Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.

Gasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation.

Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.

Dynamic Acoustic Beamshaping with Coupling-Immune Moiré Metasurfaces.

Moiré effects arising from mutually twisted metasurfaces have showcased remarkable wave manipulation capabilities, unveiling tantalizing emerging phenomena such as acoustic moiré flat bands and topological phase transitions. However, the pursuit of strong near-field coupling in layers has necessitated acoustic moiré metasurfaces to be tightly stacked at narrow distances in the subwavelength range. Here, moiré effects beyond near-field interlayer coupling in acoustics are reported and the concept of coupling-immune moiré metasurfaces is proposed. Remote acoustic moiré effects decoupled from the interlayer distance are theoretically, numerically, and experimentally demonstrated. Tunable out-of-plane acoustic beam scanning is successfully achieved by dynamically controlling twist angles. The engineered coupling-immune properties are further extended to multilayered acoustic moiré metasurfaces and manipulation of acoustic vortices. Good robustness against external disturbances is also observed for the fabricated coupling-immune acoustic moiré metasurfaces. The presented work unlocks the potential of twisted moiré devices for out-of-plane acoustic beam shaping, enabling practical applications in remote dynamic detection, and multiplexed underwater acoustic communication.

Diffuse arterial atherosclerosis presenting with acute ischemic gastritis: A case report.

BACKGROUND: Ischemic gastritis is a clinically rare disease with high mortality that infrequently reported in the medical literature and under-recognized clinically and histopathologically. Early diagnosis and treatment can only be achieved through upper gastrointestinal endoscopy after symptoms appear. CASE SUMMARY: A 68-year-old woman with a history of intracranial aneurysm developed dizziness, chest tightness and unconsciousness for 2 d. Computed tomography angiography showed diffuse coronary atherosclerosis, moderate to severe stenosis in the proximal end of the left anterior descending branch, multiple calcified plaques in the proximal end of the circumflex branch and right coronary artery, and mild to moderate stenosis. The patient also developed diffuse atherosclerosis in the splenic and mesenteric arteries, with mild lumen stenosis and atherosclerosis in the abdominal aorta and its branches. Endoscopy showed submucosal congestion and damage of the entire gastric mucosa, of which the fundus and body of the stomach were most seriously affected. The mucosa was swollen, with a deep purple color, surface erosion and dark red oozing blood. Pathological examination showed bleeding and necrosis of the gastric mucosa, with residual contours of the gastric glands, consistent with ischemic gastritis. CONCLUSION: Ischemic gastritis is a rare disease that may be difficult to diagnose as its symptoms may be similar to those of other gastrointestinal diseases. Diagnosis is usually based on endoscopic and pathological examinations, which show insufficient blood supply to the gastric mucosa leading to mucosal damage and necrosis.

Central and peripheral analgesic active components of triterpenoid saponins from Stauntonia chinensis and their action mechanism.

Triterpenoid saponins from Stauntonia chinensis have been proven to be a potential candidate for inflammatory pain relief. Our pharmacological studies confirmed that the analgesic role of triterpenoid saponins from S. chinensis occurred via a particular increase in the inhibitory synaptic response in the cortex at resting state and the modulation of the capsaicin receptor. However, its analgesic active components and whether its analgesic mechanism are limited to this are not clear. In order to further determine its active components and analgesic mechanism, we used the patch clamp technique to screen the chemical components that can increase inhibitory synaptic response and antagonize transient receptor potential vanilloid 1, and then used in vivo animal experiments to evaluate the analgesic effect of the selected chemical components. Finally, we used the patch clamp technique and molecular biology technology to study the analgesic mechanism of the selected chemical components. The results showed that triterpenoid saponins from S. chinensis could enhance the inhibitory synaptic effect and antagonize the transient receptor potential vanilloid 1 through different chemical components, and produce central and peripheral analgesic effects. The above results fully reflect that "traditional Chinese medicine has multi-component, multi-target, and multi-channel synergistic regulation".

The Impact of Physical Activity Intensity on the Dynamic Progression of Cardiometabolic Multimorbidity: Prospective Cohort Study Using UK Biobank Data.

BACKGROUND: Although many studies have reported on the associations between the amount of physical activity (PA) and the transitions of cardiometabolic multimorbidity (CMM), the evidence for PA intensity has not been fully evaluated. OBJECTIVE: This study aimed to explore the impact of PA intensity on the dynamic progression of CMM. METHODS: The prospective cohort of this study using data from the UK Biobank included 359,773 participants aged 37-73 years who were recruited from 22 centers between 2006 and 2010. The diagnoses of CMM, which included the copresence of type 2 diabetes (T2D), ischemic heart disease, and stroke, were obtained from first occurrence fields provided by the UK Biobank, which included data from primary care, hospital inpatient record, self-reported medical condition, and death registers. The PA intensity was assessed by the proportion of vigorous PA (VPA) to moderate to vigorous PA (MVPA). Multistate models were used to evaluate the effect of PA intensity on the dynamic progression of CMM. The first model (model A) included 5 transitions, namely free of cardiometabolic disease (CMD) to first occurrence of CMD (FCMD), free of CMD to death, FCMD to CMM, FCMD to mortality, and CMM to mortality. The other model (model B) used specific CMD, namely T2D, ischemic heart disease, and stroke, instead of FCMD and included 11 transitions in this study. RESULTS: The mean age of the included participants (N=359,773) was 55.82 (SD 8.12) years at baseline, and 54.55% (196,271/359,773) of the participants were female. Compared with the participants with no VPA, participants with intensity levels of >0.75 to <1 for VPA to MVPA had a 13% and 27% lower risk of transition from free of CMD to FCMD (hazard ratio [HR] 0.87, 95% CI 0.83-0.91) and mortality (HR 0.73, 95% CI 0.66-0.79) in model A, respectively. The HR for the participants with no moderate PA was 0.82 (95% CI 0.73-0.92) compared with no VPA. There was a substantially protective effect of higher PA intensity on the transitions from free of CMD to T2D and from T2D to mortality, which reveals the importance of PA intensity for the transitions of T2D. More PA and greater intensity had a synergistic effect on decreasing the risk of the transitions from free of CMD to FCMD and mortality. Male participants, younger adults, adults with a higher BMI, current or previous smokers, and excessive alcohol drinkers could obtain more benefits from higher PA intensity for the lower risk of at least 1 transition from free of CMD, then to CMM, and finally to mortality. CONCLUSIONS: This study suggests that higher PA intensity is an effective measure for preventing CMM and mortality in the early period of CMM development. Relevant interventions related to higher PA intensity should be conducted.

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 .

The associations between DNA methylation and depression: A systematic review and meta-analysis.

BACKGROUND: Growing evidence suggests that epigenetic modification is vital in biological processes of depression. Findings from studies exploring the associations between DNA methylation and depression have been inconsistent. METHODS: A systematical search of EMBASE, PubMed, Web of Science, and PsycINFO databases was conducted to include studies focusing on the associations between DNA methylation and depression (up to November 1st 2021) according to PRISMA guidelines with registration in PROSPERO (CRD42021288664). RESULTS: A total of 47 studies met inclusion criteria and 31 studies were included in the meta-analysis. This meta-analysis found that genes hypermethylation, including BDNF (OR: 1.15, 95%CI: 1.01-1.32, I2 = 90 %), and NR3C1 (OR: 1.43, 95%CI: 1.09-1.87, I2 = 88 %) was associated with increased risk of depression. Significant association of SLC6A4 hypermethylation with depression was only found in the subgroup of using original data (OR: 1.09, 95%CI: 1.01-1.19, I2 = 52 %). BDNF hypermethylation could increase the risk of depression only in the Asian population (OR: 1.18, 95%CI: 1.01-1.40, I2 = 91 %), and significant associations of NR3C1 hypermethylation with depression were found in the group for depressive symptoms (OR: 1.34, 95%CI: 1.08-1.67, I2 = 85 %), but not for depressive disorder (OR: 1.89, 95%CI: 0.54-6.55, I2 = 94 %). LIMITATIONS: More studies are needed to explore the factors that might influence the estimates owing to the contextual heterogeneity of the pooling of included studies. CONCLUSIONS: It is noted that DNA hypermethylation, namely BDNF and NR3C1, is associated with increased risk of depression. The findings in this study could provide some material evidence for preventing and diagnosing of depression.

Proteomics profiling of ertapenem challenged major porin deficient carbapenem-resistant Klebsiella pneumoniae.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an urgent threat to human health. Major outer membrane proteins (OMPs) porin mutation is one important resistance mechanism of CRKP, and may also affect the inhibition activity of ß-lactam and ß-lactamase inhibitor combinations. The ertapenem-resistant K. pneumoniae strain 2018B120 with major porin mutations was isolated from a clinical patient. Genomic and time-series proteomic analyses were conducted to retrieve the ertapenem-challenged response of 2018B120. The abundance changing of proteins from PTS systems,  ABC transporters, the autoinducer 2 (AI-2) quorum sensing system, and antioxidant systems can be observed. Overexpression of alternative porins was also noticed to balance major porins' defection. These findings added a detailed regulation network in bacterial resistance mechanisms and gave new insights into bypass adaptation mechanisms the porin deficient bacteria adopted under carbapenem antibiotics pressure. SIGNIFICANCE: Outer membrane porins deficiency is an important mechanism of carbapenem resistance in K. pneumoniae. Comprehensive genomic and proteomic profiling of an ertapenem-resistant K. pneumoniae strain 2018B120 gives a detailed systematic regulation network in bacterial resistance mechanisms. Overexpression of alternative porins to balance major porins' defection was noticed, giving new insights into bypass adaptation mechanisms of porin deficient bacteria.

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.

Ancillary ligand-regulated Ti(IV)-based metallocalixarene coordination cages for photocatalytic H2 evolution.

High-valence Ti(IV)-based metallocalixarene coordination cages that are linked by oriented ancillary ligands are unknown so far. Herein, the first family of tunable calixarene-based coordination cages of Ti(IV) with a framework formula [Ti12(OiPr)12(TBC[4])6L6] have been assembled from six {Ti2(OiPr)2(TBC[4])}2+ nodes and six pyridinedicarboxylic ligands. Furthermore, the {Ti12L6} cage showed strong photocatalytic H2 evolution activity, and DFT studies were performed to explore its electronic structure.

Efficacy and safety of vibrating capsule for functional constipation (VICONS): A randomised, double-blind, placebo-controlled, multicenter trial.

Background: Functional constipation (FC) is an intractable disease that carries large financial burden as well as emotional and physical stress. We aimed to assess the efficacy and safety of the newly developed smartphone-controlled vibrating capsule (VC) in patients with FC. Methods: From December 2018 to February 2020, we did a multicenter, blinded, placebo-controlled randomised trial in six top general hospitals in China focusing on patients aged 18 to 80 with FC. Patients were randomly assigned in a 1:1 ratio to receive VCs or placebo treatment for six weeks (two capsules per week) after a two-week baseline period. The primary outcome was the responder rate, defined as the proportion of patients with an increase of at least one complete spontaneous bowel movement (CSBM) per week during treatment compared to baseline in the full analysis set. This trial is registered with ClinicalTrials.gov, number NCT04671264, and is completed. Findings: 107 patients aged from 18 to 74 were randomly assigned to receive VC (n = 53) or placebo treatment (n = 54). The responder rate in the VC group was significantly higher than that in the placebo group (64·2% vs. 35·8%; difference, 27·7% [95% CI, 10·4-45·1]; P = 0·005). More patients in the VC group reported weekly CSBMs ≥ 1 for at least four weeks during treatment (difference, 22·7% [95% CI, 8-46]; P = 0·022) and follow-up period (difference, 17.3% [95% CI, 0-35]; P = 0·048). The mean Patient Assessment of Constipation-Symptoms score and Patient Assessment of Constipation-Quality of Life score differed significantly from the baseline in both groups (all P < 0·0001). The most common adverse event associated with VC was abdominal discomfort (3·7%). Interpretation: VCs can promote defecation, as well as ameliorating symptoms and improving the quality of life in patients with FC with sustained efficacy. VC appears to be a potential alternative physical treatment for FC with the exact mechanism and parameters warranting further investigation. Funding: The study was supported by "One hundred leading scientists for 21st century" of Health Department of Shanghai Municipal Government (to ZL, No.2017BR005).

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.

Pan-Genome Analysis of Laribacter hongkongensis: Virulence Gene Profiles, Carbohydrate-Active Enzyme Prediction, and Antimicrobial Resistance Characterization.

Laribacter hongkongensis is a new emerging foodborne pathogen that causes community-acquired gastroenteritis and traveler's diarrhea. However, the genetic features of L. hongkongensis have not yet been properly understood. A total of 45 aquatic animal-associated L. hongkongensis strains isolated from intestinal specimens of frogs and grass carps were subjected to whole-genome sequencing (WGS), along with the genome data of 4 reported human clinical strains, the analysis of virulence genes, carbohydrate-active enzymes, and antimicrobial resistance (AMR) determinants were carried out for comprehensively understanding of this new foodborne pathogen. Human clinical strains were genetically more related to some strains from frogs inferred from phylogenetic trees. The distribution of virulence genes and carbohydrate-active enzymes exhibited different patterns among strains of different sources, reflecting their adaption to different host environments and indicating different potentials to infect humans. Thirty-two AMR genes were detected, susceptibility to 18 clinical used antibiotics including aminoglycoside, chloramphenicol, trimethoprim, and sulfa was checked to evaluate the availability of clinical medicines. Resistance to Rifampicin, Cefazolin, ceftazidime, Ampicillin, and ceftriaxone is prevalent in most strains, resistance to tetracycline, trimethoprim-sulfamethoxazole, ciprofloxacin, and levofloxacin are aggregated in nearly half of frog-derived strains, suggesting that drug resistance of frog-derived strains is more serious, and clinical treatment for L. hongkongensis infection should be more cautious.

Erratum: Noncontact magnetically controlled capsule endoscopy for infection-free gastric examination during the COVID-19 pandemic: a pilot, open-label, randomized trial.

[This corrects the article DOI: 10.1055/a-1648-2238.].

Noncontact magnetically controlled capsule endoscopy for infection-free gastric examination during the COVID-19 pandemic: a pilot, open-label, randomized trial.

Background and study aims Endoscopists have been at increased risk because of their direct contact with patients during the COVID-19 pandemic. For patients, being diagnosed with and monitored for gastrointestinal cancer and digestive diseases in timely fashion has been challenging, given pandemic-related adjustments in endoscopy departments. We developed a novel noncontact magnetically controlled capsule endoscopy (ncMCE) system in our medical center. In the current study, we aimed to evaluate the feasibility and safety of ncMCE for gastric examination. Patients and methods Patients were randomly assigned to groups that received ncMCE or MCE in a 1:1 ratio from March 26, 2020 to April 26, 2020. Primary endpoints were feasibility assessed by completion rate (CR) and safety based on the occurrence of adverse events (AEs) including infection. Secondary endpoints included maneuverability of endoscopists, pre-procedure perception and post-procedure satisfaction of patients, gastric examination time (GET), and diagnostic yield (DY). Results Forty patients were enrolled with 100 % CR in both groups without any AEs. Neither the endoscopist nor the patients were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 14 days after gastric examination. There were no significant differences in maneuverability (19.3 vs. 20.0, P  = 0.179), pre-procedure perception (9 vs. 9, P  = 0.626) and post-procedure satisfaction (45 vs. 44, P =  0.999), ord DY (20 % vs. 30 %, P  = 0.465). Conclusions ncMCE is a feasible and safe method of gastric examination, which has the potential to protect both medical staff and patients from COVID-19 infection while providing serving as an essential endoscopy service.

The Impacts of Genetic and Environmental Factors on the Progression of Chronic Pancreatitis.

BACKGROUND & AIMS: Both environmental factors, such as alcohol consumption and smoking, and genetic factors are strongly associated with the risk of developing chronic pancreatitis (CP). However, comprehensive understanding of their impacts on the progression of CP remains elusive. METHODS: A prospective cohort study was performed on a large cohort of CP patients with known genetic backgrounds. The cumulative incidence of pancreatic insufficiency after the onset of CP was analyzed using Kaplan-Meier survival curves. Multivariate Cox proportional hazards regression analysis also was performed. RESULTS: A total of 798 patients were enrolled in the study and followed up for 10.5 years. Rare pathogenic genotypes in the SPINK1, PRSS1, CTRC, or CFTR genes were identified in 410 (51.4%) patients. The development of pancreatic insufficiency was significantly earlier in patients with a history of smoking and/or alcohol consumption in both the positive (P < .001) and negative (P = .001) gene mutation groups. However, the development of pancreatic insufficiency did not differ significantly between patients with and without gene mutations despite alcohol and/or smoking status, with P values of .064 and .115, respectively. Multivariate Cox regression analysis showed that age at onset of CP (hazard ratio, [HR], 1.02; P < .001) and alcohol consumption (HR, 1.86; P < .001) were independent risk factors for the development of diabetes, while male sex (HR, 1.84; P = .022) and smoking (HR, 1.56; P = .028) were predictors of steatorrhea. CONCLUSIONS: Although rare pathogenic mutations in the 4 major susceptibility genes for CP were not correlated significantly with the development of pancreatic insufficiency, environmental factors (either alcohol consumption or smoking) significantly accelerated disease progression (ClinicalTrials.gov: NCT04574297).

Post-ESWL and post-ERCP pancreatitis in patients with chronic pancreatitis: Do they share the same risks?

BACKGROUND: Endoscopic intervention combined with extracorporeal shock wave lithotripsy (ESWL) is recommended as the first line therapy for large pancreatic stones, yet both can cause adverse events. The aim of the study was to identify the risk factors for post-procedural pancreatitis. METHODS: Consecutive patients with chronic pancreatitis and pancreatic stones treated with both ESWL and subsequent endoscopic retrograde cholangiopancreatography (ERCP) from October 2016 to December 2019 were prospectively enrolled. Multivariate logistic analyses were performed to detect risk factors for post-ESWL and post-ERCP pancreatitis (PEP). RESULTS: A total of 714 patients (507 males, 45.60 ± 12.52 years) were included in this study. A total of 80 patients (11.2%) developed post-ESWL pancreatitis,while 33 patients (4.6%) suffered from PEP. Steatorrhea (P = .018), multiple stones (P = .043), and stones located at the head combined with the body or tail of the pancreas (P = .015) were identified as independent protective factors for post-ESWL pancreatitis. The history of acute exacerbations (P = .013), post-ESWL pancreatitis (P < .001) and stricture dilation during ERCP (P = .002) were identified as risk factors for PEP. CONCLUSIONS: More attention should be paid to patients with post-ESWL pancreatitis, as well as a history of acute exacerbations and stricture dilation during ERCP to prevent PEP. (ClincialTrials.gov number, NCT04619511).

SPINK1 mutations and risk of pancreatic cancer in a Chinese cohort.

OBJECTIVE: The relationship between SPINK1 and pancreatic cancer (PC) remains controversial. The current study aimed to determine the effect of SPINK1 mutations on PC development among patients with chronic pancreatitis (CP). METHODS: This is a prospective observational study including a large cohort of 965 CP patients with 11-year follow-up. Patients' demographic characteristics and clinical CP outcomes were documented in detail. Genetic testing was performed. The effect of SPINK1 mutations on the clinical development of PC was explored using Cox proportional hazards regression. Subgroup analyses conducted included the consideration of gender, onset age of CP (early- and late-onset), etiologies of CP, smoking, and alcoholic drinking status. RESULTS: PC was diagnosed in 2.5% (24/965) of patients, and the cumulative incidence rates were 0.2%, 0.8%, and 1.5% at 3, 5, and 10 years since the onset of CP, respectively. In this cohort, SPINK1 c.194+2T > C was the most common variant with a proportion of 39.1%. And the risk of PC development varied marginally between patients with and without SPINK1 mutations (Cox HR 0.39(0.14-1.04), P = 0.059). In the subgroup analyses, patients carrying SPINK1 mutations had a significantly lower risk of PC (Cox HR 0.18(0.04-0.80), P = 0.025) in the non-smoking group. SPINK1 mutations showed no significant effect in the other subgroups considered. CONCLUSIONS: CP patients harboring SPINK1 mutations do not have an elevated risk of PC development compared to mutation-negative CP patients. On the contrary, SPINK1 mutations may be a protective factor in non-smoking patients with CP.