PTEN gene, never described in TC. This mutation was present in the primary tumor and, with a lower allelic frequency, in metastases diagnosed after treatment with Sorafenib. Mutations in TP53 (p.C135Y and c.920-2A>G previously detected in anaplastic carcinomas and p.M133R never found in TC) were also detected in the primary tissue together with a mono-allelic expression of the p.C135Y mutant at RNA level. At metastatic sites level, we found only the TP53 splicing mutation c.920-2A>G. The presence of defects in mismatch repair (MMR) proteins and genomic instability was also evaluated. The primary tumor showed a partial expression of MMR proteins together with a strong genomic instability. In conclusion, we demonstrated that the rare combination of somatic PTEN and TP53 mutations in a patient with a metastatic FTC, together with the presence of tumor heterogeneity and genomic instability, might be associated with a high tumor aggressiveness and resistance to treatments.To date, the molecular mechanisms that underline aggressiveness and resistance to tyrosine kinase inhibitors in some thyroid carcinomas (TCs) are not known yet. We report the case of a young patient with a metastatic poorly differentiated (PDTC) and follicular thyroid carcinoma (FTC) refractory to conventional therapies and to Sorafenib. The patient, despite an initial partial response, died of progressive disease 21 months after diagnosis. The genetic analysis performed on the primary tumor and on lymph nodes and distant metastases allowed to identify a frameshift mutation (p.P248Tfs*5) in the  TP53 gene codifies for a master regulatory protein, also known as “guardian of genome”, involved in different cellular processes such as apoptosis, DNA repair, cell cycle arrest, and cellular senescence  TP53 mutated, more than 70% of PDTC/ATCs are associated with TP53 mutations . PTEN, through its lipid phosphatase activity inhibiting the PI3K/AKT pathway, regulates many cellular processes, including proliferation, survival, energy metabolism, cellular architecture, and motility (PTEN and TP53 mutations in a context of tumor heterogeneity and genomic instability.Well-differentiated thyroid carcinomas (WDTCs) are efficiently treated by surgery and radioiodine. On the contrary, poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are refractory to radioiodine therapy, and, in recent decades, tyrosine kinase inhibitors (TKIs) with angiogenetic and molecular targets were developed and used for these cases . The molnescence . The p53utations . Interesmotility . Althoug rarely <0% TP53 m rarely <% TP53 mumotility . Immune motility , might b2, convoluted nuclei, and absence of anaplastic features. In addition, Ki-67 immunostaining showed a proliferation index >5% in both the primary tumor and the distant metastasis  with widely invasive FTC areas with pleomorphic nuclei (20%)  , 14. Thetastasis . Due to BRAF and RAS mutations and ret/PTC rearrangements, which were negative in this patient. Therefore, now that the molecular analysis in our laboratory has been extended to numerous genes involved in thyroid carcinogenesis by means of both mass spectrometry and Sanger sequencing, we have decided to re-analyze this particular case. The molecular analysis of the DNA obtained from the formalin-fixed paraffin-embedded (FFPE) primary TC revealed the presence of a frameshift variant in exon 7 of PTEN   in heterozygosis, both absent in the corresponding contralateral normal thyroid tissue (data not shown). Analyzing different frozen primary TC sections, we confirmed the presence of the PTEN p.P248Tfs*5 mutation in all specimens (data not shown). On the other hand, a heterogeneous TP53 molecular profile was observed in these samples: one harbored the TP53 p.C135Y mutant together with a splicing mutation in intron 8 (c.920-2A>G), the second harbored the TP53 p.C135Y variant together with another missense variant , the third sample had only the p.M133R mutation, and the last had no TP53 mutations  and normal in the contralateral normal thyroid tissue , a positive nuclear staining was observed for all these markers  in the tissues analyzed  and follicular thyroid carcinoma (FTC) treated with surgery, radioiodine, and Sorafenib. The patient, despite an initial partial response, died of progressive disease 21 months after diagnosis.PTEN frameshift variant (p.P248Tfs*5) together with three TP53 mutations  in some, but not all, samples analyzed. We are tempted to speculate that TP53 mutations occur in poorly differentiated tumor area, since 80% of the primary TC is composed by PDTC. The co-occurrence of both PTEN and TP53 mutations in thyroid and other cancers has already been reported , but never in sporadic TC. On the other hand, the TP53 p.C135Y variant and the splicing mutation c.920-2A>G were already described in ATC  and in other solid and hematopoietic tumors (COSM10801 and COSM33650). Finally, the TP53 p.M133R variant was reported at germline level in Li–Fraumeni syndrome and at somatic level in solid and hematopoietic tumors (COSM43730), but never in TC. It is possible to speculate that TP53 mutations.Molecular analyses of primary tumor and metastatic tissues showed the co-occurrence of a reported , 17. In PTEN mutation is constantly found in primary TC, and all metastases analyzed were consistent with its clonal origin. It is worth to note that the allelic frequency of this mutation is lower in metastases obtained after Sorafenib treatment with respect to other samples, indicating a potential effect of the TKI treatment on tumor clones harboring the PTEN frameshift. On the other hand, a variable mutational pattern for TP53 was observed in primary TC and metastases samples (sections with either one or two or three mutations or entirely wild type for TP53). We excluded that these mutations are passenger ones, as they were previously reported in TC and other cancers and known to be non-functional pathogenic variants  or predicted to be likely pathogenic/pathogenic . The finding of three mutations affecting the TP53 gene is not surprising, since FTC exhibits remarkable genomic instability evidenced by TP53 hyper-mutability    was founutations , 28, butyndromes . Althougyndromes . The preFTC case . DefectsFTC case  or that FTC case , 35, subUnfortunately, the patient’s general conditions deteriorated rapidly after surgery in June 2009, and thus, distant liver and adrenal metastases were not available for further molecular characterization. It is well-known that TKIs exert their effect through a cytostatic action, and, once started, a continuative treatment is needed to maintain a response to the disease. When the TKI treatment is stopped, as it happened for our patient, the escape phenomenon is observed, and the progression of the disease can become even more rapid.PTEN and TP53 mutations seems to be associated with a particular tumor aggressiveness and maybe with a possible resistance to TKI. This case report highlights the importance of characterizing both primary tumor and metastases at molecular level to predict the response to treatments. Indeed, the tumor heterogeneity can evolve during tumor progression or as a consequence of drug-dependent selection of a pre-existing or newly acquired resistant clones. For this reason, further studies are needed, and new therapeutic strategies will be explored, such as drugs able to restore the transcriptional activity of mutant p53 or immune checkpoint inhibitors useful in cancers with high level of microsatellite instability or with defects in MMR genes.In conclusion, we demonstrated the presence of genomic heterogeneity and instability in a patient with metastatic poorly differentiated (PDTC) and follicular thyroid carcinoma (FTC) refractory to all treatments. The rare combination of The original contributions presented in the study are included in the article/This study was reviewed and approved by Istituo Auxologico Italiano. The patients/participants provided their written informed consent to participate in this study.CC provided clinical details. GP performed the molecular analysis of other genes, the analysis of microsatellites status, and of copy number variation. DS performed immunohistochemistry. MM performed PTC mass array. GB revised immunohistochemical results. VC conceived and designed the study; she performed molecular analysis of TP53 gene and transcript. VC, CC, LP, and LF wrote, edited, and reviewed the manuscript. All authors were involved in analyzing the data, writing the paper, and had final approval of the submitted and published versions.This study was partially funded by Ricerca Corrente Istituto Auxologico Italiano IRCCS  and by the Italian Ministry of University and Research (PRIN 2017-2017YTWKWH).The author acknowledge the support of the APC central fund of the university of Milan.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 commonly used screening tests for Parkinson’s disease (PD) are the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE), both of which only focus on cognitive function. A composite assessment that considers both cognitive and social dysfunction in PD would be helpful in detecting mild cognitive impairment (MCI) and PD dementia (PDD).We aimed to simplify the commonly used tools and combine cognitive and social functioning tests to detect early MCI and PDD.A total of 166 participants  were recruited who completed the MMSE, MoCA, PD social functioning scale (PDSFS), clock drawing test, activities of daily living, comprehensive neuropsychological assessment , and movement disorder society (MDS)-unified PD rating scale. According to the MDS diagnostic criteria, the patients were grouped into PD-nonMCI, PD-MCI, or PDD.p < 0.001) and 0.790 (p < 0.001). When the simplified MoCA was 7 or the combined test 30, the patients would be classified as having PDD. The AUCs of the two tests were 0.846 (p < 0.001) and 0.794 (p = 0.003).To detect PD-MCI, the optimal cut-off scores for the simplified MoCA and the combined test were 9 and 35. The discrimination values measured by the area under the receiver operating characteristic curve (AUC) of the two tests were 0.767 (We suggest considering both cognitive and social functions when detecting PD-MCI and PDD. Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. The number of individuals diagnosed with PD has grown significantly in the past three decades worldwide . Recent The clinical diagnostic criteria for PDD published by the movement disorder society (MDS) task force include the following core features: impairment in more than one cognitive domain, representing a decline from premorbid level, and deficits severe enough to impair an individual’s function in daily life  . PatientThe MMSE  and MoCAMost studies found that it has superior psychometric properties to the MMSE  in detecPatients’ cognitive function and independent daily life are crucial for diagnosing MCI or dementia. Clinically, physicians often use cognitive tools to examine the cognitive function and experience to determine whether the patients’ social and occupational functions are impaired and further diagnose whether the patients have MCI or dementia. There have been many studies in the past that have analysed and compared various cognitive testing tools for the detecting ability  ; moreoveOne hundred and sixty-six participants were recruited  in this study. The outpatients were diagnosed with idiopathic PD by neurologists from teaching hospitals. According to the recommendations of the MDS task group diagnosis criteria for PD with MCI  and possThe age-matched HC group was recruited from the community. Participants’ inclusion criteria were: basic speaking and reading skills (able to understand after explanation and could provide informed consent), no severe systematic disease, and no consumption of drugs affecting neurocognitive function. Participants were excluded if they had atypical parkinsonism, medical conditions that may cause cognitive dysfunction, and comorbidities, such as hepatitis B, hepatitis C, delirium, head trauma, psychiatric illness , and substance use. No HC had a global cognitive problem .All participants provided informed consent before participating in the study, and all experiments were conducted per the 1975 Declaration of Helsinki. Additionally, the ethical research committee of the hospitals approved the study protocols.The institutional review boards at National Cheng Kung University Hospital and Kaohsiung Medical University Hospital provided formal approval for the study procedures. All participants  provided written informed consent.All participants underwent a comprehensive clinical evaluation that included collecting information on demographic data, medical history, daily activities appraisal , and soThe comprehensive neuropsychological assessment  was usedp value. Continuous variables were expressed as mean with standard deviation (SD) and categorical variables as percentages. The Kolmogorov–Smirnova test or Shapiro–Wilk test determined if a data set was well-modelled by a normal distribution. The Spearman correlation coefficient was used to evaluate the relationship between different ordinal test measures and avoid collinearity.All analyses were performed using SPSS V.17 software . The level of significance was set at α = 0.05. After accounting for the number of tests performed, we modified the overall alpha criterion for significance. The Bonferroni correction was used to adjust post hoc tests were used for post hoc comparisons.First, demographic and disease-related characteristics were summarised with descriptive statistics. Analysis of Covariance (ANCOVA) was used to compare the scores of the MMSE, original MoCA, and neuropsychological tests between the groups with age, sex, and education adjusted. Dunn’s Second, the Spearman correlation coefficient was used to evaluate the relationship between variables. Highly correlated (above 0.7) variables were deleted to avoid all input variables having a high degree of collinearity and affecting the model variance. Then, we used logistic regression analysis to explore the domains/factors to achieve the best predictive power, develop simplified versions of MoCA and PDSFS, and combine the two tests. The model specifically predicted the PD-MCI and PDD groups.Third, the receiver operating characteristic (ROC) curve method was applied to find an optimal cutoff of the simplified versions of MoCA, PDSFS, and a combination of the two tests. In addition, the Wilcoxon test was used to compare two ROC curves . Generalp < 0.001).The relationships between each variable  were evaluated by Spearman correlation and excluded highly correlated variables (Spearman correlation coefficient > 0.7) . We usedp < 0.001).The AUCs for the simplified MoCA, simplified PDSFS, and a combination of these two tests were 0.767, 0.652, and 0.790, respectively. The optimal cut-off score for combining these two tests was ≤ 35 .The AUCs for the simplified MoCA, simplified PDSFS, and a combination of these two tests were 0.846, 0.672, and 0.794, respectively. The optimal cut-off score for combining these two tests was 30 . Moreover, Both the original MoCA and the simplified MoCA can be used to distinguish PD-nonMCI from PD-MCI and distinguish PD-MCI from PDD (p > 0.005). Our simplified MoCA (p = 0.001) can be used to distinguish PD-MCI and PDD.The AUCs for the simplified MoCA, MoCA-5 min, short MoCA-Czech, and short MoCA-US were equivalent in discriminating between PD-nonMCI and PD-MCI. The relevant methods  cannot be used to distinguish PD-MCI and PDD  were similar to healthy aging and better than PDD patients. The small number of people in the PD-MCI group may have contributed to the statistical insignificance. Although there was no statistical significance in the mean scores of “Family Life, Hobbies, and Self-Care” score between healthy aging and non-demented PD group , we found that the scores in the PD-MCI group were intermediate between the PD-nonMCI group and PDD group; that is, PD-MCI patients may have worse “Family Life, Hobbies, and Self-Care” function than deficit PD-nonMCI patients and better than PDD patients. The PD-MCI patients might have difficulty dealing with primary personal needs . Previous studies indicate that PD-MCI patients receive significantly lower medicine and financial management ; accordiWe considered both cognitive and social functions together to detect PD-MCI or PDD. To the best of our knowledge, no study has evaluated the two factors simultaneously. Our findings suggested that the combination of the two simplified tests had the unique advantage of providing cognitive and social functioning information to detect PD-MCI and PDD, and was more efficient to administer than the original MoCA , originaz = -0.131, p = 0.895; comparing AUCs of PD-MCI vs. PDD: z = -0.695, p = 0.486) and simplified MoCA . Our findings and previous evidence  to define PD-MCI to accurately classify and increase the reliability and validation of our results. Some patients could not complete the comprehensive assessment due to fatigue or time constraints. As a result, it was difficult to recruit participants, and the sample size was small. Second, we applied the MDS PD-MCI level II diagnostic criteria to diagnose PD-MCI patients; however, the rigorous criteria led to a small number of participants in this group. Third, the AUC of the combination version was similar to that of the original MoCA; however, the time required to complete the combination version is shorter than the original MoCA, which is beneficial to clinical use. In addition, clinicians can obtain detailed information about the patient’s cognitive and social functions through the combination version, which is helpful for diagnosis and subsequent intervention. Last but not least, to the best of our knowledge, this is the first study to examine the detection of MCI or dementia by combining cognitive and social function tests. More research is needed in the future, especially considering cultural backgrounds and languages  and specOur simplified MoCA can be used to detect PD-MCI and PDD (cut-off scores: 9 and 7) efficiently. Moreover, the patients can be classified into the PD-MCI and PDD categories when the total score of the combination of the two tests is 35 and 30, respectively. Given the cruciality of social functioning and the limitation of cognitive screening tools, combining the two tests will help evaluate cognitive and social functions efficiently and help the physician decide on further intervention. This is the first study to develop an instrument that considers both social and cognitive functions to the best of our knowledge. More study is needed to validate our findings and focus on exploring the patients’ social functioning in the disease course.RRID:SCR_000980.”“A New Instrument Combines Cognitive and Social Functioning Items for Detecting Mild Cognitive Impairment and Dementia in Parkinson’s Disease  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 National Cheng Kung University Hospital and Kaohsiung Medical University Hospital. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.All authors made substantial contributions to the conception and design of the work, acquisition, analysis and interpretation of data, drafted the work and revised it, gave final approval of the completed version, and agreed to be accountable for all aspects of the work.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 objective of this study is to investigate the outcomes of concurrent platinum-based chemoradiation therapy (CCRT), laparoscopic nerve-sparing ultra-radical hysterectomy (LNSURH), and open radical hysterectomy (ORH) on patients with locally advanced cervical carcinoma (LACC).A single-center retrospective study was conducted on LACC patients who received CCRT, ORH, or LNSURH from January 2011 to December 2019. Data on age, tumor size, overall survival (OS), disease-free survival (DFS), and early and late morbidities were collected. After 24 months of treatment, patients were asked a series of questions about their urinary, bowel, and sexual activities. Early morbidities were defined as those occurring during or within a month of treatment, whereas late morbidities and complications were defined as those occurring a month after treatment. The postoperative complications were classified with reference to the Clavien–Dindo classification (CD) system.P = 0.106 for DFS and P = 0.190 for OS). The rates of early complications in the CCRT group were comparable with those in the operated groups (P = 0.46). However, late complications were significantly lower in the ORH and LNSURH groups relative to those in the CCRT group. The scores of urinary and bowel functions were restored to the pretreatment state, although the sexual function scores were not satisfactory.The Kaplan–Meier curves revealed no significant differences in OS and DFS among the three groups (The treatments of CCRT, ORH, and LNSURH can be considered options for patients with LACC, as their OS and DFS showed no significant difference. In addition, LNSURH exhibited a lower incidence of late complications and high sexual function scores. Cervical cancer is the fourth most common malignancy in women across the world . RadicalCCRT is the first-line treatment option for LACC . HoweverNew England Journal of Medicine reported that, in 2018, minimally invasive RH was associated with a poor prognosis relative to that with open RH among women with early-stage cervical cancer , and CCRT in patients with LACC. The disease-free survival (DFS), OS, and complications were recorded and analyzed to determine the prognosis and quality of life of these patients.LACC patients in stages IB3 and IIA2 (74) who had received ORH (29), LNSURH (20), or CCRT (25) from the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University between January 2011 and December 2019 were enrolled in this study. All surgical cases were treated by the same surgical team . This study was approved by the hospital’s ethics committee .The subject inclusion criteria were as follows: (1) patients at stages IB3 or IIA2, as defined by the International Federation of Gynecology and Obstetrics (FIGO) staging system (2018) before treatment and with pathologically confirmed cervical squamous cell carcinoma, adenocarcinoma, or adenosquamous; and (2) patients who had RH, LNSURH with pelvic and para-aortic lymphadenectomy, or CCRT.The subject exclusion criteria were as follows: (1) combination with other malignant tumors, (2) incomplete medical records, and (3) abnormal vital organ functions.The surgical procedure for LNSURH with pelvic and para-aortic lymphadenectomy was performed under general anesthesia in the dorsolithotomy position. The operation platform was performed by a five-port laparoscopy. The para-aortic lymph node dissection was performed routinely up to the inferior mesenteric artery emergence. If the intraoperative frozen section examination indicated a positive common iliac lymph node, it was performed up to the renal vein level.A laparoscopic pelvic lymphadenectomy was performed following para-aortic lymphadenectomy. The critical steps of nerve preservation were the development of the anatomical space, identification, selective transection of the uterine nerve branches (UNBs) of the inferior hypogastric plexus (IHP), and sparing of the vesical nerve branches (VNBs). As cervical carcinoma patients at stage IB3 or IIA2 with larger tumor and parametrial infiltration were not deemed suitable for the nerve-sparing procedure, contralateral or partial nerve-sparing RH was performed to preserve some part of the IHP and the pelvic splanchnic nerves .LNSURH has a wider parametrial excision and safeguards the pelvic splanchnic nerve from long-term postoperative complications . The key point of LNSURH is depicted in Step 1: Resection of the uterine artery at the starting position of the internal iliac artery following the development of the pararectal space and paravesical space  is located between the bladder and the cervix and is a lamellar structure  1 of the high-risk factors such as lymph node metastases, positive resection margins, and parametrial invasion, or (2) >1 of the other risk factors that include deep stromal invasion and lymphovascular space invasion (LVSI) –16.The early complications included myelosuppression, hypohepatia, radiation enteritis, radiocystitis, pelvic lymphatic cyst, angiolymphitis, ureteral vaginal fistula, and radiothermitis. Late complications included obstructive nephropathy, lymphatic reflux disorder, and colorectal fistula. The ureteral vaginal fistula was treated with ureteral stenting. All early complications improved after the treatment.The Clavien–Dindo (CD) classification system was applied to analyze the post-operative complications . It was via a telephonic and outpatient care interview conducted every 3 months. The follow-up data included the duration of the follow-up; the general health status; complications; time of cancer recurrence; urinary, bowel, and sexual functions; and mortality.After discharge from the hospital, the patients were followed up During the follow-up, at least 24 months after the operation or CCRT, the patients were asked to answer a series of questions about their urinary, bowel, and sexual functions. The self-assessed questionnaires consisted of five questions on sexual satisfaction, dyspareunia, defecation condition, urinary incontinence, and urination requiring abdominal assistance, according to the article published by Zhuoyu Sun in 2020 . The scoDFS was considered as the period from surgery or CCRT to cancer recurrence, as identified by biopsy or evaluation by medical imaging. In case of no cancer recurrence, the last follow-up examination or death was considered as the DFS. Overall survival (OS) was regarded as the period from the time of treatment including surgery and CCRT until death from cervical cancer.SD. Comparison of the categorical data was performed by the chi-square test, and categorical data were expressed as percentages. DFS and OS were detected by Kaplan–Meier analysis. We calculated P values by log-rank test. P < 0.05 was considered to indicate statistical significance. All data were analyzed by SPSS 20.0 .We analyzed the factors associated with OS and DFS by multivariate logistic regression analyses. Comparison of continuous data was performed by one-way analysis of variance (ANOVA), and continuous data were expressed as the mean ± In our study, we assessed 74 patients, with 25, 29, and 20 patients assigned to the CCRT, RH, and LNSRH groups, respectively. Statistical analysis revealed that there were no statistically significant differences in the BMI and tumor size. However, when compared with the CCRT group, the LNSURH and RH groups were significantly younger Table 1.A total of 74 patients showed a median postoperative follow-up time of 39.6 months (0–115 months). The DFS rates were 84.0, 75.9, and 90.0%, whereas the OS rates were 96.0, 93.1, and 100% in the CCRT, ORH, and LNSURH groups in 3 years, respectively. The median DFS times were 49, 53, and 35 months, and the median OS times were 48, 50, and 28 months in the CCRT, ORH, and LNSURH groups, respectively.P = 0.106 for DFS and 0.190 for OS, The Kaplan–Meier analysis showed that there was no significant difference in the OS and DFS among the CCRT, ORH, and LNSURH groups (P = 0.46). When compared with the CCRT group, the rate of late complications in the ORH and LNSURH groups was markedly lower   , 26. Li < 0.001)  reported< 0.001) . Kalaghc< 0.001)  reported< 0.001) . Until ndalities .However, owing to the difference in the advancement of medical and healthcare facilities across the world, there is a deviation in clinical staging before surgery, an imbalance in the radiotherapy resources, limitations of regional-related medical conditions, and the subjective choice made by patients, considering that a considerable number of patients continue to opt for surgical resection as an initial treatment –35. In rAll surgery candidates in this study preferred adjuvant radiotherapy and chemotherapy according to the high-risk factors suggested by their postoperative pathological outcomes. After a median of 39.6 months’ long-term follow-up, our results showed that, when compared with conventional chemoradiotherapy, LNSURH plus chemoradiotherapy had no significant difference in the OS and DFS in LACC patients, suggesting that LNSURH preserved the pelvic nerve but did not increase the postoperative recurrence rate. It is therefore recommended that the postoperative survival rate of patients is related to the scope of surgery and the implementation of the principle of no tumor, albeit it has no obvious correlation with the surgical method. After the pelvic nerve is preserved, the bladder function of the patient recovers quickly. Moreover, this way, patients with risk factors who need postoperative adjuvant radiotherapy can receive treatment at the earliest. In this study, the early complications of CCRT, ORH, and LNSURH patients included myelosuppression, hypohepatia, and radiation enteritis, albeit the corresponding incidences were not statistically significantly different among the groups. The long-term follow-up of late complications demonstrated that the rectal and bladder functions recovered to the preoperative state and that the quality of life was improved, although the recovery of sexual functions was not satisfactory; in fact, it was lower than those reported previously , which mTo analyze the reasons for good OS and DFS after LNSRH operation, the following factors should be considered: (1) based on nerve preservation, the operation scope is sufficient; and (2) strict implementation of the principle of being tumor-free: (A) removal of the uterus through the vagina; (B) flushing with plenty of water after the operation; (C) lymph node removal on time by bagging; and (D) ensuring that pneumoperitoneum is stable and instrument replacement is minimized.Comparatively speaking, this retrospective small-sample study involved a selective deviation. Patients who selected LNSRH were younger than those in the CCRT and ORH groups, and they are more enthusiastic about undertaking laparoscopic surgery with nerve preservation. In addition, the quality of life was self-reported by the patients themselves, which implies the possibility of deviation in self-reporting. Therefore, for validation of the present findings, larger randomized trials and longer follow-ups are warranted.In summary, the present research supports that the prognosis of LACC patients should be determined by the scope of surgery and tumor-free outcome and not by the difference in the surgical approaches. No significant difference was noted in the OS and DFS among the three study groups, albeit there were more long-term complications of CCRT, such as vaginal fistula, ureteral obstruction (related to the uncleared primary lesion), and obstructive nephropathy. The response to the questionnaires revealed that the sexual life score of the LNSRH group was higher than that of the other two groups.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.This study was approved by the ethics committee of Nanjing Medical University Affiliated Changzhou Second People’s Hospital . The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.JC and RS designed the study and approved the manuscript. HZ and BT collected the clinical data. WW and HS prepared and wrote the original draft, with the reviewing of YM and XC. PS provided statistical methods. All authors contributed to the article and approved the submitted version.This work was supported by grants from the Changzhou Science and Technology Program (QN201931) and the Changzhou Sci and Tech Program (grant no. CJ20220077 and CJ20210110).The authors would like to thank those female patients who participated in the study and shared their experiences with us.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.


Globally, pancreatic cancer is the seventh most common cause of cancer-related death in both sexes, accounting for 466,003 deaths and 495,773 new cases in 2020. The purpose of this study was to synthesize and evaluate evidence on the effects of omega-3 supplementation on the nutritional status of patients with pancreatic cancer.I2 statistic. Based on the results of this test, we will verify whether the meta-analysis would be feasible. If feasibility would be confirmed, a random-effect model analysis will be performed. For data analysis, the calculation of the pooled effect estimates will have a 95% confidence interval, while the alpha will be set to 0.05 using the R statistical software version 4.0.4. All methodological steps of this review will be performed independently by two reviewers and will be conducted and managed in the EPPI-Reviewer Software™.This systematic review protocol will be guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. Five databases will be searched: MEDLINE/PubMed, CENTRAL Cochrane, EMBASE, Web of Science, and SCOPUS, with no restrictions on the publication date nor language. The internal validity and risk of bias of randomized controlled trials will be assessed using the revised Cochrane Risk-Of-Bias tool for randomized trials (RoB 2), whereas the risk of bias in non-randomized studies of interventions will be evaluated using the ROBINS-I. The heterogeneity among the studies will be assessed using the This review may be of particular interest to researchers and clinicians, given the low survival and overall burden of patients with pancreatic cancer. Furthermore, the results of this systematic review may contribute to the development of new nutritional interventions in these patients.To the best of our knowledge, this will be the first study to critically assess the scientific evidence and estimate the effect of omega-3 supplementation on the nutritional status of patients with pancreatic cancer. The review will perform a rigorous approach, adhering to the PRISMA Statement 2020 using a comprehensive and systematic search strategy in five databases and additional sources with no time period nor language restrictions. Although pancreatic cancer is not among the most prevalent neoplasm, pancreatic cancer has a relatively equivalent incidence and mortality rate. In addition, pancreatic cancer is projected to become the third leading cause of cancer-related death by 2025, as indicated by a study involving 28 European countries.Globally, pancreatic cancer is the seventh most common cause of cancer-related death in both sexes, accounting for 466,003 deaths and 495,773 new cases in 2020.In the United States, pancreatic cancer is the third leading cause of death in men and women. Additionally, mortality from pancreatic cancer has slowly increased in men, from 12.1/100,000 in the 2000s to 12.7/100,000 in 2019; however, it has remained relatively stable in women, ranging from 9.3/100,000 to 9.6/100,000 over the same period. Surgical resection is the only potentially curative treatment option; however, since these tumors present late, only 20% of pancreatic cancer patients are candidates for surgery. In addition, the prognosis is poor, even in patients with a resectable tumor.Pancreatic cancer (PC) is a highly lethal disease. In emerging countries, such as Brazil, tumors account for 2% of all neoplasms and represent 4% of deaths. Advances in survival for pancreatic cancer have been slow. The most important factor is the late stage at which most individuals are diagnosed. Additionally, the late stage 5-year survival rate is 11%. Moreover, the tumor biology is aggressive, and the involvement of other organ systems is likely due to the function and anatomical location of the pancreas. At the same time, most people with pancreatic cancer are asymptomatic until the disease progresses to an advanced stage.The 5-year survival rate is approximately 25% to 30%. In 2018, the World Cancer Research Fund and the American Institute for Cancer Research concluded that there was strong evidence that being overweight or obese increased the risk of pancreatic cancer. In addition, there is evidence that consumption of red meat, processed meat, foods containing saturated fatty acids, alcoholic beverages, and fructose-containing foods and beverages may increase the risk of pancreatic cancer. Tobacco use is another established cause of pancreatic cancer.,10Pancreatic cancer has a higher incidence in adults and the elderly. In particular, it is more common after 60 years of age. Approximately 10% of pancreatic cancer cases result from hereditary risk factors; hence, a positive family history of pancreatic cancer substantially increases an individual’s risk of developing the disease. Several studies showed that malnutrition was associated with the loss of skeletal muscle mass and fat degradation, increased length of hospital stay, increased risk of morbidity and mortality, and reduced treatment response and quality of life.,12,13Weight loss among pancreatic cancer patients is very common, both at the time of diagnosis and during the course of the disease, with up to 40% of patients having a weight loss greater than 10% within 6 months.Cachexia is characterized by pathological weight loss due to loss of skeletal muscle mass and adipose tissue as a result of reduced food intake or anorexia, abnormal metabolism, or a combination of both. Therefore, nutritional interventions play a key role in the successful management of these patients.,16For the prevention and treatment of cachexia, supplementation with omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid, has been a strategy in patients with cancer because of the omega-3 polyunsaturated fatty acids’ anti-inflammatory properties. Inflammatory disorders have been managed with EPA and docosahexaenoic acid, which have contributed to the reduction in pro-inflammatory cytokines and maintenance and/or increase in body weight. provided 20 patients with pancreatic cancer omega-3 polyunsaturated fatty acids . As a result, the patients had stabilized body weight (about 1 kg increase) after 3 weeks of supplementation, along with improvements in terms of appetite and performance status.Barber et al surgery for gastrointestinal malignancy, prostate cancer, and lung cancer undergoing radiotherapy and chemotherapy, there had been no evidence of its role in the nutritional status of patients with pancreatic cancer.Although some systematic reviews explored the modulatory role of omega-3 in patients with head and neck cancer,Thus, to fill this gap in the scientific literature, we hypothesized whether supplementation with omega-3 polyunsaturated fatty acids, applied before or during the treatment of pancreatic cancer, could help prevent malnutrition and muscle wasting in patients with pancreatic cancer. Hence, the aim of this study was to synthesize and evaluate evidence on the effects of omega-3 supplementation on the nutritional status of patients with pancreatic cancer. Furthermore, registration was performed using the PROSPERO/UK under registration, CRD42022332619.This systematic review protocol is in high compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. Table To formulate the research question, the PICOS  strategy was used.The PICOS guided the structuring of the research question. The research question is as follows: “What is the effect of omega-3 supplementation on the nutritional status of patients with pancreatic cancer?” The Boolean operators “AND,” “OR,” and “NOT” will be employed to combine the descriptors.,26 No restrictions regarding language nor period of publication will be applied in the search strategy. In addition to the electronic databases cited above, searches will be conducted on clinical trial registry sites, such as ClinicalTrials. gov , World Health Organization International Clinical Trials Registry Platform, and additional searches in sites of organizations and website searches, such as the British Library, Google Scholar, and preprints for Health Sciences [medRxiv]. In addition, we will scrutinize the reference lists of articles to search for additional studies.The search strategy will be carried out in five electronic databases: Medical Literature Analysis and Retrieval System Online (MEDLINE) via PubMed , Cochrane Central Register of Controlled Trials , Excerpta Medica database , Web of Science , and SCOPUS . The strategy for seeking studies will consist of a combination of controlled descriptors , synonyms, and keywords, as indicated in each electronic database.–27 to obtain restrictive and additive combinations, respectively. In addition, the search will be performed using the identified descriptors with their expanded meaning but without the use of database filters to preserve significant samples and to ensure a lower risk of loss. The search strategy combining the MeSH controlled descriptors and keywords used in MEDLINE will be adjusted to other electronic databases, as described in Table In this phase, the EndNote bibliographic software will be used to store, organize, and manage all retrieved studies. The search strategy will be conducted independently by two researchers (LCLJ and LBCP). First, the existence of an index of specific subject headings in each database  will be identified. Subsequently, the search terms will be combined using the Boolean operators “AND” and “OR”Inclusion criteria: All primary studies from randomized clinical trials and non-R randomized clinical trials, which assessed the effect of omega-3 supplementation in adult patients (>18 years old) of both sexes and of any ethnicity with a diagnosis of pancreatic cancer. This will include clinical trials with the nutritional status as an outcome. Notably, no date or language restrictions will be applied during study selection.•Exclusion criteria: Experimental studies conducted in animal models, in vivo, and ex vivo on this topic will be excluded. Observational studies, qualitative studies, reviews, and gray literature will also be excluded. In this step of inclusion and exclusion of articles that will compose the final sample, the Rayyan™-Qatar CRI will be used as a tool to assist in the eligibility and selection of articles.Studies will be selected by the same two reviewers independently and blindly. After this selection, a third reviewer will be responsible for analyzing and deciding on the inclusion or exclusion of each article, especially those containing conflicting decisions.,29–37 If the reviewers disagree, the article will be evaluated. If disagreement will persist, a third reviewer will make the final decision.First, the screening of the studies will be based on the information contained in their titles and abstracts and will be performed by the same two researchers (LCLJ and LBCP) using previously published data extraction forms. is detailed in Table The information to be extracted This tool will be used to assess the risk of bias in five domains: randomization process, deviations from the intended interventions, missing outcome data, outcome measurement, and selection of the reported result. The RoB 2 will be used to classify the risk of bias as follows: low risk of bias: low risk of bias for all domains; some concerns: some concerns in at least one domain, but no high risk of bias for any domain; and high risk of bias: high risk of bias in at least one domain or some concerns for multiple domains, substantially reducing confidence in the results. To assess non-R randomized controlled trials, the risk of bias in non-randomized studies of interventions (ROBINS-I) will be used. ROBINS-I will comprise of seven chronologically arranged bias domains . The domain level and overall risk of bias will be classified as low, moderate, serious, or critical. For both tools, the same two reviewers will independently assess the risk of bias for each included study. Discrepancies will be resolved through discussion at each stage until the achievement of a consensus.The internal validity and risk of bias of randomized controlled trials will be assessed using the revised Cochrane Risk-Of-Bias tool for randomized trials (RoB 2).I2 statistic to estimate the percentage of variation among studies, where I2 = 0–40% will indicate low heterogeneity; I2 = 30–60% will indicate moderate heterogeneity; I2 = 50–90% will indicate substantial heterogeneity; and I2 = 75–100% will indicate high heterogeneity.,41 Based on the I2 statistic, we will determine whether the meta-analysis would be feasible. In this case, we will check the statistical model to be used to gather the study-specific estimates, which will be in the form of fixed-effects model or random-effects model analysis.–34,42–44 For the data analysis, the calculation of the pooled effect estimates will consider a confidence interval (CI) of 95% and an α = 0.05 using the EPPI-Reviewer™ Software (UK). We will also assess the publication bias if sufficient studies would be identified per endpoint analyzed. To explore the heterogeneity across studies, a subgroup analysis will be performed using a mixed effects model according to age (young people versus adults versus aged versus added patients) and cancer staging. For the data analysis, the calculation of the pooled effect estimates will consider a 95% CI, while α alpha will be set at 0.05 using the Statistical Package for Social Sciences version 28.0 .Heterogeneity among studies will be measured using the  flowchart (Fig. The study results will be presented in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020art Fig. , tables,This protocol for systematic review will analyze the existing research studies and therefore will not involve patients nor members of the public.This study will not involve human participants or unpublished primary data. As such, ethical approval from the Human Research Ethics Committee will not be required. Plans for the dissemination of this study will include peer-reviewed publications and conference presentations to be shared with experts in this field, stakeholders and clinicians.This systematic review will help in the elucidation of the current state of knowledge and will identify gaps in the literature on nutritional status and omega-3 interventions in patients with pancreatic cancer. In addition, this review may be of particular interest to researchers and clinicians, given the low survival and overall burden of patients with pancreatic cancer. Moreover, the results of this systematic review may contribute to the development of new nutritional interventions in these patients.To the best of our knowledge, this systematic review will be the first to critically assess scientific evidence and to estimate the effect of omega-3 supplementation on the nutritional status of patients with pancreatic cancer. Thus, we will provide better insights into omega-3 supplementation in patients with pancreatic cancer, a disease with a high fatality and mortality rate in both sexes. Finally, this may provide consistent evidence that will assist decision makers and stakeholders.LCLJ and LBCP conceived the idea and planned and designed the study protocol. LCLJ and LBCP wrote the first draft. LCLJ planned the data extraction and statistical analysis. LCLJ, LBCP and LBS provided critical insights. LCLJ and LBCP critically reviewed and modified the manuscript. All authors have reviewed and approved the manuscript. LCLJ is responsible for the overall content as guarantor.Conceptualization: Luciana Bicalho Cevolani Pires, and Luís Carlos Lopes-Júnior.Data curation: Luciana Bicalho Cevolani Pires, Luciane Bresciani Salaroli, Luís Carlos Lopes-Júnior.Formal analysis: Luís Carlos Lopes-Júnior.Funding acquisition: Luís Carlos Lopes-Júnior.Investigation: Luís Carlos Lopes-Júnior.Methodology: Luís Carlos Lopes-Júnior.Project administration: Luís Carlos Lopes-Júnior.Resources: Luís Carlos Lopes-Júnior.Software: Luís Carlos Lopes-Júnior.Supervision: Luís Carlos Lopes-Júnior.Validation: Luciane Bresciani Salaroli, Luís Carlos Lopes-Júnior.Visualization: Luciana Bicalho Cevolani Pires, Luciane Bresciani Salaroli, Luís Carlos Lopes-Júnior.Writing – original draft: Luciana Bicalho Cevolani Pires, Luciane Bresciani Salaroli, Luís Carlos Lopes-Júnior.Writing – review & editing: Luciana Bicalho Cevolani Pires, Luís Carlos Lopes-Júnior.


Background and Objectives: Metformin has been found to potentially reduce the risk and improve the prognosis of a variety of tumors, but these findings remain controversial in biliary tract cancer (BTC). Therefore, this systematic review and meta-analysis was conducted to investigate the association between metformin and BTC. Materials and Methods: Two independent researchers comprehensively searched PubMed, Embase, the Cochrane Library, and Web of Science for eligible studies published from their inception to 31 March 2022. Comparisons of risk, overall survival (OS), and disease-free survival (DFS) for patients with BTC were selected as the endpoints of interest and pooled by random or fixed-effects models. Results: Eleven studies with a total of 24,788,738 participants were eligible for this analysis. The overall pooled effects showed no significant differences in biliary tract cancer risk (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.50–1.35, p = 0.436), OS , or DFS  between metformin users and non-users. When restricting participants to those with diabetes, a similar negative result was found, demonstrating that metformin use was not significantly associated with a lower risk of developing BTC compared with a lack of metformin use ; notably, the included studies exhibited significant heterogeneity in the selection of participants and the definition of metformin users. Conclusions: Metformin may not be able to reduce the risk of BTC and improve prognosis in certain populations. Based on the limited quantity and quality of the included studies, the present results should be interpreted within their limitations, and further studies are warranted to determine the optimal timing, dose, duration, and scenario of metformin administration. Biliary tract cancer (BTC), classified as gallbladder cancer, intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma, originates from the epithelial cells of the biliary tree and involves the biliary system ,2. It usDiabetes is a risk and a poor prognostic factor for several tumors, and previous studies have identified its adverse effects on BTC ,11,12. CMetformin is now extensively used as the recommended first-line treatment for type 2 diabetes. Due to the strong association between diabetes and BTC, elucidating the effects of metformin on BTC may provide new ideas for the prevention and management of BTC in clinical practice, particularly in diabetics. Given the lack of consistent evidence, this systematic review and meta-analysis was conducted in order to evaluate the correlation between metformin use and BTC.This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA 2020) statement . The proWithout any restrictions, two researchers systematically searched PubMed, Embase, the Cochrane Library, and Web of Science to identify publications relevant to metformin for BTC patients . By using Boolean operators, search strategies were developed by combining Medical Subject Headings terms  with free terms . Any dispute between the two researchers was resolved through negotiation. Otherwise, an experienced expert in this field intervened to solve the problem. The specific search strategies used are provided in the Studies meeting all of the following criteria were eligible for the current study: (1) the study populations are non-specific. Cohort studies investigating endpoints of interest in populations using metformin or case-control studies investigating the effects of metformin in patients with BTC were eligible; (2) studies on the use of metformin before and/or after the diagnosis of BTC; and (3) estimates of the effect of metformin on BTC were conducted for the following endpoints of interest: relative risk of BTC, overall survival (OS), and disease-free survival (DFS) of BTC.Studies falling under any of the following criteria were excluded: (1) repeated studies, such as conference abstracts that were published in full; (2) case reports or case series with fewer than 20 patients; (3) cross-sectional studies or single-arm studies; (4) non-human studies, such as in vitro studies or animal studies; (5) papers that did not generate primary data, including reviews, meta-analyses, commentaries, or editorials; (6) if most of the enrolled patients were substance withdrawal patients, and (7) our analyses did not identify the intersecting endpoint with the biological indicators or other measures used, or used placebos or control groups in any combination with any intervention.Based on the inclusion and exclusion criteria, two reviewers independently evaluated the relevant literature. Our first step was to automatically remove duplicate studies and remove irrelevant studies based on their titles and abstracts. Subsequently, we analyzed the full texts of studies we identified as potentially eligible. The reasons for the exclusion of ineligible studies were recorded and cross-checked. The selection of studies was conducted by two independent investigators, and any discrepancies were resolved by consulting a third expert. We downloaded and managed all citations using EndNote X9 software .Data extraction and quality assessment were carried out independently by two reviewers. Pre-designed comprehensive Excel forms were designed to collect the following key data from the included studies: first author, year of publication, country, age, gender, type of BTC, study period and design, population source, sample size in different study groups, analysis mode, adjusted/matched confounders, study endpoints, and follow-up time. By contacting corresponding authors of potential studies, we were able to obtain the essential data when not reported in the original studies.The quality of the eligible cohort and case–control studies was evaluated using the cohort design version  and the case–control design version  of the Newcastle–Ottawa Scale (NOS), respectively, as independently judged by two researchers. Studies with NOS scores ≥ 7 were considered high-quality studies; otherwise, they were reported as low-quality studies .p-value, and a substantial level of heterogeneity was evaluated by the I2 statistic. The studies were homogeneous if I2 was <50%, p > 0.05, and a fixed effects model was reported. In contrast, if I2 was ≥50% and p < 0.05, a random effects model was reported. A sequence of subgroup analyses was conducted to explain any observed heterogeneity or to explore statistically significant differences between studies; stratified analysis was performed according to participants (restricted to diabetics vs. not restricted to diabetics), median/mean age (<65 years vs. ≥65 years), pathological site, study location (Asia vs. non-Asia), and sample size. Sensitivity analysis was performed by removing each study in turn to re-estimate the effect size and its contribution. Additionally, potential bias in small studies was evaluated using a comparison-adjusted funnel plot, which serves as an intuitive visual instrument for detecting the presence of any dominant types of potential bias, such as publication bias, selective reporting, or other biases. The quantitative Egger’s test was performed to determine whether p values were less than 0.05. Otherwise, the trim-and-fill method was used to assess the impact of potentially unpublished studies on the pooled results [p < 0.05 was considered statistically significant. The above sequence of analyses were conducted in STATA, version 16.0 We conducted a traditional pairwise meta-analysis of the included trials for each existing comparison. Adjusted risk estimates were preferentially extracted for the meta-analysis. Regarding individual studies that assessed the effect of metformin on BTC but lacked the necessary data for quantitative analysis, we provided a narrative description and discussion in the corresponding results section. Hazard risk (HR) was calculated to assess the relationship between metformin and BTC in the adult population. A 95% confidence interval (CI) was used to estimate the scope of the overall parameters . We incl results . All tesA total of 311 studies were generated from PubMed, Embase, Web of Science, and the Cochrane library databases by using pre-developed search algorithms. After removing duplicates, 190 clearly ineligible studies were excluded through a review of their titles and abstracts. The remaining 34 studies were read in full, among which 13 studies did not investigate the efficacy of metformin on BTC, 4 studies did not explore risks or prognostic endpoints for BTC, 3 studies were cellular or animal studies, and 3 studies were duplicate reports of the same study. Finally, a total of 11 studies were included in the meta-analysis ,33,34,35A total of 11 studies involving 24,788,738 participants were finally included: two studies from each of the following countries: Italy, China, and the USA; and one study from each of the following countries: Thailand, Korea, Netherlands, Canada, and Sweden. Seven studies explored the effect of metformin on the risk of BTC ,32,33,34Nine cohort studies had NOS scores between 7 and 9, and each case–control study scored 8, indicating a high overall quality level in the published studies . The maiI2 = 99.4%, pheterogeneity < 0.001); therefore, a random-effects model was applied. The pooled results showed no correlation between metformin use and BTC risk   A. The otpoverall effect = 0.089) [poverall effect = 0.057) [When restricting the study population to people with diabetes, the pooled results from five studies revealed no statistically significant differences between metformin use and BTC  ,23,33,34= 0.089) ,32. Four= 0.057) ,22,23,33I2 = 0.0%, pheterogeneity = 0.657), and therefore a fixed-effects model was used. The pooled results showed no significant correlation between metformin use and OS  [poverall effect = 0.061) [Five studies comprising 306,697 participants assessed the effects of metformin on OS in patients with BTC ,29,30,35= 0.135) ,24,30,35p = 0.695), with slight heterogeneity  [poverall effect = 0.097) [poverall effect = 0.091) [p overall effect = 0.016); however, the level of significance decreased after adjusting for potential confounders  [p overall effect = 0.026) [In two studies, participants were restricted to those with diabetes, and the pooled HR was 0.95  ,24. Inte= 0.097) ,30. Ther= 0.091) . There w= 0.026) .I2 = 0.0%, pheterogeneity = 0.433), and combined results using a fixed-effects model revealed that metformin use did not significantly affect DFS   C.p-values for both Begg’s and Egger’s tests were greater than 0.05 , demonstrating that there was no evidence of risk of publication bias.The endpoints for five or more cohorts were examined for publication bias. No clear asymmetry was found in the funnel plots ; p-valueSensitivity analysis was performed by removing one study at a time and re-merging the remaining ones. There was no significant change in the pooled results and individual studies had little effect on the combined results, indicating that the current pooled results are relatively stable .This is the first systematic review and meta-analysis to synthesize the current evidence on the association between metformin use and the risk and prognosis of BTC. The current evidence suggests that, in general, the effect of metformin use on BTC incidence and survival lacks statistical significance. The results need to be interpreted cautiously due to certain limitations in our study, and more high-quality relevant research needs to be performed for the establishment of a comprehensive evidence base to verify the association between metformin and BTC.Notably, there was significant heterogeneity in the analysis of the effect of metformin on BTC risk; even in subgroup analyses based on main characteristics, the heterogeneity was still not significantly reduced. By reviewing the study characteristics and design, we considered that heterogeneity might be primarily derived from the selection of the participants and the definition of metformin users. Prior studies have identified an increased risk of BTC in diabetic patients ,11,36. THelicobacter pylori infection showing significance [Another important potential source of heterogeneity was the inconsistent definition of a metformin user. In the study conducted by Oh et al., metformin users were defined as those who had been taking oral metformin consistently for more than 90 days, while other individuals with diabetes were used as controls ; in the ificance . In addiificance . In seveificance . Future In contrast to the risk analysis, no substantial statistical heterogeneity was observed in the pooled analysis of the effect of metformin on survival. However, differences in the clinical characteristics of the included studies, such as the factors discussed above, may still impact the effect of metformin on BTC. Currently, no randomized controlled studies with metformin as a variable have been conducted. In fact, the studies included for quantitative analysis were more inclined to act as a correlational analysis rather than to explore the therapeutic effects of metformin. Only the study by Wu et al. can be considered as a clinical trial exploring metformin for BTC, but not using metformin was also the only treatment or it was used in combination with a specific regimen ; they in1, and the activation of caspase-3, thereby blocking the transition from G0 to G1 cell cycle [Several pre-clinical studies have attempted to investigate the effects of metformin on BTC, and metformin was found to affect the development and progression of BTC through several mechanisms. The Warburg effect refers to alterations in cellular metabolism from oxidative phosphorylation to glycolysis as a result of tumor development and proliferation. Tang et al. demonstrated in vitro that metformin can reverse the Warburg effect by inhibiting the expression of lactate dehydrogenase-A, thereby impacting the metabolism of cancer cells . Upregulll cycle ,54. In all cycle ,55,56. Ill cycle ,64,65,66As far as we know, this is the first attempt to summarize the available evidence to evaluate the relationship between metformin use and BTC-related outcomes. To prevent the omission of studies, potential studies were obtained by screening references of similar studies and by manual searches during the study selection process. We used the prospective or retrospective collection of data from various sources including health care records and hospital records, and the method of data collection was comparable between the exposure/case and control groups. Our study had a large sample size, although despite the battery of analyses, the association between metformin and BTC was not confirmed. To summarize, our study contributes to the latest evidence by providing a detailed summary of the evidence regarding the association between metformin and BTC. As a result of this study, policymakers, clinicians, or caregivers may be able to make better decisions and navigate the direction of clinical decision making, therefore facilitating future research and clinical applications in the future. There are several limitations to this study that need to be considered. First, there were relatively few eligible studies per endpoint and in certain populations; although population-based studies provide greater sample sizes, further investigation is still required to validate the effect of metformin on BTC in different geographical areas and populations with different characteristics. Second, registry studies identifying patients by diagnostic codes are subject to information bias, such as inevitable misdiagnosis and missed diagnoses. Third, the study designs in the risk analysis were retrospective. Therefore, some potentially confounding bias data, including the impact of physical activity, dietary habits, family history, co-morbidities, and diabetes severity, were not adjusted for. Fourth, most studies lacked clear definitions of metformin users, such as the specific doses and regimens.There is substantial heterogeneity in the current studies exploring the association between metformin and BTC, and the present study suggests that metformin may not have the capacity to inhibit the risk of carcinogenesis and exert chemotherapeutic effects. The results need to be interpreted cautiously due to certain limitations in our study. Future prospective studies are needed to further validate and elucidate the effects of metformin on different patient characteristics, particularly in non-diabetic patients, and the optimal timing, dose, and duration of application.


This study aimed to model adolescents’ cardiorespiratory fitness performance change trajectories longitudinally across high school years and its relation to school- and individual/student-level factors. We employed hierarchical linear modeling to examine longitudinal cardiorespiratory fitness performance changes, as measured by the progressive aerobic capacity endurance run (PACER), over the years, between sexes, and in association with the school-level variables. Participants were 76,227 adolescents from 80 high schools in the mid-Atlantic region of the United States. School-level academic performance (SAP), the percent of students eligible for free and reduced-price meals (FARM), and physical education student-faculty ratio were obtained with permission from the school districts. The number of laps completed in PACER test improved throughout the first three years of high school, however, proportions of those within the healthy fitness zone (HFZ) decreased overall from 9th to 11th grade. Furthermore, the number of laps completed by adolescents appeared to have plateaued at 11th grade, with a significant decline during the final year of high school. Sex-based discrepancies in performance in meeting HFZ were evident, where girls significantly outperformed boys during 9th and 10th grades, and boys significantly outperformed girls during 12th grade. Additionally, SAP and FARM were positively and negatively, respectively, significantly associated with PACER performance at the school level. The odds ratio of adolescents performing in the HFZ declined significantly over the years, even though the number of PACER laps improved in the first three years. Concerted efforts should be targeted at improving cardiorespiratory fitness in high school due to its positive relationship to academic achievement in schools, and negative association with cardiovascular disease, metabolic syndrome, obesity, and all-cause mortality in adulthood. Cardiorespiratory fitness (CF), a marker of cardiovascular health that provides a measure of the ability of the circulatory and respiratory systems to supply oxygen to skeletal muscles during sustained physical activity , has beeIt is clear that there are existing studies that have examined CF of the youth population ,6, the fInvestigation into how school-level factors influence cardiorespiratory performance among high school students is also warranted ,18. For ® . An acceptable level of consistency in validity and reliability of expert and teacher administered 20 m Progressive Aerobic Cardiovascular Endurance Run (PACER) tests has been documented [This observational study utilized existing datasets that contained multilevel, longitudinal CF data, which were accumulated over a four-year period when adolescents in high school were tested annually as they moved from ninth to twelfth grade. Data from the students were collected by certified health and physical education teachers, who entered the data into an online system named Welnetcumented , supportSchools were included in this analysis if (a) fitness education units had been taught in their physical education curriculum for the past four years and (b) fitness testing such as CF was required and assessed annually . StudentThere were 76,227 adolescents  from 80 high schools from the Mid-Atlantic region of the United States who participated the study. They averaged 15.08 ± 0.73 years old (range: 13–19) and were enrolled at the 9th- through 12th-grade levels. The racial/ethnic percentage at the school level was 10.74% Asian/Asian American, 19.64% Black/African American, 11.36% Latino/Hispanic, 51.39% White/Caucasian, and 6.84% Others. The schools were socioeconomically diverse, with FARM rate ranging from 1.79% to 72.61% at the school level.To model longitudinal changes, we included individual/student- and school-level variables. Student-level variables were grade (testing year), sex, and 20 m PACER score, which was tested annually. The PACER test is a criterion-referenced field evaluation of CF that is recommended for ease of use and convenience accommodation needs ,25. The r ranging from 0.57 to 0.82 among the 4 tested areas, we computed an aggregated average passing rate of those subject areas for each school. Specifically, for each school, SAP was computed as We collected school-level variables including FARM, SAP, and S/F-PE from the websites of the school districts and/or state department of education. S/F-PE was calculated through dividing the school enrollment by the number of fulltime health and physical educators employed. For SAP, school-level passing rate (%) in statewide assessments for reading, mathematics, science, and social science for the previous three years were collected. Given that passing rates were highly correlated at the school level, with the correlation coefficient tij is a logit variable, defined as ln(p/(1−p)), where p is the probability of PACER performance in HFZ at time t for participant i in school j. Level one model is centered on 9th grade, where π0ij is the estimated initial logit for child i in school j at grade 9, π1ij, π2ij are the first-order, and second-order growth rate for participant ij during the academic year; and etij is the Level 1 random error. At Level 2, we specified the model to examine the sex difference:We used hierarchical linear modeling (HLM) to model longitudinal CF performance change over the years, between sexes, and in association with the school-level variables . Since ttij values represented the mean PACER performance and the first-order, and second-order growth rate differences within school j. Specifically, we coded 0 for girls, and 1 for boys based on sex data. The Level 2 random error included rtij. We specified the Level 3 model to examine the association between school-level variables such as FARM, SAP and PACER performance:To model the sex differences, βγ00j were the average school-level performance and coefficients associated with a variable, holding other school-level variables constant. The Level 3 random error was u00j. We hypothesized in the model that school-level variables FARM, S/F-PE, and SAP were associated with PACER performance, and that there were sex differences in growth rates of the performances at individual level. We conducted the data analyses using HLM version 6.08 , and kept α = 0.05.At level 3, the Participants’ PACER performance . Adolescents in schools with higher SAP were more likely to be in the HFZ (OR = 1.29). When FARM was added to the model, as shown in the bottom panel in γ = −0.59), while SAP was no longer statistically significant (p = 0.09) suggesting that they were confounding factors at school level. Participants in schools with higher FARM were less likely to be in HFZ (OR = 0.55) than those in schools with lower FARM. While the new model fits better than the one with SAP alone , the amount of variance explained was only marginally improved to 0.51 (Δr2 = 0.01).There was a sex difference and significant school-level variable impact on whether adolescents performed in the HFZ. In general, girls were more likely to be in the HFZ than boys (OR = 1.74). Controlling for the school-level variables, boys and girls had significantly different second-order curves for being in the HFZ while they shared a concaving downward pattern. SAP was positively associated with adolescent PACER performance  most participants fell below the established HFZ, the lower end cutoff score. Therefore, the favorable health effects of HFZ CF levels ,8,9 may th grade The second goal of our study was to explore the potential association between individual/student- and school-level variables and CF performance among high school-aged students. In addition to sex differences at the student level, school-level variables were associated with performance in the HFZ. In this study, SAP was positively associated with likelihood of student performing in the HFZ, where those enrolled in schools with higher SAP were more likely to perform in the HFZ (OR = 1.29). This positive association contributes to the growing evidence of the positive aspect of higher CF, and other health-related fitness components, on academic performance, small sometimes at individual level, but significant at school level ,31,32. CThe research was able to address some known limitations of the existing studies. Notably, we had the opportunity to examine a large dataset that included longitudinal data and multilevel variables and examined the association with school-level variables on adolescent fitness performance (in the HFZ). The availability of data across four years of high school allowed the researchers to study likelihood of HFZ changes across those years, which adds a longitudinal dimension that researchers desired . NeverthIn conclusion, this study indicates that although PACER performance (# of laps completed) improved throughout the first three years of high school, the likelihood of those performing within or above the HFZ decreased overall from 9th to 11th grade. Furthermore, the number of laps completed by adolescents appeared to plateau among participants at 11th grade, with a steep decline in performance during the final year of high school. Additionally, SAP and FARM were positively and negatively associated with performance in the HFZ, respectively. These findings have practical implications for school districts and scholars examining CF among high school-aged students.The findings from this study illustrate declining trend of high school student meeting HFZ, and the need to help high-school adolescents to maintain CF which has shown to be positively correlated to multiple physical and mental health and academic performance. The findings also show factors at the school and individual level that are associated with the probability of the students achieving HFZ. These findings are intertwined and have several implications that would help improve CF and school health in general.Considering the declining rate of students achieving HFZ, it is important that school-based programs including those before, after school, or during school such as physical education and recess have built physical activity elements that are purposefully designed to improve student physical fitness. Promoting and implementing scalable evidence-based programs would not only benefit adolescents on their physical fitness, but also benefit school and the society, particularly during late high school years as these students are entering the labor force and/or higher education as young adults.At the school level, it is important for school administrators to recognize the importance of student physical fitness such as CF on academic achievement which was confounding variable with FARM. The lack of physical educators as indicated by the high student/faculty ratio and discontinuance of offering required physical education during higher grades in our research context further limited students’ opportunity to engage in activities to improve or maintain their physical fitness. Extending more physical education or physical activity programs to students in higher grades  would help these students as move into early adulthood. For schools with higher FARM, these physical activity programs which would help improve physical fitness and academic performance, would be particularly recommended.


The COVID-19 pandemic has been accompanied by a worsening of mental health levels in some, while others manage to adapt or recover relatively quickly. Transdiagnostic factors such as personality functioning are thought to be involved in determining mental health outcomes. The present study focused on two constructs of personality functioning, Criterion A of the Alternative Model for Personality Disorders  and mentalization, as predictors of depressive symptoms and life satisfaction during the COVID-19 pandemic. A second focus of the study was to examine whether this relationship was mediated by resilience.N = 316 individuals from the general population were collected.Linear regression analyses were used to examine the relationship between personality functioning measured by Criterion A  and mentalizing abilities as predictors, and depression and life satisfaction as mental health outcomes. To assess the hypothesis that this relationship is mediated by resilience a structural equation modeling approach was conducted. Data from Linear regression models revealed highly significant associations between Criterion A/mentalization and both outcome measures. Structural equation models showed a significant partial mediation by resilience of these relationships.Our results support the hypothesis that mentalizing serves as a protective function by promoting resilience to the impact of stress and threats. Criterion A and mentalization performed similarly as predictors of mental health outcomes, providing empirically overlapping operationalizations of personality functioning. This finding emphasizes the importance of personality functioning in positive and negative mental health outcomes. Furthermore, our results are consistent with a mediating role of resilience. Humans have had to adapt to disasters, trauma, adversity, threats, and other significant life stressors. Although the COVID-19 pandemic has directly or indirectly affected almost everyone worldwide, recently published data showed, that most individuals from non-clinical populations remained mentally healthy . Beside Public health research has been drawing attention to the importance of the severity of personality disorders (PD) for mental health, where “severity” refers here not only to a clinical condition but is meant to describe functioning at various levels in the healthy or non-clinical population as well . PersonaAnother construct related to personality functioning is mentalization, the capacity to elaborate on other people’s state of mind and intentions . MentaliDiagnostic systems for PD such as the AMPD or ICD-11 are well suited to current conceptualizations of psychological resilience, which adopt a transdiagnostic framework  and embrIn the current study we aimed to improve our understanding of the interplay between personality functioning  on the one hand and depressive symptoms and life-satisfaction on the other hand in the context of the COVID-19 pandemic. Along with other pre-pandemic studies  we expecThe headings of this paper are organized as follows: In the remaining introductory part, we will explain the constructs of Criterion A and mentalization adopted in the present work in the light of the current literature. After providing details on the sample and the instruments in the Methods section, we will report the results on the expected associations between Criterion A/mentalization and our two outcome measures. Structural equation models will further investigate the mediation role of resilience on these two outcomes, irrespective of whether personality functioning was measured by Criterion A or mentalization capacity. In the discussion, we will summarize the implications of these findings for the dimensional characterization of personality functioning as a mental health predictor and point to some important limitations of the present study.Criterion A  in DSM-5, at its core, is characterized by basic psychological human capacities in the domains of self  and interpersonal relationships  close in time to the third Austrian lockdown . During this lockdown all stores, restaurants, bars, clubs, fitness studios and parks were closed with only few exceptions. Home office was recommended, but not mandatory. Schools and universities applied distance learning, indoor sport and entertainment events were prohibited. Some of these restrictions were successively relaxed on January 18 for individuals who tested negative. At that time, a vaccine against COVID-19 was not yet available for the general population.via email to complete the survey and to forward it to their relatives and friends. Overall, 453 participants enrolled in the online survey. After excluding all participants with missing, incomplete, or incorrect data, the dataset included 316 participants. Data were collected in pseudo-anonymized form. Ethical approval was granted by the Review Board for of the Institute of Psychology (N° 34/2020).The current study is a quantitative cross-sectional online study. The participant sample consisted of students from the University of Innsbruck and their family and friends who gave informed consent to the study. Initially, all students on the campus were invited We assessed the following socio-demographic variables: age, sex, student status, and the social status in childhood. Student status was assessed with a simple Yes/No-question, whereas social status in childhood was assessed with a 10-point Likert scale, ranging from 1  to 10 .The UCLA loneliness scale UCLA LS;  was usedCriterion A was assessed with the Level of Personality Functioning Scale LPFS-BF;  in the GFor assessing mentalization capacity we used the mentalization questionnaire MZQ; . The scaWe used the Satisfaction with Life Scale  in its GTo examine depression symptoms we included the “Allgemeine Depressionsskala” ADS;  as a GerResilience was measured using the Resilience Scale RS-13;  as a Gerr < 0.3), medium effects (0.3 ≤ r ≤ 0.5), and large effects (r > 0.5).We computed Pearson’s correlations to determine whether we find significant association between age, gender, student status, social status in childhood, social connectedness, Criterion A, mentalization, depression symptoms, life satisfaction and resilience. Following In preliminary analyses, we examined the data for accuracy of the entries and missing or incorrect values. Participants with missing or incorrect data were excluded.x < 0.01) and the variance inflation factor .To test the association between Criterion A and mentalization with depressive symptoms and life satisfaction in our sample, we estimated several separate linear regressions. Age, gender, student status, social status in childhood, and social connectedness were selected as nuisance variables. Criterion A and mentalization were used as predictor variables in separate models. For regression analyses and structural equation modeling (SEM), we report standardized beta values (ß). The linear relations between predictors and residuals, and homoscedasticity were analyzed using scatter plots. Cook’s distance was used to screen for potential influential data points. Multicollinearity was assessed using tolerance , Root-Mean-Square Error of Approximation (RMSEA), Standardized Root-Mean-Square Residual (SRMR), and the Comparative FIT Index (CFI). In accordance with the literature, we define the criteria as followed: RMSEA < 0.06 for a good and <0.08 for an acceptable fitting, SRMR < 0.05 for a good fitting and CFI best if above 0.95 (X2) not as a strict non-fitting indicator  varied from 18 to 68 with a mean age of 26.15 years (SD = 10.40). Females represented 65.19% of the sample, while 34.81% of the participants were male. 64.6% of our sample were active students at the time of data collection, while social status in childhood ranged from 1 to 10 with a mean 6.35 (SD = 1.63). Descriptive statistics and correlations between all the variables are presented in The age of our sample (t-tests) for the following measurements: resilience . In direct comparison with a German norm sample, we were not able to find any statistical differences to our study sample . Criterion A: The LPFS-BF averaged mean resulted in M = 23.21, (SD = 6.06). When we compare our data with norm values reported by t(315) = 16.32, p ≤ 0.001], whereas no significant statistical difference were found with sample 2 . Life satisfaction: The results of satisfaction for life  showed no difference  compared to a German norm sample with 2,519 participants. Depressive symptoms: The ADS norm sample showed a mean sum score of 14.33  = 3.92, p < 0.001]. Further, we found in total 123 participants, representing 38,91% of the sample, that exceeded the suggested screening cut-off for depression of M = 23. In the norm sample only 17.4% exceeded this cut-off, indicating that our sample included significantly more individuals with depressive symptoms. Mentalization: Inspecting the MZQ, our sample achieved a mean of 2.41 (SD = 0.68), which is not significantly different  from a German norm sample .Examining the RS-13 scale our sample achieved a mean score of In summary, our analyses indicated that our study sample showed increased depressive symptoms in comparison with a healthy norm sample, similarly to other studies during the pandemic. No other scales showed significant differences with normative values.Because of the strong empirical and conceptual overlap between mentalization and Criterion A , we decip < 0.001; gender, ß = 0.16, p = 0.004), with lower childhood social status  showed higher depressiveness scores, while student status  did not reach any level of significance. However, participants′ answers about life satisfaction revealed a positive association with age  and higher childhood social status  when they are more satisfied. Women reached only a statistical trend  in the association with life satisfaction. No effect was found of student status .In a first step, to describe the sample’s demographic characteristics, a model was estimated with the variables age, gender, social status in childhood, and student status as independent variables and depressive symptoms and life-satisfaction scores as outcome variables. This analysis indicated that young women  and life-satisfaction scores (Model B1 and B2) as outcome variables. Each regression model included the covariates age, gender, social status in childhood, student status, and social connectedness. We entered social connectedness as a control variable in the models because it is considered as a relevant factor for resilience and the current pandemic situation . ResultsStatistical analysis with Criterion A as a predictor showed a highly significant association with both outcome variables  in the expected direction. In addition, we also found a highly significant association between mentalization as a predictor and depressive symptoms (Model A2) and life satisfaction (Model B2) as outcome. Thus, participants with lower capacities in Criterion A and mentalization reported higher depressive symptoms and, conversely, participants who scored high in Criterion A and MZQ showed higher life satisfaction. In line with the current literature, we found a significant contribution of social connectedness predicting participant’s depressive symptoms and life-satisfaction. An increase in social connectedness was associated with lower depressive symptoms and a higher life satisfaction.F = 44.44, p < 0.001, Model A1], and in addition, 51% of the variance in life-satisfaction . Moreover, overall models using mentalization as the main predictor variable reached again significance and explained 38% of the variance in depressive symptoms among the participants , and 44% of the variance in participants’ life-satisfaction .The results of the overall models of all regression analyses (Model A1 and A2 and Model B1 and B2) were statistically significant. Using Criterion A as main predictor participants′ depressive symptoms explained 45% of the variance . Similarly, the overall model with mentalization explained 34% of the variance in participants’ resilience . The results indicated that Criterion A and mentalization are relevant and almost comparable predictors in terms of the sign and value of the regression coefficients on resilience. Furthermore, it seems justified to include social connectedness as a control variable because of its strong association with resilience.Finally, we estimated a multivariate linear regression using Criterion A and mentalization as separate predictors and resilience as an outcome variable to test the eligibility of resilience as a mediator . Again, Structural equation modeling was applied to test the mediating role of resilience in the impact of mentalization and Criterion A on depressive symptoms and life satisfaction as indices of mental health. Similar to the linear regression analyses, we calculated two different models differing only in the predictor variable . Since student status and social status in childhood were not significantly associated with the outcomes in the regression analysis, they were omitted in these models.X2 = 123.2, df = 48, p < 0.001; RMSEA = 0.071; SMR = 0.037; and CFI = 0.972 and SEM2: X2 = 115.8, df = 48, p < 0.001; RMSEA = 0.067; SMR = 0.039; and CFI = 0.974). All factor loadings on the latent variables reached significance (p < 0.001), indicating that all latent variables were well represented by their respective observed variables.In both measurement models we included four latent variables  and 12 observed variables. The models showed acceptable fit to the data . Standardized path coefficients can be seen in p < 0.05) effects. Thus, as can be seen in Both models were composed of 2 direct paths  and 2 indirect paths . Since we found strong associations between social connectedness and the other variables in the models, we added social connectedness, beside age and gender as covariates in the structural models to control for possible influences. The results of the structural modeling indicated an acceptable fit to the data for both models  as well as a low positive indirect effect  mediated via resilience. The direct effect showed on the path between Criterion A and the mediator resilience  a significant large effect and on the path between the mediator to depressive symptoms  a negative moderate effect and to life satisfaction a positive moderate effect . To sum up, as expected, individuals with higher Criterion A scores are generally more resilient and satisfied in life and are less depressed. Higher levels of life satisfaction and lower depressive symptoms predicted by Criterion A were partly mediated through resilience.Structural equation modeling 1 – Path Model Criterion A : First, via resilience. The mediation model for life satisfaction was divided into a small positive direct effect  as well as a small positive indirect effect  mediated via resilience. Regarding the direct effects, we found a significant moderate effect between the path mentalization and the mediator resilience , a large negative effect on the path between mediator and depressive symptoms , and a moderate positive effect between mediator and life satisfaction .Structural equation modeling 2 – Path Model Mentalization : First, To summarize, the results of the mentalization structural equation model (SEM2) showed comparable results to the model with Criterion A (SEM1) in terms of path coefficient and total, direct, and indirect effects. As predicted, higher personality functioning  was associated with higher resilience and life satisfaction scores and lower depressive symptoms. However, the effect of Criterion A and mentalization on depressive symptoms and life satisfaction decreased but remained significant when the effect of the mediator (resilience) was considered in the analysis. This suggests that resilience may be only one of the factors involved in mediating the effect of personality on the outcomes. Furthermore, the results are in line with our results revealed by regression analyses.Several studies have provided evidence on the impact of personality functioning  on pandemic-related effects on mental health during the COVID-19 pandemic . In our In the current study, we focused on two research questions. First, we wanted to investigate the predictive capacity of either Criterion A and mentalization on mental health outcomes. Our modeling strategy was to use differing but related assessments of personality functioning  during the COVID-19 pandemic in a population sample. The hypothesis of resilience as mediator of the positive effects of personality functioning on mental health outcomes has been formulated by Against the theoretical background of these two instruments, the results concerning personality functioning would therefore imply that individuals with stable self- and interpersonal functioning or self-other representations are able to flexibly integrate the impacts of the external world and internal demands into their own in order to adapt to current circumstances. In individuals with low functioning, by contrast, distressing events may be likely to be perceived as disorganizing due to an inaccurate or non-mentalized representation of the situation and possible actions that could be taken . These aFocusing on personality functioning abilities is of particular interest because it may be improved by interventions that focus on specific self-other domains , which aFirst, our results support In conclusion, we suggest that it may be fruitful for further research to explore personality functioning as resilience-promoting factor or mechanism and their possible influence not only on life satisfaction and depression, but also on psychological functioning in general. Whether personality functioning can be considered as a general factor in terms of severity indicating a core self-other vulnerability of human health still needs future research. However, there is compelling evidence that a dimensional approach has the potential to stimulate and improve research on mental health issues as well as attempts to assess, prevent, and treat mental illness more adequately.The present study is affected by several limitations. First, its scope is limited since a large proportion of participants were young students in their 20s and women were generally overrepresented. Personality functioning was comparable to population values, but this group of participants may have reacted to the restrictions during the pandemic with increased distress. Second the study was conducted with a cross-sectional design. Only a longitudinal design would have allowed comparing the effects of the pandemic with pre-pandemic data; here, we had to rely on comparison with population normative data to assess the effect of the pandemic on mental health. Third, the use of self-report measures for assessing Criterion A and mentalizing capacities may have led to over-emphasizing consciously available information at the expense of more implicit aspects of these constructs. Fourth, to avoid bias, the mediator variable resilience must be controlled. Hence, we included social connectedness as a confounding covariate in the models, as social connectedness is a known predictor of resilience. However, we cannot exclude the existence of other possible confounders for resilience, which may have led to overestimating the extent of the mediation. Finally, associations between rating scales should be considered with caution, as they may ensue from semantic similarities in the questions asked to participants.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study is in accordance with the Declaration of Helsinki and was reviewed and approved by the Review Board for ethical questions in scientific research of the Institute of Psychology of the University of Innsbruck (N° 34/2020) before data were collected. Written informed consent to participate in this study was provided by the participants.KL and JM conceptualized the study, organized and conducted the study setup and data collection. JM, KL, and LR conducted the raw data analysis. JM, KL, and RV conducted the statistical data modeling. AB and RV provided the important intellectual contributions in commenting and revising the manuscript. KL, JM, AB, RV, LR, and DR wrote the manuscript and edited its final version. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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