Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice.

OBJECTIVE: Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice. DESIGN: A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models). RESULTS: The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process. CONCLUSION: One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.

Classification of PRSS1 variants responsible for chronic pancreatitis: An expert perspective from the Franco-Chinese GREPAN study group.

BACKGROUND: PRSS1 was the first reported chronic pancreatitis (CP) gene. The existence of both gain-of-function (GoF) and gain-of-proteotoxicity (GoP) pathological PRSS1 variants, together with the fact that PRSS1 variants have been identified in CP subtypes spanning the range from monogenic to multifactorial, has made the classification of PRSS1 variants very challenging. METHODS: All currently reported PRSS1 variants (derived primarily from two databases) were manually reviewed with respect to their clinical genetics, functional analysis and population allele frequency. They were classified by variant type and pathological mechanism within the framework of our recently proposed ACMG/AMP guidelines-based seven-category system. RESULTS: The total number of distinct germline PRSS1 variants included for analysis was 100, comprising 3 copy number variants (CNVs), 12 5' and 3' variants, 19 intronic variants, 5 nonsense variants, 1 frameshift deletion variant, 6 synonymous variants, 1 in-frame duplication, 3 gene conversions and 50 missense variants. Based upon a combination of clinical genetic and functional analysis, population data and in silico analysis, we classified 26 variants (all 3 CNVs, the in-frame duplication, all 3 gene conversions and 19 missense) as "pathogenic", 3 variants (missense) as "likely pathogenic", 5 variants (four missense and one promoter) as "predisposing", 13 variants (all missense) as "unknown significance", 2 variants (missense) as "likely benign", and all remaining 51 variants as "benign". CONCLUSIONS: We describe an expert classification of the 100 PRSS1 variants reported to date. The results have immediate implications for reclassifying many ClinVar-registered PRSS1 variants as well as providing optimal guidelines/standards for reporting PRSS1 variants.

A novel capsule endoscopy for upper and mid-GI tract: the UMGI capsule.

BACKGROUNDS AND AIMS: Complete and consecutive observation of the gastrointestinal (GI) tract continues to present challenges for current endoscopy systems. We developed a novel upper and mid gastrointestinal (UMGI) capsule endoscopy using the modified detachable string magnetically controlled capsule endoscopy (DS-MCE) and inspection method and aimed to assess the clinical application. METHODS: Patients were recruited to undergo UMGI capsule endoscopy followed by esophagogastroduodenoscopy. All capsule procedures in the upper gastrointestinal (UGI) tract were conducted under the control of magnet and string. The main outcome was technical success, and the secondary outcomes included visualization of the UMGI tract, examination time, diagnostic yield, compliance, and safety evaluation. RESULTS: Thirty patients were enrolled and all UMGI capsule procedures realized repeated observation of the esophagus and duodenum with detection rates of 100.0%, 80.0%, and 86.7% of Z-line, duodenal papilla, and reverse side of pylorus, respectively. String detachment was succeeded in 29 patients (96.7%) and the complete examination rate of UMGI tract was 95.45% (21/22). All UMGI capsule procedures were well tolerated with low discomfort score, and had a good diagnostic yield with per-lesion sensitivity of 96.2% in UGI diseases. No adverse events occurred. CONCLUSIONS: This new capsule endoscopy system provides an alternative screening modality for the UMGI tract, and might be indicated in cases of suspected upper and small bowel GI bleeding. Trial registration DS-MCE-UGI and SB, NCT04329468. Registered 27 March 2020, https://clinicaltrials.gov/ct2/results?cond=&term=NCT04329468 .

Translation and validation of a Chinese version of the pancreatitis quality of life instrument (PANQOLI) in patients with chronic pancreatitis.

PURPOSE: Chronic pancreatitis (CP) is a chronic fibroinflammatory pancreatic disease that severely impacts patients' quality of life (QoL). The Pancreatitis Quality of Life Instrument (PANQOLI) is an 18-item measure specifically designed to assess QoL amongst patients with CP. This study aimed to develop a Chinese version of PANQOLI and assess its reliability and validity in the Chinese CP cohort. METHODS: Translation was performed according to forward-backwards translation steps and transcultural adaptation. Five hundred Mandarin Chinese-speaking patients with CP were enrolled, 250 for the exploratory factor analysis (EFA) and 250 for the confirmatory factor analysis (CFA). Item analysis, reliability analysis (internal consistency, split-half reliability, test-retest reliability), and validity analysis (content validity, construct validity, and convergent validity) were performed. RESULTS: Item analysis of the Chinese version of PANQOLI revealed that the absolute t values of all items were > 3. Reliability analysis showed that Cronbach's α coefficient was 0.868, split-half coefficient was 0.934, and intraclass correlation coefficient was 0.859, demonstrating excellent reliability. For content validity, item level content validity index (I-CVI) ranged from 0.8 to 1.0, and average of I-CVI scores across all items (S-CVI/Ave) was 0.91. In construct validity analysis, EFA produced four dimensions after rotation, and results of CFA showed χ2/df = 2.346, comparative fit index (CFI) = 0.929, Tucker-Lewis index (TLI) = 0.915, and root-mean-square error of approximation (RMSEA) = 0.074. The analysis of convergent validity indicated that the Chinese version of PANQOLI was moderately correlated with the physical (r = 0.436, P < 0.001) and mental component summary (r = 0.518, P < 0.001) of the 36-Item Short Form Health Survey. CONCLUSION: The Chinese version of PANQOLI appears to be culturally appropriate, reliable, and valid for assessing the QoL amongst Chinese patients with CP.

Magnetically controlled capsule endoscopy in one-time gastro-small intestinal joint examination: a two-centre experience.

BACKGROUND: The lesions of certain diseases are widely distributed in both stomach and small intestine, while the step-by-step strategy of gastroscopy followed by enteroscopy can be burdensome and costly. We aimed to determine if magnetically controlled capsule endoscopy (MCE) could be used in one-time gastro-small intestine (GSI) joint examination. METHODS: In this study, data of patients in Chinese PLA General Hospital and Changhai Hospital who underwent MCE GSI examination from January 2020 to August 2021 were retrospectively analysed. The primary outcome of this study was the success rate of one-time GSI joint examination, and secondary outcomes included visualization and cleanliness of gastrointestinal tract, gastrointestinal transit times, diagnostic yield and safety of MCE examination. RESULTS: A total of 768 patients were included. The success rate of one-time GSI joint examination was 92.58%. There were 94.92% MCEs observed > 90% gastric mucosa in the 6 anatomic landmarks. The rate of complete small bowel examination was 97.40%. The median gastric examination time, gastric transit time and small intestine transit time were 8.18 min, 63.89 min and 4.89 h, respectively. Magnetic steering of MCE significantly decreased gastric transit time (8.92 min vs. 79.68 min, P = 0.001) and increased duodenal lesion detection rate (13.47% vs. 6.26%, P = 0.001) when compared with non-magnetic steering group. Two capsules were retained and were removed by enteroscopy or spontaneously excreted. CONCLUSIONS: MCE is feasible to complete GSI joint examination and the detection of both gastric and small intestinal diseases can be achieved simultaneously. Trial registration Clinical Trial Registration ClinicalTrials.gov, ID: NCT05069233.

Homozygosity of short VNTR lengths in the CEL gene may confer susceptibility to idiopathic chronic pancreatitis.

OBJECTIVE: The carboxyl-ester lipase (CEL) gene contains a variable number of tandem repeats (VNTR) region. It remains unclear whether the number of repeats in the CEL VNTR is related to the risk of pancreatic diseases. The aim of this study was to investigate whether CEL VNTR length is associated with idiopathic chronic pancreatitis (ICP), alcoholic chronic pancreatitis (ACP), or pancreatic cancer in a cohort of Chinese patients. METHODS: CEL VNTRs were genotyped in patients diagnosed with ICP (n = 771), ACP (n = 222), or pancreatic cancer (n = 263), and in healthy controls (n = 927). CEL VNTR lengths were determined using a screening method combining PCR and DNA fragment analysis. RESULTS: Overall, the CEL VNTR lengths ranged from 5 to 22 repeats, with the 16-repeat allele ('normal' size, N) accounting for 73.82% of all observed alleles. The VNTR allele frequencies and genotype distributions were not significantly different between healthy controls and patients with ACP or pancreatic cancer. For the ICP group, allele frequencies did not differ significantly from the controls, while the frequency of the SS genotype (homozygosity for 5-15 repeats) was significantly higher in the patients (4.67%) than in the controls (1.94%) (p = 0.0014; OR = 2.47; 95% CI = 1.39-4.39). CONCLUSIONS: There were no associations between the CEL VNTR length and ACP or pancreatic cancer. However, homozygosity for short VNTR lengths may confer susceptibility to ICP.

Use of artificial intelligence for detection of gastric lesions by magnetically controlled capsule endoscopy.

BACKGROUND AND AIMS: Magnetically controlled capsule endoscopy (MCE) has become an efficient diagnostic modality for gastric diseases. We developed a novel automatic gastric lesion detection system to assist in diagnosis and reduce inter-physician variations. This study aimed to evaluate the diagnostic capability of the computer-aided detection system for MCE images. METHODS: We developed a novel automatic gastric lesion detection system based on a convolutional neural network (CNN) and faster region-based convolutional neural network (RCNN). A total of 1,023,955 MCE images from 797 patients were used to train and test the system. These images were divided into 7 categories (erosion, polyp, ulcer, submucosal tumor, xanthoma, normal mucosa, and invalid images). The primary endpoint was the sensitivity of the system. RESULTS: The system detected gastric focal lesions with 96.2% sensitivity (95% confidence interval [CI], 95.7%-96.5%), 76.2% specificity (95% CI, 75.97%-76.3%), 16.0% positive predictive value (95% CI, 15.7%-16.3%), 99.7% negative predictive value (95% CI, 99.74%-99.79%), and 77.1% accuracy (95% CI, 76.9%-77.3%) (sensitivity was 99.3% for erosions; 96.5% for polyps; 89.3% for ulcers; 87.2% for submucosal tumors; 90.6% for xanthomas; 67.8% for normal; and 96.1% for invalid images). Analysis of the receiver operating characteristic curve showed that the area under the curve for all positive images was 0.84. Image processing time was 44 milliseconds per image for the system and 0.38 ± 0.29 seconds per image for clinicians (P < .001). The kappa value of 2 times repeated reads was 1. CONCLUSIONS: The CNN faster-RCNN-based diagnostic program system showed good performance in diagnosing gastric focal lesions in MCE images.

Prevalence and Risk Factors for Osteopathy in Chronic Pancreatitis.

BACKGROUND AND AIMS: The high incidence of osteopathy among patients with chronic pancreatitis (CP) has garnered increased attention over recent years. The aims of this study were to assess the prevalence and risk factors for osteopathy in Chinese patients with CP. METHODS: This was a cross-sectional study of CP patients from a large center in China; patients were recruited between 31 January 2017 and 31 January 2018. Bone density and laboratory tests, including bone-related biochemical, inflammatory, and hormone parameters, were assessed prospectively. Differences between patients with and without osteopathy were analyzed. Logistic regression analysis was used to investigate associations between variables. RESULTS: In total, 104 CP patients were enrolled in this study (68.3% idiopathic and 31.7% alcoholic). According to the M-ANNHEIM classification, 87.5% of the patients were at an early stage (0-II). Osteopenia was diagnosed in 30.8% of patients and osteoporosis in 5.8%; thus, a total of 36.5% of patients presented with osteopathy. In multivariate analysis, the independent risk factors for osteopathy in CP patients were age (OR = 1.04; 95% CI = 1.00-1.08; P = 0.030), BMI (OR = 0.72; 95% CI = 0.58-0.89; P = 0.003), and PTH (OR = 0.96; 95% CI = 0.93-1.00; P = 0.022). CONCLUSIONS: This study is the first to report the prevalence of osteopathy in Chinese patients with CP. It found that age and low BMI are significant risk factors for osteopathy. Low PTH (but within the normal range) showed a weak association with osteopathy, which warrants further exploration.

Farnesoid X receptor (FXR) inhibits coagulation process via inducing hepatic antithrombin III expression in mice.

Farnesoid X receptor (FXR) has been identified as an inhibitor of platelet function and an inducer of fibrinogen protein complex. However, the regulatory mechanism of FXR in hemostatic system remains incompletely understood. In this study, we aimed to investigate the functions of FXR in regulating antithrombin III (AT III). C57BL/6 mice and FXR knockout (FXR KO) mice were treated with or without GW4064 (30 mg/kg per day). FXR activation significantly prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), lowered activity of activated factor X (FXa) and concentrations of thrombin-antithrombin complex (TAT) and activated factor II (FIIa), and increased level of AT III, whereas all of these effects were markedly reversed in FXR KO mice. In vivo, hepatic AT III mRNA and protein expression levels were up-regulated in wild-type mice after FXR activation, but down-regulated in FXR KO mice. In vitro study showed that FXR activation induced, while FXR knockdown inhibited, AT III expression in mouse primary hepatocytes. The luciferase assay and ChIP assay revealed that FXR can bind to the promoter region of AT III gene where FXR activation increased AT III transcription. These results suggest FXR activation inhibits coagulation process via inducing hepatic AT III expression in mice. The present study reveals a new role of FXR in hemostatic homeostasis and indicates that FXR might act as a potential therapeutic target for diseases related to hypercoagulation.

TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population.

Chronic pancreatitis (CP) is a progressive fibroinflammatory syndrome of the pancreatic tissue caused by genetic and environmental factors. Previously reported susceptibility genes in CP explain less than half of the apparent heritability. To uncover novel pathogenic mechanisms, we initially performed low-coverage whole-genome sequencing on 464 Chinese CP patients and 504 controls. The transient receptor potential cation channel, Subfamily V, Member 6 (TRPV6) gene was found to be significantly associated with CP after a burden test of aggregated rare nonsynonymous variants with a combined annotation dependent depletion score > 20 (p = .020). In the replication stage, we analyzed the entire coding sequence and exon/intron boundaries of the TPRV6 gene by Sanger sequencing in another 205 patients with CP and 105 controls. Integration of the findings from the two stages resulted in the identification of 25 TRPV6 variants: 1 rare nonsense variant, 20 rare missense variants, and 4 common missense variants. Loss-of-function variants, as determined by intracellular Ca2+ concentration in transfected HEK293T cells, were significantly overrepresented in patients as compared to controls (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29; p = .022). This study provides evidence suggesting that TRPV6 is a novel susceptibility gene for CP.

Second-generation magnetically controlled capsule gastroscopy with improved image resolution and frame rate: a randomized controlled clinical trial (with video).

BACKGROUND AND AIMS: Compared with conventional endoscopy, magnetically controlled capsule gastroscopy (MCCG) can be further optimized in gastric examination time and complete visualization of upper GI (UGI) mucosa. The second-generation MCCG (MCCG-2) was developed with higher image resolution and adaptive frame rate, and we aimed to evaluate its clinical availability for UGI examination in this study. METHODS: Consecutive patients undergoing MCCG examination between May to June 2019 were prospectively enrolled and randomized to swallow the first-generation MCCG (MCCG-1) or MCCG-2 in a 1:1 ratio. The main outcomes included visualization of the esophagus and duodenum, operation-related parameters, image quality, maneuverability, detection of lesions, and safety evaluation. RESULTS: Eighty patients were enrolled. In the MCCG-2 group, frames captured for esophageal mucosa and Z-line were 171.00 and 2.00, significantly increased from those in the MCCG-1 group (97.00 [P = .002] and .00 [P = .028], respectively). The gastric examination time was shortened from 7.78 ± .97 minutes to 5.27 ± .74 minutes (P < .001), with the total running time of the capsule extended from 702.83 minutes to 1001.99 minutes (P < .001). MCCG-2 also greatly improved the image quality (P < .001) and maneuverability (P < .01). No statistical difference existed in the detection of lesions between the 2 groups, and no adverse events occurred. CONCLUSIONS: MCCG-2 showed better performance in mucosal visualization, examination duration, and maneuverability, making better diagnosis of UGI diseases a possibility. (Clinical trial registration number: NCT03977935.).

Adverse events of video capsule endoscopy over the past two decades: a systematic review and proportion meta-analysis.

BACKGROUND: A full spectrum of video capsule endoscopy (VCE) adverse events over the past two decades has not been evaluated. We aimed to determine pooled rates, predictors and temporal-trend of VCE adverse events over the past two decades. METHODS: Systematic search of PubMed and EMBASE for English-language publications reporting VCE adverse events (January 1, 2000 to March 31, 2019). Data were extracted independently by two investigators. Pooled VCE adverse event rates were calculated using the random or fixed model as appropriate. Predictors and temporal-trend of each adverse event were performed by meta-regression analyses. RESULTS: In total, 402 studies were identified, including 108,079 VCE procedures. Rate of retention, swallow disorder, aspiration, technical failure, and procedural adverse events were 0.73% (95% confidence interval [CI] 0.59-0.89%), 0.75% (95% CI 0.43-1.13%), 0.00% (95% CI 0.00-0.00%), 0.94% (95% CI 0.65-1.28%), 0.67% (95% CI 0.32-1.10%), respectively; incomplete examination rate of esophagus, stomach, small bowel, and colon were 9.05%, 7.69%, 12.08%, 19.19%, respectively. Patency capsule reduced retention rate by 5.04%, whereas known inflammatory bowel disease increased retention rate by 4.29%. Elder was the risk and protective factor for small bowel incomplete examination (0.30%) and swallow disorder (- 0.72%), respectively. Rates of retention and small bowel incomplete examination significantly declined over time (P = .0006 and P < .0001).. CONCLUSIONS: VCE adverse event rates were generally low, and retention and small bowel incomplete examination rates declined over the past two decades. Patients with known inflammatory bowel disease or elder should be alerted to high risk of retention or small bowel incomplete examination (PROSPERO: CRD42019139595).

[The immune microenvironment in maternal-fetal interface contributes to the parturition and preterm labor].

The maintenance of human pregnancy and the initiation of parturition are closely related with the dynamic balance of the maternal-fetal immune microenvironment. Implantation of the blastocyst into the maternal decidua is the first step in pregnancy establishment, which is favored by the abundant blood flow and the immunotolerant microenvironment maintained by the balance of immune cells. The parturition resembles an inflammatory response that includes secretion of cytokines by resident and infiltrating immune cells into reproductive tissues and the maternal-fetal interface, which promotes the delivery of fetus from maternal organism. Therefore, the immune microenvironment in maternal-fetal interface regulates the critical steps of pregnancy and parturition. When the maternal-fetal immune microenvironment is imbalanced or impaired, miscarriage or preterm labor would happen. This article reviews the roles and mechanisms of several important immune cells in the maternal-fetal interface during the parturition and preterm labor.

Repetitive Position Change Improves Gastric Cleanliness for Magnetically Controlled Capsule Gastroscopy.

BACKGROUND AND AIMS: Good gastric preparation is essential for magnetically controlled capsule gastroscopy (MCCG) examination. This study aims to determine if repetitive position change after dimethicone premedication could further improve gastric cleanliness for MCCG. METHODS: Consecutive patients referred for MCCG in our center from May 7 to May 31, 2018 were prospectively enrolled and randomized to undergo repetitive position change for 15 min (position change group) or not (conventional group) after ingesting dimethicone. Primary outcome was gastric cleanliness score and secondary outcomes were detection rate of positive findings, number of lesions per patient, gastric examination time, and safety of MCCG. RESULTS: Totals of 43 and 40 were included in the position change and conventional groups, respectively. Gastric cleanliness score in the position change group was significantly higher than in the conventional group (21.2 ± 1.0 vs. 18.6 ± 2.0, P  < 0.001), as was the proportion of acceptable gastric cleanliness (gastric cleanliness score ≥ 18) (100% vs. 72.5%, P  < 0.001). There was no statistical difference in detection rate of positive findings between the two groups (27.9% vs. 27.5%, P  = 0.97). In the position change group, the gastric examination time was significantly reduced (13.2 ± 4.0 vs. 15.3 ± 5.1, P = 0.043). No adverse events were observed. CONCLUSIONS: Repetitive position change after dimethicone premedication significantly improves gastric cleanliness for MCCG examination. Clinical Trial Registration ClinicalTrials.gov, ID: NCT03514966.

Anti-hepatitis C virus seropositivity is not associated with metabolic syndrome irrespective of age, gender and fibrosis.

Although many studies have tried to clarify the association between hepatitis C virus (HCV) infection and metabolic syndrome, few studies have comprehensively assessed their relationship stratified by different demographic characteristics. We aimed to investigate the correlation between metabolic syndrome and anti-HCV seropositivity in Taiwan. This study enrolled consecutive subjects who had received health check-up services at Taipei Veterans General Hospital from 2002 to 2009. Metabolic syndrome was diagnosed according to the criteria defined by the International Diabetes Federation Task Force on Epidemiology and Prevention. Among the 30616 subjects enrolled in this study, the prevalence of positive anti-HCV serology was 2.7%, and 28.8% were diagnosed with metabolic syndrome. By multivariate analysis, metabolic syndrome was associated with higher body mass index, older age, male sex, a higher level of alanine aminotransferase, gamma-glutamyltransferase, platelet count and the presence of fatty liver whereas anti-HCV seropositivity was not an independent variable for metabolic syndrome. Further stratifying the subjects by age and sex, and there was still no significant difference in HCV status between those with and without metabolic syndrome. Moreover, the stage of liver fibrosis represented by aspartate aminotransferase to platelet ratio index was also not correlated with metabolic syndrome in the subjects with anti-HCV seropositivity. In conclusion, although subjects with anti-HCV seropositivity had higher fasting glucose levels and lower cholesterol and triglyceride levels compared to those with negative anti-HCV test, anti-HCV seropositivity was not associated with metabolic syndrome based on the current diagnostic criteria irrespective of age, gender and the stage of hepatic fibrosis.

Genetic Factors Associated With Adverse Pregnancy Outcomes in Chronic Pancreatitis.

INTRODUCTION: The effects of genetic factors on pregnancy outcomes in chronic pancreatitis (CP) patients remain unclear. We evaluated the impacts of clinical features and mutations in main CP-susceptibility genes ( SPINK1 , PRSS1 , CTRC , and CFTR ) on pregnancy outcomes in Chinese CP patients. METHODS: This was a prospective cohort study with 14-year follow-up. The sample comprised female CP patients with documented pregnancy and known genetic backgrounds. Adverse pregnancy outcomes were compared between patients with and without gene mutations. Univariate and multivariate analyses were performed to determine the impact factors for adverse pregnancy outcomes. RESULTS: Totally, 160 female CP patients with a pregnancy history were enrolled; 59.4% of patients carried pathogenic mutations in CP-susceptibility genes. Adverse pregnancy outcomes occurred in 38 patients (23.8%); the prevalence of adverse outcomes was significantly higher in those harboring gene mutations than those without (30.5% vs 13.8%, P = 0.015). Notably, the rates of preterm delivery (12.6% vs 3.1%, P = 0.036) and abortion (17.9% vs 4.6%, P = 0.013) were remarkably higher in patients with gene mutations (especially SPINK1 mutations) than those without. In multivariate analyses, both CP-susceptibility gene mutations (odds ratio, 2.52; P = 0.033) and SPINK1 mutations (odds ratio, 2.60; P = 0.037) significantly increased the risk of adverse pregnancy outcomes. Acute pain attack during pregnancy was another risk factor for adverse pregnancy outcomes. DISCUSSION: Pathogenic mutations in CP-susceptibility genes, especially SPINK1 , were independently related to adverse pregnancy outcomes in CP patients. Significant attention should be paid to pregnant females harboring CP-susceptibility gene mutations (ClinicalTrials.gov: NCT06055595).

Effects of exercise by type and duration on quality of life in patients with digestive system cancers: A systematic review and network meta-analysis.

BACKGROUND: There is scant evidence regarding the effects of exercise type and duration on quality of life (QoL) in digestive system cancer (DSC) survivors. We aim to investigate the optimal type and duration of exercise to improve QoL for DSC survivors through a systematic review and network meta-analysis. METHODS: A systematic literature search of PubMed, Embase, and Web of Science was performed. Eligibility for study inclusion was limited to studies that were randomized controlled trials involving all kinds of exercise in adult patients with DSCs, and the comparator was in standard care or other types of exercise. The primary outcome was QoL, including general health, physical health, mental health, and role function. Secondary outcomes included cancer-related symptoms such as fatigue, insomnia, depression, anxiety, and duration of hospital stay. The network meta-analyses were performed using a random-effect model. RESULTS: The analysis included 32 eligible articles and a total of 2558 participants. Our primary outcome indicated that short-term aerobic exercise significantly enhanced general health (standardized mean difference (SMD) = 0.66, 95% credible intervals (CrIs): 0.05 to 1.30), and also contributed to a better mental health (SMD = 0.38, 95%CrI: -0.05 to 0.81) and role function (SMD = 0.48, 95%CrI: -0.27 to 1.20). Although without significant changes, short-term resistance exercise tended to increase the physical health of patients with DSCs (SMD = 0.69, 95%CrI: -0.07 to 1.50) and effective in alleviating fatigue (SMD = -0.77, 95%CrI: -1.50 to 0.01). Short-term aerobic exercise was related to a lower score of insomnia (SMD = -1.20, 95%CrI: -2.40 to 0.06), depression (SMD = -0.51, 95%CrI: -1.50 to 0.45), and anxiety (SMD = -0.45, 95%CrI: -1.30 to 0.34). All types of exercise related to a trend of declined hospital stays (-0.87 to -5.00 day). Long-term resistance exercise, however, was negatively associated with general health (SMD = -0.33, 95%CrI: -1.70 to 1.00), physical health (SMD = -0.18, 95%CrI: -1.30 to 0.90), and role function (SMD = -1.20, 95%CrI: -2.50 to 0.11). CONCLUSION: This study suggests that short-term aerobic exercise, with or without resistance exercise programs, enhances QoL (especially for general health) as well as relieves cancer-related symptoms for DSC survivors, while long-term resistance exercise may have negative effects, and thus should be adopted cautiously. These results provide important evidence for the management of DSCs.

Increased severity of complications after therapeutic ERCP in geriatric patients with chronic pancreatitis: An observational study.

Studies of therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in geriatric patients have mainly examined patients with biliary diseases, rather than chronic pancreatitis (CP). This study aimed to evaluate the safety and success rate of therapeutic ERCP in geriatric patients with CP. The medical records of patients with CP aged over 65 years (group A) were retrospectively collected in a tertiary hospital from January 2013 to December 2018. Sex-matched CP patients under 65 years (group B) were randomly selected into the control group (matching ratio = 1:2). The success rate and the complication rate of therapeutic ERCP in 2 groups were compared. The risk factors for post-ERCP pancreatitis were investigated by univariate and multivariate analyses. A total of 268 ERCPs were performed in 179 patients of group A and 612 ERCPs in 358 patients of group B. The success rate of ERCP in group A was similar to that of group B (92.16% vs 92.32%; P = .936). The overall incidence of post-ERCP complications was 7.09% (19/268) and 5.72% (35/612) in group A and B, respectively (P = .436). However, geriatric patients had a significantly increased occurrence of moderate to severe complications (2.61% vs 0.16%; P = .002). Female gender (odds ratio [OR] = 3.40; P = .046), pancreas divisum (OR = 7.15; P = .049), dorsal pancreatogram (OR = 7.40; P = .010), and lithotripsy (OR = 0.15; P = .016) were significantly associated with risk of post-ERCP pancreatitis in geriatric patients. Therapeutic ERCP is safe and feasible in elderly patients with CP. However, occurrence of moderate to severe complications after ERCP increased in geriatric patients.

The CEL-HYB1 Hybrid Allele Promotes Digestive Enzyme Misfolding and Pancreatitis in Mice.

BACKGROUND & AIMS: A hybrid allele that originated from homologous recombination between CEL and its pseudogene (CELP), CEL-HYB1 increases the risk of chronic pancreatitis (CP). Although suggested to cause digestive enzyme misfolding, definitive in vivo evidence for this postulate has been lacking. METHODS: CRISPR-Cas9 was used to generate humanized mice harboring the CEL-HYB1 allele on a C57BL/6J background. Humanized CEL mice and C57BL/6J mice were used as controls. Pancreata were collected and analyzed by histology, immunohistochemistry, immunoblotting, and transcriptomics. Isolated pancreatic acini were cultured in vitro to measure the secretion and aggregation of CEL-HYB1 protein. Mice were given caerulein injections to induce acute pancreatitis (AP) and CP. RESULTS: Pancreata from mice expressing CEL-HYB1 developed pathological features characteristic of focal pancreatitis that included acinar atrophy and vacuolization, inflammatory infiltrates, and fibrosis in a time-dependent manner. CEL-HYB1 expression in pancreatic acini led to decreased secretion and increased intracellular aggregation and triggered endoplasmic reticulum stress compared with CEL. The autophagy levels of pancreata from mice expressing CEL-HYB1 changed at different developmental stages; some aged CEL-HYB1 mice exhibited an accumulation of large autophagic vesicles and impaired autophagy in acinar cells. Administration of caerulein increased the severity of AP/CP in mice expressing CEL-HYB1 compared with control mice, accompanied by higher levels of endoplasmic reticulum stress. CONCLUSIONS: Expression of a humanized form of CEL-HYB1 in mice promotes endoplasmic reticulum stress and pancreatitis through a misfolding-dependent pathway. Impaired autophagy appears to be involved in the pancreatic injury in aged CEL-HYB1 mice. These mice have the potential to be used as a model to identify therapeutic targets for CP.