Mycobacterium avium complex (MAC) disease without culture-positive sputum. The aim of this study was to identify the risk factors associated with clinical progression of pulmonary MAC disease diagnosed by bronchoscopy.Limited data are available on the progression of pulmonary A single-center, retrospective, observational study was conducted. Pulmonary MAC patients diagnosed by bronchoscopy without culture-positive sputum from January 1, 2013, to December 31, 2017 were analyzed. Clinical progression after diagnosis was defined as having culture-positive sputum at least once or initiation of guideline-based therapy. Then, clinical characteristics were compared between clinically progressed patients and stable patients.Ninety-three pulmonary MAC patients diagnosed by bronchoscopy were included in the analysis. During the 4-year period after diagnosis, 38 patients (40.9%) started treatment, and 35 patients (37.6%) had new culture-positive sputum. Consequently, 52 patients (55.9%) were classified into the progressed group, and 41 patients (44.1%) were classified into the stable group. There were no significant differences between the progressed and the stable groups in age, body mass index, smoking status, comorbidities, symptoms, or species isolated from bronchoscopy. On multivariate analysis, male sex, monocyte to lymphocyte ratio (MLR) ≥ 0.17, and the presence of combined lesions in the middle (lingula) and lower lobes were risk factors for clinical progression.Some patients with pulmonary MAC disease without culture-positive sputum progress within 4 years. Therefore, pulmonary MAC patients, especially male patients, having higher MLR or lesions in the middle (lingula) and lower lobes might need careful follow-up for a longer time. The incidence and prevalence of pulmonary nontuberculous mycobacterial (NTM) disease are increasing worldwide –3. The rMycobacterium avium complex (MAC), such as Mycobacterium abscessus and Mycobacterium kansasii. Because the species distribution of NTM isolates varies widely by region, and MAC is the most common species in many locations, with particularly high detection rates reported in Australia and Japan  = −0.77).Because no reference value for MLR has been established in healthy subjects, a cutoff value of 0.17, the value of MLR at which Logp value < 0.1 on univariate analysis, as well as age and sex, were included in the multivariate analysis. Adjusted odds ratios with 95% confidence intervals and p values were calculated. To analyze the cumulative rate of clinical progression after diagnosis, the Kaplan–Meier method with the log-rank test was used. Receiver-operating characteristic (ROC) curve analysis was performed to assess the predictive value of MLR to identify disease progression. All tests of significance were two-sided, and p values < 0.05 were considered significant. Pairwise deletion was used to handle missing data. All statistical analyses were performed with IBM SPSS 28.0 .Variables with a Mycobacterium avium (67.7%) and Mycobacterium intracellulare (31.2%). Isolated bacterial species other than MAC from the specimens were also evaluated as co-infections. Veillonella species (57.0%) were the most common co-infecting species.The clinical characteristics of the patients at diagnosis are shown in Table The radiological characteristics of the two groups are shown in Table p = 0.033). Monocyte counts  and MLRs  were higher in the progressed group than in the stable group    Table .On multivariate analysis, male sex, MLR ≥ 0.17, and the presence of combined lesions in the middle (lingula) and lower lobes were independent predictors of disease progression within 4 years after diagnosis (Table p = 0.014)  Fig. . ROC cur14) Fig. A, B. The14) Fig. B.Fig. 2CTo examine the relationship between the extent of lung lesions and leukocyte counts, the MLRs were compared among three groups according to the number of involved lobes Fig. . No signThis retrospective study investigated the risk factors for progression of pulmonary MAC disease diagnosed by bronchoscopy. More than half of the patients deteriorated clinically, and one-third had culture-positive sputum within 4 years of diagnosis. The risk factors for disease progression were found to be male sex, MLR ≥ 0.17, and the presence of combined lesions in the middle (lingula) and lower lobes. This study is the first to show a relationship between the MLR and activity of pulmonary MAC disease, although the MLR has been investigated as a biomarker in some infectious diseases, including tuberculosis , 18–20. Positivity for GPL–IgA antibody was not associated with progression in the present study. Previous reports suggested that GPL antibody levels may be associated with disease progression , 22. A rThe association between the location of pulmonary MAC disease and disease progression has rarely been reported. Severe pulmonary MAC patients were reported to have more lesions in S2 and S6 of the lungs . FurtherPseudomonas aeruginosa or Aspergillus species infections may have negative impacts on patients with pulmonary MAC disease [Veillonella species, anaerobic bacteria, were detected in almost half of the pulmonary MAC patients in both groups. This result supports the previous study showing that anaerobic bacteria were detected more frequently in patients with NTM [Previous studies suggested that  disease –29. Furt disease , 31. On with NTM .Mycobacterium intracellulare, male mice had more extensive lesions in various organs and a higher bacterial load than female mice [In the current study, male sex was found to be a factor associated with a poor prognosis. In mice given intravenous ale mice . This stale mice –36, and M. kansasii and M. abscessus in addition to MAC, in patients diagnosed with pulmonary NTM disease by bronchoscopy, male, BMI < 18.5 kg/m2, ICS user, and AFB smear ≥ grade 2 on bronchoscopic specimens were independent predictors of radiographic progression [In a previous study including patients infected with gression . Becausegression –39, the There are some limitations to the present study. First, this study was conducted with a small sample size at a single institution in Japan. The present findings need to be confirmed in a larger, multicenter study. Second, cases of patients who were not followed for more than 4 years after diagnosis were excluded. These might have included fatal cases or dropout cases with mild symptoms. Third, the timing of sputum examination and initiation of treatment after diagnosis depends on the attending physician’s judgment based on symptoms and radiological deterioration, and thus inter-physician bias should be considered.This single-center, retrospective, observational study identified male sex, higher MLR, and the presence of lesions in the middle (lingula) and lower lobes as the risk factors for clinical progression of pulmonary MAC patients without positive sputum cultures. Since more than half of patients with pulmonary MAC disease diagnosed by bronchoscopy progressed clinically within 4 years, careful follow-up, especially in patients with the risk factors identified in the present study, is warranted.


Most of the existing data on the resection of liver metastases with inferior vena cava infiltration come from case reports or small case series. This systematic review on the subject found postoperative morbidity and mortality rates and overall survival to be acceptable, offering a surgical alternative to these patients previously considered unresectable.Combined hepatic and inferior vena cava (IVC) resection is the only potentially curative treatment for patients with colorectal liver metastases (CRLM) involving the IVC. Most of the existing data come from case reports or small case series. In this paper, a systematic review based on the PICO strategy was performed in accordance with the PRISMA statement. Papers from January 1980 to December 2022 were searched in Embase, PubMed, and the Cochrane Library databases. Articles considered for inclusion had to present data on simultaneous liver and IVC resection for CRLM and report surgical and/or oncological outcomes. From a total of 1175 articles retrieved, 29, including a total of 188 patients, met the inclusion criteria. The mean age was 58.3 ± 10.8 years. The most frequent techniques used were right hepatectomy ± caudate lobe for hepatic resections (37.8%), lateral clamping (44.8%) for vascular control, and primary closure (56.8%) for IVC repair. The thirty-day mortality reached 4.6%. Tumour relapse was reported in 65.8% of the cases. The median overall survival (OS) was 34 months , and the 1-year, 3-year, and 5-year OS were 71.4%, 19.8%, and 7.1%, respectively. In the absence of prospective randomized studies, which are difficult to perform, IVC resection seems to be safe and feasible. Hepatic resection is the only potentially curative treatment for metastatic and primary tumours of the liver, with 5-year survival rates of up to 50% for colorectal liver metastases (CRLM) ,2,3,4. TClassically, patients with CRLM involving the inferior vena cava (IVC) were not considered surgical candidates, with poor overall survival rates. The suspected involvement of the IVC was considered a contraindication for surgery due to the high risk of massive intra-operative bleeding or air embolisms .The continuous development of surgical innovations, such as total hepatic vascular exclusion (THVE), venovenous bypass, and ex vivo hepatic resection, combined with new chemotherapy regimens, has allowed the performing of combined hepatic and IVC resections. For this reason, the patient candidates for surgery have increased, with the publishing of more and more favourable data regarding clinical outcomes ,9,10,11.However, the number of articles published on the subject, and the number of patients described, are low. For this reason, drawing conclusions about the value of this procedure is difficult. Most of the existing data come from case reports or small case series emphasizing surgical innovations, and the long-term results and oncological outcomes are still confusing.This paper is a systematic review of the literature for the purpose of collecting data from patients who underwent surgery for CRLM involving IVC and evaluating the safety, clinical, and oncological long-term outcomes.www.researchregistry.com (accessed on 11 April 2023), with the unique identification number: reviewregistry1579. A systematic review was performed based on the PICO strategy , followi(‘venae cavae’/exp OR ‘venae cavae’ OR (venae AND cavae) OR ‘cavae, venae’ OR  OR ‘vena cava’/exp OR ‘vena cava’ OR ((‘vena’/exp OR vena) AND cava) OR ivc) AND ((‘neoplasm metastasis’/exp OR ‘neoplasm metastasis’ OR ((‘neoplasm’/exp OR neoplasm) AND (‘metastasis’/exp OR metastasis)) OR ‘neoplasm metastases’ OR ((‘neoplasm’/exp OR neoplasm) AND (‘metastases’/exp OR metastases)) OR ‘metastases, neoplasm’ OR  AND (‘neoplasm’/exp OR neoplasm)) OR ‘metastasis, neoplasm’ OR  AND (‘neoplasm’/exp OR neoplasm)) OR metastase OR ‘metastases’/exp OR metastases OR ‘metastasis’/exp OR metastasis) AND ) OR ‘colorectal neoplasm’/exp OR ‘colorectal neoplasm’ OR ) OR ‘neoplasm, colorectal’ OR  AND colorectal) OR ‘neoplasms, colorectal’ OR  AND colorectal) OR ‘colorectal tumors’ OR ) OR ‘colorectal tumor’/exp OR ‘colorectal tumor’ OR ) OR ‘tumor, colorectal’/exp OR ‘tumor, colorectal’ OR  AND colorectal) OR ‘tumors, colorectal’ OR  AND colorectal) OR ‘colorectal cancer’/exp OR ‘colorectal cancer’ OR ) OR ‘cancer, colorectal’ OR  AND colorectal) OR ‘cancers, colorectal’ OR  AND colorectal) OR ‘colorectal cancers’ OR ) OR ‘colorectal carcinoma’/exp OR ‘colorectal carcinoma’ OR ) OR ‘carcinoma, colorectal’/exp OR ‘carcinoma, colorectal’ OR  AND colorectal) OR ‘carcinomas, colorectal’ OR  OR ‘colorectal carcinomas’ OR ) OR ‘colorectal liver metastases’/exp OR ‘colorectal liver metastases’ OR  AND (‘metastases’/exp OR metastases))) AND (‘liver’/exp OR liver OR livers). The search terms used in PubMed were: ((Venae Cavae) OR  OR (Vena Cava) OR (IVC)) AND (((Neoplasm Metastasis) OR (Neoplasm Metastases) OR  OR  OR (Metastase) OR (Metastases) OR (Metastasis)) AND  OR  OR  OR  OR  OR  OR  OR  OR  OR  OR  OR  OR  OR  OR  OR ) OR )) AND ((Liver) OR (Livers)). The search term used in the Cochrane Library was inferior vena cava. Searched bibliographies of the retrieved studies were checked to collect additional studies.A systematic literature search was conducted using Embase, PubMed, and the Cochrane Library to identify relevant articles published from January 1980 to December 2022. The search terms used in Embase were Four authors reviewed the studies retrieved that met the inclusion criteria. Possible discrepancies between all the authors were resolved by discussion and consensus among all of them. A cluster search identified some additional papers.Papers considered for inclusion had to (a) have patients with simultaneous liver and IVC resection for CRLM; (b) publish original data; (c) report patients’ surgical and/or oncological outcomes.(a) Non-English language articles; (b) papers without original data; (c) IVC resection for any type of tumour other than CRLM; (d) duplicate series.The data compiled included the following variables for the study: (a) journal and year of publication; (b) demographic variables and characteristics of the patients: country of origin, number of patients included, mean age in years, sex, the mean number of metastatic lesions, and size of the closest lesion to the IVC; (c) surgical variables: type of hepatectomy, type of vascular control, size of resected IVC, type of IVC reconstruction , combined resection of other visceral structures, and operative time; (d) morbidity and mortality results, according to the Clavien–Dindo classification  when posThe literature search yielded 1175 articles , of whicn = 140), and 52.3% of the patients were men (79/151). The mean number of resected metastases was 2 ± 3.8 (n = 68). The mean metastasis size was 61 ± 53 mm (n = 80). The most frequent hepatic resections were right hepatectomy ± caudate lobe (CL) resection , right trisectionectomy ± CL resection (14.8%), extended right hepatectomy ± CL resection (14.1%), wedge resection (10.4%), segmentectomy (6.7%), and CL resection (4.4%). Combined organ resections mainly included the diaphragm (five cases), right adrenal gland (three), diaphragm and right adrenal gland (two), and right kidney (one). The most commonly used vascular control techniques were lateral clamping , THVE (28.4%), and IVC clamping (6%). Some authors described the vascular control length. IVC clamping was used for 12–15 min in two cases [A total of 188 patients with combined liver and IVC resection for CRLM were initially included . The meawo cases , 17 min wo cases . The vaswo cases  210–280 wo cases  and extr® patch–tube (3.1%), and an autologous patch graft (7.4%). The autologous patch grafts were used in the following sites: the pericardium (four cases), middle hepatic vein (MHV) (three), saphenous vein (two), external iliac vein (one), ovarian vein (one), and IVC (one).The most frequently used technique for IVC repair was primary closure (PC) , followed by a polytetrafluoroethylene (PTFE) tube graft (23.5%), a PTFE patch (5.6%), a Dacronn = 26).The laparoscopic approach was performed in one case . The mean = 31). The thirty-day mortality was 4.1% (7/169). The overall mortality rate  rose by 48.2% (66/137). A total of 46 patients (69.7%) died of disease progression. Two patients died with evidence of disease [Half of the patients developed complications of some kind . A blood transfusion was not considered a complication, and it was required in 58.8% (20/34). Clavien–Dindo classification  could on disease ,37. No iHistological infiltration of the IVC was demonstrated in 52.6% of the cases (40/76). The margins were infiltrated by tumours in 10.5% (9/86).n = 31). Combined organ involvement was common: liver and lung (8.3%), liver and other organs (4.2%), lung and other organs (8.3%), and multi-visceral involvement (4.2%). Oncological redo surgery was performed in 30.6% (15/49).Tumour relapse was recorded in 65.8% of the cases (73/111). The most commonly affected organ was the liver , followed by the lung (16.7%) and lymph nodes (10.4%). The mean time of relapse was 8.5 ± 7.7 months , free or affected margins (n = 81), and the presence/absence of relapse  (n = 102). Statistical differences were found when comparing the OS of patients with or without relapse (p = 0.016) (p = 0.001). However, the OS in patients with or without histological invasion of the IVC   and the  the IVC  or with  the IVC  did not Liver tumours involving the IVC generally have poor oncological outcomes. The fundamental principle of oncological surgery is the en bloc resection of the tumour and the affected organs. In many of these tumours, low survival rates due to recurrence and limited organ availability have made liver transplantation not a viable option in advanced hepatic tumours with vascular invasion. Since the first combined liver and IVC resection described by Starzl in 1980 , an incrThis review is based on original data and includes the largest number of patients with combined liver and IVC resection for CRLM described to date, thus providing clear evidence of the value of this surgical technique. Considering the complexity of this technique compared with a standard hepatic resection, the postoperative mortality rate of 4.6% can be considered acceptable. Long-term survival is the most important parameter to assess oncological outcomes for malignant tumours. In the case of IVC resection, the 5-year OS rate ranged from 0%  to 51.9%The histological study of the resected specimens in the different published studies showed that 40% of hepatic tumours with radiological-suspected IVC involvement had only fibrous adhesion without true tumour infiltration. Distinguishing between inflammatory adhesions and true vascular invasion both pre-operatively and intra-operatively is often impossible. Malde et al.  suggesteVascular control was adapted in all the cases during surgery with the objective of minimizing intra-operative bleeding, shortening the ischaemia time, maintaining haemodynamic stability, and improving the tolerance to ischaemia–reperfusion injury of the remnant liver ,45.The type of IVC reconstruction depends on the degree of involvement. Usually, if a < 2 cm wall is excised, a direct suture of the IVC is performed. When the vascular involvement is greater than 2 cm, an autologous or synthetic patch is usually used to avoid stenosis. Finally, when the infiltration is at least half the circumference, IVC replacement is required .An autologous vein is the preferred material for IVC replacement to avoid thrombosis and postoperative infection, but it may not be technically feasible, especially if a relatively long segment of IVC needs to be replaced. Therefore, in many cases, reconstructions with prostheses are performed. Infection is an important concern, although no cases have been published in the literature review carried out. In patients in which tumour contact with the IVC is low, it can be controlled by placing tangential vascular clamps to preserve the blood flow.In those patients in whom tumour involvement requires the resection of a significant segment of the IVC, THVE, which includes continuous clamping of the hepatic hilum and suprahepatic and infrahepatic IVC, with or without a venovenous bypass, is the standard procedure. If the IVC involvement is below the hepatic veins and there is sufficient space to clamp above the tumour, IVC occlusion could be performed below the suprahepatic veins after the hepatic section to minimize the ischaemia time . If therThis study has several limitations. First, the studies included in this review were retrospective, with an inherent risk of bias. The possible differences in several variables, including the institutions’ and surgeons’ experience, study populations, peri-operative management, surgical procedures, IVC resections, and reconstructions, may have influenced the postoperative and long-term clinical outcomes. Second, the favourable survival rate may be due in part to the fact that patients were highly selected. Third, as the studies included ranged in time more than 30 years, it must be kept in mind that the results may be influenced by the period of time in which the surgery was performed. Fourthly, the survival of patients with CRLM has increased in recent decades, not only because of technically more aggressive surgeries, but also because of the development of new lines of chemotherapy with better disease control. In fact, in most studies, the percentage of patients receiving adjuvant chemotherapy is above 50%, and in some cases, even reaches 80% .Despite the difficulty of IVC resection, the numerous technical advances recorded in recent years have meant that this procedure is now possible in patients with CRLM involving the IVC. The studies published so far are retrospective, and many of them include resection of the IVC for tumours other than CRLM. In the absence of prospective randomized studies, which are difficult to perform, IVC resection seems to be safe and feasible in experienced centres.


This study aimed to compare the short-term and survival outcomes in laparoscopic low rectal cancer surgery with three different specimen extraction techniques, and whether it affects loop ileostomy closure.A consecutive series of patients with low rectal cancer who underwent laparoscopic low anterior resection plus protective loop ileostomy (LAR-PLI) were enrolled. Three main techniques, namely specimen extraction through auxiliary incision (EXAI), specimen extraction through stoma incision (EXSI), and specimen eversion and extra-abdominal resection (EVER), were employed. The postoperative short-term and survival outcomes of the three techniques and the impact on loop ileostomy closure were compared.In all, 254 patients were enrolled in this study: 104 (40.9%) in the EXAI group, 104 (40.9%) in the EXSI group, and 46 (18.1%) in the EVER group. For primary surgery, EXAI group had significantly longer operative time (P < 0.001), more intraoperative bleeding (P < 0.001), longer length of abdominal incision (P<0.001), longer time to first flatus (P < 0.001), longer time to first defecation (P < 0.001), longer time to first eat (P < 0.001), and longer postoperative hospital stays (P = 0.005) than the EXSI and EVER groups. The primary postoperative complication rate in the EXAI and EVER group was significantly higher than in the EXSI group (P = 0.005). In loop ileostomy closure, EXAI group had significantly longer operative time (P = 0.001), more bleeding volume, and longer postoperative hospital stays (P < 0.001) than the EXSI and EVER groups. For survival outcomes, the 3-year local recurrence-free survival (LRFS) is 92.6% for all patients. The 3-year LRFS for patients in EXAI, EXSI, and EVER were 90.1%, 95.4%, and 92.7%, with P = 0.476.Our single-center results found that in LAR-PLI surgery for low rectal cancer, the short-term outcomes of specimen extraction through the stoma incision or anus were better than that through the auxiliary incision, but the 3-year LRFS was no statistically different. The latest data from the Chinese National Cancer Center (CNCC) showed that there were 408,000 new cases of colorectal cancer and 196,000 deaths in 2016, colorectal cancer ranks second and fourth, respectively, in terms of morbidity and mortality, with both showing a continuing upward trend .With the increasing inclination of patients to preserve the anus and the continuous advancement of surgical techniques such as the clinical application of double stapler technology, low intestinal anastomosis has been greatly improved. Low anterior resection (LAR) with TME has become the most widely used surgery for low rectal cancer. In our center, patients with low rectal cancer routinely undergo LAR plus protective loop ileostomy (LAR-PLI). Objectively, PLI can reduce the complications caused by postoperative rectal anastomotic leakage , but theOver the past decade, surgical techniques and instrumentation platforms have continued to improve and innovate, and minimally invasive concepts have found widespread application in colorectal surgery . For LARHowever, there is still a lack of relevant research on whether these specimen extraction techniques affect loop ileostomy closure. In our retrospective study, we enrolled patients who underwent LAR-PLI to compare the short-term and survival outcomes of three different specimen extraction techniques, and evaluate whether different specimen extraction methods affected loop ileostomy closure.A consecutive series of patients with low rectal cancer who underwent laparoscopic LAR-PLI at the Cancer Hospital of the Chinese Academy of Medical Sciences between April 2015 and September 2019 were enrolled in this retrospective study. The inclusion criteria were: (1) All patients were pathologically diagnosed with rectal adenocarcinoma; (2) The primary tumor was a low rectal cancer ; and (3) All patients underwent laparoscopic LAR-PLI and successful loop ileostomy closure. Patients with distant metastasis and recurrent disease; those who underwent transanal local excision or open rectal surgery; those with ASA classification > grade 3; those with a history of other malignancies; and those lost to follow-up were excluded. According to the procedures of specimen extraction, patients were divided into three groups: EVAI group, EXSI group, and EVER group. To assess the safety of LAR-PLI, we analyzed perioperative data including postoperative complications, stoma-related complications, operative time, estimated blood loss, time to first flatus, time to first defecation, time to first eat, time to remove the urinary catheter, length of postoperative hospital stay, 30-day re-operation rate, 30-day mortality, and interval to loop ileostomy closure. The American Joint Committee on Cancer TNM staging standard of rectal cancer (7th edition) was used for staging. The decision regarding preoperative or postoperative adjuvant therapy (capecitabine or CAPOX with or without pelvic radiotherapy) was made according to experienced senior oncologists in our hospital. If the patient died during the follow-up period, it was considered as a censored case.All procedures were conducted by an experienced surgical team, and a modified lithotomy position and five-trocar laparoscopic approach were used. All patients received standard bowel preparation, and prophylactic antibiotics were started 30–60 min before commencement of surgery. The ileostomy site was determined preoperatively by a professional stoma nurse.The whole surgical procedure  was compEXSI: The proximal bowel can be resected either intra-abdominally or extra-abdominally Fig. A. A 3–5 EVER: After resection of the proximal rectum, use a ring clamp to grasp the rectal stump and gently drag it outside the body Fig. A. the diAfter reconstruction of the digestive tract, the terminal ileum approximately 30–40 cm proximal to the ileocecal junction was chosen as the stoma position. An appropriate position of the stoma was usually selected in the lower right abdominal wall within the rectus abdominis muscle. The position was determined at the discretion of the chief surgeon according to the patient’s opinions, preoperative stoma marking, intraoperative abdominal wall thickness, and ileal diameter.Details of stoma-related complications were also recorded. Loop ileostomy closure was usually performed approximately 3–6 months after primary surgery in the absence of complications or adjuvant chemoradiotherapy. For those patients who receive adjuvant chemotherapy or radiotherapy after primary surgery, the ileostomy closure usually occurs about 4 weeks after treatment ends. If the patient has postoperative complications, such as anal dysfunction, the time for ileostomy closure surgery will be longer. The operation was undertaken by the surgeon who performed the primary operation, and the stoma closure was performed by functional end-to-end anastomosis using linear staplers  were used to evaluate continuous variables. Two-sided P values < 0.05 were considered to indicate statistical significance. All data analysis was performed using SPSS software .The data are presented as a number for categorical variables and the mean ± standard deviation for continuous variables. The chi-square test and Fisher’s exact test were used to evaluate differences in categorical variables, and Student’s A total of 254 patients were enrolled in this study, including 104 (40.9%) in the EXAI group, 104 (40.9%) in EXSI group, and 46 (18.1%) in the EVER group. Except for the variable distance of the tumor from the anal verge (P = 0.001), there were no statistically significant differences in clinical characteristics between the groups. The distance of the tumor from the anal verge in the EVER group was closer than that in the other groups (P < 0.001), but the mean distance was also greater than the 2-cm safe margin standard. The details are shown in Table For primary surgery, the EXAI group had significantly longer operative time (P < 0.001), more intraoperative bleeding (P < 0.001), longer length of abdominal incision (P < 0.001), longer time to first flatus (P < 0.001), longer time to first defecation (P < 0.001), longer time to first eat (P < 0.001), and longer postoperative hospital stays (P = 0.005) than EXSI and EVER group Table . The timFor loop ileostomy closure, the operative time (P = 0.001), length of stoma incision (P < 0.001), and postoperative hospital stays (P < 0.001) in the EXAI group were significantly longer than EXSI and EVER group, bleeding volume was also higher in the EXAI group (P = 0.004). The time to remove the urinary catheter in the EXSI group was significantly shorter than the other two groups (P = 0.008). Multiple comparisons showed that there was no significant difference in the time to first flatus, first defecation and first eat between the groups Table .The total postoperative complication rate in the EXSI group was significantly lower than that EXAI and EVER group . The rates of serious complications (Clavien-Dindo ≥ grades 3) in the EXSI/EXAI/EVER groups were 5.8%, 14.4%, and 13.0%, respectively (P = 0.108). In each group, the most common complication was anastomotic stenosis. There was no statistical difference in blood transfusion among the three groups. No 30-day readmission occurred in each group. Stoma-related complications, there was no difference in the total complications among the three groups . The most common complication was stomal fecal dermatitis  time for all patients in this study was 36.0 months. The 3-year LRFS was 92.6% for all patients. The 3-year LRFS for patients in EXAI, EXSI, and EVER were 90.1%, 95.4%, and 92.7%, with P = 0.476  . In our In the short-term efficacy analysis after primary tumor surgery (the first surgery), patients in the EXAI group had more abdominal auxiliary incisions in the surgical procedure than the EXSI group and EVER group, which increased the surgical trauma and operative time, resulting in more intraoperative blood loss, longer hospital stay, and longer time for early recovery of eating and defecation. For primary surgery, the total postoperative complication rate in the EXAI group was higher than that in the EXSI group , and the proportion of complications related to auxiliary incision was 6.7% (7/29) and 0% (0/12), respectively. This indicated that increased auxiliary incision may increase the incidence of postoperative complications and slow down the postoperative recovery speed of the patients . There wThe current clinical practice of ileostomy closure is usually after about 3–6 months of the primary surgery. Stoma closure performed after 6 months could lead to atrophy of the distal colon muscle and mucosa, resulting in anal dysfunction , but optOur study has some limitations. First is the lack of functional outcomes such as postoperative anal function and quality of life. Second, although there was no significant difference at baseline among the groups, it was still impossible to control for differences in surgeons’ procedures and patient selection. Third, owing to the inherent limitations of retrospective studies, further large-sized clinical trials may need to be conducted in the future to validate our findings. We believe that our results provide valuable information regarding specimen extraction for low rectal cancer.Our single-center results found that in LAR-PLI surgery for low rectal cancer, the short-term outcomes of specimen extraction through the stoma incision or anus were better than that through the auxiliary incision, but the 3-year LRFS was no statistically different.


Lilium oriental hybrid ‘Siberia’. The emission of both methyl benzoate and ethyl benzoate in L. ‘Siberia’ was found to be tepal-specific, floral development-regulated and rhythmic. Through transcriptome profiling and bioinformatic analysis, a BAHD acyltransferase gene designated LoAAT1 was identified as the top candidate gene for the production of ethyl benzoate. In vitro enzyme assays and substrate feeding assays provide substantial evidence that LoAAT1 is responsible for the biosynthesis of ethyl benzoate. It was interesting to note that in in vitro enzyme assay, LoAAT1 can also catalyze the formation of methyl benzoate, which is typically formed by the action of benzoic acid methyltransferase (BAMT). The lack of an expressed putative BAMT gene in the flower transcriptome of L. ‘Siberia’, together with biochemical and expression evidence, led us to conclude that LoAAT1 is also responsible for, or at least contributes to, the biosynthesis of the floral scent compound methyl benzoate. This is the first report that a member of the plant BAHD acyltransferase family contributes to the production of both ethyl benzoate and methyl benzoate, presenting a new mechanism for the biosynthesis of benzoate esters.Lily is a popular flower worldwide due to its elegant appearance and pleasant fragrance. Floral volatiles of lily are predominated by monoterpenes and benzenoids. While a number of genes for monoterpene biosynthesis have been characterized, the molecular mechanism underlying floral benzenoid formation in lily remains unclear. Here, we report on the identification and characterization of a novel BAHD acyltransferase gene that contributes to the biosynthesis of two related floral scent benzoate esters, ethyl benzoate and methyl benzoate, in the scented  Subsequicotiana , and Hedronarium .O-acetyltransferase (BEAT), anthocyanin O-hydroxycinnamoyltransferase (AHCT), anthranilate N-hydroxycinnamoyl/benzoyltransferase (HCBT) and deacetylvindoline 4-O-acetyltransferase (DAT) -2-hexenyl acetate and (Z)-3-hexenyl acetate during fruit ripening  . Phylogese (DAT) . The AATse (DAT) . For exazoyl-CoA . Furtherripening . Ethyl bripening  and is oripening . Howeverripening . Thus, iMdAAT2 in transgenic tobacco leaves led to significant increase of methyl benzoate concentration and new formation of other methyl esters  collection and GC-MS analysis. Of the eight tissues examined, only the outer tepals and inner tepals released methyl benzoate and ethyl benzoate , while it decreased by 82.44% at night (BM_D) , which belong to the SABATH family . Only twraw data  were add1,038 bp . HoweverSiberia’ .C. breweri CbBEBT as the query sequence  and then declined to a low level in the senescence stage , reached a maximum at 16:00, decreased at night (2:00 to 4:00), and reached a minimum at 4:00  hybrid ‘Manissa’, and the nonscented Asiatic hybrids ‘Brunello’ and ‘Val di Sole’ was investigated using headspace collection and GC-MS analysis . Thus, the gene expression of AAT1 orthologues and substrate availability contribute to the floral benzoate ester production in lily.The emission variation of floral benzoate esters in the scented C. breweri BEAT is the first isolated and functionally characterized plant AAT, which catalyzes the formation of floral benzylacetate, a major constituent of the C. breweri floral scent  . PMEs plL. ‘Siberia’. This observation might be due to the abundant methanol and small ethanol internal pool in tepals, as well as the absence of an internal pool for other alcohols. This speculation could be verified by the infiltration assays of exogenous alcohols into tepals, which caused the release of corresponding benzoate esters and decreased the emission of methyl benzoate  under natural light from March to June. The lily cut flowers used for volatile analysis and gene expression analysis in different flower developmental stages, different sampling times, and different cultivars were purchased from the Lingnan flower market in Guangzhou. Flowers with three buds were selected and immediately placed in tap water after being brought back to the laboratory. The flower buds with ~2 cm pedicels were separated two days ahead of anthesis and cultured in a light incubator at 25°C under 12-h light and 12-h dark cycles.L. ‘Siberia’ plants at anthesis were divided into eight tissues. Each tissue was detached carefully at its junctions, and approximately 3 g of tissue sample was enclosed in a 200-ml glass bottle for headspace collection. For analysis of benzoate ester emissions in different flower developmental stages, different sampling times, and different cultivars, one intact flower or flower bud with an ~2 cm pedicel was enclosed in an 8-L glass chamber for headspace collection. For alcohol substrate feeding, various alcohol substrates with excess amounts for catalytic reaction (2 mM each) were infiltrated into an inner tepal by a needleless syringe as previously performed (P = 0.05).The erformed . The inferformed . BrieflyL. ‘Siberia’ tepals in the bud stage and the blooming stage at 16:00 (BM_L) and 4:00 (BM_D) were extracted using a HiPure Plant RNA Mini Kit (Magen) according to the manufacturer’s instructions. The transcriptome sequencing library was pooled by mixing equal quantities of total RNA from the three samples. For transcript quantification, three libraries were generated independently for the above three samples. The sequencing libraries were prepared using an Illumina TruSeq RNA Sample Preparation Kit and sequenced on an Illumina HiSeq 2000 platform as described previously (de novo assembly without a reference genome (2(fold change) > 1 and q value < 0.005 was set as the threshold to judge the differentially expressed genes (DEGs).Total RNA of eviously . The 100e genome . All asse genome . For trae genome . Subseque genome . Differee genome . The absC. breweri CbBEBT  with the primers listed in The full-length cDNA sequence of LoAAT1 was amplified using high-fidelity DNA polymerase KOD-Plus (TOYOBO) with the primers in EcoRI and HindIII. The sequencing results showed that no errors had been introduced. The recombinant vectors were transformed into E. coli Rosetta (DE3) competent cells (Invitrogen) for recombinant protein induction as described previously . The mixture was incubated at 28°C for 30 min, and then the volatile products were trapped by a SPME fiber for 30 min and identified through a GC-MS system. The GC temperature was initially maintained at 40°C for 2 min, followed by an increase to 250°C at a rate of 5°C/min, and held at 250°C for 5 min. The reaction products were validated by comparing the retention times and/or mass spectra with authentic standards.LoAAT1 and the reference gene LoGAPDH are listed in LoAAT1 was calculated according to the 2-ΔΔCt method  according to the manufacturer’s instructions. The sequence-specific primers for t method . Analysihttps://www.ncbi.nlm.nih.gov/genbank/, OR288168 https://www.ncbi.nlm.nih.gov/genbank/, PRJNA996359.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: YCY: Conceptualization, Data curation, Formal Analysis, Investigation, Visualization, Writing – original draft. LW: Formal Analysis, Investigation, Writing – original draft. ML: Formal Analysis, Investigation, Writing – original draft. FL: Investigation, Writing – original draft. JY: Investigation, Writing – original draft. LH: Investigation, Writing – original draft. BZ: Data curation, Writing – original draft. XL: Formal Analysis, Writing – original draft. YYY: Formal Analysis, Writing – original draft. FC: Writing – review & editing. RY: Writing – review & editing, Funding acquisition, Supervision. YF: Conceptualization, Funding acquisition, Project administration, Writing – original draft.


Konjac glucomannan (KGM) is produced from the porang root, which has several properties. For example, it can reduce oxidative stress. The current study analyzed the osteoclastogenesis inhibitory and antioxidant properties of KGM based on histomorphometric findings, RANKL/OPG ratio, and ROS levels in the Swiss Webster mouse periodontitis model.  Periodontitis is an inflammatory disease caused by specific microorganisms that gradually damage the periodontal and tooth-supporting tissues, thereby reducing a person's quality of life. Periodontal disease is closely associated with high reactive oxygen species (ROS) levels, with a high receptor activator of nuclear factor kPorphyromonas gingivalis, and ligation + P. gingivalis + KGM groups. KGM suspension was administered for 14 days. Periodontitis induction was performed from 7th to 14th day. On the 14th day, maxillae, gingival, and gingival crevicular fluid samples were collected to assess the histomorphometry of bone damage, gene expression ratio of RANKL/OPG, and ROS protein levels.  Eight-week-old male Swiss Webster mice were divided into the nonligation, nonligation + KGM, ligation +  The periodontitis group pretreated with KGM presented with significantly reduced alveolar bone damage, RANKL/OPG ratio, and ROS level than without KGM group. KGM treatment had no harmful/toxic effects in mice.  Administration of KGM could act as an adjunctive in periodontal therapy by suppressing periodontal disease via osteoclastogenesis inhibitory and antioxidant properties. Periodontitis is the leading cause of tooth loss in the adult population, and it can significantly affect the patients' quality of life , 2. The According to the European Federation of Periodontology S3 level clinical practice guidelines, subgingival biofilm and calculus can be eliminated with subgingival instrumentation and adjunctive therapy, such as physical or chemical agents, locally or systemically delivered host-modulating agents, and locally or systemically delivered antimicrobials . HoweverAmorphophallus konjac [β ligand (RANKL)/osteoprotegerin (OPG), and reactive oxygen species (ROS) protein levels in a Swiss Webster mice periodontitis model.Konjac glucomannan (KGM) is a water-soluble polysaccharide isolated from the root of the porang plant s konjac –11. KGM s konjac –12. KGM s konjac . Konjac s konjac . Moreoves konjac , 16, whis konjac . Porang s konjac . HoweverKGM powder was obtained from Shimizu Chemical Corporation, Hiroshima-ken, Japan. Carboxymethyl cellulose (CMC)  was used to make a suspension.Porphyromonas gingivalis, and ligation + P. gingivalis + KGM groups. Each group comprised 12 mice. Mice were weighed daily using a digital scale until the 14th day to assess cytotoxicity. All research procedures were approved by the Ethics Committee of the Faculty of Medicine, Universitas Indonesia (No. KET-163/UN2.F1/ETIK/PPM.00.02/2022).Eight-week-old male Swiss Webster mice were obtained from the National Institute of Health Research and Development, Indonesian Ministry of Health . Mice were acclimated for 7 days prior to the procedures and were given food and drink ad libitum during the experimental period. The cages were cleaned twice a week to provide a clean environment. Picric acid  was used to tag the mice based on the treatment groups. Forty-eight mice were randomly classified into the nonligation, nonligation + KGM, ligation + P. gingivalis W83 was cultured, as described in a previous study [us study . The numµl/day of 80 mg/kg body weight of KGM or CMC suspension was administered daily for 14 days via oral gavage.To obtain the final concentration of 10 mg/mL, KGM suspension was synthesized by mixing KGM powder  (80 mg/kg body weight) with 0.5% CMC suspension according to the dosage . In the P. gingivalis suspension and wire ligature  on the 7th day. Mice were anesthetized with intraperitoneal injection of 10% ketamine  and 2% xylazine  (2 : 1) at a dose of 1.2 µl/g body weight prior to wire ligature installation. A 0.25-mm wire ligature was cut into 3-mm long pieces, shaped into L-shape, and then inserted from the palatal side to the buccal side at the interproximal distance of the right maxillary first and second molars. The excess side of the ligature was bent to the shape/contour of the tooth to improve retention. P. gingivalis (109 colony-forming units/mL) combined with 2% CMC at a dose of ∼200 µl/day was administered to the ligation + P. gingivalis group via oral gavage every 3 days. The mice were euthanized under anesthesia with a cardiac puncture on day 14. Next, the maxillae, gingival tissues, and gingival crevicular fluid were collected. Periodontitis was induced by administering After removing the tissues and muscles attached to the bone, the maxillae samples were stored in 10% formalin solution and stained with 1% methylene blue  to differentiate the cementoenamel junction line and the alveolar bone crest . The roo∆∆Ct− method, which was compared to the glyceraldehyde-3-phosphate dehydrogenase value [Gingival tissue samples were obtained from the right maxillary first and second right molar. Gingival sample collection was performed by making an incision with a scalpel. Then, the scalpel was gently withdrawn with a dental explorer. Samples were then stored in phosphate-buffered saline liquid and stored in −80°C freezer , 21. These value . The prise value . The prise value .Gingival crevicular fluid samples were obtained by placing paper points ISO 15 into the interproximal sulcus of palatal maxillary first and second right molars. Paper points were applied for 10 s before euthanasia was performed. Samples were stored in phosphate-buffered saline solution and stored in −80°C freezer . ROS wast-test. P-values of <0.05 were considered as statistically significant.All data were presented as mean ± standard deviation. Statistical analyses were performed using GraphPad Prism version 9 . Data processing was started with the normality test using the Shapiro–Wilk test. Comparative linear histomorphometric findings, RANKL/OPG ratio, and ROS protein levels with a normal distribution between the two groups were analyzed using the All mice were considered healthy at the end of the experiment as there were no abnormalities or changes in body weight after KGM treatment during the experimental period . TherefoP. gingivalis  via a metabolic pathway referred to as respiratory burst, which is catalyzed by NADPH oxidase during phagocytosis. Next, O2– is released in the phagosomal and extracellular environment and converted into different radical and nonradical derivatives [P < 0.05) (P < 0.05), thereby reducing ROS under physiological condition. The reduction of ROS with KGM pretreatment may be attributed to the ability of KGM to enhance antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD)) and nonenzymatic enzymes ) [2O2 scavenging capability [After identifying bone alveolar loss histomorphologically in a mouse periodontitis model and the cause of ROS-induced bone loss, the ROS levels were assessed. As expected, the ROS values were significantly higher in the gingival crevicular fluid. Periodontal disease is closely associated with excessive ROS levels . ROS caubiofilms . Neutropivatives , 35. Pativatives . With thivatives . We foun < 0.05) . The orae (GSH)) . Moreovepability . Moreovepability . HO-1 enpability .P. gingivalis were not assessed. To better understand the efficacy of KGM against periodontitis, further studies must be conducted to assess these properties. Further, the drug delivery system of KGM should be investigated.The current study had several limitations. That is, the anti-inflammatory and antibacterial effects of KGM against The current study first showed that KGM had osteoclastogenesis inhibitory and antioxidant properties by reducing alveolar bone destruction, gene expression ratio of RANKL/OPG, and ROS in our mouse periodontitis model. Thus, KGM can be a host modulation therapy for periodontal diseases in the future.


Fatigue is a debilitating and highly relevant symptom in patients with inflammatory bowel disease (IBD). However, awareness of fatigue and treatment options remains limited. This study was aimed at elucidating the influence of disease activity and common complications  on fatigue in patients with IBD to identify potential interventional targets for treating physicians.n = 250) at a university IBD clinic. Additionally, demographic data, laboratory data, IBD history, treatment and current disease activity  were recorded.A cross-sectional survey including five questionnaires  was performed on patients with IBD , diminished quality of life , female sex  and younger age , whereas the influence of anemia or disease activity was non-significant.A total of 189 patients were analyzed (59.8% with Crohn’s disease (CD) and 40.2% with ulcerative colitis (UC)). A total of 51.3% were fatigued, and 12.2% were extremely fatigued. Multiple factors showed significant correlations in univariate analysis. Multivariate analysis revealed that fatigue was correlated with depression (CD, Fatigue is burdensome and highly prevalent in patients with active and inactive IBD. Considerations for fatigue treatment, beyond targeting inflammation and anemia, should include investigation of underlying sub-clinical depression.The online version contains supplementary material available at 10.1186/s12876-023-02906-0. Inflammatory bowel diseases (IBDs) are relapsing inflammatory bowel conditions characterized by unclear etiology and an unpredictable disease course. In addition to inflammatory activity, psychosocial symptoms such as fatigue, persistent and extreme forms of mental and/or physical exhaustion, tiredness or weakness occur . In someAlthough fatigue is highly relevant , 8, it iIn previous studies, fatigue has been associated with depression –13, painThe aim of this study was to further elucidate the influence of disease activity and common complications, such as pain, anemia, depression, anxiety and decreased quality of life, on fatigue in patients with IBD, to identify potential interventional targets for daily practice. In a cross-sectional study, a sizeable IBD cohort was assessed with the Fatigue Assessment Scale (FAS), IBD disease activity clinical scores, paraclinical activity parameters and a large set of validated questionnaires.This cross-sectional paper-based survey study was performed at the Department of Internal Medicine, Jena University Hospital, a third-level IBD clinic with approximately 2,100 patients with IBD. Patients were recruited by the hospital staff during outpatient visits. The inclusion criteria were 1) patients 18 years of age and older, 2) diagnosis of Crohn`s disease (CD) or ulcerative colitis (UC) and 3) German language proficiency.A total of 250 patients were asked to participate in the study between June 27, 2018 and November 11, 2018. After providing written consent, the patients completed five questionnaires evaluating fatigue, depression and anxiety, pain, health related quality of life and general well-being. Additionally, demographic information on sex, age, occupation and current medications was recorded. Disease activity was assessed by the treating physician. Laboratory values were obtained from blood results measured no more than 4 weeks before or after the appointment. Patients were included in the analysis when at least 95% of questionnaire items were completed.Disease activity in CD was assessed with the Harvey-Bradshaw Index (HBI) . Scores The FAS is a unidimensional ten item fatigue scale, which has previously been used for the general public , 27 and Anxiety and depression were assessed with the German version of the Hospital Anxiety and Depression Scale, a 14-item self-reported questionnaire with seven items each for the dimensions of depression (HADS-D) and anxiety (HADS-A). Each item is rated 0–3 according to severity, thus resulting in scores of 0–21 for each dimension . A scoreThe Inflammatory Bowel Disease Questionnaire (IBDQ) is a disease specific instrument used to assess the health-associated quality of life (QoL) in patients with IBD. We used the German version, which has been validated by Janke et al. It contains 32 items, each ranging from 1 (worst) to 7 (best), and assesses the QoL in four dimensions  and provides a total score. Higher scores indicate better QoL . For ourThe Short-Form McGill Pain Questionnaire is a well-established and widely used measure to evaluate pain , 33. It Patients were asked to rate their current general well-being on a Global Assessment Scale ranging from 0 (very poor) to 100 (very good).To identify anemia, we evaluated hemoglobin (Hb), mean corpuscular volume and mean corpuscular hemoglobin. Systemic inflammation was assessed on the basis of the C-reactive protein (CRP), which we rated as normal for all values under 7 mg/l. For IBD specific inflammation, we used fecal calprotectin, a surrogate parameter for mucosal inflammation. Values under 100 mg/kg stool were rated as normal/remission, whereas values above 100 mg/kg indicated mucosal inflammation .Descriptive analysis was performed with simple statistical standards, such as percentages and mean values. Bar charts, histograms, and box plots with percentages were used for presentation.All metric scaled scores and age were tested with the determined fatigue score with Pearson`s correlation coefficient and are presented in scatter plots. Values above 0.5 indicated a strong effect.For mean value comparison, the variables to be tested were divided into groups, which were tested against each other on the basis of the achieved fatigue score. The groupings were as follows.P values < 0.05 were considered significant. The Kruskal–Wallis test was used to assess fatigue differences within the disease location, behaviour and age at diagnosis groups.Laboratory values for CRP and fecal calprotectin: "normal" vs "elevated"; anemia: "yes" vs "no"; sex: "male" vs "female"; diagnosis: "CD" vs "UC"; disease activity: "remission" vs "moderate to severe disease"; anxiety and depression: "inconspicuous" vs "conspicuous, severe to very severe symptoms"; and overall assessment of intensity of pain: "non-low/mild" vs “distressing or worse.” Group analysis was performed with the Mann–Whitney U-test. P values < 0.05 were considered significant.For nominal  or ordinal  variables, rank chi squared test (with trend test from three variables) was performed, and cross tables were created. p < 0.05) in the univariate analysis, as well as sex and age, were included in multiple linear regression analysis. Multiple regression analysis was performed for CD and UC separately. All variables were tested for collinearity. Analyses were performed in IBM SPSS Statistics version 25 .To avoid a high number of missing cases in multiple linear regression analysis, we conducted a univariate analysis for each variable to screen for significant factors correlating with fatigue. For all metric scores  and age, Pearson´s correlation coefficient was used. All nominal factors  were tested by median comparison with Mann–Whitney U-test. All variables showing a significant correlation , and all patients provided signed informed consent, according to the Declaration of Helsinki.A total of 250 patients were asked to participate in the study; 210 patients consented to participate, among whom a total of 189 patients (76% response rate) completed at least 95% of the questionnaire items and thus were included in the analysis. A total of 113 (59.8%) patients had CD, and 76 (40.2%) patients had UC. Clinical and socio-demographic characteristics are presented in Table p = 0.838, Table p < 0.001, Table The mean FAS fatigue scores were 24.72  and 24.71  for CD and UC, respectively  but not UC (p = 0.80). In CD, 82.1% of the patients without fatigue were in remission, whereas 54.5% of those with extreme fatigue had moderate to severe disease. This weak positive correlation was statistically significant in univariate analysis (p < 0.001). Regarding disease characteristics beyond disease activity, no correlations were found between fatigue and age at diagnosis (H(2) = 0.183, p = 0.913), disease location (H(3) = 1.09, p = 0.779), or disease behaviour (H(3) = 2.36, p = 0.501) in patients with Crohn's disease (CD) or disease location (H(3) = 0.507, p = 0.917) in patients with ulcerative colitis (UC). In the HBI documented complications for CD  did not correlate with higher levels of fatigue. 22 patients reported having undergone bowel surgery. There was no significant influence of surgery on fatigue (p = 0.864). 5 patients had a stoma which also did not impact fatigue scores (p = 0.881). IBD specific medication did not influence fatigue levels .Fatigue was more often present in patients with moderate to severe disease activity than in patients in remission . This finding was significant in only CD . A total of 83.8% of patients without fatigue showed unremarkable anxiety symptoms, whereas 60.9% of patients with extreme fatigue were classified as anxious with HADS-A (p < 0.001).Patients without conspicuous anxiety symptoms had significantly lower mean fatigue scores than patients with conspicuous anxiety symptoms . Whereas 95.6% of the group without fatigue had no quantifiable depressive symptoms, the depression was severe to very severe in 43.5% of the extremely fatigued group.Similar strong effects were found regarding depression. Whereas patients without depression had median fatigue scores of 22 points, the group classified as depressed according to HADS-D had a median fatigue score of 33 points (p < 0.001). A total of 64.9% of the patients with IBDQ scores > 171 (suggestive of remission) had “no fatigue.” In contrast, 84.4% of the patients with low IBDQ scores experienced either fatigue or extreme fatigue. The majority of the 32 items and all of the 4 domains of the IBDQ showed a significant correlation with fatigue, as determined by Pearson’s correlation coefficient  = -0.750, p =  < 0.001), item 6 (energy) (UC: r(74) = -0.655, p =  < 0.001); CD: r(110) = -0.641, p =  < 0.001) and item 15 (depressed / discouraged) (UC: r(74) = -0.686, p =  < 0.001;CD: r(112) = -0.653, p =  < 0.001).Patients with fatigue or extreme fatigue significantly more often had low scores for the magnitude of active disease IBDQ < 171) .Pearson's correlation coefficient indicated linear correlations of current pain intensity on the VAS (Rp = 0.437). In addition, the inflammatory values in the blood and stool were not found to be predictive factors for fatigue .Univariate factor analysis of the total fatigue score and laboratory values is shown in Table p = 0.015), depression (p = 0.002) and quality of life (p = 0.003) in CD, and age (p = 0.024) and depression (0.02) in UC were significantly associated with fatigue. Trends were observed for age (p = 0.057) in CD and for anxiety (p = 0.055) in UC. Unexpectedly, an antiproportional trend was found for disease activity and fatigue in UC. All other factors were found to be confounders. The results are shown in Table In the multivariate analysis, we stratified by IBD diagnosis and included all factors that were significant in the univariate analysis as well as sex and age Table . After cFatigue in patients with IBD remains poorly understood. This cross-sectional study of 189 patients with IBD, aimed to investigate the prevalence of fatigue, explore its associations with various factors, and identify important implications for clinical practice. It indicated three major findings. First, fatigue was highly prevalent: 63.5% of patients with IBD experienced either fatigue or severe fatigue, regardless of disease type and activity. Second, to address fatigue, physicians should look beyond laboratory parameters, because anemia and lab values which reflect disease activity do not reliably correlate with fatigue. Third, the diagnostic workup of patients presenting with fatigue should include screening for depression.In this study, the observed prevalence of fatigue in patients with IBD was 63.5% (51.3% with fatigue and 12.3% with severe fatigue)—a percentage four times higher than that reported in the general population . The FASManagement of fatigue in patients with IBD is challenging. If following guidelines, laboratory testing for, and supplementing with, vitamin B12, folate and iron are recommended .Anemia is one of the most frequent complications in patients with IBD , 39. HowThe influence of disease activity on fatigue development has been investigated in previous studies. Most studies that performed multivariate regression analysis, to account for possible confounders, did not find an association between fatigue and disease activity, in accordance with our data , 45, 46.In agreement with the observations of clinical scores, fecal calprotectin, which correlates well with disease activity , and CRPIn our study, depression, measured by the HADS-D, showed the strongest associations with fatigue in both CD and UC in the multivariate analysis. Similar results have been reported by previous studies , 50, 51.Despite strong correlations in the univariate analysis, the variables anxiety, current well-being and pain did not remain significant in the multivariate analysis and were found to be confounders. Nevertheless, they should not be completely disregarded in the assessment of fatigue, regarding anxiety there was a tendency for correlation in the multivariate analysis in UC. Age-related effects on fatigue exhibited a weak and inconsistent correlation, possibly stemming from variations in age and gender distribution between the two disease types .As in any scientific investigation, this study has several limitations. The participants in this study were patients from the outpatient department of a tertiary referral center. This may limit the generalizability of the findings to the entire IBD population, e.g., the level of fatigue among outpatients in an oncological study was observed to be higher compared to that of inpatients . LaboratThe FAS, which has been shown to be a reliable instrument to assess fatigue , 27, is The strengths of the study include the broad assessment of possible factors influencing fatigue through a broad set of validated questionnaires as well as clinical and paraclinical data in almost 200 patients with IBD.In conclusion, we demonstrated that fatigue is burdensome and highly prevalent in patients with IBD. Fatigue should receive attention in patients with active disease as well as disease in remission, because it did not significantly correlate with anemia or disease activity. Thus, we recommend implementing an easy to fill-out fatigue survey, such as the FAS which takes about 2 min to complete, in daily practice. The strong associations with depression highlight the importance of investigating and addressing possible underlying sub-clinical depression in patients reporting fatigue symptoms.Additional file 1. Correlation between IBDQ items / domains and the total fatigue score by Pearson´s correlation coefficient.


Conduct Disorder (CD) is defined as aggressive, antisocial, and rule-breaking behavior during childhood. It is a major risk factor for developing antisocial personality disorder (ASPD) in adulthood. However, nearly half the CDs do not develop ASPD. Identification of reversion factors seems crucial for proper interventions. We identified 40 subjects with childhood history of CD (CC) and 1166 control subjects (HC) from Human Connectome Project. Their psychiatric, emotional, impulsivity, and personality traits were extracted. An emotion recognition task-fMRI analysis was done. We also did subregion analysis of hippocampus and amygdala in 35 CC and 69 demographically matched HCs. CC subjects scored significantly higher in antisocial-related evaluations. No differences in task-fMRI activation of amygdala and hippocampus were observed. CCs had larger subfields of the left hippocampus: presubiculum, CA3, CA4, and dentate gyrus. Further, an interaction model revealed a significant presubiculum volume × group association with antisocial, aggression, and agreeableness scores. Our study shows that healthy young adults with a prior history of CD still exhibit some forms of antisocial-like behavior with larger left hippocampal subfields, including presubiculum that also explains the variability in antisocial behavior. These larger left hippocampal subfield volumes may play a protective role against CD to ASPD conversion. It affects school-aged children and is more prevalent in boys. Its etiology is complex with various genetic (mainly affecting serotonergic and dopaminergic neurotransmission) and environmental risk factors 3. CD may accompany many psycho-developmental issues such as substance abuse, depression, anger problems, and in some instances, the lack of empathy, which is the hallmark of callous-unemotional (CU) traits. CD is also a major risk factor for developing antisocial personality disorder (ASPD)4. The behavioral hallmarks of the ASPD are the same as CD, and it also follows the same gender difference: it is more prevalent in males. Although it’s prevalence is approximately 2–3% in general population, it has been found in prisons to a higher degree as 47% in male inmates5.Conduct disorder (CD) is a serious neurodevelopmental disorder defined by a persistent pattern of violence and flouting rules and social norms that significantly impact families and society6. In line with this finding, reduced amygdala response in tasks involving emotions has also been seen in CD7. A recent functional MRI meta-analysis also revealed a constant brain activation decrease in right basolateral amygdala, the dorsomedial prefrontal cortex, and lateral prefrontal cortex in psychopathy8. The basolateral nuclei of amygdala is involved in anxiety, fear conditioning, and social network size and complexity. Its connections to the hippocampal CA1 regulates anxiety, social behavior, and emotion-modulated spatial memory9, the behaviors that are generally disturbed in both CD and ASPD11. Structural MRI studies also supported a lack of social cognition and emotion in CD subjects. There is evidence of decreased gray matter in various parts of the brain associated with such responses, including lower volumes of the left amygdala, right insula, left medial superior frontal gyrus, and left fusiform gyrus in CD patients12. On the other hand, some studies observed increased gray matter of the orbitofrontal cortex while others reported reduced volume comparing CD adults with healthy subjects14. Also, voxel-based analysis of patients with ASPD revealed grey matter reduction in the left frontopolar cortex and the paralimbic region associated with memory and emotional problems in these subjects16. Smaller left hippocampus and amygdala are observed in CD patients17. However, in another study, no differences in amygdala volume and a smaller right hippocampus is noted in CD with behavioral correlates18. This discrepancy in results may be due to using different imaging protocols, analytical pipelines, or looking at the structures as a whole, rather than looking directly into substructures.Similar patterns of functional or structural disturbances have been seen in both CD and ASPD. For example, functional MRI (fMRI) studies in patients with ASPD suggest significant deficits in the networks related to social cognition and responses to threats19. However, there is a lack of research regarding neural changes and socio-emotional profiles in healthy young adults with a history of CD in their childhood. In one of the few studies in this regard, women with prior history of CD have reduced grey matter volume in the hippocampus, associated with antisocial behavior20.Structural and functional changes in the orbitofrontal-paralimbic system and hippocampal-amygdala complex both in CD and ASPD suggest them as a possible prognostic neural marker for children with CD for developing into ASPD in the futureTherefore, we aimed to investigate the psychiatric and socio-emotional aspects of current healthy adults who had a prior history of CD in their childhood, detecting any possible deviation from normal psychiatric or emotional states. Moreover, we aimed to identify neural correlates of childhood CD by evaluating whole-brain volumetric measures, hippocampal subfields, and amygdala subnuclei, their activity during an emotional task-fMRI, and their respective associations with psychiatric and emotional evaluations. We are specifically interested in hippocampus and amygdala structures due to their possible involvement in CD and ASPD psychopathology based on the literature. Studying the substructures using a high-resolution imaging and a hippocampoamygdalar-directed analytic pipeline helps us to first, overcome the discrepancy in results due to analytical approaches, and second, better delineate the possible psychopathology based on the substructures involved. These measurements may lead us to identify the neural underpinnings of the different neurodevelopmental pathway which encourages the conversion of CD into healthy adults rather than developing ASPD.21. It includes 1206 young adults from 25 to 36 years old who have no current psychiatric or neurologic disorders. They have acquired high-resolution structural, diffusion-weighted, and functional MRI data, plus several neuropsychological and cognitive tests and tasks. We identified 40 subjects who had a diagnosis of conduct disorder in their childhood (CC) based on the DSM-5  conduct disorder criteria extracted from Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) questionnaires22 answered by the participants. The antisocial history part of the SSAGA obtained by HCP includes 24 questions regarding the presence of conduct-, or antisocial-like behavioral patterns during childhood and adolescence, their prevalence, duration, and starting date. We identified questions corresponding to the DSM-5’s conduct disorder criteria and their duration. The subjects scoring the minimum three out of fifteen criteria, with at least one symptom present for more than six months were considered to have conduct disorder history in their childhood (Supplementary Table We used the Human Connectome Project young adults (HCP-YA) for the current study23. The subjects were recruited after signing an informed consent. We accessed the de-identified data after accepting open and restricted data access agreements of the HCP. Moreover, our data analysis was performed in accordance with ethical guidelines of the Iran University of Medical Sciences, Tehran, Iran.All procedures in subject recruitment and data sharing were approved by Washington University Institutional Review Board (IRB)24.Subject demographics included age, sex, and years of education provided by HCP. We included total household income level as an indicator of socioeconomic status of the subjects, categorized into eight levels from one to eight: 1 = less than 10,000$, 2 = 10,000 to 19,999$, 3 = 20,000 to 29,999$, 4 = 30,000 to 39,999$, 5 = 40,000 to 49,999$, 6 = 50,000 to 74,999$, 7 = 75,000 to 99,999$, and 8 = 100,000$ and more. Penn Progressive Matrices (PMAT) was also included as a measure of fluid intelligence25 and Penn Emotion Recognition Task (ER40)26 for evaluating the emotional aspects of the subjects. The NIHTB-EB includes a variety of tests evaluating negative affect , psychological well-being , social relationships , and stress and self-efficacy . In the ER40, each subject is asked about the emotion of a set of 40 faces in five categories: angry, sad, happy, fear, and neutral. The number of correct responses and median response time for the right answers is measured.We used the NIH Toolbox Emotion Battery (NIHTB-EB)27 to evaluate the psychiatric and life function of the subjects. ASR has two components: the syndrome scale and the DSM-oriented scale. We included the anxious/depressed scale, withdrawn, somatic complaints, thought problems, attention problems, aggressive behavior, rule-breaking behavior, intrusiveness, internalizing and externalizing behaviors, and total ASR scores from the syndrome scale. From the DSM-oriented scale, we included DSM depressive, anxiety, somatic, avoidant personality, attention-deficit/hyperactivity, and antisocial personality problems. We included all the ASR-based scores of the subjects in the current study as sex and age-adjusted T-scores.We used scores based on Achenbach Adult Self Report (ASR)28. This 60-item questionnaire can be used to study the personality construct of an individual to “agreeableness,” “openness,” “neuroticism,” “extraversion,” and “conscientiousness”.Personality traits of subjects were acquired based on NEO five-factor inventory (NEO-FFI)29. In this task, the subjects are given the choice of a reward now or a more valuable reward with a delay. The trials are repeated with changes following a set of rules until an indifference point is achieved: the subjective value of the later more valuable reward is equal to the present less valuable reward. Plotting the indifference point reward values against delay time  results in a hyperbolic graph. The area under the curve (AUC) of this graph is considered as a measure of impulsivity: higher impulsivity results in smaller present reward values preferred  to a shorter delay interval, resulting in a steeper hyperbolic chart and lesser AUC30. We included delay discounting AUCs of trials with 200$ and 40,000$ from HCP.We used delay discounting task as a measure of impulsivity31. The analysis pipeline, which resulted in the minimal preprocessed structural data, is briefly as follows: All structural acquisitions were first corrected for gradient distortion, aligned and averaged, skull stripped, corrected for readout distortion, and then fed to the recon-all pipeline of FreeSurfer32, using both high-resolution T1 and T2 weighted images for better identification of pial surfaces. Finally, morphometric measures of cortical parcellations and subcortical segmentations were calculated based on the Deskian-Killiany atlas33. The preprocessed data were available for 35 CC subjects. We matched these subjects with 69 HCs based on age, and education using matchIt library in R34.High-resolution T1 and T2 scans were acquired using 3 T Connectome Siemens Skyra with the following parameters: T1: 3D-MPRAGE, TR = 2400 ms, TE = 2.14 ms, TI = 1000 ms, FOV = 224 × 224, Voxelsize = 0.7 mm isotropic; T2: T2-SPACE, TR = 3200 ms, TE = 565 ms, FOV = 224 × 224, Voxelsize = 0.7 mm isotropic. We used the minimally preprocessed structural data, available as structural extended preprocessed36. This automated approach provides the hippocampus and amygdala segmentation based on a high-resolution probabilistic atlas derived from fifteen autopsy samples. We used high-resolution (starting with hires_) T1 and T2 scans provided in the FreeSurfer output /mri folder in structural extended preprocessed data by renaming the associated files as an input for segmentHA_T2.sh command .We used segmentation of hippocampal subfields and subnuclei of the amygdala implemented in FreeSurfer v7.1.138. The emotion task fMRI is adapted from Hariri et al.39, in which the subjects were asked to match the two shown pictures of faces or shapes on the lower part of the screen to the one presented above. The faces had either fearful or angry expressions and the shapes were depicting fearful or threatening situations. It was shown by Hariri et al., that face vs. shapes contrast shows a reliably strong activation of the bilateral amygdala indicating selective activation of amygdala to negative facial stimuli. Task fMRI data was minimally preprocessed and made available by HCP31. In brief, the data were gradient distortion corrected, motion-corrected, EPI distortion corrected, and then registered non-linearly with the “surface-based” method to MNI registered subject’s T1 scans. The minimally preprocessed data was then fed to FSL FEAT to apply contrasts and derive betas 40. We used the faces vs. shapes contrast grayordinates stats (cope3.feat/cope1.dtseries.nii) analyzed with 2 mm FWMH  smoothed task fMRI data of 1039 subjects (36 CC and 1003 HC) provided by HCP. Mean beta values of bilateral amygdala and hippocampi were extracted using cifti-matlab commands (https://github.com/Washington-University/cifti-matlab). CIFTI-indices associated for each region is as follows: left amygdala = 59,688 to 60,002, right amygdala = 60,003 to 60,334, left hippocampus = 84,561 to 85,324, and right hippocampus = 85,325 to 86,119.We chose this paradigm to evaluate differences in emotion processing between CC and HC, considering the differences observed in the previous studies between subjects with CD or ASPD. The whole-brain EPI acquisition done by the same 3 T Siemens Skyra scanner parameters were as follows: 32 channel head coil, TR = 720 ms, TE = 33.1 ms, flip angle = 52 deg, BW = 2290 Hz/Px, FOV = 208 × 180 mm, 2.0 mm isotropic voxelsize, with a multi-band acceleration factor of 8. Two task fMRI runs were done, one with right-to-left and another with left-to-right phase encoding directions. The procedure of task fMRI is described elsewhere42. Subject demographics and evaluations were compared between 40 CC and the rest of the HCP subjects , using chi-square, t test, or Mann–Whitney test based on the type and distribution of the data.We used Rstudio software based on R statistical package version 3.6.1mri_glmfit-sim command in FreeSurfer) with 5000 permutations, vertex-wise p value < 0.001 and cluster-wise p < 0.05 covarying age and gender to identify between group differences in cortical parcellation thickness43. To evaluate structural volumetric differences between two groups, differences between FreeSurfer generated subcortical volumes were evaluated and were adjusted for age, sex, and total intracranial volume. The same model was also applied for hippocampal and amygdala segmentation volumes with the addition of education and subject income level to the covariates. Next, we decided to evaluate how the differences in behavioral evaluations (part 2.2) can be described by the different structural volumetry seen in the segmentation analysis. Thus, we used a GLM using the former as the outcome and the interaction between significantly different segmentation volumes and group variable  as the predictor variable with the same covariates as the previous model in the age-, and education-matched subsample of the subjects . To overcome the multiple testing problem, we used the Benjamini-Hochberg’s False Discovery Rate (FDR) method to correct the p values wherever applicable44. Corrected p values less than 0.05 were considered to be statistically significant.We used clusterwise correction for multiple comparisons  and agreeableness compared to HCs. Significant differences are shown in Table We investigated between-group differences after randomly matching HCs with CCs. Most of the differences above remained significant; the significant differences for thought problems and anger affect disappeared. Also, in this subsample, CCs showed higher attention problems (Supplementary table 3).p) of a significant vertex: left hemisphere = 3.27, right hemisphere = 2.84). There were no significant differences between CC and HC after Benjamini–Hochberg correction in subcortical volumes : 68.38 (10.07) versus 61.52 (9.23), corrected p = 0.036). There were no differences between amygdala subnuclei or right-side hippocampal subfields between two groups  of the dentate gyrus, in the left side compared to the controls using a statistical model adjusted for age, sex, education, income, and total intracranial volume Fig. . Left hip = 0.42) and right (HC versus CC (mean (SD)): 31.55 (18.57) versus 29.73 (17.21), F  = 0.27, p = 0.60) amygdala. There were also no significant differences between mean beta values of the two groups in the left (HC versus CC (mean (SD)): 8.69 (14.67) versus 11.12 (14.07), F  = 0.68, p = 0.40) and right (HC versus CC (mean (SD)): 9.95 (13.04) versus 10.69 (14.46), F  = 0.09, p = 0.75) hippocampus.Faces versus shapes contrast beta values of emotion task fMRI was available for 1039 subjects (36 CC and 1003 HC). Using an ANCOVA model and adjusting for age, sex, education, and income level, there were no significant differences between mean beta values of the two groups in the left (HC versus CC (mean (SD)): 30.22 (18.12) versus 32.77 (18.60), F  = 0.64, p < 0.05; Fig. We then entered the significant between-group difference results of evaluations and hippocampal subfields into an interaction analysis. We were specifically interested in the extent of behavioral differences that may be explained by the differences in the subfield volumes. After correcting the interaction model results for multiple comparisons, the models were significant for left hippocampal presubiculum and DSM antisocial T score, ASR aggression T score, anger aggression, and agreeableness from personality assessments , and the mere difference might be in the trait of the symptoms.There is robust evidence regarding the significant association between child- and adolescent-onset CD and adulthood antisocial personality disorder48. Although subjects with the previous CD still exhibited some antisocial traits, the emotion and personality domains were found within an almost normal range, confirming the low levels of CU traits in our participants which help their improvement over time in antisocial behaviors.Callous-unemotional (CU) traits are a personality-related subgroup of psychopathic personality traits, characterized by low empathy, restricted affect, interpersonal callousness, and lack of motivation and are significantly associated with more severe and more persistent antisocial behaviors3. Particularly, according to a meta-analysis of six studies, youths with child-onset conduct problems showed decreased grey matter volume in the left amygdala and anterior insula compared to typically developing ones12. Notably, all previous studies have investigated the alterations in brain structures in patients with current conduct problems. For the first time, this study showed that adults with prior CC and current healthy status exhibit larger subfields in the left hippocampus  compared to individuals with no history of conduct problems during their lifetime. It was suggested that children with CD have smaller hippocampus compared to matched healthy controls, which was found associated with higher impulsive behaviors17. Childhood maltreatment, as a major risk factor for developing CD, is associated with smaller CA1, CA3, presubiculum, and DG on the left side49. In another study, Dahmen et al., replicated smaller CA1, CA3, and DG in the subjects with early life adversity50. On the other hand, our CC group consists of participants with a history of CD that have experienced behavioral recovery. Based on the association between smaller subfields of the left hippocampus and CD, the larger hippocampus in the CC group might be justified by the hypothesis that the larger hippocampus has a protective role in CD and increases the chance of recovery. The protective role of the hippocampus volume has been mentioned in a number of previous studies52.Literature has addressed alterations in brain structure or structural connectivity of youths with CD, oppositional defiant disorder (ODD), and conduct problems54 and schizophrenia56. In a relevant finding to our study, left presubiculum volume was negatively correlated with the severity of childhood maltreatment 57 which is a major contributor to the emergence of conduct disorder58. On the other hand, behavioral studies pinpoint its activation in viewing scenery59, and that it positions cells involved in the head-direction system61. Older studies in animal models showed that it is involved in connecting the hippocampus to anterior thalamic nuclei63. Interestingly, in a study using tracers, it was shown that the dorsolateral prefrontal cortex (DLPFC) is connected to the presubiculum via two pathways: the medial pathway traverses through the cingulum bundle, and the lateral pathway via the fronto-occipital pathway64. Altered DLPFC structure and function is a common finding in antisocial behavior, esp. on the left side65. Lesions to DLPFC, either due to trauma66 or artificially induced due to inhibitory transcranial magnetic stimulation67, result in a higher tendency to aggressive behavior in the affected subjects. The effects are more pronounced in the left side DLPFC inhibition. Our study is the first to show that the left hippocampal presubiculum may contribute to antisocial and aggressive behavior, and probably its connections with left DLPFC may be an important factor.We showed that in addition to the enlarged left hippocampus subfields in the normal participants with CC, there is a negative association between presubiculum volume and antisocial-like traits observed in our population. The behavioral and clinical correlates of the presubiculum are not clearly understood. Clinical studies have shown its involvement in the early stages of Alzheimer’s disease68 and the neurodevelopmental nature of the conduct disorder2. Previous studies on the hippocampal asymmetry in violent offenders and psychopathy has concluded a larger right-sided hippocampal volume69, and lower activity in the left side In a positron-emission-tomography study70. Accordingly, Soderstrom et al.71 showed an association between reduced left hippocampal activaty and high psychopathy scores in violent offenders. This association was not observed in right hippocampal activity. These findings are all consistent with our study on the protective role of left hippocampus against antisocial behavior.One interesting finding in our study was a left-sided hippocampal laterality considering the neurodevelopmental differences in hippocampus72. Amygdala is considered the key region for regulating aggressive tendencies74. It has been shown that aggressive behaviors are correlated with the size of the amygdala. A negative association was reported between amygdala size and aggressiveness in healthy individuals75. On the other hand, several studies have suggested that CD patients have lower amygdala size as well as higher aggressive tendencies. A few studies have attributed the CD-induced aggression to changes in amygdala structure and function77. Despite these studies, our study showed no differences in amygdala volumes nor their activity in a emotion-recognition task fMRI between two groups.Numerous studies have addressed the association of aggressive behaviors with amygdala function. Patients with refractory aggressive behaviors have benefited from amygdala surgeriesSeveral limitations should be considered. First, the limited sample size restricted the generalizability of the results. Second, the cross-sectional setting of this study prevents us from understanding the specific disease course over the subjects’ lifetimes. Although we have used the high-resolution structural MRI data of the human connectome project and latest FreeSurfer hippocampal and amygdala segmentation pipeline, it has to be advised that using neuroimaging to study subnuclei that are small and hard to define may not be an ideal choice. Furthermore, diagnosis of CD has been done retrospectively in this study. Studying the children with CD in a prospective cohort design could overcome this limitation.In conclusion, we, for the first time, evaluated the behavioral, emotional, and neurobiological performance of healthy adults with a previous history of CC. Examining the brain structure in this population, we found enlarged left hippocampal subfields and a negative association between the volume of presubiculum of left hippocampus and antisocial-traits in people who have recovered from childhood conduct disorder. This study suggests that CC does not necessarily progress to antisocial personality disorder; however, some antisocial traits remain in adulthood and left presubiculum volume may play a protective role against conduct to antisocial conversion. Further studies are required to confirm our preliminary results.Supplementary Information.


Early diagnosis and treatment effectiveness of early-onset coronary artery disease (EOCAD) are crucial, and non-invasive predictive biomarkers are needed for young adults. We aimed to evaluate the usefulness of the triglyceride-glucose (TyG) index, a novel marker of insulin resistance, in identifying young CAD patients and predicting their risk of developing target lesion failure (TLF).We recruited EOCAD patients  and controls free from CAD , both aged 45 years or younger, from 38 hospitals in China between 2017 and 2020. EOCAD patients who underwent successful percutaneous coronary intervention were followed for incident TLF. TyG index was defined as Ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. We used logistic regression and Cox proportional hazards modeling to evaluate the association of TyG index with prevalent EOCAD and incident TLF, respectively. The discriminatory ability of TyG index was assessed by the area under the receiver-operating characteristic curve (AUC).p = 0.005). During a medium of 33 month (IQR: 31–34 months) follow-up, 43 (3.3%) patients experienced TLF. Multivariate Cox regression model revealed that TyG index was an independent risk factor for TLF . Compared with a model of conventional risk factors alone, the addition of the TyG index modestly improved the AUC  to predict TLF.Among the included 1513 EOCAD patients  and 1513 age-matched controls , TyG index was positively associated with the prevalence of EOCAD . The addition of TyG index to an empirical risk model provided an improvement in diagnostic ability for EOCAD, with a net reclassification improvement of 0.10 (95% CI 0.03–0.17, TyG index is positively associated with prevalent EOCAD and incident TLF. TyG index appeared to be a valuable component of future efforts to improve CAD risk stratification and TLF outcome prediction among young adults.The online version contains supplementary material available at 10.1186/s12933-023-02004-1. Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of premature death worldwide . The incHerein, we conducted an analysis of the multicentre GRAND  study participants to examine whether the TyG index is associated with the prevalence of severe atherosclerotic obstructive CAD in young adults aged 45 years or younger and can also predict the occurrence of TLF after successful PCI.The design and protocol of the GRAND study have been previously reported elsewhere . BrieflyData regarding the demographics and conventional CAD risk profiles were obtained for all eligible participants, whereas in-hospital information, including modes of clinical presentation, angiographic findings, medications, and choice of revascularization were collected for post-PCI patients by trained abstractors from electronic medical records. Additionally, the overall disease severity was quantified by the Genisini score as previously described . Interve2). BMI was classified into normal (BMI 18.5–23.9 kg/m2), overweight (BMI 24–27.9 kg/m2), and obesity (BMI ≥ 28 kg/m2) [2. [Blood samples were collected at 6 am after overnight fasting. The levels of biochemicals were measured routinely in the clinical laboratory of each hospital. The TyG index was calculated as Ln [fasting TG (mg/dL) × FBG (mg/dL)/2] . Body ma/m2) . SiAs young patients in our cohort were selected for severe atherosclerotic obstructive CAD , they represent a relatively homogenous high-risk population. TyG-index may provide greater discrimination of atherosclerotic disease severity in a more heterogeneous population such as in previous studies that included young and elderly patients with CAD  , 26, 27.Early-onset CAD is not a benign condition –7. Most Sex disparities in the TyG index remain uncertain. Some studies found a link between the TyG index and ASCVD risk in females, but not in males , 29. HowThis study does have important limitations. To begin, the causal association of the TyG index and disease susceptibility and outcome is difficult to establish due to the observational nature of the study design. Moreover, we eliminated cases with extremely high TG or FBG to account for the factors like stress hyperglycemia and familial hypertriglyceridemia. However, residual confounders including medications, physical activities, dietary habits and family history of CAD may exist. What’s more, the baseline case–control study was conducted using 1:1 matching only by age, while sex was unable to be further matched. Furthermore, all studies using the TyG index suffer from limitations related to biological variability and intraindividual variation. Nonetheless, the cumulative effect of the TyG index over time seemed to be better than the TyG index at baseline in predicting CAD risk . UnfortuThis is the first multicenter study to date to assess the association between the TyG index and the risk of prevalent EOCAD and incident TLF. In the current study, the TyG index, a surrogate of IR, presented an incremental diagnostic power for EOCAD beyond well-known risk factors. The prognostic value of the TyG index is moderate for TLF, and incorporating the TyG index would improve the predictive accuracy of the conventional risk model. Our results suggested the usefulness of the TyG index in screening subjects who have severe atherosclerotic CAD among young adults and in identifying EOCAD patients who are at high risk of future TLF, so that intensive strategies can be provided.Additional file 1: Table S1. Baseline characteristics of male participants with and without EOCAD. Table S2. Baseline characteristics between controls and cases from different locations. Table S3. Correlations between TyG index and traditional cardiovascular risk factors. Table S4. The association between TyG index and the prevalent EOCAD in males. Table S5. Univariate Cox regression analysis for TLF in EOCAD. Figure S1. ROC analysis of the diagnostic ability of TyG index at hospitalization to identify EOCAD in males.