM by improving insulin sensitivity .Proteobacteria, but had no influence on Enterobacteriaceae and Desulfovibrionaceae [Firmicutes, Proteobacteria, and Verrucomicrobia, and a decrease in Bacteroidetes and Candidatus arthromitus were observed. Those modifications were reversible after starting a normal diet or one week treatment with rosiglitazone [db/J (db/db) mice that received rosiglitazone for 8 weeks developed changes in segment-specific host gene expression, without modifications of gut bacterial composition [In experimental studies, pioglitazone was reported to decrease the alpha diversity and to shift the beta diversity of gut microbiota in C57BL/6J mice . In a stionaceae . In a rolitazone . In a reposition . These dAcarbose has a therapeutic effect in DM by inhibiting α-glucosidase, resulting in a reduction in the conversion of oligosaccharides into mono- and disaccharides and delaying postprandial intestinal glucose absorption. By its mechanism of action, it plays a role in providing nutrients to gut bacterial population. An older study showed that acarbose could also increase colonic butyrate production by a mechanism involving an increase in the concentrations of starch-fermenting and butyrate-producing bacteria .Butyricicoccus, Phascolarctobacterium, and Ruminococcus and an increase in Lactobacillus, Faecalibacterium, and Dialister [Bifidobacterium longum [Lactobacillus and Bifidobacterium and depleting Bacteroides. T2DM patients with an abundance of Bacteriodes treated with acarbose had more changes in plasma bile acids and greater improvement in metabolic parameters than T2DM patients that had gut microbiota abundant in Prevotella. This findings might be used to stratify the T2DM population based on their gut microbiota composition prior to treatment and to identify those patients that may have more beneficial effects after administration of acarbose [Acarbose has also been recently indicated to have the potential to modify microbiota composition in people with prediabetes and T2DM. In a crossover trial with patients diagnosed with prediabetes, acarbose administration was followed by a modification of intestinal microbiome, meaning a reduction in ialister . In T2DMm longum . Acarbosacarbose . To dateacarbose .Blautia, Roseburia, Clostridium, and Baceroides, Erysipelotrichaeae, respectively) and to correct the gut Firmicutes/Bacteroidetes ratio [Candidatus Arthromitus, was significantly reduced after treatment with saxagliptin [Lactobacillus spp. and propionate and decreased Oscillibacter spp. and toll-like receptor ligands 2 and 4 [Dipeptidyl-peptidase IV (DPP-4) inhibitors have an indirect effect on glucose metabolism by inhibiting the degradation of the incretins, glucagon-like peptide-1 (GLP-1) . In expees ratio ,86. Inteagliptin . In an e 2 and 4 .The results of rodent studies differ from those obtained in human clinical trials. A clinical study published by Smits et al. analyzed the fecal microbiota in patients with DM2 after 12 weeks of treatment with either sitagliptin or liraglutide. These drugs had been added to the previous treatment with metformin and/or sulphonylurea. The results showed that the added treatment had no significant effect on the composition of the fecal microbiota .GLP-1 receptor agonists (GLP-1 RAs) are injected subcutaneously or are administered orally.Allobaculum, Turicibacter, Anaerostipes, Blautia, Lactobacillus, Butyricimonas, and Desulfovibrio and reducing the abundance of the order Clostridiales (phylum Firmicutes) and Bacteroidales (phylum Bacteroidetes) [Firmicutes  and an increase in the abundance of Proteobacteria and Verrucomicrobia  or Firmicutes  [In animal studies, modification of gut microbiota was observed, probably due to the fact that GLP-1 RAs modify gastric emptying  and gut transit time, altering the intestinal environment and microbiota composition . In a mioidetes) . Similaridiales) .Bacteroides, Lachnospiraceae, and Bifidobacterium) was observed [In another experimental study, an enhancement of SCFA-producing bacteria  on gut microbiota has been evaluated in clinical trials in patients with DM2. A significant difference in the composition of the gut microbiota was observed between respondents and non-responders to GLP-1RA treatment. Thus, in the GLP-1RAs respondent group, the decrease in blood glucose level was positively correlated with es obese .Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of oral antidiabetic drugs. An anti-hyperglycemic effect is exerted by inhibiting SGLT2 in the proximal convoluted tubule in order to prevent reabsorption of glucose and facilitate its excretion in urine .Ruminococcaceae and Proteobacteria , but Lactobacillaceae and Bifidobacteriaceae, two important beneficial bacteria, did not increase after this treatment [The scientific data about the potential effect of SGLT2 inhibitors (SGLT-2i) on gut microbiota are limited. One animal study showed that dapagliflozin treatment caused subtle changes in the richness and diversity of microbiota in diabetic mice, with minor effects on the microbiota in a control group and that the Firmicutes/Bacteroidetes ratio was reduced in dapagliflozin-treated diabetic mice as compared with the other groups. It remains unclear what could be the relevance of these changes to treatment efficacy . In anotreatment .A recently published study proved that 12 weeks of treatment with dapagliflozin had no impact on the diversity and composition of gut microbiota in T2DM patients and there was no significant association between microbiome composition and clinical parameters .Sotagliflozin is a newly developed drug, being the first dual SGLT inhibitor. By inhibiting SGLT1 present in the gut, sotagliflozin increases the concentration of glucose in the colon where it could promote changes in microbiota and increase production of SCFAs . In expeInsulin has been saving the lives of patients with T1DM since 1922, and is also used in the therapy of T2DM to improve glycemic control. Despite a century of use in human therapy, there are little data about its effect on gut microbiota. Due to its route of administration by subcutaneous injection, it is not expected to have a significant effect on gut microbiota.norank_f_Bacteroidales_S24-7_group and a decreased abundance of Lactobacillus and unclassified_f_Peptostreptococcaceae were observed [In an experimental study, it was observed that the administration of oral porcine insulin did not alter gut microbiota composition of NOD mice . This laobserved .Data about direct effects of insulin therapy on human microbiota are not yet available, but there is evidence that gut dysbiosis plays a role in the response to insulin therapy in T2DM. In a recently published study including 480 hospitalized patients (aged 65–95 years) with newly diagnosed T2DM and 180 healthy subjects without glucose metabolism abnormalities, IL-37 was observed to have a protective role in the elderly T2DM patients and sensitized them to insulin therapy through suppressing the gut microbiota dysbiosis. The expression of IL-37 was negatively correlated with the Bacteroidetes/Firmicutes ratio .Gut microbiota seem to be promising targets to treat DM . ModificOne of the most powerful therapies for treating obesity and related diseases, such as T2DM, is lifestyle optimization, namely healthy diet and daily physical activity.Bifidobacterium spp., which play important gut barrier-protecting roles, were nearly absent in all animals [Bacteroidetes  and the amount of Firmicutes and Enterobacteriaceae (Shigella and Escherichia) were reduced. These changes in microbiota composition were associated with more SCFA in children with a plant-based diet [Diet is a major factor that promotes gut microbiota composition. Animal studies have shown that variations in gut microbiota structure can be explained in a proportion of 57% by dietary changes and only in a proportion of 12% by host genetic mutation . In the  animals . A humansed diet . The autsed diet .Bifidobacterium and Lactobacillus and a decreases in Bacteroides fragilis and Clostridium perfringens, while animal proteins induced an increase in Bacteroides, Alistipes, and Bilophila [Roseburia and Eubacterium rectale, and decreased levels of SCFA, that might be detrimental to colonic health [Fiber content to not the only food that has the potential to modulate gut microbiota. Studies analyzing protein content of the diet showed that protein intake was positively associated with overall microbial diversity, but with notable differences between animal or plant sources. Proteins from plants were associated with an increase in ilophila . In addic health .Prevotella and augmented the Roseburia and Oscillospira genera, changes that were accompanied by improved insulin sensitivity [A Mediterranean dietary pattern is recommended by the guidelines for the prevention and clinical management of DM . Partialsitivity . A recensitivity . A recensitivity .Clostridiales and Lachnospiraceae and decreasing Bifidobacterium (4 spp.), Lachnospiraceae (2 spp.), Blautia, Dorea (longicatena and another sp.), E. hallii, and A. hadrus [Proteobacteria and inhibits the growth of Bacteroidetes and Firmicutes, whereas in patients without symptoms, it modifies Bifidobacteria count per gram of feces [A gluten-free diet modifies the abundance of intestinal bacteria in healthy patients, by increasing unclassified species of . hadrus . In patiof feces .Akkermansia muciniphilia , but this change was not persistent after returning to a regular dietary pattern [Intermittent fasting is a dietary pattern very popular among adults around the globe. There are several types of intermittent fasting behaviors, among which is included the religious fasting, Ramadan. During the holy month of Ramadan, people fast from sunrise to sunset, eating a large meal after sunset and a light meal before sunrise. It was observed that, at the end of the holy month, there was an increase in the abundance of  pattern .Bacteroides genus and Clostridiales order associated with a reduction in Lactobacillus reuteri) which induced glucose intolerance [Artificial sweeteners are present in the modern diet, especially in people with obesity and DM, in the effort to prevent high caloric intake and hyperglycemia. Suez, J. et al. showed, in animal studies, that saccharin caused a dysbiosis , TNF-α, and Il-6. Metabolic effects appear to be the consequence of downregulation of glucose-6-phosphatase expression in the liver of rats with streptozotocin-induced diabetes [One of the most studied probiotics is  profile . Anotherdiabetes . The effMicrobiota metabolites have a strong influence in DM, through their various relationships with the host metabolism and implications in several pathways. There is a bidirectional relationship between DM and gut microbiota, i.e., DM changes the composition of the microbiota, and the changed microbiota influence the pathophysiology of the disease. Current therapeutical approaches that aim at restoring the microbiota through various pharmacological and non-pharmacological therapies have seen mixed results. Most nutraceuticals seem to have a positive effect on DM symptoms and complications, but it is not yet clear which product is the better one and for which patients. Future clinical studies and meta-analyses of the current research are needed in order to successfully establish an efficient therapeutic agent.


Background: The population is aging and advances in multimodal imaging and transcatheter valve intervention have been prominent in the past two decades. This study investigated temporal trends in demographic characteristics, use of multimodal imaging, treatments, and outcomes in patients with bicuspid aortic valve (BAV).Methods and Results: A total of 1,497 patients  first diagnosed with BAV between January 2003 and December 2020, in a single tertiary center were divided into three groups according to year of diagnosis: group 1 , group 2 , and group 3 . The patients' demographic characteristics, comorbidities, BAV morphology, BAV function, BAV-related disease, use of multimodal diagnostic imaging, treatment modality for BAV, and clinical outcomes were compared among the three groups. The ages at diagnosis and at the time of surgery/intervention increased considerably from group 1 to 3. The patients' comorbidity index also increased progressively. The proportion of non-dysfunctional BAV and significant AS increased, while that of significant AR decreased. The frequency of infective endocarditis as an initial presentation significantly decreased over time. Additionally, the use of multimodal imaging increased markedly in the most recent group. The results also indicated increasing trends in the use of bioprosthetic valves and transcatheter aortic valve replacement. Overall and cardiovascular survival rates improved from group 1 to 3 (log rank p < 0.001).Conclusions: For the past two decades, remarkable temporal changes have occurred in patient characteristics, use of multimodal diagnostic imaging, choice of treatment modality, and clinical outcomes in patients with BAV. Bicuspid aortic valve (BAV) is the most common congenital heart valve disease, and the burden of BAV disease is greater than for other congenital anomalies –3. BAV cWe systemically analyzed a single-center Korean registry that consisted of 1,497 consecutively enrolled BAV patients 19 years of age or older. This retrospective and prospective registry contains echocardiographic data and clinical information from medical records of the patients from January 2003 to December 2020, in Severance Cardiovascular Hospital, Seoul, Korea. All patients were diagnosed with BAV through transthoracic echocardiography, and additional diagnostic imaging was performed according to the clinical judgement of the physician. When there was discrepancy between imaging tests, we determined exclusion after comprehensive consideration of all imaging studies and intraoperative findings. There were 14 exclusions in this study. The Institutional Review Board of Severance Hospital approved this study, which was conducted in compliance with the Declaration of Helsinki. The need for informed consent was waived.Baseline characteristics at the time of diagnosis were age, sex, height, weight, body mass index, and comorbidities. The Charlson comorbidity index was calculated to determine patient risk . All parCongenital BAV was diagnosed when only two cusps were identified unequivocally in systole and diastole in the short-axis view, with a clear “fish-mouth” appearance during systole, as previously described –8. Type All measurements of the aorta were performed on the QRS complex of the electrocardiogram according to recommendations . The dimWe investigated whether transesophageal echocardiography (TEE) and MDCT were performed in addition to transthoracic echocardiography. Diagnostic multimodal imaging was performed based on the clinician's judgement. Surgery or intervention was conducted according to the guidelines at time of diagnosis, based on patient symptoms, cardiac function, and BAV function and clinician decision. Eligibility for transcatheter AVR was determined by a multidisciplinary heart team.n = 269), group 2 , and group 3 . The baseline characteristics, ages at diagnosis and at the time of surgery or intervention, use of multimodality imaging, number of surgeries or interventions, and survival from all-cause death and cardiovascular death were compared among the groups.The study population was divided into three groups according to year of diagnosis with six-year increments: group 1  <0.05 was considered statistically significant. Statistical analyses were conducted using R version 4.1.0 .Categorical variables are expressed as percentage or frequency and compared using the χDuring the study period, a total of 1,497 patients  was diagnosed with BAV. The absolute numbers of patients diagnosed with BAV in groups 1, 2, and 3 were 269, 594, and 634, respectively. Baseline characteristics of the study population are shown in P for trend < 0.001), and sex distribution was not significantly different between groups according to diagnosis year, with males accounting for more than 70% of all groups. From group 1 to 3, a tendency for an increase in body mass index was observed (P for trend = 0.036). Analysis of patient comorbidities indicated that the more recent patients experienced more frequent hypertension and dyslipidemia, and the Charlson comorbidity index increased in this group (P for trend = 0.029). Analysis of BAV morphology indicated that type 1 was dominant in all groups, and there was no difference according to group. In terms of BAV function, the diagnosis of non-dysfunctional BAV increased in groups 2 and 3 compared to group 1 (P for trend=0.039), the proportion of significant AR decreased (P for trend = 0.002), and the significant AS increased steadily  and likely was attributable to the increased use in additional diagnostic imaging from groups 1 to 3. In group 3, TEE and MDCT were used in 38.6 and 33.9% of patients, respectively  and reached about 25% in groups 2 and 3. In terms of indications for surgery or intervention, surgery due to severe AR or infective endocarditis decreased over time .P for trend = 0.002). In addition, transcatheter AVR gradually increased over time . During the 3.8 years (interquartile range 1.0–6.9 years) of follow-up, all-cause death and cardiovascular death significantly decreased from group 1 to group 3  a significant temporal increase was observed in both age at the time of diagnosis and age at the time of surgery or intervention; (2) over time, the proportions of non-dysfunctional BAV and significant AS increased and significant AR decreased in patients with BAV; (3) a temporal change in the incidence of infective endocarditis was observed in patients with BAV; (4) surgical AVR using bioprosthetic valve and transcatheter AVR increased; (5) the frequency of additional diagnostic imaging, such as TEE or MDCT, remarkably increased in patients with BAV; and (6) there was a recent significant improvement in all-cause and cardiovascular death among all patients diagnosed with BAV. Understanding these temporal changes and trends in patient characteristics, BAV function, diagnosis, treatment, and outcome will be important for further diagnostic and treatment advances.BAV is the most common adult congenital heart defect and has associated increased risk for severe AS or AR, thoracic aortic disease or acquired complications such as IE , 22, 23.The diagnosis of non-dysfunctional BAV had increased in this study. In Korea, the number of TTE as screening tool is continuously increasing . The incThe present study also showed a decreasing trend for prevalence of IE as the first manifestation of BAV disease. The rate of IE was 1.7% in group 3, and the incidence of IE in BAV has been reported around 2%, which was comparable to our results , 24. A rMultimodality imaging has become increasingly important because BAV is not only a valve disease, but also is associated with other diseases such as aortopathy and cardiomyopathies –8, 10. TThis study also showed clinical outcome improvements in the more recent group despite an increase in mean age with a higher comorbidity index. There are several factors that could impact these results. Notably, as the proportion of non-dysfunctional BAV increased in group 3, it is possible that fewer clinical events were diagnosed because those events likely were attributable to previously undetected non-dysfunctional BAV in patients. In addition, recent advances in diagnostic imaging, surgical techniques , medicalOur study had several limitations. First, this study was conducted at a single tertiary center by comprehensively reviewing retrospective and prospective data; therefore, selection and referral bias were inevitable, and our results could not be generalized. The proportions of significant BAV dysfunction and severe aortopathy were higher than reported in previous studies , 26. TheIn past two decades, there have been remarkable temporal changes in patients with BAV. Patient characteristics, proportion of BAV dysfunction, diagnosis, and treatment strategy have changed, and the demand for bioprosthetic valves has increased. Temporal trends were observed with improvements of clinical outcomes in patients with BAV.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 Severance Hospital, Yonsei University College of Medicine. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.KK and CS contributed to the conception, design of the work, and drafted the manuscript. D-YK, JS, and IC assisted in data collection and analysis. G-RH and J-WH contributed to the review and revision of the manuscript. All authors contributed to the article and approved the submitted version.This research was supported from the Korean Cardiac Research Foundation (202103-02).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The obsessive–compulsive spectrum refers to disorders drawn from several diagnostic categories that share core features related to obsessive–compulsive disorder (OCD), such as obsessive thoughts, compulsive behaviors and anxiety. Disorders that include these features can be grouped according to the focus of the symptoms, e.g., bodily preoccupation  or impulse control , and they exhibit intriguing similarities in phenomenology, etiology, pathophysiology, patient characteristics and clinical outcomes. The non-competitive N-methyl-D-aspartate receptor (NMDAr) antagonist ketamine has been indicated to produce remarkable results in patients with treatment-resistant depression, post-traumatic stress disorder and OCD in dozens of small studies accrued over the past decade, and it appears to be promising in the treatment of SUD and ED. However, despite many small studies, solid evidence for the benefits of its use in the treatment of OCD spectrum and addiction is still lacking. Thus, the aim of this perspective article is to examine the potential for ketamine and esketamine in treating OCD, ED and SUD, which all involve recurring and intrusive thoughts and generate associated compulsive behavior. A comprehensive and updated overview of the literature regarding the pharmacological mechanisms of action of both ketamine and esketamine, as well as their therapeutic advantages over current treatments, are provided in this paper. An electronic search was performed, including all papers published up to April 2021, using the following keywords (“ketamine” or “esketamine”) AND (“obsessive” OR “compulsive” OR “OCD” OR “SUD” OR “substance use disorder” OR “addiction” OR “craving” OR “eating” OR “anorexia”) NOT review NOT animal NOT “in vitro”, on the PubMed, Cochrane Library and Web of Science online databases. The review was conducted in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The use and efficacy of ketamine in SUD, ED and OCD is supported by glutamatergic neurotransmission dysregulation, which plays an important role in these conditions. Ketamine’s use is increasing, and preliminary data are optimistic. Further studies are needed in order to better clarify the many unknowns related to the use of both ketamine and esketamine in SUD, ED and OCD, and to understand their long-term effectiveness. Sev019, for ,17 the t019, for ,17,18. M019, for  The rapiKetamine is a racemic mixture composed of both R and S enantiomers (50% each). Compared to R-ketamine, esketamine (the S-enantiomer of racemic ketamine) is a more potent antagonist at the phencyclidine site of the ionotropic glutamate receptor, N-methyl-D-aspartate (NMDA), and it therefore offers a stronger analgesic potency than either R-ketamine or the racemic mixture . KetaminThe excitatory neurotransmitter glutamate is prevalent throughout the central nervous system (CNS), and it has been found to play important physiological roles in neurodevelopment, cognition, learning and memory formation, as well as in the modulation of brain plasticity . GlutamaAim of the study: To the authors’ knowledge, no review has synthesized the published data on the therapeutic potentials of ketamine and esketamine in the OCD spectrum by focusing on OCD, SUDs and EDs. In this perspective article, we have analyzed and reviewed current evidence on the drug efficacy of ketamine and esketamine in these mental disorders, and we have evaluated their advantages compared with currently available therapeutic tools. We have also outlined potential therapeutic opportunities for further investigation.The review was conducted in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines . A literThe search of results was carried out individually by five investigators (A.M. (Alessio Mosca), A.M. (Andrea Miuli), F.D.C., G.D., R.C., I.D.M.) and supervised by S.C. and M.P.; doubtful cases were discussed by G.M., M.D.G. and SS. The selection and eligibility phases of the articles were carried out independently by the five selected members and, afterwards, the papers were subjected to a final cross-check. Any questions not solved by the team related to understanding the topic covered in the articles were requested directly from authors, if they were contactable. The data were collected in a Word table containing first names and year of publication of the study, the design, demographic variables , details of the NPS taken  and any other substances in combination, as well as the drugs’ effects on suicidal behaviors, suicidal ideation or abuse. Data synthesis was carried out by three independent members of the team (A.M. (Alessio Mosca), F.D.C. and G.D.) and compared at the end of the extraction process. All titles/abstracts were examined, and full texts of potentially relevant papers were obtained. Relevant works were selected in order to obtain a full representation of the available literature data on the selected topic. Experimental and observational studies, post-marketing surveillance reports, case reports, case series and fatality reports were included. The exclusion criteria included non-original research , non-full-text articles , works in a language other than English and studies involving animal/in vitro experiments. Although letters to the editor, conference proceedings and book chapters were excluded from the literature review, they were still considered in the retrieval of further secondary searches. A.M. (Alessio Mosca), A.M. (Andrea Miuli), F.D.C., G.D., R.C. and I.D.M. independently extracted and collected relevant data; S.C., M.P., G.M., S.L.S. and M.D.G. contributed to the analysis of the results and discussed possible issues and disagreements during the revision of the paper. From an initial list of 1125 studies, duplicates (n = 257) were eliminated, as were papers unrelated to the topic (n = 631) and those that did not meet the inclusion criteria . A total of n = 113 full-text articles were assessed for eligibility. From them, a number of 83 full-text articles were excluded, as they were considered irrelevant to the subject when reading their titles and abstracts . Finally, 30 studies were included in the qualitative synthesis .A total of 30 eligible articles were finally identified and included in this systematic review. The findings are described in detail and organized in relation to the specific type of article and order of publication see .Studies retrieved were represented by nine case series/case reports ,46,47,48According to the literature ,40,55, kA single-case trial with repeated ketamine IV infusions (0.5 mg/kg) over the course of 6 weeks produced positive results in a TRD patient with a co-occurring SUD  . KPT wasIn Cocaine Use Disorder (CUD), a comparison with lorazepam infusion revealed that IV ketamine effectively enhanced the motivation to quit and reduced cocaine cravings. Remarkably, these results were obtained after the first ketamine infusion . A compaAn evaluation of ketamine treatment in a 2-year follow-up study, including 70 heroin-dependent patients with Opioid Use Disorder (OUD) and randomized to a single low dose IM ketamine (0.2 mg/kg) injection or a high dose one (2 mg/kg), showed that KPT was effective at maintaining abstinence and reducing cravings within the first two years of follow-up. A greater and longer-lasting reduction in cravings was obtained with high doses rather than low doses of ketamine, indicating a dose dependence of the effects . MoreoveThe first attempt to treat non-responder AN subjects with ketamine infusions was made in the late 1990s by Mills et al., who reported prolonged symptom remissions in 15 patients with a chronic, complex history of AN  after treatment with 2–9 ketamine infusions at intervals of 5–21 days . IM ketaTo the very best of our understanding, current data represent the first literature review focusing on the use of ketamine and esketamine as a treatment for OCD, SUDs and EDs. Overall, studies have been recorded in the past ten years, a signal that increased interest in the use of ketamine for the treatment of depression, as well as psychiatric disorders, has developed among researchers. Regarding current findings on ketamine as a therapeutic tool in OCD, SUD and ED, some considerations are needed.The anti-obsessional effects of ketamine and NMDA receptor antagonists do show therapeutic potential. However, studies appear to be heterogeneous, and comparative studies with conventional therapeutic strategies were not reported in the current literature. The current evidence is still not strong enough to recommend ketamine for clinical practice at this time. The acute benefit of ketamine on OCD symptoms needs to be confirmed in controlled trials and cannot be divorced from the psychomimetic and dissociative effects of ketamine. Additionally, we cannot eliminate the possibility that other environmental effects caused acute changes in OCD symptoms. Current speculations are that the clinical effects may relate to the ketamine-induced mystical experiences rather than to a direct effect on NMDA receptors causing a transient increase in glutamate release ,66. A seChronic use of addictive drugs produces enduring neuroadaptations in the corticostriatal glutamatergic brain circuitry. Increased susceptibility to relapse in drug-experienced individuals, even after long periods of withdrawal, might be associated with drug-related long-term morphological and electrophysiological changes in the glutamatergic synapses in the nucleus accumbens which, together with drug-induced transient morphological and electrophysiological changes, might both impair normal information processing and contribute to the uncontrollable motivation to relapse . In the The number and quality of studies regarding ketamine and ED is still in its infancy, although glutamatergic neurotransmission plays an important role in ED, particularly in Anorexia Nervosa (AN) ,83. AfteTreatment strategies for OCD, ED and SUD are complex and difficult, and they often involve pharmacological and psychological interventions. To date, several drugs have been approved for the treatment of patients affected by symptoms belonging to the OCD spectrum, ED and SUD ,37,90,91As mentioned before , the impTo summarize, the advantages of using ketamine or esketamine can be recapitulated as the following: (i) no requirement for daily administration, as the molecules are administered for limited periods, thereby increasing a patient’s compliance and reducing the stigma of prolonged and daily intake of medications; (ii) the availability of nasal spray formulations that, in the case of esketamine, provide better handling and fewer safety profile issues and side effects; and (iii) in the case of concomitant medications, the possibility to reduce doses, thereby again improving safety profiles and reducing side effects ,101.Considering the heterogeneity of the articles selected, the risk of bias was computed using RoB v.2.0 . Parameters “Mising outcome data” and “Selection of the reported results” were found to have a low risk or some concerns while, for selected parameters , the assessment of risk of bias was not applicable.Despite the important data, the present review represents only a first assessment of data on the use of ketamine and esketamine and its effectiveness on OCD, ED and SUD. The first limitation of the present review was the predominance of heterogeneous studies, small samples and crossover designs. Comparative studies with conventional therapeutic strategies were not reported in the current literature. A second limitation was related to the use of a saline placebo and not of a real control for ketamine’s psychotomimetic effects. Moreover, studies had limited duration of follow-up; therefore, it was not possible to estimate the long-term benefit and potential long-term consequences of ketamine use. This point will require additional attention from researchers. Lastly, this review only included studies published in English.For several reasons, it is not an easy task to establish a clear relation between glutamatergic dysfunction and OCD spectrum, or to understand this relationship’s exact functional meaning. Firstly, glutamatergic neurons are present in almost all brain circuitries and are therefore difficult to specifically localize a glutamatergic dysfunction in a specific brain area . SecondlMany interesting new angles are offered by the implementation of ketamine and esketamine or, in general, psychedelic drugs for the treatment of many psychiatric and neurological conditions. These methods could be useful in those situations of non-response/resistance to standard pharmacological and psychological therapies that are currently observed in everyday clinical practice. Research efforts are needed to clarify the many unknowns related to the effects of these substances. These uncharted waters include short- and long-lasting neurobiological changes, impacts on the modulation of network activity and the functional connectivity of the brain, as well as the effects of drug-driven structural and functional modulations on mind function. However, a safe assumption is that joint efforts employing psychedelic-assisted psychotherapy can provide much-needed therapeutic options for OCD, MDD, SUD, ED and more. This is a brave new world that we need to explore.


During the COVID-19 pandemic, every domain of industry has experienced a severe economic downturn with concomitant stress throughout the economy. Employees working in government and private sectors are experiencing different psychological problems. The current study was conducted to investigate the role of work-related flow in the relationship of job insecurity with financial anxiety in the employees working in private and government sectors of Saudi Arabia. The sample comprised 1,195 employees, 886 females, and 309 males. The participants' ages ranged from 25 to 60 years. The Financial Anxiety Scale, Work-Related Flow Inventory, and Qualitative Job Insecurity Measures were found valid and reliable. Structural equation modeling was applied to test the associations. As hypothesized, the results indicated that job insecurity was positively related to financial anxiety, work-related flow was negatively associated with financial anxiety, and work-related flow mediated the relationship between job insecurity and financial anxiety. All these associations were significant regardless of gender, age, marital status, sector of employment, income, self-rated health, and COVID-19 infection status. Further research is needed to understand the impact of job insecurity on financial anxiety in-depth through the paths of work-related flow, especially in the midst of COVID-19. The current situation of the novel coronavirus 2019 (COVID-19) pandemic has increased levels of anxiety and depression in individuals , with more females (74.1%) than males. Regarding age, the modal category was middle-aged between 36 and 45 years (42.7%), and for the sector, the majority worked in the government (84.5%).Different quantitative research-based techniques were used in the current study, which was conducted in a correlational structure. There were 1,195 participants involved in the study. The research was conducted using a purposive probability sampling technique. Employees of government and private sectors working in Saudi Arabia were selected as research participants. The participant age range was 25–60 years . This scale was developed by Archuleta et al.  by adaptThis inventory was developed by Bakker  and consThis scale was developed by Blotenberg and Richter  and compBefore the data collection, the researcher mailed the authors of the scales used in the present study to get permission for their use. Then the researcher translated the scales into Arabic and later invited employees by email and social media to participate in an online questionnaire. The invitation informed the employees about the study's aim and stated that their participation was voluntary and that they could end their participation at any time. The researcher also contacted the relevant public and private employer sectors seeking formal permission from their heads. Informed consent was obtained from the employee participants, and the researcher explained the study's aim and purpose. Their confidentiality and anonymity were ensured. They were instructed to be honest while responding to the items of the scales. Permissions to conduct this study were obtained from the Umm Al-Qura University in Saudi Arabia. In order to ensure the accuracy and originality of items, translation and back translation methods were employed with three experts in the field.*Power, this sample size corresponded to a sampling power of 0.982, which according to Wywial (This study sought to investigate the relationship between job insecurity (JINS), work-related flow (WOLF), and financial anxiety (FAS). To achieve this, the data was collected using a Likert-scale-based structured questionnaire, and a total of 1,195 questionnaires were collected. Using Go Wywial  and Kyrio Wywial  was moreo Wywial . In thiso Wywial  was usedThis study investigated three broad constructs, that is Job Insecurity (JINS), Financial Anxiety (FAS), and the Work-Related Flow (WOLF). WOLF was a latent variable measured by three sub-constructs, namely, absorption (ABS), work enjoyment (WE), and intrinsic work motivation (IWM). Nevertheless, prior to their use in testing the study hypotheses, construct reliability, and construct validity were tested as prescribed by Blunch  and HarrConstruct validity was tested using both convergent validity and discriminant validity. The Average Variance Explained (AVE) measured the convergent validity, the minimum threshold of which is 0.60 , for financial anxiety the average score was 21.8 (SD = 13.3), and for work-related flow it was 57.1 (SD = 16.6). Most of respondents were females (74.1%), married (78.2), working in government sector (84.5%), earing between 9000 and 13000SR (41.5%), with very good health (32%), and had no COVID infections (86%).The mean score for job insecurity was 26.05  = −0.300; p < 0.05. There was also a weak negative correlation between FAS and work-related flow, r = −0.227; p < 0.05. However, the correlation between JINS and FAS was moderate and positive, r = 0.437; p < 0.05. Additionally, a higher level of FAS was associated with a higher level of JINS.In relation to the correlations, the results are presented in Structural equation modeling was carried out because of the latent nature of the constructs. This SEM analysis was performed with the lavaan package Rosseel, . The resp < 0.001), the first hypothesis was then accepted, meaning that there was sufficient statistical evidence at α0.05 that job insecurity was significantly related to financial anxiety. A negative relationship was found between work related flow and financial anxiety . The second hypothesis was accepted. All these paths were significant while controlling for gender, age, marital status, employment status, income, sector of employment, self-rated health, and COVID infection status. The validity of the SEM model was confirmed by the favorable model fit indices in The association between job insecurity and financial anxiety was positive and statistically significant  was 0.06, which was <0.08, the prescribed maximum. As all the model fit measures were within their prescribed thresholds, the tested model was validated . Secondly, job insecurity was significantly related to work-related flow . Thirdly, work-related flow was significantly related to financial anxiety . Fourthly, a reduction in the effect of job insecurity on financial anxiety was observed when controlling for work-related flow . Therefore, work-related flow mediated the relationship between job insecurity and financial anxiety. The third hypothesis was also accepted as there was enough evidence against the null hypothesis. The average causal mediation effects (ACME), the average direct effects, and the proportion mediated were calculated using the “mediation” package , Work-Related Flow (WOLF), and Financial Anxiety (FAS) in employees of private and government sectors. It was hypothesized that a positive relationship would be found between job insecurity and financial anxiety, a negative association would be found between work-related flow and financial anxiety, and finally that a mediation role of work-related flow would be found in the relationship of job insecurity with financial anxiety. The findings supported our first hypothesis, as the results indicated a positive relationship present between JINS and FAS. The second hypothesis was also supported as a negative relationship was found between work-related flow and financial anxiety. A significant mediation of work-related flow was found in the relationship between job insecurity and financial anxiety which supported our third hypothesis. All these associations were significant while controlling confounding variables.The results are consistent with prior studies that found that job insecurity was associated with financial anxiety  and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it 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.


Primary central nervous system lymphoma (PCNSL) is a rare but highly aggressive non-Hodgkin lymphoma. Treatment-related cardiovascular lesion has become one of the most common complications in patients with tumor. However, very little is known about the cardiovascular death (CVD) of the patients with PCNSL. This study aims at identifying the cardiovascular outcomes of PCNSL patients and making comparison on CVD with extra central nervous system lymphoma (ECNSL). Clinical information of PCNSL and ECNSL was retrieved from the Surveillance, Epidemiology and End Results database. The risk factors of CVD in PCNSL patients and the comparison on the CVD hazard between PCNSL and ECNSL were assessed with the competing risks regression. A 1:2 propensity score matching was used to reduce the imbalanced baseline characteristics between PCNSL and ECNSL. Four thousand thirty-eight PCNSL subjects and 246,760 ECNSL subjects were enrolled in this retrospective study. CVD was the leading cause (41.2%) of non-cancer death in PCNSL patients and mostly occurred within the first year of diagnosis. Age over 60s and diagnosis in 2000–2008 were significantly associated with the elevated risk of CVD in PCNSL patients, while chemotherapy and radiotherapy play no role on the cardiovascular outcomes. Compared with ECNSL patients, the risk of CVD in PCNSL patients were 40% approximately lower. The risk of CVD in the patients with PCNSL still remains unclear currently. Clinicians ought to pay more attention on the risk of CVD in PCNSL patients, especially the elder patients within the first year of diagnosis. Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive non-Hodgkin Lymphoma (NHL) that involves the brain, eyes, spinal cord, and cerebrospinal fluid. Although the response rate of PCNSL treatment has been ascending over the past decades, the long-term prognosis of PCNSL patients still remains poor due to the delayed treatment-related complications .Cardiovascular death (CVD) has been regarded as one of the most common late complications of cancer therapy , 3. DespFirstly, PCNSL originates from intracranial site with blood brain barrier, leading to the poor access and efficacy in the brain for the chemotherapeutic drugs used in NHL , 8. As aTherefore, considering the disparities in chemotherapy standard, radiotherapy-induced cerebrovascular risk and median age at diagnosis, patients with PCNSL might be suffering from a greater hazard of dismal cardiovascular prognosis.To date, the clinical outcomes of CVD in the patients with PCNSL still remains unknown. Hence, there is an urgent necessity to differentiate the risk of CVD in the patients with PCNSL from other with NHL, in order to provide more precise references for clinicians on clinical decision making. This study aims to carry out an analysis on cardiovascular outcomes of CVD in the PCNSL patients and its comparison with the extra central nervous system lymphoma (ECNSL).The cases used in this retrospective cohort study were retrieved from the Surveillance, Epidemiology and End Results (SEER) database, consisting of 18 nationwide cancer registries and covering 35% of the population in the United State . All theThe inclusion criteria were as follows: (1) Year of diagnosis = “2000~2016”; (2) Histological diagnosis = “non-Hodgkin lymphoma”; (3) Type of follow-up = “Active follow-up”; (4) Sequence number = “One primary only”. The exclusion criteria were as follows: (1) Cause of Death and follow-up = “Dead (missing/unknown)”; (2) Race recode = “Unknown”; (3) Marital status at diagnosis = “Unknown”.Subjects were classified into two groups by primary site: PCNSL  and ECNSL (Primary Site-labeled = others). Patient variables comprised age at diagnosis , sex , race , marital status , histology , chemotherapy , radiotherapy , surgery , and year of diagnosis . Subject follow-up outcomes included being alive, cancer-related death, CVD, and other death. As recorded in SEER database, CVD includes disease of heart, hypertension without heart disease, cerebrovascular disease, atherosclerosis, aortic aneurysm and dissection, and other diseases of arteries, arterioles, and capillaries. CVD-specific survival was defined as the period from the date of diagnosis to the patient’s death due to CVD.Baseline characteristics were compared with Chi-square Test for the categorical variables. Fine and Gray’s competing-risks regression was used for univariate and multivariate analyses to assess the risk factors of CVD in the patients with PCNSL. Endpoint was defined as CVD and competing event was defined as non-CVD death.P value over 0.05 was regarded as an acceptable balance. Before and after the PSM, we applied the Fine and Gray’s competing-risks regression to the comparison on the hazard of CVD between PCNSL and ECNSL. The CVD-specific cumulative incidence was displayed by using cumulative curves.A 1:2 Propensity Score Matching (PSM) which was computed with logistic regression was to reduce the imbalanced baseline characteristics between PCNSL group and ECNSL group. All the variables were enrolled into the propensity score calculation: age at diagnosis, sex, race, marital status, histology, chemotherapy, radiotherapy, surgery, and year of diagnosis. The match was conducted using nearest-neighbor algorithm with caliper width of 0.02. A P value was less than 0.05.Stata/MP software (version 14.0) was used to perform the competing-risks regression. R software (version 3.6.1) was utilized to carried out the PSM. Hazard ratio (HR) were reported within ninety-five percent confidence interval (95% CI). Difference was defined as statistical significance if a two-tailed P > 0.05) between 4,017 cases of PCNSL and 7,981 cases of ECNSL  and most of them were defuse large B-cell lymphoma (DLBCL)  and white . The median age of PCNSL patients was 63 years. As for treatments, while 2,715 (67.2%) patients received chemotherapy, only 1,437 (35.6%) patients received radiotherapy. Over a half  patients did not underwent surgery. After the 1:2 PSM, all the baseline characteristics were well balanced  were dead due to cancer-related death and the remaining 357 (13.1%) died of non-cancer death, among which CVD accounted for 147 (41.2%) deaths, being the principal cause of non-cancer death Figure 2As shown in Throughout the analysis period, 68 (46.3%) CVD took place within the first year of diagnosis, 46 (31.3%) CVD occurred between the first and the fifth years, and the remaining 33 (22.4%) CVD arose 5 years later. Heart disease was the most frequent  CVD among patients with PCNSL and this proportion kept enlarging slightly, followed by cerebrovascular disease  and hypertension , with only 1 (0.7%) atherosclerosis death Table 2.P < 0.001) and those diagnosed in 2009–2016 were related to a lower risk of CVD . Specifically, a significant decreased risk of CVD was observed in the patients with chemotherapy  in univariate analysis, but not in multivariate analysis . Other variables, including marital status, radiotherapy, surgery, histology, race, and sex, played no role on the risk of CVD.As shown in P < 0.001; after PSM: HR = 0.601, 95% CI = 0.494–0.731, P < 0.001). As illustrated in Before and after the 1:2 PSM, the risk of CVD among PCNSL patients were both approximately 40% lower compared with ECNSL patients  demises. The majority of CVD occurred within the first year and heart disease was the most frequent CVD. In addition, in the subgroup by no matter age period or survival time, CVD all demonstrated an ascending trend. It is worth noting that in the subgroup of age 80+, the proportion of CVD even exceeded that of cancer-related death after 5 years follow-up time. This result is similar to the previous study. A SEER-based research published on European Heart Journal showed that after 12 years of diagnosis, the cumulative mortality of heart disease even exceeded that of cancer itself in the breast patients with age 75+ . BesidesIn the investigation of risk factors, we utilized the competing-risk regression, which is considered as a more suitable and accurate method when estimating the incidence of competing events, rather than using the Kaplan-Meier survival function .The median age of PCNSL patients was 63, which is close to the result of the previous study . Our resChemotherapy seems to be a favorable factor of CVD in the univariate analysis, whereas not in the multivariate analysis after enrolling age at diagnosis and year of diagnosis. This inconsistency might be due to the treatment bias on ages: patients younger than 60 were more likely to receive and tolerate the chemotherapeutic regimen because of their better cardiovascular condition, while those over 60 presumably had more contraindications to chemotherapy as a result of dismal cardiovascular comorbidity. Thus, after the adjustment of age of diagnosis, the treatment bias was amended in multivariate analysis.HD-MTX has been recommended as an indispensable agent in the chemotherapeutic regimen by the clinical guideline . InteresIn the previous studies, radiation to head and neck was found to be an independent risk factor of ischemic cerebrovascular disease –13, wherAfter the 1:2 PSM, all the clinical variables, including age, sex, histology, chemotherapy, radiotherapy, and surgery, were well-balanced, which avoided the selection biases as much as possible and allowed the data to be more comparable. The relative risk of CVD in PCNSL patients was 40% lower compared with that in ECNSL patients before and after the PSM. We hypothesized that this disparity might be caused by the different chemotherapeutic drugs for PCNSL and ECNSL. R-CHOP regimen, standard treatment for ECNSL, were confirmed that was significantly associated with elevated risk of congestive heart failure and other cardiovascular diseases . Apart fSeveral limitations should be noted due to the inherent drawbacks of a retrospective study. The incomplete information of chemotherapy and radiotherapy, such as dosage, drugs, and courses, limited us from a further investigation into these therapeutic risks of CVD. In addition, the SEER database lacked the cardiovascular comorbidity of patients at baseline characteristics, which might result in the potential biases on cardiovascular outcomes. Moreover, we had no access to the profile of other recognized risk factors of CVD, encompassing smoking, hypertension, diabetes, etc. Despite these shortcomings mentioned above, the methods applied in the analyses were rigorously designed and the results still provide certain referential value on cardiovascular outcomes.In conclusion, this is a study providing insights into the risk of CVD in the patients with PCNSL. CVD was the leading cause of non-cancer death in PCNSL patients. The proportion of CVD demonstrated an increasing trend among PCNSL patients by different age period and survival time. Thus, clinicians ought to pay more attention on the risk of CVD in PCNSL patients, especially the elder patients within the first year of diagnosis. Chemotherapy and radiotherapy were not relevant with the cardiovascular outcomes of PCNSL patients, which might mitigate the concern of the treatment-induced cardiovascular risk. Compared with ECNSL patients, a more favorable cardiovascular outcome was demonstrated in PCNSL patients. More clinical trials are required to further inspect the risk of CVD in the patients with PCNSL.https://seer.cancer.gov/data-software/.Publicly available datasets were analyzed in this study. This data can be found here: Ethical approval was not required for publicly available information.ZQ, YC, and XX designed the study. ZQ, MS, and XW downloaded, analyzed, and interpreted the data. ZQ, YT, and YJ prepared the draft manuscript. YC and XX provided the critical revisions. All authors contributed to the article and approved the submitted version and agreed with the order of presentation of the authors.This study was funded by the Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation.  (pdjh2021a0407 and pdjh2021b0416).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Autonomic nervous system (ANS) dysfunction has been suggested to contribute to the high prevalence of cardiovascular complications in individuals with anorexia nervosa (AN), yet has not been thoroughly investigated. The current review aimed to synthesize the evidence of basal ANS function in individuals with a current diagnosis of AN and those with a previous diagnosis who had achieved weight restoration, as compared to controls.Methods: A systematic review of nine databases was conducted and studies that were published in a peer-review journal, in English, that included at least one assessment of ANS function in individuals with a current or previous diagnosis of AN were selected. Forty-six studies were included with a total of 811 participants with a current diagnosis of AN and 123 participants with a previous diagnosis of AN.Results: ANS function was assessed through heart rate variability (n = 27), orthostatic challenge, blood pressure variability or baroreflex sensitivity (n = 11), adrenergic activity (n = 14), skin conductance level (n = 4), and pupillometry (n = 1). Individuals with AN demonstrated increased parasympathetic activity and decreased sympathetic activity, suggestive of autonomic dysregulation. Following weight restoration, autonomic function trended toward, or was equivalent to, control levels.Discussion: Autonomic dysregulation is indicated through a range of assessments in individuals with AN. Future investigations should utilize a variety of assessments together in order to conclusively establish the nature of autonomic dysfunction in AN, and following extended weight restoration. Moreover, investigation into the co-occurrence of ANS function and cardiovascular risk is required. Anorexia Nervosa (AN) is an eating disorder characterized by restriction of food intake, an intense fear of gaining weight and a distorted self-perception of body image  provides the link between the cardiovascular system and the central nervous system, and is responsible for the regulation of internal bodily processes in response to physiological and environmental changes   Moher e and was www.covidence.org) by HW. Two authors  independently screened records on title and abstract and then full text against the following exclusion criteria: primary condition not AN, no diagnostic criteria referenced, no control group, no basal ANS assessment outcome, protocol paper, review article, dissertation, conference abstract, case series/study. A third reviewer (N.E.) resolved any conflicts. Studies that included at least one of the ANS measures in basal conditions listed in Search results were exported to Endnote bibliographic management software, duplicates removed, and the remainder uploaded to Covidence systematic review software (Two reviewers (Z.J. and E.L.) independently extracted data and consensus was confirmed by a third reviewer (N.E. or A.P.) Extracted data included information on study characteristics and basal ANS assessment and outcomes.The risk of bias among included studies was assessed independently by two authors (Z.J. and D.C.) using a modified version of the Newcastle-Ottawa Quality Assessment Scale NOS; see  for cohoGiven the large number of included studies that assessed HRV, we used a modified version of a previously published measure of study quality in studies of HRV in functional somatic disorders to specifically evaluate quality of HRV methods , 17 were at moderate risk (37.0%), and 27 were at low risk (58.7%) see . The HRVResting HRV was an outcome measure in 27 articles , two found decreased α  as compared to controls , or baroreflex sensitivity (BRS) as an outcome measure  and/or diastolic BP (DBP)  as an outcome measure in individuals with a current diagnosis of AN see ; two repThe only study that assessed pupil response (PLR) found decreased PLR response in individuals with a current diagnosis of AN, which did not persist after weight restoration , or randomness, in heart period series that has been demonstrated to be reduced in individuals with congestive heart failure  was repeatedly highlighted as a distinguishing feature of HRV profile HRV function in AN. Similarly, future investigations in individuals with an extended duration of weight restoration are still required. Determination of autonomic function through a variety of assessment methodologies in individuals with a current, and previous, diagnosis of AN alongside assessments of cardiovascular risk will aid in determining the contributing factors to cardiovascular complications. This will allow clinicians to identify individuals at risk and aid in the prevention, treatment and development of interventions to reduce the inadvertent mortality rate of AN.The original contributions presented in the study are included in the article/ZJ conceived the project and drafted the manuscript. HW conducted the search. ZJ, EL, and NE conducted the study selection. ZJ, NE, AP, DC, and EL conducted the data extraction and risk of bias. All authors designed and approved the protocol, reviewed, and approved.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.