The aim of this retrospective cohort study was to provide a single-center clinical audit of complications for single chamber permanent pacemaker implantation (PPI) techniques and determine if the clinical parameters, PPI technique or complications were associated with outcome. The electronic medical records were searched for dogs treated for bradyarrhythmia with PPI. Data related to presenting complaint, signalment of the dog, ECG diagnosis, echocardiographic findings, PPI technique, and programing of the pacemaker were recorded. Survival length (days) was recorded as the last veterinary visit; if the dog was dead the reason was documented. Cumulative survival of each pacemaker was examined by a Kaplan-Meier survival curve and the two techniques compared with a logrank test. Chi-square was used to determine the association between major complications and death. A total of 66 dogs with 52 transvenous and 30 epicardial PPIs were included. All epicardial pacemakers were implanted via transdiaphragmatic approach. A total of 31 life-threatening complications were reported. There were nine deaths related to major complications (13.6% of the study sample). The median follow-up period was 366 days, with a median survival of 255 days, and a significant difference in cumulative survival of each pacemaker (P = 0.01) between epicardial  and transvenous  PPIs but no significant difference in cumulative survival between the two techniques when only the first pacemaker was considered (p = 0.07). The presence of a major complications had a significant association with death due to pacemaker complications (P<0.001). The decision to perform epicardial PPI in failed transvenous PPI patients may have skewed the cumulative survival as was evident in the lack of significant difference in survival when only first PPI were examined. Major complication rates between the two techniques were similar and the authors consider both techniques equally reliable to manage symptomatic bradycardia in dogs. Permanent pacemaker implantation (PPI) in dogs is indicated for the management of symptomatic bradyarrhythmia, including high grade second-degree atrioventricular (AV) block, complete AV block (CAVB), both paroxysmal and persistent forms, and sick sinus syndrome (SSS) that no longer responds to medical management . Less coOutcome and complications of cardiac pacing in dogs using single chamber pacing, including both epicardial and endocardial techniques of PPI, with programming as ventricular demand pacing, have been published in the veterinary literature. The largest outcome study is a multicenter retrospective published in 2001, where major life-threatening events related to loss of pacemaker function were documented in 33% of dogs . In thatA direct comparison of risks and complications between transvenous and a single standardized epicardial technique in a single center has not been previously reported. Our veterinary teaching hospital historically has had a unique cohort of dogs that underwent epicardial PPI via transdiaphragmatic surgical technique, not necessarily due to contra-indications related to a transvenous PPI method, but because of historical limitations of the available personnel to perform a transvenous procedure. Therefore, in this is single institution, complication rates between the two groups could be directly compared. The primary aim of this retrospective study was to describe anesthetic time, temporary pacing time, anesthetic complications, surgical and post-operative complications, and pacemaker programing/sensing complications for single-chamber, VVI/VVIR, transvenous and epicardial pacemakers. The second outcome was to examine the effect and the cumulative survival of pacing techniques. In addition, the associations between selected clinical parameters, and complications with pacemaker related death were examined. The authors of this paper hypothesized there would be no differences in the complications and cumulative survival between transvenous and epicardial permanent pacemaker implantation for the management of symptomatic bradycardia.This was a single institution retrospective cohort study using the electronic health record database of the University of Tennessee from April 2012 to March 2022. Animal owners sign a hospital consent form upon checking in that data from the medical record and imaging studies pertaining to their pet can be used for research and publication. An excerpt from the current consent statement reads as follows, ’I hereby authorize the University of Tennessee College of Veterinary Medicine and its authorized designees to record, transmit, and store in any format and/or medium  my own and my animal’s name, likeness, images, voice, appearance, data, diagnostics, and/or medical records arising out of and relating to the performance, care, and medical treatment hereunder and, further, hereby grant the institution and its authorized designees the perpetual and irrevocable right to use the same, in whole or part, for any commercial or non-commercial purpose including, but not limited to, research’. The electronic medical record database was searched for canine patients with a diagnosis code of ‘permanent pacemaker implantation’. Exclusion criteria included incomplete medical record or indications for PPI other than symptomatic bradycardia.Patient information collected included signalment, presenting complaint, ECG diagnosis, concurrent structural heart disease, anesthetic and temporary pacing time, PPI technique, lead type, fixation technique, suture size (diameter) for fixation of the lead tip to the epicardium or the collar to the jugular vein for epicardial and transvenous technique respectively, pacing mode and rate, and use of antibiotics. Demographic variables recorded included age in months, weight in kg, sex and neuter status, and breed. The electrocardiographic diagnosis of symptomatic bradycardia was categorized as one of the following diagnoses: CAVB, high-grade second-degree AV block, infranodal 2:1 AV block, SSS, or atrial standstill. A 2:1 AV block was considered infranodal if not exercise or vagolytic responsive, the patient had clinical signs, or a 24 hr ECG demonstrated progression to a more advanced AV-block. If an atropine response test was documented in the electronic medical record it was recorded as was the interpretation as responsive (post-atropine heart rate is ≥ 150 or at least a 50% increase in heart rate from baseline) or not . Other iAttempts to determine follow-up and survival time (in days) were made by examining the last entry in the medical record. If the last visit for pacemaker interrogation was within the scheduled time frame, this was recorded. If the patient status was not known, due to the time lapsed from the last visit exceeding the anticipated revisit schedule, or in the scenario where a dog would be examined by a cardiologist or pacemaker technician for interrogation at a site other than our hospital, the referring veterinarian was contacted to determine the status of the animal. If the animal was deceased, the reason and date of death were recorded, as well as if the death was pacemaker complication related or not.®, version 16.0.0, SAS Institute Inc., Cary, NC). Data was separated into two age categories (young dogs under 72 months of age versus older dogs) guided by the findings by Wess et al. (2006) and two weight categories (at least 10 kg and greater than 10 kg) guided by the findings by Visser et al. (2013). A Chi-square test was performed to determine the association between either the age group or body weight group, and major complications; and between the PPI technique and the clinical signs . Complications related to temporary pacing technique i.e., transvenous versus transthoracic, were compared using the Mann-Whitney U test . The association between major complications and the implantation lead type, as well as the suture material thickness and lead dislodgement, was tested using Fisher’s exact test .Descriptive statistics were used for all variables with the median and range reported . The survival analysis was repeated when only the first pacemaker was included, to exclude the bias of death related to a scenario of acute loss of capture, without lead dislodgement, that persisted despite repeated implantation, which is independent of the technique. The logrank test was used to test the effect of age, sex, structural heart disease, and complication by each type of pacemaker, type of clinical signs and the number of clinical signs . Deaths related to pacemaker failure was considered as the event. All other causes of death were considered censored. P <0.05 was considered significant.Sixty-nine dogs underwent a PPI during a 10-year period at a single academic institution. Three were excluded due to lack of clear indications for PPI or incomplete medical records. Of the 66 remaining dogs, 17 (25.75%) were mixed breed dogs, 10 (15.15%) miniature schnauzers, 5 (7.58%) Labrador retrievers, 4 (6.06%) Boston terriers, 3 (4.55%) of each of the boxer, cocker spaniel, German shepherd, and jack Russel terrier breed, 2 (3.03%) of each of the dachshund, bulldog, golden retriever, and Maltese breed, and 1 (1.52%) of each of the Bichon Frise, cairn terrier, Doberman, Dogue de Bordeaux, German shorthair pointer, great Dane, Irish terrier, pug, Shetland sheepdog, and Weimaraner breed.The median age of the population was 125 months (range 36–180). The population was comprised of 42 females, of which 41 (97.62%) were spayed, and 24 male dogs, with 22 (91.67%) neutered. Client complaint and reason for referral were recorded as total loss of consciousness (TLoC) or collapse , exercise intolerance and/or lethargy , gastro-intestinal signs , and/or miscellaneous . In 6 dogs (9.09%), the bradycardia was an incidental finding on clinical examination by the referring veterinarian, and subsequently diagnosed with advanced AV blocks with a potential risk of sudden cardiac death, warranting artificial pacing. In 25 dogs (37.88%), the PPI was considered an emergency procedure, while 41 dogs (62.12%) were presented for a routine appointment for PPI.There was no significant association between the clinical signs and the type of pacemaker technique chosen by the clinician (P = 0.06). According to the log-rank test, there was no difference between the clinical signs in the survival probability due to pacemaker implantation at any time point (P = 0.14), and there was no significant effect of the number of clinical signs in the survival probability due to pacemaker implantation at any time point (P = 0.20).The association between the 10 most common breeds and their ECG diagnoses is depicted in Concurrent heart disease or abnormalities described on the echocardiography report at the time of diagnosis of bradyarrhythmia, are listed. Fourteen dogs (21.21%) had cardiomegaly documented in the initial echocardiogram as either left ventricular dilation and left atrial enlargement, or subjective appearance of all chambers being enlarged in the absence of valvular disease or systolic dysfunction. The cause was likely to be related to the bradycardia rather than primary structural heart disease, as the normalized dimensions of the left ventricle and atrium were within reference intervals on follow-up examination post-PPI in many of the dogs and the absence of valvular disease or subnormal systolic function. Two additional dogs (3.03%) had isolated tricuspid insufficiency with normal valve morphology, and ascites, consistent with right-sided congestive heart failure (R-CHF), and related to the bradycardia, as the signs of R-CHF resolved after PPI in one dog and the second dog had an escape rate of 25 bpm and suffered a peri-procedural death. A total of 29 dogs (43.94%) had a description of structural heart disease on echocardiogram. Volume overload could have caused misclassification of disease stage and is therefore not stated. Twenty-three dogs (34.85%) had myxomatous mitral valve disease (MMVD), 2 dogs (3.03%) had dilated cardiomyopathy (DCM) phenotype, 1 dog (1.52%) had a tentative diagnosis of a cardiac associated tumor (chemodectoma), 2 dogs (3.03%) had congenital disease , and 1 dog had pulmonary hypertension (1.52%).Additional recorded ECG abnormalities included ventricular ectopy , concurrent to either CAVB or high-grade second-degree AV block. Three of these dogs (42.86%) had ventricular tachycardia, 2 (28.57%) had advanced MMVD and 1 dog (14.29%) had R-CHF without structural heart disease diagnosed. Four dogs (57.14%) had singlet ventricular premature complexes (VPCs), with a boxer with VPCs having a structurally normal heart but later presumptively diagnosed with arrhythmogenic ventricular cardiomyopathy; and the other 3 dogs (42.86%) having no structural heart disease.Sixty-six dogs had a total of 82 pacemakers implanted, 30 (36.59%) epicardial and 52 (63.41%) percutaneous transvenous endocardial. In the transvenous endocardial technique, all leads were single chamber; a total of 26 (50.00%) tined and 19 (36.53%) active leads were used, with the remainder not documented in the surgical report. Medtronic Inc.  was the exclusive manufacturer for all the pacemaker leads and generators. All leads  and generators  were first time use and sourced from Companion Animal Pacemaker Registry and Repository.et al. ..et al. (. (2007) , 29–31. . (2007) , 33. TheVentricular perforation, a major complication, was responsible for one death due to hemothorax , and one case of synchronous diaphragmatic contraction in another (transvenous PPI), in this study. Lead perforation has been previously described with transvenous endocardial active leads , 22, 24.Lead fracture has been previously reported related to transvenous PPI , we alsoDescribed surgical approaches for epicardial pacemaker implantation in dogs include techniques that are reported to be associated to increased surgical time and trauma such as lateral thoracotomy , 18, 19 The anesthesia related complications were similar to a previous report in the literature . Our stuStatus for all dogs was available with a median of 366-days follow-up. The median survival (255 days or 8.5 months) was shorter than previous reports for transvenous VVI (median of 14–19.9 months) , 36 and The effect of age, sex, indication for pacing, and presence of concurrent heart disease on cumulative survival were not significant . This is in contrast to previous published results which demonstrated that older dogs, dogs over 10 kg in the case of epicardial PPI, and the presence of congestive heart failure have a shorter survival , 16, 36.et al. (2006) were ascribed to the center being a high-volume implantation center and surgical experience being the likely reason [et al. (2001), in that our center and some contributing institutions would be considered to have a low volume implantation case load and likely experience with the technique is inferior [The effect of a major complication on survival probability (P<0.001) has similarly been noted previously . This moet al. 06 were ainferior . Major cinferior . Two stuinferior , and 5.8inferior , which winferior . The cauet al. 06 were ainferior . One doginferior . UndeniaThere are several limitations that the authors recognize, mostly inherent to the nature of a retrospective study, including several omissions in the medical records leading to many absent data points. The population was small, and the possibility remains that the study’s lack of power could have led to a type I error where, due to chance or unrelated factors, a significant difference between the technique of PPI in cumulative survival was detected. The shorter cumulative survival in epicardial is unlikely to be related to the technique but rather the motivation for this technique. In some of the dogs that had short-term death with epicardial PPI also had previous acute loss of capture without dislodgement with transvenous, and this could indicate an exit block that is unrelated to technique. The last pacemaker implanted would have been epicardial and an unfair association with survival.There are several additional limitations in this study. Statistical comparison in complication rates between the two groups could not be made due to the few instances recorded. The study suffers from the selection bias inherent in a retrospective study, particularly related to the lack of standardized care and variation in owners’ willingness to treat their pets or variation in perception of quality of life, which creates disparity when humane euthanasia is elected. The direct comparison between epicardial versus transvenous approach may have been biased as the decision could have been influenced by whether this was in office hours or out of hours and staffing availability. The exclusion criteria eliminated only a few dogs from this study (n = 3), all related to lack of clear indication for PPI, as an attempt to avoid potential confounding factors on survival. Previous studies have had variation in reports of complications, some differentiating major from minor and others reporting complications overall. Our study defined a major complication as life-threatening if not corrected. Conditions including lead thrombus, sensing abnormalities and seroma were not considered major complications. The inferences regarding the differences found in the type of temporary pacemaker technique (transthoracic versus transvenous), in terms of complications and effectiveness of pacing, could not be examined. There was no data on the placement of the pacing electrodes and complications for transthoracic was not described further than failure to capture; no description was included detailing attempts to replace the position of the electrodes. In addition, there was no indication why one technique was used over the other i.e., based on body size, thoracic wall shape or the type of PPI technique employed. Our study found equal number of complications between transthoracic and transvenous temporary pacing approaches. A retrospective study examining transvenous versus transthoracic temporary pacing found both techniques to be efficient in temporary pacing, however, transvenous increased the time of the procedure by delaying the duration from pre-medication to anesthesia induction . This daThis retrospective descriptive study detailed the complications in both epicardial and transvenous PPI. No significant association was found between the clinical signs and the choice of PPI technique and pacemaker associated death. The cumulative survival with an event being death directly related to the pacemaker found that epicardial was significantly shorter survival than transvenous. This was likely skewed by the inevitable replacement of a transvenous PPI with an epicardial lead, where lead dislodgement was not the cause of acute loss of capture i.e. rising threshold, and the problem persisted. When dogs with only the first PPI were considered, this difference was no longer apparent. Both techniques offer reliable management of artificial pacing in dogs for a variety of bradyarrhythmia. From the results of this and previous studies, it cannot be ignored that PPI is associated with an unacceptable high major complication rate and despite unequivocally having a strong indication for the management of symptomatic bradycardia, these complications should be included as part of the informed consent. Major complications necessitate the need for revision of the procedure, and the associated costs involved are high. Due to similar incidence of complications between the two techniques, the authors feel it is reasonable to advocate for PPI via epicardial technique in facilities that lack personnel with minimally invasive technique expertise or fluoroscopy, or when geographic constraints in decision making play a role.S1 FileThe excel file categorizes the data under the following sheets: signalment and complaint; cardiac pacing, temporary pacing, anesthesia, surgery, and outcome. The cardiac pacing sheet lists the findings per visit rather than per PPI as is the case for the other sheets.(XLSX)Click here for additional data file.


Chronic gastritis is accompanied by varying degrees of gastrointestinal symptoms, which affect people’s quality of life. The association between dietary behaviors and gastrointestinal symptoms of patients with chronic gastritis has been proved recently. However, no studies have been conducted to investigate the relationship between dietary behaviors, gastrointestinal symptoms, and quality of life.A cross-sectional survey of 176 patients diagnosed with chronic gastritis aged 18 to 65 years, comprising their information on demographic characteristics, dietary behaviors, gastrointestinal symptoms, and quality of life, was collected. A descriptive analysis and a correlation matrix were used to illuminate the characteristics of the subjects and bivariate correlation, respectively. The mediation model was analyzed using the PROCESS macros for SPSS.Demographic characteristics were found to influence the symptoms, dietary behaviors, and quality of life of chronic gastritis patients; in particular, students categorized by occupation had higher levels of gastrointestinal symptoms and lower levels of quality of life and dietary behavior. The study variables were all pound related. We found that gastrointestinal symptoms played a partial mediating role between dietary behavior and both the physical components summary and mental components summary, and the ratios of mediating effects to the total effect on the physical components summary and mental components summary were 23.5% and 21.5%, respectively.Our survey discovered that dietary behavior, gastrointestinal symptoms, and quality of life were all pairwise related. The effect of dietary behavior on quality of life was partially mediated by gastrointestinal symptoms. These results may provide a novel perspective for medical staff in improving the quality of life of patients with chronic gastritis. One may estimate that more than half of the world population have this disease to some degree and extent, indicating that many hundreds of millions of people worldwide may have chronic gastritis in one form or another . In ChinClinically, changes in dietary habits and lifestyle adjustments are part of the treatment of CG. According to the 2022 China consensus on chronic gastritis . A recenHowever, few studies have discussed whether dietary behavior affects the QOL of CG patients or whether symptoms play a role in the influence of dietary behavior on the QOL of CG patients. This study aims to explore the influencing factors of QOL in Chinese adult patients with CG. We speculate that in addition to demographic factors, QOL is also affected by GI symptoms and dietary behaviors, that is, higher GI symptoms and worse dietary behaviors are associated with lower QOL. In addition, we will also explore whether dietary behavior may affect quality of life by causing GI symptoms.2.2.1.A cross-sectional design was conducted in this study. A convenient sample of 176 patients with CG was included. Participants were recruited from the gastroenterology department and gastroenteroscopy center of a level III hospital in Wuxi, China. Participants were chosen based on the following criteria: (a) aged 18–65; (b) having the endoscope examination and reaching the pathological diagnostic criteria of non-atrophic gastritis; (c) all consecutive patients with gastrointestinal symptoms for a week or longer; (d) volunteering to participate in the questionnaire survey. Exclusion criteria included: (a) subjects who reported having other digestive system diseases such as peptic ulcer, pancreatitis, hepatitis, and cirrhosis; (b) having serious heart, brain, liver, kidney, or hematopoietic system dysfunction or other serious diseases; (c) having a severe mental illness ; (d) food or drug allergies and pregnancy or breastfeeding; (e) taking a medication that had caused side effects of gastrointestinal symptoms for the past 3 months.The sample size was 5–10 times the number of variables using the Kendall sample size calculation method. This study included 30 survey variables, multiplied by 5, and 20% of the incorrect questionnaires were taken into account. The total number of cases in the sample was 180.2.2.http://www.chictr.org.cn/index.aspx Identifier: ChiCTR2200062781). All patients signed an informed consent before completing the measures.The study was approved by the medical ethics committee of the Affiliated Hospital of Jiangnan University (LS2021012) and was performed in accordance with the principles of the Helsinki Declaration of 1964. Moreover, it was registered at the Chinese Clinical Trials Registry , secondary (9–12 years), some college (13–17 years), college graduate or higher (≥18 years); body mass index (BMI): BMI was defined as the body weight (in kilograms) divided by the square of the body height (in meters); occupation: student, staff, retired, others; chronic diseases history: gastric chronic diseases, others, none; smoking and drinking history: yes (more than one cigarette per day for more than a year or/and drinking more than 30 g a day for more than 6 months) or no.2.4.A survey of dietary behaviors was conducted using the dietary behaviors scale , 11. The2.5.With the clinical experience of clinical digestive experts, we evaluated five common symptoms: stomachache, belching, acid reflux, gastric distention, and early satiety. Each symptom was assessed on a four-point Likert scale, ranging from no discomfort to very severe discomfort. The higher the scores, the more severe the symptoms.2.6.The CSF-36 showed good validity and reliability in the general Chinese population . Physica2.7.All interviewees were medical professionals undergoing unified and standardized training to lower measurement variance. The participants were instructed to complete the questionnaire after giving their permission. The medical staff conducted the survey by interview, read the questions, and filled out the questionnaire under the responses. The participants also filled out the questionnaire on their own initiative or at their request.2.8.p <0.05 was considered to be statistically significant. Categorical variables (demographic characteristics) were presented using frequency and percentage. Continuous variables  were presented using means, standard deviation, and range. Distributed differences of categorical variables were assessed using an independent sample t-test  or one-way ANOVA . The association between dietary behaviors, GI symptoms, and QOL was examined using Pearson correlation. Hierarchical regression was used to examine the association between dietary behaviors, symptoms, and quality of life. After adjusting for demographic factors, the hierarchical regression analysis was completed using Hayes’ test steps, and the mediation effect test was run using the bootstrap technique 5,000 times ; that is, a history of stomach problems, and the student group had a higher score, with the symptoms being relatively more severe. (b) Dietary behaviors: educational level, age, and occupation had a significant impact on dietary behavior scores (p < 0.05); the higher the education level and the younger the participant, the worse the dietary behavior. (c) PCS: PCS was affected by different age groups and occupations (p < 0.05). People between the ages of 25 and 54–65 had a lower PCS score, corresponding to students and retirees in occupations. (d) MCS: Age, education level, occupation, and smoking and drinking history all had a significant impact on MCS (p < 0.05), with those under 25 years old, with a master’s degree or higher, students, and those who do not smoke or drink scoring lower. (e) Sex and BMI had no significant effect on dietary behavior, symptoms, PCS, and MCS in our study.The influencing factors on the research variables were analyzed based on demographic characteristics , and the3.4.r = −0.3, p < 0.01) while positively related to PCS  and MCS . Symptoms were negatively related to PCS  and MCS . Furthermore, PCS was moderately related to MCS .The bivariate correlation analysis  revealed3.5.β = 0.3, p < 0.05) and negatively predict symptoms . PCS was significantly predicted by dietary behaviors  and symptoms . The addition of symptoms to equation 3 based on equation 1 improved the explanatory degree, implying that symptoms acted as a moderator in the influence of dietary behaviors on PCS. The effect of GI symptoms on dietary behaviors and MCS was investigated . In addition, the mediation model showed that GI symptoms played a partial mediating role between dietary behavior and both PCS and MCS, and the ratios of the mediating effects to the total effect were 23.5 and 21.5%. The findings suggested that better dietary behavior was associated with lighter GI symptoms, which, in turn, was associated with better QOL in both PCS and MCS. With fewer and milder GI symptoms, CG patients can endure less pain and have a more relaxed life. The mediating effects in our study accounted for 23.5% and 21.5% of the variance. It is possible that some variables we did not take into account occupied more weight, such as the covariates we accounted for, age and occupation, and the quantity of unhealthy diets that we did not consider in our study. This study can provide medical workers with a recommendation for patients with symptomatic CG; indeed, the evaluated and corrected dietary behavior of patients can reduce symptoms and improve their quality of life.Our survey discovered that dietary behavior, GI symptoms, and QOL are all pairwise related. The effect of dietary behavior on QOL is partially mediated by GI symptoms. These results may provide a novel perspective for medical staff in improving the quality of life of patients with CG. There are some limitations in the study. First, the study was a cross-sectional survey, which means it can only offer causal hypotheses and cannot carry out extensive causal verification. Second, the results could not reflect the entire target population due to the small sample size, and age subgroups have not been examined. Third, incorporating food frequency and quantity into the reference range may enhance the influencing variables. In the future, we will conduct a multi-center study, adopt probability sampling to increase the sample size, and focus on the quality of life of patients with chronic gastritis of different ages to strengthen the research results.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.FZ and DK: conception and design. LZ and FZ: analysis and interpretation of the data and drafting of the paper. LZ, DL, JiY, JuY, QW, YW, JS, YL, and YX: data collection and its critical revision for intellectual content. HC: supervision, project administration, and writing—reviewing and editing. All authors contributed to the article and approved the submitted version.We are grateful to the Natural Science Foundation of Jiangsu Province (BK20210060 and SBK2022023007); Scientific Research Project of Jiangsu Commission of Health (M2021055); the funding for Leading Talents and Advanced Talents in Medical and Health Profession in Wuxi Taihu Lake Talent Plan; Science and Technology Program Project of Jiangsu Market Supervision and Administration (KJ2022028); Jiangsu Scientific Research Project of Elderly Health (LK2021035); Jiangsu Scientific Research Project of Women’s and Children’s Health (F201741); Scientific Research Project of Wuxi Commission of Health (ZZ003 and Q201762); Wuxi Scientific and Technological Development Project ; and Translational Medicine Research Program of Wuxi Translational Medicine Center (2020ZHYB08).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 prognostic significance of radiotherapy (RT) for colorectal cancer (CRC) has shown conflicting results, particularly among different pathological subtypes, including adenocarcinoma (AC), mucinous adenocarcinoma (MC), and signet-ring cell carcinoma (SR). This study analyzed the prognosis of three pathological CRC types and focused on the prognostic significance of RT on three CRC histological subtypes. Patients diagnosed with AC , MC (n = 3813), and SR (n = 664) in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database (2010–2017) were evaluated. Cox regression models and competitive risk models were built to assess the effect of RT on the risk of CRC-associated death. Potential interactions between RT and stratified variables including age, sex, and tumor location were examined by multiplicative models. Compared with AC patients, SR patients had the worst overall survival (OS) among 3 subtypes of CRC . Compared with patients who did not receive radiotherapy, RT was associated with a 1.09-fold  elevated risk of death among AC patients. In the SR group, RT significantly reduced the risk of death by 39% . However, RT did not appear to independently influence survival in the MC group . In the subgroup analysis, tumor location (colon and rectum) significantly modified the association between RT and the risk of death among the AC and SR patients (p for interaction < 0.05). SR patients exhibited a worse OS  than AC patients, and the effect of RT varied according to CRC histological subtypes. This can ultimately lead to more personalized and effective treatment strategies for CRC patients. Notably, the 2021 projections are based on currently available incidence and mortality data and thus do not reflect the impact of COVID-19 on cancer cases and deaths. Overall, CRC (colon and rectum cancers) ranks fourth in terms of incidence, with 104,270 colon cancer (both sexes) and 45,230 rectum cancer cases (both sexes), and it is the second leading cause of cancer-related deaths . Despite advances in CRC detection, diagnosis, and treatment, it remains a serious threat to people’s lives and health.Colorectal cancer (CRC) is one of the most frequent cancers in the world. According to the 2021 American cancer statistics4. Mucinous adenocarcinoma (MC) and signet-ring cell carcinoma (SR) are thought to represent separate subgroups that account for 4–30% and 1% of all colorectal malignancies, respectively. The survival in these three types of CRC is inconsistent8. Results from several studies showed MC and SR had a worse prognosis compared with AC9, however, other studies have found no difference in survival outcomes when compared to AC11.CRC is characterized by several histological subtypes, with adenocarcinoma (AC) being the most frequent type16. However, the prognostic significance of RT for CRC has been conflicting, especially among different pathological subtypes. A prior study found that RT did not affect overall survival in either AC or MC patients17. In addition, a previous study has found cell subpopulations exhibiting intrinsic radio-resistance persist following RT, potentially leading to increased clinical risks due to their revived proliferation and successful colonization at local or distant sites18. Xu et al.19, on the other hand, discovered that CRC patients with MC/SR could benefit more from surgery combined with radiotherapy than surgery alone. There has been no large-scale population-based investigation focusing on the survival benefit of RT in distinct histological subtypes of CRC.Treatment strategies for CRC include surgery, chemotherapy, radiotherapy (RT), targeted therapy and immunotherapy. Surgery, chemotherapy, and radiotherapy are the three most commonly used method in clinical practice, and the implications as well as benefits of the first two have been well-studied previouslyIn the current study, we used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2017 to assess the prognosis and survival benefit of RT in CRC patients with AC, MC, and SR.We analyzed CRC patients registered in the SEER national cancer registry from 2010 to 2017. The SEER database, an authoritative source of information concerning cancer incidence and survival in America, is a population-based cancer registry. It records information on patients’ clinicopathological characteristics, the information on adjuvant therapy, and their vital status during follow-up. From 2010 SEER began to collect data on chemotherapy, radiotherapy and other important variables. In short, a total of 100,645 CRC patients were identified in the SEER database from 2010 to 2017. Patients were excluded if they (1) had T0 or Tis local disease (n = 2150); (2) were combined with other primary malignant tumors to exclude the impact of other cancer types ; (3) had a survival time of 0 months or uncertain survival months (n = 5183); and (4) had other pathological categories, except AC, MC and SR  (n = 7498). Finally, 58,651 patients were included in the final analysis  , surgery, chemotherapy (CT), and radiotherapy (RT). CT and RT  were defined as received CT (RT) at any point of treatment. Patients who did not receive CT (RT) or with missing data on CT (RT) were categorized as not received CT (RT) or unknown, since the SEER database included “No” and “Unknown” in the chemotherapy and radiotherapy grouping. In accordance with previous studies, variables that had missing data were classified as “Unknown” for analysis purposesAll statistical analyses were performed using a commercially accessible software program . Continuous variables were described and compared using means ± standard deviations and one-way analysis of variance (ANOVA) or t-test based on the grouping method. Categorical variables were expressed as absolute values with percentages and were compared using the chi-square test. To examine the differences in survival probability over time across the three groups , Kaplan–Meier survival curves were employed, and the equality of these curves was assessed using a log-rank test. The Nelson-Aalen cumulative risk curve was used to compare distributions of time to CRC-related death because CRC unrelated death was a competing risk event.Person-years were calculated starting from the date of cancer diagnosis, to the date of CRC-related death, non-CRC-related death, or the date utilized as a cutoff for our analysis , whichever occurred first. The Schoenfeld residual test was used to examine the proportional hazard assumption. Cox regression models were used to describe the association between RT and the risk of CRC-associated death among different CRC pathological types. Three models were fitted as follows: model 1 was an unadjusted analysis; model 2 was adjusted for sex and age (every 10 years); model 3 was further adjusted for race, location, grades, T, N, and M stages, surgery, CEA, perineural invasion, and CT based on model 2. Subgroup analyses were carried out for three pathological categories of CRC that were stratified by age, tumor sites, and sex. The interactions between RT and these variables were further tested using multiplicative models.22. In that case, the competing risk analysis, the cause-specific hazard (CS) model and the sub-distribution proportional hazards (SD) models, were utilized to quantify the risk of CRC-related death, it allows for the estimation of event-specific cumulative incidence functions, providing a more accurate representation of the probabilities of each event occurring in the presence of competing risks. We further employed propensity score matching (PSM) analysis to mitigate selection bias and enhance the evidential strength of our nonrandomized observational study. Statistical significance was defined as a two-sided p value less than 0.05.During the follow-up, other causes of failure may arise before the cancer event, making it difficult to detect the presence of incident cancer. Because people who have a competing event (and hence are censored) are thought to develop cancer in the future, traditional predictions such as Cox regressions may significantly overestimate the cancer risk in this competing risk settingThe present study used previously collected anonymized and de-identified data from the SEER database. Therefore, no additional informed consent was required. The study was complied with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards and deemed exempt from review by the Ethics Board of the Peking University International Hospital.p < 0.001). MC (63.73%) and SR (61.75%) were more commonly found in the right colon than AC . Moreover, SR was more likely to present with later stage lesions  than MC  and AC . In addition, SR patients were more likely to receive chemotherapy than MC patients and AC patients. The percentage of race, marital status, sex, T, N, and M stages, CEA, perineural invasion, liver, bone, brain, and lung metastases, surgery, and radiotherapy differed significantly across the three groups. We also analyzed the baseline characteristics of the population stratified with and without radiotherapy for each pathological type  months among 58,651 participants, 14,973 CRC patients died . In addition, 4166 non-CRC-related death cases were observed before the occurrence of CRC-related death . Results from the Kaplan–Meier method  SR patients had the worst OS of the three subtypes of CRC; (2) RT significantly increased the risk of death among patients with adenocarcinoma CRC, particularly among patients who were elderly, male, and had a tumor in the colon; and (3) RT significantly reduced the risk of death in SR patients, particularly among patients who were older, male, and with the tumor located the rectum.5, the 5-year survival rate in SR patients was only 26.8%, which was significantly worse than MC  and AC . By analyzing 244,794 CRC patients from the National Cancer Data Base (NCDB), Hyngstrom et al.11 found patients with signet ring cells colorectal AC had poorer outcomes compared with non–signet ring AC of either the colon or rectum. The association of MC with the risk of mortality of CRC patients was controversial. According to a population-based study in Singapore7, MC is an independent prognosis factor for poorer outcomes of CRC-related death. Whereas, other studies found that poor MC outcomes were more related to tumor stage or specific tumor sites, suggesting that MC is not an independent prognostic factor24.The current study’s findings of poor prognosis in SR patients were in line with the majority of previous research. In a Korean study25 found the overall survival rate among eligible patients at two years was 82.0% in the group receiving both radiation and surgery and 81.8% in the group receiving surgery alone (p for difference = 0.840). Also, results from the randomized multicenter TME trial observed there was no improvement in survival of 10-year OS for AC patients 17. Unfortunately, no existing studies found that RT elevated the risk of death among AC patients with colon cancer. However, the advantages of RT should be noted as well. RT could reduce the incidence of local recurrence, down-stage locally advanced cancer, and increased resection rate for tumors, as well as raise the likelihood of anus reservation28. Despite the therapeutic effects of radiation being primarily attributed to DNA double-stranded breaks, a subset of cancer cells with intrinsic radio-resistance can survive this treatment. Reactivation of proliferation in these cells and their successful colonization at local or distant organs can lead to local regrowth and distant metastasis, increasing the risk of poor clinical outcomes. Recent studies have observed a more aggressive phenotype in radioresistant cancer cells, with altered gene expression related to cell cycle progression, DNA damage repair, migration, and invasion31.RT was discovered to be a risk factor for AC patients’ prognosis in this study. Subgroup analyses further confirmed the elevated risks of RT for the prognosis of AC patients were observed among patients with colon cancer, however, not with rectum cancer. Several previous studies partly supported our results. A randomized controlled trial (RCT) involving 1861 CRC patients conducted by Kapiteijn et al.32. Furthermore, Guan et al.19 discovered that RT might improve survival in patients in stages II and III by evaluating data from 1808 rectum cancer patients in the SEER database, which is corroborated by another research by Wu33.We did not find a significant association between RT and OS in MC patients which was similarly shown in a prior study. Importantly, RT significantly lowered the risk of death for SR patients, particularly when the tumor was situated in the rectum rather than the colon. Consistent with our findings, Ling and his colleagues found that RT was an independent prognostic factor associated with improved survival in stage III rectal SR, rectal patients with stage III underwent preoperative RT had a better prognosis than patients who received surgery alone 34.We provided evidence that RT is closely associated with worse prognosis among AC patients and better prognosis in SR patients was not yielded to analytical methods that consider the competing risk of cancer-free death. The occurrence of the event of interest is frequently prevented by another event in time-to-event studies, making it difficult to observe the occurrence of the event of interest. During an average follow-up of 27 months, 4166 people died from causes other than CRC. Compared to the results of Cox regression, the results were slightly strengthened in the competitive risk approaches, confirming the primary conclusions of the current study. In the current study we applied both the CS models and the SD models. Despite comparable conclusions, the CS model and SD model are distinct. The CS model would be more appropriate for investigating the causal association. The SD model would be more suited to predicting the likelihood of the result35. The presence of wild-type p53 in cancer cells has been linked to susceptibility to radiation or chemotherapy-induced damage, whereas mutant p53 has been linked to radio- and chemotherapeutic resistance36. Second, SR cancer showed significantly negative/lower expression of epidermal growth factor receptor (EGFR), compared with other pathologic types of CRC37. EGFR regulates a variety of physiological responses, including cell proliferation, apoptosis, and differentiation, and is suspected to have a role in a variety of cancers. In in vitro tests of malignant cell research, overexpression of EGFR has been linked to radio-resistance39. Third, the expression of cyclooxygenase (COX)-2 was reduced in SR cancer compared to other colorectal cancer subtypes. COX-2 overexpression was found to be more likely to demonstrate a poor response to chemoradiotherapy40. Overall, the high expression of p53, EGFR, and COX-2 in AC results in poor response to chemoradiotherapy, and may confer early and late toxicity from RT, affecting patients’ long-term health-related quality of life. However, the previous statements were speculative, and further experimental studies are needed to better understand the mechanisms behind the variation in the effects of RT across different histological subtypes of CRC.The underlying mechanism remains uncertain. However, several mechanisms may help to explain our findings. First, the expression of the p53 protein was found to be higher in the AC component of the tumor than in the signet ring carcinoma componentThe current study's strength is that it offers a unique perspective on the possible link between RT and the prognosis of various CRC histological subtypes. Other strengths included the enormous amount of data on CRC patients, which allows for accurate extrapolation of the findings. In addition, competing risk regressions were used to confirm our findings, which improved the study's accuracy. On the other hand, the limitations must be acknowledged. First, SEER, in particular, is lacking in precise data on chemotherapy and RT. It does not distinguish between “unknown” and “no. ” Second, there was no information on the patient’s comorbidities, family history, body measures, clinical exams, or laboratory testing, which might have been associated with CRC outcomes and survival. Third, targeted therapy and immunotherapy are becoming more common in clinical practice for the treatment of CRC, However, due to the limited data, we could not assess the effect of targeted therapy and immunotherapy on the association of RT with the risk of CRC-related death. Forth, pathologic data was collected from a variety of hospitals and not submitted to a centralized review. Fifth, this is an observational study, therefore, while associations and correlations can be identified, it is not possible to establish a cause-and-effect relationship between variables solely based on observational data. Sixth, RT significantly reduced the risk of death in SR patients but not in MC patients. Nevertheless, a biological explanation for this phenomenon could not be identified in our study. Further investigations with longer follow-up and broader assessment of covariates are necessary to enhance our understanding of CRC subtypes and their responses to RT.The results of this retrospective cohort analysis revealed that the effect of RT varied according to CRC histological subtypes. This can ultimately lead to more personalized and effective treatment strategies for CRC patients. Future research on CRC is required in several areas, including molecular pathology, risk factors, genetic contributions, and diagnostic and therapeutic techniques.Supplementary Information.


Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease, which is caused by severe fever with thrombocytopenia syndrome virus (SFTSV) with high fatality. Recently, the incidence of SFTS increased obviously in Jiangsu Province. However, the systematic and complete analysis of spatiotemporal patterns and clusters coupled with epidemiological characteristics of SFTS have not been reported so far.Data on SFTS cases were collected during 2011–2021. The changing epidemiological characteristics of SFTS were analyzed by adopting descriptive statistical methods. GeoDa 1.18 was applied for spatial autocorrelation analysis, and SaTScan 10.0 was used to identify spatio-temporal clustering of cases. The results were visualized in ArcMap.P < 0.001) located in southwestern Jiangsu Province from January 1, 2017 to December 31, 2021. The Secondary cluster also covered one county (Lishui county)  from January 1, 2017 to December 31, 2021.The annual incidence of SFTS increased in Jiangsu Province from 2011 to 2021. Most cases (72.4%) occurred during May and August with the obvious peak months. Elderly farmers accounted for most cases, among which both males and females were susceptible. The spatial autocorrelation and spatio-temporal clustering analysis indicated that the distribution of SFTS was not random but clustered in space and time. The most likely cluster was observed in the western region of Jiangsu Province and covered one county (Xuyi county) (Relative risk = 8.18, Log likelihood ratio = 122.645, The annual number of SFTS cases showed an increasing tendency in Jiangsu Province from 2011 to 2021. Our study elucidated regions with SFTS clusters by means of ArcGIS in combination with spatial analysis. The results demonstrated solid evidences for the orientation of limited sanitary resources, surveillance in high-risk regions and early warning of epidemic seasons in future prevention and control of SFTS in Jiangsu Province. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus (SFTSV). It was firstly discovered in China in 2009 . The vasThe main clinical manifestation of SFTS included high fever, leukopenia and thrombocytopenia, and multiple organ , with a Haemaphysalis longicornis (H. longicornis) whose distribution is closely associated with the meteorological factors accompanied by remarkable seasonal features. Along with the variation of these factors, the occurrence and spread of SFTS vary over space and time. Therefore, the widespread adoption of geographic information systems and spatial statistics in describing the distribution characteristics and transmission patterns of diseases might not only be conducive to timely surveillance, but also to effective intervention against infectious diseases.The predominant vector of SFTS is However, so far, there are few studies on spatial epidemiological characteristics at the county level in Jiangsu Province. Tick-borne diseases have different spatial and temporal distribution characteristics in different regions, which is affected by factors such as meteorologic factors, social and economic condition and geographical location , 20. PreJiangsu is a coastal province located in the middle of east coast of China , featuring a monsoon climate transitioning from a subtropical to a temperate one  and presented other symptoms  also exhibiting risk factors related to epidemiology (ticks exposure two weeks before illness onset or working as a farmer) and clinical testing data included thrombocytopenia and leukocytopenia, was considered a suspected case. The suspected patient meeting one or more of the following conditions:  SFTSV RN8.0℃ and The data of SFTS cases between January 2010 and December 2021 in Jiangsu Province were obtained from the Nationwide Notifiable Infectious Diseases Reporting Information System (NIDRIS). Every case was identified by laboratory or clinical diagnosis. Information including the residential address, age, gender, occupation and date of illness onset of the SFTS cases was contained. In addition, the demographic information was obtained from Jiangsu statistical annual report (tj.jiangsu.gov.cn/col/col87172/index.html).ArcGis 10.7  was applied for the visualization of geographical distribution.IBM SPSS Statistics for Windows, version 25.0  was used for analyzing and processing basic data, while I, and how closer its value is to 1. The closer the relationship between the spatial units is, the more similar their properties become, and conversely, the closer it is to − 1, the greater the difference between the spatial units  range of Global Moran’s al units  will be.When spatial heterogeneity is defined as the presence of significant variation in spatial autocorrelation within the study area, it is necessary to describe the variation of spatial autocorrelation in the study area. Herein, local indicators of spatial association were depicted by local indicators of spatial autocorrelation (LISA) , and werArcGIS10.7 were used for spatio-temporal scanning analysis and spatio-temporal clustering visualization, respectively, while the clusters of temporal aggregation was monitored using spatial scan statistics. Additionally, the analysis was extended to three-dimensional space-time cluster by Kulldorff, which had been widely used in epidemiology and other fields [P-value was obtained by Monte Carlo randomization, and P < 0.05 was considered as spatio-temporal aggregation.SaTScan10.0 software and r fields . The staHerein, the maximum spatial scanning radius was set as 50% of the risk population, and the scanning time ranged from January 1, 2011 to December 31, 2021. The time interval was set to ‘Year’ and the region was also set to ‘None’.This present research reported here has been approved by the Ethics Committee of Jiangsu Provincial CDC.2 = 31.02, P < 0.05) and the average case fatality rate (CFR) was 5.39% (29/538).A total of 538 confirmed SFTS cases were reported from 2011 to 2021 in Jiangsu Province. The incidence interval ranged from 0.020/100,000 (2011) to 0.140/100,000 (2021), with an annual average incidence of 0.059/100,000. The annual case was 19, 8, 11, 26, 29, 55, 39, 42, 65, 125 and 119, presenting an increasing tendency from 2011 to 2021  occurred during May and August. Additionally, the peak of incidence in 2021 was earlier than that in previous years  between males and females in all age groups.Of the 538 cases, 284 were males and 254 were females . The age distribution was mainly between 50 and 70 years old, accounting for 80.85% of all cases. However, there was no significant difference , indicating the positive correlation property of the regional distribution of SFTS cases (Table The Moran’s As shown in Table Jiangsu Province is located in the core area of the beautiful and rich Yangtze River Delta of China, whose the terrain is mainly plains and hills. In this study, we analyzed the changing epidemiological characteristics of SFTS cases in Jiangsu Province between 2011 and 2021. We found an annual average incidence of 0.059/100,000. The average incidence of SFTS in Jiangsu Province was lower than that in Shandong province in China . We alsoHaemaphysalis longicornis, as the predominant population carrying SFTSV [The SFTS in Jiangsu Province were highly seasonal. The heat map of the monthly distribution indicated that the epidemic season spanned from May to August, which was similar to the results found in a previous study , 27–30. ng SFTSV , 32, theng SFTSV . Of inteWe also found that the majority of the cases were farmers. The results were in accordance with the previous studies . What isI index to detect whether the positive spatial autocorrelation existed and using LISA to explore the high-risk hotpot, our observations shed light on gathering centers, which were mainly concentrated in Lishui County and its adjacent areas including Gaochun County and Liyang County. Of note, the high-risk areas were relatively fixed without expanding tendency for now. Meanwhile, the results of the spatiotemporal clusters analysis indicated that the gathering areas were concentrated in Xuyi County, Lishui County and Pukou County. Overall, the concentrated areas of SFTS in Jiangsu Province were mainly in Xuyi County and Lishui County by combining two methods of analysis. In these gathering areas, there were a lot of mountains and hills with a high density of ticks. Therefore, local people or people travelling to these areas could get more chances of SFTSV infection. What’s more, several other factors such as meteorological factors, birds migration and SFTSV-carrying rate of ticks might be also associated with SFTS occurrence in these gathering areas [By using the global Moran’s ng areas , 34–37. However, this study had a few limitations. Firstly, the datas obtained from NIDRIS might be underestimated because of underreporting. For example, those who did not go to the hospital for treatment, or those who had died before being sent to the medical facility, were not included. Second, due to the time interval set “year”, the spatiotemporal scanning analysis might hide the monthly local SFTS clusters.This present study demonstrated epidemiological characteristics and spatiotemporal patterns of SFTS in Jiangsu Province from 2011 to 2021. Our results revealed that the annual number of SFTS cases and the affected counties had an increasing trend in Jiangsu Province. SFTS cases concentrated from May to August. Moreover, our study clearly elucidated that the distribution of SFTS was not random but clustered in space and time, with high-high clusters located in the western and southwestern areas of Jiangsu Province, China. Overall, our study threw light on epidemiological and spatial clues for finding out the factors of influence related to the incidence of SFTS. Meanwhile, the results provided solid evidence for the orientation of limited sanitary resources, surveillance in high-risk regions and early warning of epidemic seasons in future prevention and control of SFTS in Jiangsu Province.


This study aimed to establish novel nomograms that could be used to predict the prognosis of gastric carcinoma patients who underwent D2 + total gastrectomy on overall survival (OS) and progression-free survival (PFS).Lasso regression was employed to construct the nomograms. The internal validation process included bootstrapping, which was used to test the accuracy of the predictions. The calibration curve was then used to demonstrate the accuracy and consistency of the predictions. In addition, the Harrell’s Concordance index (C-index) and time-dependent receiver operating characteristic (t-ROC) curves were used to evaluate the discriminative abilities of the new nomograms and to compare its performance with the 8th edition of AJCC-TNM staging. Furthermore, decision curve analysis (DCA) was performed to assess the clinical application of our model. Finally, the prognostic risk stratification of gastric cancer was conducted with X-tile software, and the nomograms were converted into a risk-stratifying prognosis model.LASSO regression analysis identified pT stage, the number of positive lymph nodes, vascular invasion, neural invasion, the maximum diameter of tumor, the Clavien–Dindo classification for complication, and Ki67 as independent risk factors for OS and pT stage, the number of positive lymph nodes, neural invasion, and the maximum diameter of tumor for PFS. The C-index of OS nomogram was 0.719 (95% CI: 0.690–0.748), which was superior to the 8th edition of AJCC-TNM staging . The C-index of PFS nomogram was 0.694 (95% CI: 0.654–0.713), which was also better than that of the 8th edition of AJCC-TNM staging . The calibration curves, t-ROC curves, and DCA of the two nomogram models showed that the prediction ability of the two nomogram models was outstanding. The statistical difference in the prognosis between the low- and high-risk groups further suggested that our model had an excellent risk stratification performance.We reported the first risk stratification and nomogram for gastric carcinoma patients with total gastrectomy in Chinese population. Our model could potentially be used to guide treatment selections for the low- and high-risk patients to avoid delayed treatment or unnecessary overtreatment. Gastric carcinoma is one of the most common malignant tumors worldwide, and it mainly occurs in the northwest and eastern coastal China –3. ThereBetween May 2002 and December 2020, 1708 patients who had undergone radical gastric surgery for gastric carcinoma were retrospectively analyzed. To be included in this study, the patients should be histologically diagnosed as gastric carcinoma and have received curative surgery (R0-R1). Finally, a total of 944 patients who underwent D2 + total gastrectomy were enrolled in this study and were randomly divided into the training cohort (660 cases) and the validation cohort (284 cases) at a ratio of 7:3 .The specific inclusion criteria were 1) gastric cancer confirmed by histological pathology; (2) had curative total gastrectomy for stages I, II, and III; (3) complete clinicopathological and follow-up data available; (4) no severe organ damage after surgery; and (5) no other malignant tumors. The exclusion criteria were (1) with other systemic tumors; (2) missing or with incomplete clinical data; (3) had palliative surgery or bypass surgery; (4) pathological classification confirmed as non-gastric cancer; (5) had distal gastrectomy or primal gastrectomy; and (6) had total gastrectomy of stage IV. Due to the retrospective nature of the study, informed written consent form could not be obtained from patients; however, the Ethics Committee of Shanxi Cancer Hospital reviewed and approved the study protocol. Furthermore, in accordance with the Declaration of Helsinki, all patient data were anonymous and strictly confidential . A detai gastric The following clinical information of each patient was collected: gender, age at surgery, vascular invasion, neural invasion, pT stage, number of positive lymph nodes, TNM stage (according to the 8th edition of the American Joint Committee on Cancer Staging), Lauren classification, maximum diameter of tumor, omentum metastasis, surgical margin, multiple organ resection, histological classification, Clavien–Dindo classification for complication, AE1/AE3, Ki67 (%), CK7, CK20, CDX-2, SATB-2, SYN, CGA, CD56, MLH1, PMS2, MSH2, MSH6, overall survival (OS), and progression-free survival (PFS). OS was calculated based on the time the patient died or the last follow-up time , while PWe determined the follow-up time by analyzing medical records from both the hospital and oncologists during the patient's stay. The follow-up time was calculated based on the patient’s last hospital visit or the last contact to doctor.P values. P < 0.05 was considered statistically significant. A variety of software was utilized to process data, including R software (version 4.1.2), SPSS 25.0, and GrandPad Prism 9.3.Descriptive statistical analysis was expressed as an absolute percentage of a categorical variable, while the median of a continuous variable was derived as a median of its interquartile range. We presented OS and PFS using Kaplan–Meier curves. The Lasso regression method was applied to analyze and identify factors related to OS and PFS. The results were presented as hazard ratios, 95% CI, and –Meier survival analysis was used to compare the survival times of different risk groups. Data were presented as the mean ± standard deviation (SD), median , or number (%). All statistical analyses were performed using SPSS  and R software (version 4.1.2). A two-tailed p value < 0.05 was considered statistically significant.The main goal of this study was to construct nomograms to predict 1-year, 3-year, 5-year OS, and PFS of patients with gastric cancer after D2 + total gastrectomy. The parameters used for the model construction were derived from the Lasso regression analysis. The performance of the models was then computed through 10,000 repetitions. We tested the accuracy of the nomograms by discrimination and calibration in both the internal and external validation cohorts. Furthermore, the discriminative capability of the established model was evaluated according to Harrell’s concordance index (C-index), the time-dependent receiver operating characteristic curve (t-ROC), and area under the ROC curve (AUC). Calibration curves were constructed to compare the predicted OS and PFS with the observed OS and PFS using a bootstrap approach with 1000 resamples, while a DCA assessed the clinical implication of the model . HarrellAccording to the inclusion and exclusion criteria, 944 eligible patients with gastric carcinoma who underwent D2 + total gastrectomy were enrolled in this study, including 660 in the training cohort and 284 in the validation cohort. The flowchart of this study was shown in Fig. We performed a Lasso regression analysis to select the reliable variables to be used for the construction of predictive model for OS. Most of the covariate coefficients shrank to zero, and only 7 remaining nonzero parameters were selected as the independent prognostic factors of the model Figs.  and 3. ABased on these diagnosis-related factors, we developed a prognostic nomogram for predicting the OS of gastric carcinoma patients Fig. . In the The accuracy of this predictive nomogram was further verified using the internal validation (1000 bootstrapping from training cohort) and the external validation . As shown in Figs. P values in all three cohort were less than 0.001, suggesting the statistically significant difference between the low- and high-risk groups, which demonstrated that our model had an excellent risk stratification performance.The cutoff point of the total score of patients in the training group was generated by the X-tile software. According to the cutoff point of –0.370, the total patients from both the training and the validation groups were divided into 2 groups: the low- and the high-risk groups. We found that the survival probability was associated with the risk score Figs. , and 19.Furthermore, Lasso regression was carried out to identify the reliable variables to construct the prediction model for PFS. Similar to the analyses used in OS predictive model, most of the covariate coefficients shrank to zero, and only 4 remaining nonzero parameters were selected as the independent prognostic factors of the model Figs.  and 21. The accuracy of this predictive nomogram was also verified using the internal validation (1000 bootstrapping from training cohort) and the external validation . As shown in Figs. P values in the three cohorts were less than 0.001, indicating the statistically significant difference in the prognosis among the two risk stratification groups, which further demonstrated that our model had an excellent risk stratification performance.The cutoff point of the total score of PFS in the training cohort was calculated by the X-tile software. Based on the cutoff point of − 0.150, all the patients were divided into 2 groups: low- and high-risk groups. We found that the PFS probability was associated with the risk score Figs. , and 37.The clinical studies related to total gastrectomy of gastric carcinoma are mainly focused on the anastomotic leakage and the quality of life after total gastrectomy. Esophagojejunal anastomotic leakage is regarded as the most serious complication and is responsible for the morbidity and mortality after total gastrectomy. Therefore, it is crucial to identify risk factors associated with anastomotic leakage after total gastrectomy. Nevertheless, the findings vary greatly depending on the patient population and external factors involved in the studies –16. AddiRegarding to the risk stratification of total gastrectomy, a study from Japan developed and validated the preoperative risk models of morbidities associated with total gastrectomy using a Japanese web-based nationwide registry . Lack ofIn this study, we were the first to perform a risk stratification study using the information of Chinese patients after total gastrectomy. Here, we incorporated various factors, including clinical characteristics, pathological parameters, and tumor molecular markers, to select variables by performing Lasso regression analysis and utilized Cox regression to validate the result. We finally established a reliable nomogram to predict the 1-, 3-, and 5-year OS of patients after total gastrectomy by using seven independent risk factors: pT stage, number of positive lymph nodes, vascular invasion, neural invasion, maximum diameter of tumor, Clavien–Dindo classification for complication, and Ki67 (%). Similarly, a nomogram for predicting PFS of patients with total gastrectomy was also developed by using four variables: pT stage, number of positive lymph nodes, neural invasion, and maximum diameter of tumor. Importantly, to exclude the bias that might cause differences in the prognosis of patients after radical gastrectomy in different medical centers, we evaluated the performance of our model with both internal and external validation groups. Our internal and external validation results demonstrated the satisfying performance of our model in risk prediction. In addition, we performed a population-based analysis to divide the patients into two risk groups, and the nomogram was further improved as a risk-stratifying prognosis model. This allowed us to further improve the nomogram's performance and generate a risk-stratified prognosis model, which could provide guidance to clinicians for prognosis prediction.Currently, TNM staging is the most clinically used approach for predicting the prognostic risk; however, it has limitations in accuracy and reliability –23. SeveIn this study, we established two prognostic nomograms models to predict OS and PFS, respectively, and conducted risk stratification to distinguish different risk degree for patients who underwent total gastrectomy. Specifically, for patient with total gastrectomy, we calculated the risk score and performed the risk stratification of the patient. We found that the risk score was associated with the prognosis of the patient. This finding is potentially clinically useful in guiding the treatment decision-making. If the patient is predicted as low risk in OS, other postoperative treatments may not be necessary. Conversely, if the patient is predicted as high risk in OS, other combination therapies such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy should be considered. Similarly, if a patient is predicted with low-risk-related PFS, suggesting a smaller chance of recurrence and mortality, it will be unnecessary for the patient to receive other postoperative treatments. However, if the patient is predicted with high-risk linked PFS, the patient will have a higher probability to experience tumor recurrence and more aggressive malignancy. Appropriate therapies should be taken not only for the treatment of tumor recurrence but also for the alleviation of the postoperative complications, including anastomotic leakage, gastrointestinal bleeding, intestinal obstruction, and nutritional complications.Nevertheless, the current study had several limitations. First, the training and the validation cohorts used in our model construction and validation were from a single center. Validation with samples from other medical centers will be performed in the future. Second, the C-index of nomogram model for PFS was less than 0.7, and the accuracy of the nomogram related to PFS was unsatisfactory. Further investigation with larger sample size is needed. Lastly, this study did not distinguish patients between early stage and advanced stage, which may show different response to the nomograms.This study was the first to report the risk stratification and nomograms for total gastrectomy of gastric carcinoma for Chinese population. Combination therapies are recommended for patients in the high-risk score group, but not for the low-risk group patients. In addition, treatment for various postoperative complications and tumor recurrence are recommended to improve the PFS of patients in high-risk group.


The prevalence of type 2 diabetes is increasing among adolescents and clear strategies are needed to prevent it. The aim of this study was to determine the effect of peer education on knowledge, health beliefs and preventive behaviors of type 2 diabetes in female adolescents.In this cluster randomized trial study, 168 students (84 people in each group) were enrolled. The data collection instrument was a questionnaire of knowledge (30 questions), health beliefs (16 questions) and behavior (20 questions) whose validity and reliability were confirmed. Then eight capable students were chosen as peer educators after being trained. The intervention group received 8 sessions of 90-min education through training, lectures, question and answer, and group discussion and with teaching aids such as pamphlets, educational clips and text messages. The post-test was administered two months after the treatment. Data collected using software SPSS16 and Chi-Square and ANCOVA test were used.P < 0.001).The result showed that the mean and standard deviation of general knowledge, disease symptoms, behavioral risk factors, mid-term outcomes and long-term outcomes, perceived self-efficacy, behavioral beliefs, perceived susceptibility, perceived severity, prevention of stress, healthy food/healthy diet, unhealthy food/unhealthy diet, high-risk behavior, and self-care in the intervention group has increased significantly 2 months after intervention compared of control group (Peer education increased knowledge and improved adolescents' health beliefs and behaviors. Therefore, training in adolescence in order to prevention of diabetes can be considered as an effective step, and the use of peer-led education in this field is recommended.Trial registration number IRCT20200811048361N1 from School of Public Health & Neuroscience Research Center—Shahid Beheshti University of Medical Sciences. Date applied: 30/12/2020. Date assigned: 01/12/2020. Diabetes is a chronic and metabolic disease with high levels of blood sugar that leads to several complications . AccordiIn addition, this serious disease is witnessed as a new clinical condition among children. There has been a surge in the number of type-2 diabetics among children and adolescents across all ethnic groups . ReporteInflicting harm to different parts of the body, Type-2 diabetes can increase the long-term possibility of death . This diMultiple factors such as social, cultural, geographical, and environmental ones can contribute to type-2 diabetes . The finHealth education programs can empower young people to change themselves by raising their knowledge, influencing their beliefs and health beliefs, and improving their decision-making skills . EducatiOne of such methods is that of peer education. Peer-based health education entails a group of peers receiving health tips and lessons as well as acquiring relevant skills to teach their peers. The purpose of this method is not only to raise knowledge but also to help change health beliefs and behavior through peer education . RelyingParticipants were enrolled from July 2021 to October 2021 and participated in the intervention from November 2021 to April 2022.In this cluster randomized trial study, was performed in Tehran. 168 eighth grade female students (84 students in the intervention group and 84 in the control group) based on their interest and informed consent and their Parents written informed consent participated in the study in 2021.Initially, 14 district (a downtown area) in Tehran was selected out of the 22 districts by cluster randomly. Then four schools among the 20 girls' schools in this area, were chosen and allocated two groups of intervention and control randomly (Simple (. (2 schools for intervention groups and 2 schools for control groups)  and Content Validity Index (CVI) were evaluated by 11 experts. Then, questions with CVR of 0.59 and CVI of 0.79 and higher were preserved in the questionnaire. In order to evaluate the tool’s reliability, Cronbach’s alpha was calculated. Cronbach’s alpha of between 70 and 80% was set to be adequate and acceptable for internal consistency [Test–retest was employed to investigate the stability of the instrument over time. The questionnaire was completed by 40 adolescents with an interval of 2 weeks. A correlation coefficient of higher than 0.7 was considered acceptable for internal correlation coefficient (ICC). The following formulas were used to evaluate the content validity ratio (CVR) and content validity index (CVI):Finally, the designed questionnaire had two parts:Part one: Demographic questions about fathers’ job, mothers job, fathers’ education level, mothers’ education level and self-report economic situation.Part two: Constructs of the knowledge , health beliefs  and behavior  Table .Table 1DThe educational intervention was through peer education. Peer education has been employed as an effective strategy to combat diseases around the globe. Accordingly, people with shared characteristics such as age, gender, culture, education, and place of residence are assigned the task of imparting information with the aim of building knowledge and changing attitude and behavior among individuals, groups, and communities. Also, relying on all five senses, this method fosters thinking and creativity.” size , research team decided to choose eight peers for education and communication with 84 students in intervention group.Based on recommended number for small groupsTherefore, eight students known to be bright and keen on teaching were chosen as peer educators following suggestions from teachers and students themselves.Training and briefing the peer educators was carried out by the researcher through a 2-day 2-h after-school workshop with lectures, questions and answers, and other educational tools. These sessions primarily focused on the purpose of education, communicating with students, implementing the intervention program, and the relevant type-2 diabetes discussions. Peers were evaluated by the researcher through pre-test and post-test in each training session. Then, the intervention process for the participants began. The pre-test was administered to both intervention and control groups to determine the educational needs with the aim of designing educational content. The results of statistical analysis helped to design the educational content. And educational content was extracted and prepared based on reliable sources. Educational and communicative strategies were used to implement intervention: eight sessions of 90 min each in a 45-day period. The peer educators taught the students by offering a definition of type-2 diabetes, as well as risk factors, symptoms, the complications of the disease, and the preventive measures. The intervention group received education through lectures, questions and answers, group discussions, pamphlets, messages, and educational video clips (motion graphics).The control group received no treatment or education. Two months after the intervention, the questionnaire was completed again by the members of the control and intervention groups and the data was collected.During the peer education, a school teacher and researcher were present to help maintain classroom order, attracting the cooperation and attention of students, provide support, trouble shooting, monitoring the work of peers and assess of adherence of peers to the protocol. Table In this study Chi-square was used to check the homogeneity of samples as well as the consistency of contributing demographic factors in the research.To check the normality of the data, Skewness and Kurtosis  were calculated. Also, the ANCOVA was performed considering some of assumption, for example: The dependent variable and covariate were continues. Independent variable was consist of two categorical .There was no relationship between the observation in each group and between groups themselves. There was different participant in each group with no participant being in more than one group. There was homogeneity of variances (by using of Levine’s test) and there were no outliers among the research data.Analysis of Covariance (ANCOVA) was utilized to compare the mean scores between the groups by adjusting for pretest effects. The level of statistical significance was set to be lower than 0.05. SPSS16 was used to analyze of collected data (pre-test) and to determine the effect of intervention 2 months after the educational intervention.This study was conducted on 168 female students in the 14-year-olds age group. See the study steps in the CONSORT diagram  had fathers with their own business (freelancers). Most mothers (82.1%) were homemakers. 50% of students’ fathers and 51.2% of their mothers had high-school diploma. Most of the participants (50%) were reported to come from good -income families, with an exception of 14.3% who came from rich families.In the control group, most of the students' fathers were retired (28.6%). Also, most mothers (54.8%) were homemakers. 44% of students’ fathers and 38.2% of their mothers had high-school diploma. In this group too, most of the participants (33.3%) were reported to come from good -income families, with an exception of 27.4% who came from rich families.P < 0.001) The results of revealed that the intervention was successful in improving components of knowledge, attitude and behavior significantly in participants. , also since the questionnaire has been validated internally thus, the generalizability of the result is limited.This study benefited from some strength including face-to-face education, use peers for education and having a control group and equal chance of being selected in the interventional or control groups in a cluster-randomized trial.The results of the study show that educational intervention of School-based within peer education framework can contribute to enhanced knowledge and Improve health beliefs and behaviors among female students. Applying this study to a similar population may reduce the risk of Type 2 diabetes in them.Therefore, implementing healthcare policies in schools should be prioritized by authorities and public health experts. The results of this research can be used in Peer intervention strategies so as to effect health measures changes. Future studies are recommended to Inclusion of educational materials about prevention of diabetes in textbooks and enriching the school libraries with books about health issues. Also, the use of effective and useful method of peers in educational interventions to prevent of type 2 diabetes.