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Abstract Background Minimally invasive pancreaticoduodenectomy (MIPD) has seen increased adoption due to advancements in surgical techniques and technology. However, the impact of hepatic artery variations (HAV) and clinically relevant HAV (CR-HAV) on MIPD outcomes remains under-investigated. This study aims to explore the differences in surgical and oncological outcomes of MIPD with or without HAV and CR-HAV. Methods We enrolled 267 consecutive patients who underwent MIPD at Peking Union Medical College Hospital between January and December 2023. HAV was identified preoperatively through enhanced abdominal CT and three-dimensional reconstruction, and classified according to the Michels and Hiatt systems. Clinically relevant hepatic artery variations (CR-HAV) were defined based on their potential impact on the surgical approach. We collected and analyzed perioperative data and oncological outcomes between patients with and without HAV and CR-HAV. Propensity score matching (PSM) was used to minimize baseline confounding. Survival analysis was performed using the Kaplan-Meier method with log-rank tests. Results HAV was identified in 26.1% of patients, and CR-HAV in 18.9%. The median operation time was significantly longer in HAV (+) group compared to HAV (-) group (6.72 vs. 5.80 h, p = 0.013). No significant differences were found between HAV/CR-HAV (+) and (-) groups regarding intraoperative blood loss, conversion to laparotomy, postoperative complications, surgical mortality, length of stay, re-operation, and re-admission. Kaplan-Meier survival analysis showed no significant differences in overall survival or progression-free survival between HAV/CR-HAV (+) and (-) groups in the malignant cohort. Conclusion HAV and CR-HAV do not significantly impact overall or progression-free survival in patients undergoing MIPD. While HAV is associated with longer operation times, other perioperative and oncological outcomes remain comparable between HAV/CR-HAV (+) and (-) groups.

Abstract Background The benefits of low-pressure laparoscopic cholecystectomy (LPLC) in patients with cardiopulmonary comorbidities remain unclear. This study aimed to explore the feasibility and pulmonary effects of LPLC in patients with cardiopulmonary comorbidities. Methods This was a multicenter, parallel, double-blind, randomized controlled trial. Eligible patients included patients with cardiac or pulmonary comorbidities, who were randomly assigned (1:1) to undergo LPLC (10 mmHg) or standard-pressure laparoscopic cholecystectomy (SPLC) (14 mmHg). The primary outcome was postoperative partial pressure of carbon dioxide (CO2). Surgical safety variables, patient recovery, pulmonary function parameters, and surgeon comfort were also compared between groups. Results This study enrolled 144 participants, with 124 participants extracted for the final analysis (62 in LPLC and 62 in SPLC group, respectively). The median postoperative PaCO2 was similar in the LPLC (43.3 mmHg) and SPLC (43.0 mmHg) groups (p = 0.988). Pulmonary parameters including postoperative pH, PaCO2, HCO3, and lactate levels were similar between the two groups. Postoperative base excess was significantly higher in the LPLC group (− 0.6 mmol/L [− 6.9 ~ 7.5] vs. −1.9 mmol/L [− 6.6 ~ 5.4]; p = 0.031). There was no between-group difference regarding intraabdominal operative time, rate of intraoperative bile spillage, blood loss, surgeon comfort during surgery, and conversion rate. Moreover, postoperative major complication rates, the median time to the first flatus, postoperative hospital stay, or mean postoperative visual analog scale score for pain were similar in both groups. Conclusions This study found no reduction of partial pressure of CO2 with LPLC compared with SPLC for patients with cardiopulmonary comorbidities. LPLC with a pneumoperitoneum pressure of 10 mmHg may be safe and feasible for these patients when performed by experienced surgeons, although it does not improve pulmonary parameters. Registration The trial is retrospectively registered at ClinicalTrials.gov (NCT04670952) on December 17, 2020.

Abstract Background Current research on delayed gastric emptying (DGE) after pancreatic surgery is predominantly focused on pancreaticoduodenectomy (PD), with little exploration into DGE following total pancreatectomy (TP). This study aims to investigate the risk factors for DGE after TP and develop a predictive model. Methods This retrospective cohort study included 106 consecutive cases of TP performed between January 2013 and December 2023 at Peking Union Medical College Hospital (PUMCH). After applying the inclusion criteria, 96 cases were selected for analysis. These patients were randomly divided into a training set (n = 67) and a validation set (n = 29) in a 7:3 ratio. LASSO regression and multivariate logistic regression analyses were used to identify factors associated with clinically relevant DGE (grades B/C) and to construct a predictive nomogram. The ROC curve, calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were employed to evaluate the model's prediction accuracy. Results The predictive model identified end-to-side gastrointestinal anastomosis, intraoperative blood transfusion, and venous reconstruction as risk factors for clinically relevant DGE after TP. The ROC was 0.853 (95%CI 0.681–0.900) in the training set and 0.789 (95%CI 0.727–0.857) in the validation set. The calibration curve, DCA, and CIC confirmed the accuracy and practicality of the nomogram. Conclusion We developed a novel predictive model that accurately identifies potential risk factors associated with clinically relevant DGE in patients undergoing TP.

Summary: Pancreatic cancer liver metastasis is an important factor leading to dismal prognoses. The details of adaptive immune remodeling in liver metastasis, especially the role of neutrophils, remain elusive. Here, combined single-cell sequencing with spatial transcriptomics results revealed that liver metastases exhibit more aggressive transcriptional characteristics and higher levels of immunosuppression compared with the primary tumor. We identified neutrophils_S100A12 (S100 calcium binding protein A12) cells as the pivotal pro-metastatic cluster, specifically distributed at the invasive front of the metastatic lesions. Mechanistically, our findings indicated that nuclear factor erythroid 2 (NFE2) is a key transcription factor regulating neutrophil phenotypic polarization. Metastatic tumors produce transforming growth factor β to activate the SMAD3 pathway within neutrophils, inducing NFE2-driven polarization. NFE2 promotes the transcription of peptidylarginine deiminase 4 by binding to its promoter, leading to the generation of neutrophil extracellular traps at the invasive front. Collectively, our data demonstrate that NFE2-driven neutrophil polarization is a potential target for anti-metastatic therapy.

Abstract Background Existing research on chyle leak (CL) after pancreatic surgery is mostly focused on pancreaticoduodenectomy and lacks investigation on total pancreatectomy (TP). This study aimed to explore potential risk factors of CL and develop a predictive model for patients with pancreatic tumor undergoing TP. Methods This retrospective study enrolled 90 consecutive patients undergoing TP from January 2015 to December 2023 at Peking Union Medical College Hospital. According to the inclusion criteria, 79 patients were finally included in the following analysis. The LASSO regression and multivariate logistic regression analysis were performed to identify risk factors associated with CL and construct a predictive nomogram. Then, the ROC analysis, calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were performed to assess its discrimination, accuracy, and efficacy. Due to the small sample size, we adopted the bootstrap resampling method with 500 repetitions for validation. Lastly, we plotted and analyzed the trend of postoperative drainage volume in CL patients. Results We revealed that venous resection (OR = 4.352, 95%CI 1.404–14.04, P = 0.011) was an independent risk factor for CL after TP. Prolonged operation time (OR = 1.473, 95%CI 1.015–2.237, P = 0.052) was also associated with an increased incidence of CL. We included these two factors in our prediction model. The area under the curve (AUC) was 0.752 (95%CI 0.622–0.874) after bootstrap. The calibration curve, DCA and CIC showed great accuracy and clinical benefit of our nomogram. In patients with CL, the mean drainage volume was significantly higher in venous resection group and grade B CL group. Conclusion Venous resection was an independent risk factor for chyle leak after TP. Patients undergoing vascular resection during TP should be alert for the occurrence of CL after surgery. We then constructed a nomogram consisted of venous resection and operation time to predict the odds of CL in patients undergoing TP.

In promoting the construction of prefabricated residential buildings in Yunnan villages and towns, the use of precast concrete elements is unstoppable. Due to the dense arrangement of steel bars at the joints of precast concrete elements, collisions are prone to occur, which can affect the stress of the components and even pose certain safety hazards for the entire construction project. Because the commonly used the steel bar obstacle avoidance method based on building information modeling has low adaptation rate and cannot change the trajectory of the steel bar to avoid collision, a multi-agent reinforcement learning-based model integrating building information modeling is proposed to solve the steel bar collision in reinforced concrete frame. The experimental results show that the probability of obstacle avoidance of the proposed model in three typical beam-column joints is 98.45%, 98.62% and 98.39% respectively, which is 5.16%, 12.81% and 17.50% higher than that of the building information modeling. In the collision-free path design of the same object, the research on the path design of different types of precast concrete elements takes about 3–4 minutes, which is far less than the time spent by experienced structural engineers on collision-free path modeling. The experimental results indicate that the model constructed by the research institute has good performance and has certain reference significance.

Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a poor prognosis due to inefficient diagnosis and tenacious drug resistance. Obg-like ATPase 1 (OLA1) is overexpressed in many malignant tumors. The molecular mechanism of OLA1 underlying gemcitabine (GEM)-induced drug resistance was investigated in this study. An enhanced expression of OLA1 was observed in a GEM acquired resistant pancreatic cancer cell lines and in patients with pancreatic cancer. Overexpressed OLA1 showed poor overall survival rates in patients with pancreatic cancer. Dysregulation of the OLA1 reduced expression of CD44+/CD133+, and improved the sensitivity of pancreatic cancer cells to GEM. OLA1 highly expression facilitated the formation of the OLA1/Sonic Hedgehog (SHH)/Hedgehog-interacting protein (HHIP) complex in nuclei, resulting in the inhibition of negative feedback of Hedgehog signaling induced by HHIP. This study suggests that OLA1 may be developed as an innovative drug target for an effective therapy of pancreatic cancer.

Abstract Pancreatic cystic neoplasms (PCNs) are recognized as precursor lesions of pancreatic cancer, with a marked increase in prevalence. Early detection of malignant PCNs is crucial for improving prognosis; however, current diagnostic methods are insufficient for accurately identifying malignant PCNs. Here, we utilized mass spectrometry (MS)-based glycosite- and glycoform-specific glycoproteomics, combined with proteomics, to explore potential cyst fluid diagnostic biomarkers for PCN. The glycoproteomic and proteomic landscape of pancreatic cyst fluid samples from PCN patients was comprehensively investigated, and its characteristics during the malignant transformation of PCN were analyzed. Under the criteria of screening specific cyst fluid biomarkers for the diagnosis of PCN, a group of cyst fluid glycoprotein biomarkers was identified. Through parallel reaction monitoring (PRM)-based targeted glycoproteomic analysis, we validated these chosen glycoprotein biomarkers in a second cohort, ultimately confirming N-glycosylated PHKB (Asn-935, H5N2F0S0; Asn-935, H4N4F0S0; Asn-935, H5N4F0S0), CEACAM5 (Asn-197, H5N4F0S0) and ATP6V0A4 (Asn-367, H6N4F0S0) as promising diagnostic biomarkers for distinguishing malignant PCNs. These glycoprotein biomarkers exhibited robust performance, with an area under the curve ranging from 0.771 to 0.948. In conclusion, we successfully established and conducted MS-based glycoproteomic analysis to identify novel cyst fluid glycoprotein biomarkers for PCN. These findings hold significant clinical implications, providing valuable insights for PCN decision-making, and potentially offering therapeutic targets for PCN treatment.

Pancreatic cancer (PC) combined with situs inversus totalis (SIT) is rare, and the treatment strategy is obscure. We report the first patient with PC and SIT who underwent robot-assisted pancreaticoduodenectomy. A 57-year-old male patient presented to our hospital with epigastric pain, nausea, and weight loss over 1 month. Preoperative diagnostic modalities revealed a resectable pancreatic ductal adenocarcinoma at the head and neck junction of the pancreas. The patient also had a rare condition called SIT. Then, the patient underwent Da Vinci robot-assisted pancreaticoduodenectomy (RPD) in our center. After the operation, the patient recovered well without complications. Until now, the patient was followed up 5 months, and the quality of life was well without tumor recurrence or metastasis. To the authors’ knowledge, this is the first RPD for PC in SIT patients.

Objective:. Robotic distal pancreatectomy (RDP) has become a routine procedure in many pancreatic centers. This study aimed to describe a single-center experience with RDP since the first case, identify the learning curves of operation time and complication rate, and discuss the safety and feasibility of RDP. Methods:. We collected and retrospectively analyzed the single-center surgical experience of 301 patients undergoing RDP at Peking Union Medical College Hospital (PUMCH) between 2012 and 2022 and described the change in operation proficiency and occurrence of perioperative complications in this observational study. The learning curve was assessed using the cumulative sum method. Results:. We observed a three-phase pattern of RDP learning with operation time, complications, and postoperative pancreatic fistula as indicators and a two-phase pattern for spleening-preserving success. The mean operation time was 3.9 hours. The incidence rate of clinically significant postoperative pancreatic fistula (CRPOPF) was 17.9% and overall Clavien-Dindo complication rate (≥3) was 16.6%. The change of postoperative complicate rate was correlated with percentage of malignant cases. Conclusion:. In the last decade, an evident decrease was seen in operation time, complication rate, and an increase in the spleen-preserving rate of distal pancreatectomy. With proper training, RDP is a safe and feasible procedure.

BackgroundTotal pancreatectomy (TP) has been increasingly performed in recent years. However, studies on diabetes management after TP during different postoperative periods are still limited.ObjectivesThis study aimed to evaluate the glycemic control and insulin therapy of patients undergoing TP during the perioperative and long-term follow-up period.MethodsNinety-three patients undergoing TP for diffuse pancreatic tumors from a single center in China were included. Based on preoperative glycemic status, patients were divided into three groups: nondiabetic group (NDG, n = 41), short-duration diabetic group (SDG, preoperative diabetes duration ≤12 months, n = 22), and long-duration diabetic group (LDG, preoperative diabetes duration >12 months, n = 30). Perioperative and long-term follow-up data, including the survival rate, glycemic control, and insulin regimens, were evaluated. Comparative analysis with complete insulin-deficient type 1 diabetes mellitus (T1DM) was conducted.ResultsDuring hospitalization after TP, glucose values within the target (4.4-10.0 mmol/L) accounted for 43.3% of the total data, and 45.2% of the patients experienced hypoglycemic events. Patients received continuous intravenous insulin infusion during parenteral nutrition at a daily insulin dose of 1.20 ± 0.47 units/kg/day. In the long-term follow-up period, glycosylated hemoglobin A1c levels of 7.43 ± 0.76% in patients following TP, as well as time in range and coefficient of variation assessed by continuous glucose monitoring, were similar to those in patients with T1DM. However, patients after TP had lower daily insulin dose (0.49 ± 0.19 vs 0.65 ± 0.19 units/kg/day, P < 0.001) and basal insulin percentage (39.4 ± 16.5 vs 43.9 ± 9.9%, P = 0.035) than patients with T1DM, so did those using insulin pump therapy. Whether in the perioperative or long-term follow-up period, daily insulin dose was significantly higher in LDG patients than in NDG and SDG patients.ConclusionsInsulin dose in patients undergoing TP varied according to different postoperative periods. During long-term follow-up, glycemic control and variability following TP were comparable to complete insulin-deficient T1DM but with fewer insulin needs. Preoperative glycemic status should be evaluated as it could guide insulin therapy after TP.

Background: S-1 has been recognized as one of the standard adjuvant chemotherapies for pancreatic ductal adenocarcinoma (PDAC) in East Asia, but the optimal adjuvant chemotherapy regimen has not been determined. We aimed to compare the efficacy and safety of adjuvant gemcitabine plus S-1 (GS) with S-1 monotherapy for PDAC. Methods: Patients with resected PDAC who received adjuvant GS or S-1 chemotherapy in Peking Union Medical College Hospital between May 2014 and May 2022 were reviewed. Data retrieved from medical records were used to evaluate efficacy and toxicity. Results: A total of 241 patients were included, with 167 receiving GS and 74 receiving S-1. The patients who received GS were generally younger (median [range] age: 62 [36-78] versus 64 [44-87] years, p = 0.004), but chemotherapy began later (median [range] interval between chemotherapy and surgery: 49 [17-125] versus 40 [16-100] days, p < 0.001). The median disease-free survival (DFS, 15.1 versus 15.9 months, p = 0.52) and overall survival (OS, 34.8 versus 27.1 months, p = 0.34) did not differ significantly between the GS and S-1 groups, even after adjustment for the biases. However, the chemotherapy completion rate was higher in the patients treated with S-1 (52.4% versus 75.7%, p = 0.006), while grade 3-4 neutropenia occurred more frequently in the GS group (49.5% versus 18.2%, p = 0.015). Conclusions: Adjuvant S-1 monotherapy demonstrated noninferiority to the GS regimen in DFS and OS with better tolerability for PDAC following surgery.

Objective: To analyze the characteristics of foot and ankle deformity with ulceration in patients with spina bifida, to conclude experiences on management with improved Ilizarov method in one stage. Methods: 77 cases suffering foot and ankle deformity with ulceration of spina bifida were included from January 2008 to June 2019, in which 30 male and 47 female, aged 6–46 years with an average age of 22.86 years. There were 10 cases on left, 14 on right and 53 on both. The improved Ilizarov method combined soft tissue surgery, bone osteotomy and Ilizarov technique in one stage, by which the ulcer was dressed aseptically and avoid weight bearing preoperatively, no special treatment, no debridement, no flap coverage and no bacterial culture. Antibiotics were given for 3 days routinely, and the dressing was removed 5 days later. If there was exudation, gauze could be used to wrap continually, if there was no swelling and exudation, no need further more caring. General appearance and radiological image of ulcer and deformity were observed during the period of evaluation and treatment, surgical method and complications, foot & ankle function and overall function were evaluated using AOFAS scoring system and special table designed by authors. Results: 77 cases were followed up for 6–132 months with an average of 50.5 months. Achilles tendon subcutaneous lengthening was performed in 2 cases, posterior tibial tendon and Achilles tendon simultaneous released for 31cases, subtalar joint arthrodesis 25 cases, calcaneus osteotomy 5 cases, triple osteotomy 28 cases, ankle arthrodesis 19 cases, internal rotation osteotomy of tibia was performed in 1 case and 1 case in external rotation osteotomy. There were 67 cases using Ilizarov fixators and 10 cases using Hybrid fixators for immobilization and correction. Stable feet were obtained and ulcers healed simultaneously when all deformities of foot and ankle had been corrected. The healing time of ulcer was average 26.5 days ranging 7–36 days, and there was no infection or delayed healing occurred in any case. Ankle ankylosis in 25 cases, 3 cases of pin tract infection, 2 wires were broken. The AOFAS score significantly increased from 70.5 ± 4.5 preoperative to 81.6 ± 3.9 postoperative; based special table evaluating, Excellent 28 cases, Good 42 cases, Fair7 cases. Conclusion: The patients with foot & ankle deformity and ulceration suffered from spinal bifida can be treated by improved Ilizarov method in one stage, and the results are satisfactory with short treatment period and decreased complications. Translational potential of this article: The characteristics of foot and ankle deformity with ulceration inpatients with spina bifida have been analyzed and the experiences on management with improved Ilizarovmethod in one stage have been summarized in this study, which updated treatment concept of neurogenic deformity with ulceration on foot and ankle joint.

Abstract Objectives Pancreatic cancer (PC) is one of the most lethal malignancies with an increasing death rate over the years. We performed targeted sequencing and survival analyses on 90 Chinese pancreatic cancer patients, hoping to identify genomic biomarkers associated with clinical outcomes and therapeutic options. Method Genomic DNA was extracted from formalin‐fixed paraffin‐embedded (FFPE) tissue specimens of 90 pancreatic cancer patients and sequenced. The associations with clinicopathological factors were analyzed. Result High prevalence of driver mutations in KRAS, TP53, CDKN2A, SMAD4, and ARID1A genes were found. Most mutated genes in PC belonged to cell cycle and DNA damage repair pathways. Tumors that arise from the pancreas’ body and tail (BT tumors) displayed a higher ratio of mutated KRAS and TP53 than those that arise from the pancreas’ head and neck (HN tumors), who showed less diverse KRAS subtypes. Patients with a KRAS p.G12R mutated tumor tended to have a prolonged disease‐free survival (DFS) and overall survival (OS) than other KRAS subtypes. Those with an altered ARID1A gene and more than two mutated driver genes tended to have a shorter DFS and OS. Conclusion HN and BT tumors of the pancreas displayed different mutational profiles, which had prognostic significances and indicated different potential therapeutic options.

Abstract Pancreatic cancer is one of the main causes of tumor-related deaths worldwide because of its low morbidity but extremely high mortality, and is therefore colloquially known as the “king of cancer.” Sudden onset and lack of early diagnostic biomarkers directly contribute to the extremely high mortality rate of pancreatic cancer patients, and also make it indistinguishable from benign pancreatic diseases and precancerous pancreatic lesions. Additionally, the lack of effective prognostic biomarkers makes it difficult for clinicians to formulate precise follow-up strategies based on the postoperative characteristics of the patients, which results in missed early diagnosis of recurrent pancreatic cancer. Long non-coding RNAs (lncRNAs) can influence cell proliferation, invasion/migration, apoptosis, and even chemoresistance via regulation of various signaling pathways, leading to pro- or anti-cancer outcomes. Given the versatile effects of lncRNAs on tumor progression, using a single lncRNA or combination of several lncRNAs may be an effective method for tumor diagnosis and prognostic predictions. This review will give a comprehensive overview of the most recent research related to lncRNAs in pancreatic cancer progression, as targeted therapies, and as biomarkers for the diagnosis and prognosis of pancreatic cancer.

Abstract Cancer remains one of the major culprits causing disease-related deaths and leads to a high morbidity and similar mortality. Insidious onset, difficult early detection and a lack of broad-spectrum and effective multi-cancer therapeutic targets have limited the prolongation of cancer patients’ survival for decades. Therefore, a versatile therapeutic target which is involved in various cancer-related signaling pathways and different cancers may be more effective for cancer targeted therapy. USP4, one of the DUBs members which participates in deubiquitination, an inverse process of ubiquitination, can regulate various classical cancer-related signaling pathways, and thereby plays a vital role in some pathological and physiological processes including tumor initiation and progression. Recently, USP4 has been found to exert versatile influences on cells proliferation, migration and invasion, also apoptosis of various tumors. Moreover, USP4 can also act as a prognostic biomarker in several cancers. This review will give a comprehensive introduction of USP4 about its regulatory mechanisms, related signaling pathways, pathophysiological functions and the roles in various cancers which may help us better understand its biological functions and improve future studies to construct suitable USP4-targeted cancer therapy system.

Abstract Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis due to limited therapeutic options. This study examines the roles of genome-wide association study identified PDAC-associated genes as therapeutic targets. We have identified HNF4G gene whose silencing most effectively repressed PDAC cell invasiveness. HNF4G overexpression is induced by the deficiency of transcriptional factor and tumor suppressor SMAD4. Increased HNF4G are correlated with SMAD4 deficiency in PDAC tumor samples and associated with metastasis and poor survival time in xenograft animal model and in patients with PDAC (log-rank P = 0.036; HR = 1.60, 95% CI = 1.03–2.47). We have found that Metformin suppresses HNF4G activity via AMPK-mediated phosphorylation-coupled ubiquitination degradation and inhibits in vitro invasion and in vivo metastasis of PDAC cells with SMAD4 deficiency. Furthermore, Metformin treatment significantly improve clinical outcomes and survival in patients with SMAD4-deficient PDAC (log-rank P = 0.022; HR = 0.31, 95% CI = 0.14–0.68) but not in patients with SMAD4-normal PDAC. Pathway analysis shows that HNF4G may act in PDAC through the cell-cell junction pathway. These results indicate that SMAD4 deficiency-induced overexpression of HNF4G plays a critical oncogenic role in PDAC progression and metastasis but may form a druggable target for Metformin treatment.

Abstract. Objectives:. Timing of drain removal and its effects on complications after major pancreatectomy remain controversial. We designed this study to assess whether early drain removal after major pancreatectomy influences the incidence of complications in the patients with low risk of postoperative pancreatic fistula (POPF). Methods:. This is a single-center randomized controlled trial (RCT). A total of 144 patients undergoing pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) who met the criteria, including drain amylase on postoperative day (POD) 1 and 3 less than 5000 U/L and drain output within POD 3 less than 300 mL/d, were randomly assigned to early drain removal (POD 3) or standard drain removal (≥POD 5). The primary outcome was major complications (Clavien-Dindo grades 2–4), and the secondary outcome was POPF, reintervention treatment, readmission, and total medical expense within 3 months after surgery. Results:. A total of 5 patients in early drain removal group had at least 1 major complications (grades 2–4), compared to 15 patients in standard drain removal group (P = .028). The incidence of grade B/C pancreatic fistula was not significantly different (2.8% vs 0%). Multivariate analysis demonstrated that early drain removal was an independent factor associated with a reduced risk of major complications (P = .039, odds ratio = 0.314). Majority of major complications occurred in PD patients, and only very few cases occurred in DP patients. Stratified analysis showed that early drain removal significantly reduced the major complications only in the patients undergoing PD. Conclusion:. This single-center RCT shows early drain removal on POD 3 is safe for both DP and PD patients, under our criteria. Early drain removal could reduce the incidence of major complications in patients undergoing PD.

Pancreatic cancer is a highly malignant tumor with a poor survival prognosis. We attempted to establish a robust prognostic model to elucidate the clinicopathological association between lncRNA, which may lead to poor prognosis by influencing m6A modification, and pancreatic cancer. We investigated the lncRNAs expression level and the prognostic value in 440 PDAC patients and 171 normal tissues from GTEx, TCGA, and ICGC databases. The bioinformatic analysis and statistical analysis were used to illustrate the relationship. We implemented Pearson correlation analysis to explore the m6A-related lncRNAs, univariate Cox regression and Kaplan-Meier methods were performed to identify the seven prognostic lncRNAs signatures. We inputted them in the LASSO Cox regression to establish a prognostic model in the TCGA database, verified in the ICGC database. The AUC of the ROC curve of the training set is 0.887, while the validation set is 0.711. Each patient has calculated a risk score and divided it into low-risk and high-risk subgroups by the median value. Moreover, the model showed a robust prognostic ability in the stratification analysis of different risk subgroups, pathological grades, and recurrence events. We established a ceRNA network between lncRNAs and m6A regulators. Enrichment analysis indicated that malignancy-associated biological function and signaling pathways were enriched in the high-risk subgroup and m6A-related lncRNAs target mRNA. We have even identified small molecule drugs, such as Thapsigargin, Mepacrine, and Ellipticine, that may affect pancreatic cancer progression. We found that seven lncRNAs were highly expressed in tumor patients in the GTEx-TCGA database, and LncRNA CASC19/UCA1/LINC01094/LINC02323 were confirmed in both pancreatic cell lines and FISH relative quantity. We provided a comprehensive aerial view between m6A-related lncRNAs and pancreatic cancer’s clinicopathological characteristics, and performed experiments to verify the robustness of the prognostic model.

Ankle sprain is the most common injury during parachute landing. The biomechanical behavior of the tissues can help us understand the injury mechanism of ankle inversion. To accurately describe the injury mechanism of tissues and assess the effect of ankle protection, a stable time of landing was obtained through the dynamic stability test. It was used for the boundary condition of the foot finite element (FE). The FE model was provided a static load equal to half of the bodyweight applied at the distal tibia and fibula; a foot-boot-brace FE model was established to simulate the landing of subjects on an inversion inclined platform of 0–20°, including non-, external, and elastic ankle braces. Compared with the non-ankle brace, both the external and elastic ankle braces decreased the peak strains of the cal-fibular, anterior Ta-fibular, and posterior Ta-fibular ligaments (15.2–33.0%), and of the peak stress of the fibula (15.2–24.5%). For the strain decrement of the aforementioned ligaments, the elastic brace performed better than the external ankle brace under the inversion of the 10° condition. The peak stress of the fibula (15.6 MPa) decreased up to 24.5% with an elastic brace and 5.6–10.3% with an external brace. The findings suggested that the behaviors of lateral ankle ligaments and fibula were meaningful for the functional ability of the ankle. This provides some suggestions regarding the optimal design of ankle protection.

Objective: Exercise has been reported to be beneficial for people with type 2 diabetes (T2DM), but exercise, especially weight-bearing exercise, may increase the risk of diabetic foot ulcers (DFUs). This study aimed to explore the associations between different volumes of weight-bearing physical activities and plantar microcirculation and tissue hardness in people with T2DM.Methods: 130 elderly people with T2DM were enrolled for this cross-sectional study. They were classified into the high exercise volume group and the low exercise volume group based on their weekly energy expenditure (metabolic equivalents per week) in the past year. Weekly energy expenditure was calculated using the International Physical Activity Questionnaire and the Compendium of Physical Activities. The plantar oxygen saturation (SO2) and soft tissue hardness of each participant’s right foot were measured.Results: A total of 80 participants completed the trial. The average exercise energy expenditure of the high exercise volume group and the low exercise volume group were significantly different (p < 0.05). The results showed that the SO2 of the high exercise volume group (67.25 ± 6.12%) was significantly higher than the low exercise volume group (63.75 ± 8.02%, p < 0.05). The plantar tissue hardness of the high exercise volume group was lower than the low exercise volume group in the big toe, midfoot and hindfoot regions (p < 0.05).Conclusion: This study demonstrates that higher volumes of exercise are associated with better plantar microcirculation and lower plantar tissue hardness in people with T2DM. The findings of this study indicate that weight-bearing exercise may not increase risk of developing diabetic foot ulcers.

Rolling bearings are important parts of mechanical equipment. However, the early failures of the bearing are usually masked by heavy noise. This brings about difficulties to the extraction of its fault features. Therefore, there is a need to develop a reliable method for early fault detection of the bearing. Considering this issue, a novel fault diagnosis method using the improved wavelet threshold denoising and fast spectral correlation (Fast-SC) is proposed. First, to solve the discontinuity of the hard threshold function and avoid the constant deviation triggered by the soft threshold function, a piecewise continuous threshold function is proposed by using a new threshold selection rule to denoise the original signal. In the new threshold function, the adjuster α is introduced to improve the traditional wavelet denoising algorithm, so as to enhance the signal-to-noise ratio (SNR) of the original signal more effectively. Then, the denoised signal is analysed by Fast-SC to identify the rolling bearing fault features. Finally, simulation analysis and experimental data demonstrate that the proposed approach is effective for rolling bearing fault detection compared with Fast-SC and the combined method based on traditional wavelet threshold and Fast-SC.

Introduction Several previous studies have reported the incidence of new-onset diabetes mellitus (NODM) after pancreatectomy. Nevertheless, the results were inconsistent. The true rate of NODM after distal pancreatectomy (DP) is still unknown.Research design and methods The aim of this study was to investigate the incidence of and the risk factors for NODM after DP. This study enrolled patients who underwent DP between January 2004 and February 2016 at Peking Union Medical College Hospital. Patients with preoperative diabetes mellitus or diagnosed with pancreatic cancer were excluded. The primary outcome was NODM.Results A total of 485 patients were enrolled. The median (IQR) of follow-up duration was 30.95 (9.26–180.30) months. The accumulative incidence of NODM was 8.9% at postoperative 6 months, 14.0% at postoperative year one, 22.3% at year three, 27.1% at year five, and 35.5% at year ten. Multivariate analysis showed that the risk of postoperative NODM was positively correlated with age (HR 1.029 (1.013–1.045), p

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with one of the worst prognoses worldwide and has an overall 5-year survival rate of only 9%. Although chemotherapy is the recommended treatment for patients with advanced PDAC, its efficacy is not satisfactory. The dense dysplastic stroma of PDAC is a major obstacle to the delivery of chemotherapy drugs and plays an important role in the progression of PDAC. Therefore, stroma-targeting therapy is considered a potential treatment strategy to improve the efficacy of chemotherapy and patient survival. While several preclinical studies have shown encouraging results, the anti-tumor potential of the PDAC stroma has also been revealed, and the extreme depletion might promote tumor progression and undermine patient survival. Therefore, achieving a balance between stromal abundance and depletion might be the further of stroma-targeting therapy. This review summarized the current progress of stroma-targeting therapy in PDAC and discussed the double-edged sword of its therapeutic effects.

Background: Pancreatic ductal adenocarcinoma (PDAC) leads to the majority of cancer-related deaths due to its morbidity with similar mortality. Lack of effective prognostic biomarkers are the main reason for belated post-operative intervention of recurrence which causes high mortality. Numerous systematic reviews and meta-analyses have explored the prognostic value of biomarkers in PDAC so far. In this article, we performed an umbrella review analyzing these studies to provide an overview of associations between prognostic biomarkers and PDAC survival outcome and synthesized these results to guide better clinical practice.Methods: Systematic reviews and meta-analyses investigating the associations between PDAC survival outcomes and prognostic biomarkers were acquired via the PubMed and Embase databases from inception till February 1, 2020. Associations supported by nominally statistically significant results were classified into strong, highly suggestive, suggestive, and weak based on several critical factors such as the statistical significance of summary estimates, the number of events, the estimate of the largest study included, interstudy heterogeneity, small-study effects, 95% predictive interval (PI), excess significance bias, and the results of credibility ceiling sensitivity analyses.Results: We included 41 meta-analyses containing 63 associations between PDAC survival outcomes and prognostic biomarkers. Although, none was supported by strong evidence among these associations, an association between C-reactive protein to albumin ratio (CAR) and PDAC overall survival (OS) and an association between neutrophil-lymphocyte ratio (NLR) and PDAC OS were supported by highly suggestive evidence. Otherwise, the association between lactate dehydrogenase (LDH) and PDAC OS was supported by suggestive evidence. The remaining 60 associations were supported by weak or not suggestive evidence.Conclusion: Associations between CAR or NLR and PDAC OS were supported by highly suggestive evidence. And the association between LDH and PDAC OS was supported by suggestive evidence. Although the methodological quality of the included systematic reviews and meta-analyses which were evaluated by AMSTAR2.0 is generally poor, the identification of the relatively robust prognostic biomarkers of PDAC may guide better post-operative intervention and follow-up to prolong patients' survival.

Background: It is challenging to identify the prevalence of lymph node metastasis (LNM) and residual tumor in patients with early gastric cancer (EGC) who underwent noncurative endoscopic resection (ER). This present meta-analysis was aimed to establish imperative potential predictive factors in order to select the optimal treatment method. Methods: A systematic literature search of PubMed, Embase, and Cochrane Library databases was performed through 1 February 2019 to identify relevant studies, which investigated risk factors for LNM and residual tumor in patients with EGC who underwent noncurative ER. Eligible data were systematically reviewed through a meta-analysis. Results: Overall, 12 studies investigating the risk factor of LNM were included, totaling 3015 patients, 7 of which also involved cancer residues. After the present meta-analysis, six predictors, including tumor size >30 mm, tumor invasion depth (⩾500 μm from the muscularis mucosae), macroscopic appearance, undifferentiated histopathological type, positive vertical margin, and presence of lymphovascular invasion (including lymphatic invasion and vascular invasion) were significantly associated with LNM, whereas tumor size >30 mm, positive horizontal margin, and positive vertical margin were identified as significant predictors for the risk of residual tumor. No evidence of publication bias was observed. Conclusions: Six and three variables were established as significant risk factors for LNM and residual tumor in patients with EGC who underwent noncurative ER, respectively. Patients with EGC who present these risk factors after noncurative ER are strongly suggested to receive additional surgery, while others might be suitable for strict follow-up. This might shed some new light on the selection of follow-up treatment for noncurative ER.

Background: Transducin-like enhancer of split-1 (TLE1), a member of the Groucho/TLE family of transcriptional corepressors, has been reported to be involved in the tumorigenesis of various cancers and function as a clinical prognostic indicator. However, the mechanisms and prognostic significance of TLE1 in pancreatic ductal adenocarcinoma (PDAC) have not been elucidated.Methods: In this study, western blot analyses and real-time polymerase chain reaction (RT-PCR) were employed to evaluate the expression of TLE1 and related proteins in PDAC cell lines. Wound healing, transwell migration and invasion, and Cell Counting Kit-8 (CCK-8) assays were used to determine cell line-specific differences in metastasis and proliferation. Flow cytometry was performed for cell cycle detection. RNA sequencing and bioinformatics were undertaken to explore the molecular mechanisms and potential targeted molecules of TLE1. TLE1 expression in tumor and para-tumor tissues was evaluated by tissue microarray-based immunohistochemistry using a semiquantitative method (H-score) in 262 patients with radical PDAC resection. Correlation, Kaplan–Meier survival, univariate, and multivariate analyses were also performed.Results: Our findings showed that TLE1 expression was common in PDAC cell lines. Upregulation of TLE1 inhibited PDAC cell migration, invasion, and proliferation in vitro by delaying the G0/G1 transition. Immunohistochemistry revealed that TLE1 was specifically expressed in the nucleus and at higher levels in tumor tissues compared with para-tumor tissues. Generally, high TLE1 expression was associated with no vascular invasion. In univariate analyses, high TLE1 expression was associated with longer disease-specific survival (DSS) in all patients and in 16 patient subgroups. In multivariate analyses, TLE1 expression was independently associated with DSS in all patients and four patient subgroups.Conclusion: In conclusion, these results suggest that TLE1 has an inhibitory role in PDAC progression and is a favorable prognostic indicator for patients with resectable PDAC.

Abstract Background Programmed death ligand 1 (PD-L1) has shown potential as a therapeutic target in numerous solid tumors. Its prognostic significance has also been established in pancreatic ductal adenocarcinoma (PDAC). The present study aimed to explore PD-L1 expression in PDAC cases in a large Chinese cohort using an in vitro diagnostic (IVD) assay to provide further insight into the potential value of programmed cell death protein 1 (PD-1) as a therapeutic target. Methods Three hundred seventy-three PDAC patients were retrospectively recruited in this study. Tissue microarray (TMA) blocks were made from available formalin-fixed and paraffin-embedded (FFPE) tumor and matched adjacent tissue specimens. We evaluated PD-L1 protein expression via immunohistochemistry (IHC) using a U.S. Food and Drug Administration (FDA)-approved IVD assay. The relationships between PD-L1 positivity and both clinicopathological characteristics and patient prognosis were analyzed. PD-1 expression and clinicopathological significance were also evaluated. Results PD-L1 and PD-1 positivity were observed in 3.2% and 7.5% of cases, respectively. PD-L1 showed a predominantly membranous pattern in tumor cells, while no positive PD-L1 staining was observed in normal regions. Statistical analyses revealed that PD-L1 expression was associated with lymph node metastasis. PD-L1 positivity was a prognostic indicator of progression-free survival (PFS) and overall survival (OS) in univariate analyses, but only PFS remained statistically significant in multivariate analysis. PD-1 expression was detected in lymphocytes and was not associated with any clinicopathological feature except a history of pancreatitis. Conclusions The PD-L1 positivity rate is low in PDAC when evaluated using a companion diagnostic assay. It remains an independent prognostic factor for poor PFS.

To realize the accurate fault detection of rolling element bearings, a novel fault detection method based on non-stationary vibration signal analysis using weighted average ensemble empirical mode decomposition (WAEEMD) and modulation signal bispectrum (MSB) is proposed in this paper. Bispectrum is a third-order statistic, which can not only effectively suppress Gaussian noise, but also help identify phase coupling. However, it cannot effectively decompose the modulation components which are inherent in vibration signals. To alleviate this issue, MSB based on the modulation characteristics of the signals is developed for demodulation and noise reduction. Still, the direct application of MSB has some interfering frequency components when extracting fault features from non-stationary signals. Ensemble empirical mode decomposition (EEMD) is an advanced nonlinear and non-stationary signal processing approach that can decompose the signal into a list of stationary intrinsic mode functions (IMFs). The proposed method takes advantage of WAEEMD and MSB for bearing fault diagnosis based on vibration signature analysis. Firstly, the vibration signal is decomposed into IMFs with a different frequency band using EEMD. Then, the IMFs are reconstructed into a new signal by the weighted average method, called WAEEMD, based on Teager energy kurtosis (TEK). Finally, MSB is applied to decompose the modulated components in the reconstructed signal and extract the fault characteristic frequencies for fault detection. Furthermore, the efficiency and performance of the proposed WAEEMD-MSB approach is demonstrated on the fault diagnosis for a motor bearing outer race fault and a gearbox bearing inner race fault. The experimental results verify that the WAEEMD-MSB has superior performance over conventional MSB and EEMD-MSB in extracting fault features and has precise and effective advantages for rolling element bearing fault detection.

The planetary gearbox is at the heart of most rotating machinery. The premature failure and subsequent downtime of a planetary gearbox not only seriously affects the reliability and safety of the entire rotating machinery but also results in severe accidents and economic losses in industrial applications. It is an important and challenging task to accurately detect failures in a planetary gearbox at an early stage to ensure the safety and reliability of the mechanical transmission system. In this paper, a novel method based on wavelet packet energy (WPE) and modulation signal bispectrum (MSB) analysis is proposed for planetary gearbox early fault diagnostics. First, the vibration signal is decomposed into different time-frequency subspaces using wavelet packet decomposition (WPD). The WPE is calculated in each time-frequency subspace. Secondly, the relatively high energy vectors are selected from a WPE matrix to obtain a reconstructed signal. The reconstructed signal is then subjected to MSB analysis to obtain the fault characteristic frequency for fault diagnosis of the planetary gearbox. The validity of the proposed method is carried out through analyzing the vibration signals of the test planetary gearbox in two fault cases. One fault is a chipped sun gear tooth and the other is an inner-race fault in the planet gear bearing. The results show that the proposed method is feasible and effective for early fault diagnosis in planetary gearboxes.

Background: Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare, low-grade malignant pancreatic tumor with a highly favorable prognosis. Most SPN patients are young and middle-aged women. The main controversial topic for SPN is local resection (LR) versus radical resection (RR). Theoretically, LR could lead to better gastrointestinal function (GIF) and less mental stress. However, no data is available to support this hypothesis. Methods: All SPN patients undergoing surgical treatment in Peking Union Medical College Hospital from 2001 to 2021 were included in the study. A cross-sectional online multiquestionnaire survey containing 110 questions was sent to them (Clinicaltrial.org, NCT05604716). This online multiquestionnaire survey focused on GIF and mental stress and consisted of eight questionnaires. Multiple linear regression analysis was conducted to identify independent factors impacting GIF and mental stress. Results: A total of 183 cases provided valid results. Among them, 46 patients (25.1%) underwent LR, and 137 (74.9%) underwent RR. Ninety-four cases (51.4%) underwent minimally invasive surgery (MIS), while 89 (48.6%) underwent open surgery. The average GSRS score of the patients was 1.9 ± 0.7, indicating that most suffered frommild gastrointestinal dysfunction. The scores of PHQ-9 and GAD-7 in 16 patients (8.7%) and 27 (14.8%) patients, respectively, were beyond 10.0, which indicated clinical depression and anxiety. Additionally, 19 (10.4%) patients reported poor ability to work, and 31(16.9%) patients had significant body image concerns. Compared to other clinicopathological characteristics, LR (LR vs. RR: PHQ-9 score, P=0.018; WAI average score, P=0.010; EORTC QLQ-C30, nine subdomains, P<0.05; GSRS average score, P=0.006) and MIS (MIS vs. open surgery: EORTC QLQ-C30, three subdomains, P<0.05; GSRS average score, P=0.006) were the most significant factors predicting improved GIF and reduced mental stress. Conclusions: This study systematically presents postoperative GIF and mental stress of SPN patients using validated multiquestionnaires for the first time. It provides solid evidence that LR and MIS can improve GIF and reduce mental stress after surgery for SPN patients, which could be helpful for the surgeons to make more personalized surgical plans for their patients. [ABSTRACT FROM AUTHOR]

Objective: To present comprehensive information on the clinicopathological, molecular, survival characteristics, and quality of life (QOL) after surgery for solid pseudopapillary neoplasm (SPN) of the pancreas in a large cohort after long-term follow-up. Background: SPN is a rare tumor with an uncertain malignant potential, and solid information on long-term prognosis and QOL remains limited. Methods: All hospitalized patients with SPNs who underwent surgery between 2001 and 2021 at the Peking Union Medical College Hospital were retrospectively reviewed. The clinicopathological characteristics of the patients were retrieved. A cross-sectional telephone questionnaire was administered to inquire about the QOL. Molecular analyses were performed using whole-exome sequencing. Results: Exactly 454 patients with SPNwere enrolled, of whom 18.5%were males and 81.5%were females. The mean patient age was 31 ± 12 years. In total, 61.3% of the patients had no symptoms. The size of the tumors was 5.38 ± 3.70 cm; 83.4% were solid cystic tumors, and 40.1% had calcifi- cations. The proportions of local resection, distal pancreatectomy with or without splenectomy, and pancreaticoduodenectomy with or without pylorus preservation were 29.7%, 28.9% or 22.9%, and 11% or 6.8%, respectively. Over the years, there has been a significant shift from open to minimally invasive surgery. Among all surgical procedures, pylorus-preserving pancreaticoduodenectomy (PPPD) had the highest incidence of grade 2 to 4 complications (up to 32.3%), compared with 6.7% in distal pancreatectomy (P < 0.001). Regarding histopathology, tissue invasion, perineural invasion, cancerous microvascular emboli, lymph node metastasis, and distant metastasis were present in 16.5%, 2.2%, 0.7%, 2.0%, and 3.1% of patients, respectively. Sixty patients were lost to follow-up. Sixteen of the 390 patients who underwent resection (4.1%) experienced local recurrence or distant metastasis after surgery. In total, 361 patients responded to the telephone survey. Nearly 80% of patients claimed their QOL was not significantly affected after surgery; however, the remaining 20% complained of lower QOL during 3 to 6 years of follow-up after surgery. No clinicopathological factor could reliably predict clinical recurrence or metastasis after resection. A total of 28 driver genes were detected with mutations in at least 2 tumor samples and the top 3 frequently mutated genes were CTNNB1, ATRNL1, and MUC16. Conclusions: This study presented the largest cohort of patients with SPN after surgery from a single center and reported the QOL of these patients. SPN is associated with extremely favorable long-term survival, even in patients with metastasis, and most patients have a good QOL after surgery. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but its clinical benefit is limited in advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) have been reported to be associated with ICB resistance, but the underlying mechanism has not been fully elucidated. Our previous single-cell RNA-seq analysis of GC revealed that POSTN+FAP+ extracellular matrix CAFs (eCAFs) communicate with macrophages. Here, we evaluated the correlation between eCAFs and ICB response in TCGA-STAD and real-world cohorts. Immune infiltration analysis and correlation analysis were performed to assess the relationship between eCAFs and macrophages. We first confirmed a negative correlation between the abundance of eCAFs and the overall response rate (ORR) to anti-PD-1 treatment in TCGA-STAD and real-world GC cohorts. Overexpression of POSTN in CAFs enhanced macrophage chemotaxis, while POSTN interference showed the opposite effect in vitro and in vivo. Furthermore, the cell density of POSTN+ CAFs was positively correlated with the infiltration level of CD163+ macrophages in GC patient tissues. The results demonstrated that POSTN secreted by CAFs enhances macrophage chemotaxis by activating the Akt signaling pathway in macrophages. Additionally, we found that POSTN+FAP+ eCAFs may exist in multiple solid tumors and are associated with ICB resistance. eCAFs promote macrophage chemotaxis through the secretion of POSTN, thereby leading to ICB resistance. High expression of POSTN is likely to predict a poor response to ICB. POSTN downregulation may be considered as a candidate therapeutic strategy to improve ICB efficacy. [ABSTRACT FROM AUTHOR]

Background: Postoperative intra-abdominal infection (PIAI) is one of the most serious complications of abdominal surgery, increasing the risk of postoperative morbidity and mortality and prolonging hospital stay. Rapid diagnosis of PIAI is of great clinical value. Unfortunately, the current diagnostic methods of PIAI are not fast and accurate enough. Methods: The authors performed an exploratory study to establish a rapid and accurate diagnostic method of PIAI. The authors explored the turnaround time and accuracy of metagenomic next-generation sequencing (mNGS) in diagnosing PIAI. Patients who underwent elective abdominal surgery and routine abdominal drainage with suspected PIAI were enroled in the study. The fresh midstream abdominal drainage fluid was collected for mNGS and culturing. Results: The authors found that the median sample-to-answer turnaround time of mNGS was dramatically decreased than that of culture-based methods (< 24 h vs. 59.5-111 h). The detection coverage of mNGS was much broader than culture-based methods. The authors found 26 species from 15 genera could only be detected by mNGS. The accuracy of mNGS was not inferior to culturebased methods in the 8 most common pathogens detected from abdominal drainage fluid (sensitivity ranged from 75 to 100%, specificity ranged from 83.3 to 100%, and kappa values were higher than 0.5). Moreover, the composition of the microbial spectrum established by mNGS varied between upper and lower gastrointestinal surgery, enhancing the understanding of PIAI pathogenesis. Conclusion: This study preliminarily revealed the clinical value of mNGS in the rapid diagnosis of PIAI and provided a rationale for further research. [ABSTRACT FROM AUTHOR]