Introduction

Chronic pancreatitis (CP) is a multifactorial, fibroinflammatory disease in which chronic inflammation leads to irreversible structural and functional damage to the pancreas. The incidence of the disease is steadily increasing, but no specific therapy is currently available therefore the identification of new therapeutic targets is a significant unmet need. A major morphological feature of chronic inflammation is the fibrotic transformation of the tissue, in which the TGF-β pathway plays a prominent role. In the complex profibrotic signalling the potential role of plasminogen activator inhibitor-1 (PAI-1) has been suggested in chronic inflammatory diseases with diverse localization, however the role of PAI-1 in the development of CP is currently unknown.

Aims & Methods

We therefore aimed to explore the role of PAI-1 in the development of CP and assess the therapeutic potential of PAI-1 inhibitors as antifibrotic agents to prevent the progression of CP.
The PAI-1 expression of the pancreatic tissue was determined in mouse and human pancreatic tissue samples with immunohistochemistry. CP was induced in FVB/N mice with 8X50 µg/kg bw i.p. cerulein injection, given every hour, every 3 days for a total of 5 times. PAI-1 activity was inhibited with a specific inhibitor – TM5275 – which was administered per os at a dose of 10 mg/kg bw for 6 consecutive days after the 3rd cerulein treatment. To assess the extent of inflammation and fibrosis hematoxylin-eosin and Crossman’s trichrome staining were performed, and biochemical assays were used to determine amylase activity and hydroxyproline concentration. PAI-1 expression in the pancreas was examined by RT-qPCR and immunofluorescence staining.

Results

PAI-1 expression was significantly higher in pancreatic tissue samples obtained from CP patients. After induction of CP in mice, the body weight and the pancreatic weight/body weight ratio significantly reduced, whereas histopathology showed significant pancreatic atrophy and fibrosis. This was also confirmed by the increased hydroxyproline concentration and decreased amylase activity of the pancreatic tissue. The expression of SERPINE1 (the gene encoding PAI-1) and PAI-1 protein was significantly higher in the pancreatic tissues in the CP group. The decreases of the body weight were impaired by the per os TM5275 treatment, whereas the pancreas weight/body weight ratio significantly increased in the TM5275-treated group. Moreover, the parenchymal atrophy, tissue fibrosis, hydroxyproline concentrations and SEPRINE1 gene expression were significantly decreased by TM5275 treatment.

Conclusion

Our results suggest that PAI-1 expression is increased in CP moreover, the inhibition of PAI-1 can reduce fibrosis and tissue atrophy in CP. These data suggest that inhibition of PAI-1 could potentially be a new therapeutic target for the treatment of CP.

Introduction

Abdominal pain is the cardinal symptom of acute pancreatitis (AP), often requiring opioid therapy. We aimed to investigate the dose-response relationship between exposure to opioids and the development of moderately severe and severe AP.

Aims & Methods

This was a post-hoc analysis of the prospective PAINAP database, which recruited patients with first-time AP from 118 centres across 27 countries between April 1 and June 30, 2022. From this database, we extracted baseline patient characteristics, post-pancreatitis outcomes and information regarding the dosage of opioid treatment. The morphine-equivalent doses (MEDs) of each opioid administered were calculated based on daily doses and duration of treatment and subsequently summarized into total cumulative MEDs for each patient. Using multivariable regression analysis, we identified risk factors for developing moderately severe or severe AP.

Results

The final cohort for this post-hoc analysis consisted of 1,030 AP patients receiving various doses of opioids (51% male; median age 54 (IQR, 40-69) years). The median pain severity on admission was 7 (IQR, 6-8), and in 504 (50%) patients, the pre-admission duration of pain was more than 24 hours. Most patients (78%) had mild AP, whereas 14% and 8% of patients developed moderately severe and severe AP. On multivariable analysis, a high burden of comorbidity (CCI>2), alcohol aetiology, pre-admission pain duration >24 hours and higher pain severity on admission were independent risk factors for moderately severe or severe AP. There was a significant increase in the risk of moderately severe or severe AP, per mg MED (OR 1.00 (95% CI, 1.00-1.00), P=0.039). Accordingly, receiving >40 mg MED (compared to <10 mg MED) increased the risk of moderately severe or severe AP (OR, 3.51 (95% CI, 2.09-5.93), P<0.001).

Conclusion

The association between opioid exposure and severity of AP was dose dependent. Further studies are warranted to explore this association as this may have clinical implications for pain management in AP.

Introduction

Etiology of acute pancreatitis can be established in the majority of patients. However, in 25 % of cases it remains elusive. Biliary microlithiasis/sludge is detected in up to 75% of patients with idiopathic acute pancreatitis (IAP). As recurrent biliary pancreatitis can be prevented, the underlying etiology of IAP should be established. The aim of this multicentre retrospective study was to develop a machine learning-aided non-invasive prediction tool to guide clinicians in the selection of idiopathic acute pancreatitis patients to be referred to endosonography to establish etiology and allow treatment.

Aims & Methods

We retrospectively used routinely recorded clinical and laboratory parameters of 218 consecutive patients with confirmed acute pancreatitis admitted to our tertiary care hospital between 2015 and 2020. Patients who did not receive endosonography as part of the diagnostic work-up and whose pancreatitis episode could be adequately explained by other causes than biliary sludge and microlithiasis were excluded. We trained supervised machine learning classifiers using H2O.ai automatically selecting the best suitable predictor model to predict microlithiasis/sludge. The predictor model was validated in two independent retrospective cohorts from two tertiary care centers (TU Munich & University Medical Center Göttingen).

Results

28 categorized patients’ variables recorded at admission were identified to compute the predictor model with an accuracy of 0.84 [95% CI 0.791, 0.9185], positive predictive value of 0.84 and negative predictive value 0.80 in the identification cohort (218 patients). In the validation cohort, the robustness of the prediction model was confirmed with an accuracy of 0.76 [95% CI 0.673, 0.8347], positive predictive value of 0.76 and negative predictive value of 0.78 (117 patients).

Conclusion

We present a robust and validated machine learning-based predictor model consisting of routinely recorded lab work at admission that can predict biliary sludge and microlithiasis as cause of acute pancreatitis and select patients for EUS.

Introduction

Upper gastrointestinal bleeding (UGIB) is still a significant cause of hospitalization with mortality as high as 10%. While there is a seasonal trend of UGIB, studies have also illustrated the potential association between air pollution exposure and UGIB. However, the relationship between exposure to ambient pollutants and emergency attendance for UGIB, particularly concerning seasonal changes, is still unknown.

Aims & Methods

We aimed to determine the association between high concentrations of ambient pollutants exposure and the risk of emergency attendance for UGIB during different seasons. This population-based time-series study was based on the Hong Kong population of 7.6 million. We retrieved detailed daily data on UGIB emergency attendance, ambient pollutants (PM_2.5, PM₁₀, CO, NO₂, SO₂, O₃), and meteorological data (including temperature, wind speed, and humidity) between January 1, 2016, and December 31, 2021. Emergency attendance was obtained from the Clinical Data Analysis and Reporting System (CDARS) of the Hong Kong Hospital Authority. Ambient pollutants and meteorological data were obtained from the Environmental Protection Department and the Hong Kong Observatory, respectively. The distributed lag non-linear model (DLNM) was adopted to investigate the association between ambient pollutants exposure and UGIB emergency attendance, considering the effects of lag days and confounding meteorological factors. To avoid issues caused by multi-collinearity, Spearman’s correlation coefficients of less than 0.7 were adopted to select the covariates. Subgroup analysis was performed after stratification by sex, age (<65 vs ≥65 years), or season (cold season: October to March; warm season: April to September). The risk ratio(RR) for ambient pollution exposure on UGIB emergency attendance was presented with 95% confidence interval (CI).

Results

Total number of UGIB emergency attendance during the six-year period was 22,109, of which 11,798 (53.4%) were male and 11533 (52.2%) were aged ≥65 years. PM₁₀(r=0.703), CO(r=0.709), and SO₂(r=0.717) were eliminated from the final regression model due to a close relationship with PM_2.5. Exposure to the high concentrations (90th percentile) of PM_2.5 and NO₂ significantly increased the UGIB emergency attendance risk, but not high concentration of O₃. High concentration of PM_2.5 exposure significantly increased the risk from lag days 5 to 7 (RR:1.08; 95% CI:1.01-1.15 to 1.09; 95%CI:1.02-1.16). For high concentrations of NO₂ exposure, single-day lag association shows a significantly higher risk from lag 3 to lag 5 (RR:1.13; 95%CI:1.01-1.27 to 1.12; 95%CI:1.02-1.22). For both high PM_2.5 and NO₂, stratified analysis showed that elderly, female and cold season are at higher risk of emergency attendance for UGIB.

Conclusion

High PM_2.5 and NO₂ exposure are associated with an increased risk of UGIB emergency attendance. The risk is further increased among elderly, female, or during cold seasons.

Introduction

Previous observational studies reported a higher effectiveness of colonoscopy in preventing distal vs. proximal colorectal cancer (CRC) which we could not reproduce in a recently published observational study using target trial emulation (TTE). The design of the previous studies suffered from “time zero violation”, i.e. eligibility check, treatment assignment (screening vs. no screening) and start of follow-up were not synchronized.

Aims & Methods

We aimed to assess whether this “time zero violation” falsely induces a site-specific difference in the effect of colonoscopy. We used the same dataset underlying our recently published analysis (Braitmaier et al. 2022) based on German claims data (20% population coverage). We assessed the effect of screening colonoscopy in preventing distal and proximal CRC over 11 years of follow-up in 55–69-year-old persons at average CRC risk. Unlike in our recently published analysis, we used the design of previous observational studies with “time zero violation”. We compared the findings of both analyses.

Results

While in the recently published analysis using TTE, the relative risk (RR) of distal and proximal CRC in the screening colonoscopy vs. control group was similar (RR: 0.67 for distal, 0.70 for proximal), the analysis with “time zero violation” indicated a difference in site-specific performance. In this latter analysis, the RR was 0.41 for distal CRC and 0.66 for proximal CRC.

Conclusion

Our study demonstrates that “time zero violation” can substantially bias the results of observational studies. In our example, it falsely suggested an almost double preventive effect of colonoscopy in the distal vs. the proximal colon. The difference disappeared when the same data were analyzed using a TTE approach, which is known to avoid design-induced biases.

References

Braitmaier M, Schwarz S, Kollhorst B, Senore C, Didelez V, Haug U (2022) Screening colonoscopy similarly prevented distal and proximal colorectal cancer: a prospective study among 55-69-year-olds; Journal of Clinical Epidemiology; 149: 118-126

Introduction

The quality of colonoscopy is influenced by patient and operator factors. Studies investigating operator attentional fatigue on adenoma detection rate (ADR) have yielded conflicting results.

Aims & Methods

This study aims to compare ADR, polyp detection rate (PDR) and sessile serrated lesion detection rate (SSLDR) and complication rates between elective colonoscopies performed early and late in the list, across multiple operators (n>15), over 10 years, in a tertiary Brisbane (Australia) hospital.
A retrospective study was conducted on elective colonoscopies performed between 2012 and 2022 at The Prince Charles Hospital. ‘Early procedures’ are defined as procedures starting in the first hour of the first procedure starting and ‘late procedures’ are defined as procedures starting within the last hour of the last procedure starting. This pre-defined early and late procedures were used as surrogate markers for operator fatigue, accounting for a possible non-linear relationship between time and onset of fatigue, as well as the variation in number of colonoscopies performed every hour. Timing and the order of colonoscopy were used as alternative surrogates, in a secondary analysis.
Logistic regression was performed on all categorical outcome variables, and Poisson regression was modelled on continuous outcome variables, due to their non-linear distribution. Multivariate analysis included all potential confounding variables related to outcomes of interest. Statistical significance was defined as a P-value less than 0.05. Statistical analyses were performed using the SAS® statistical software (SAS Institute Inc, USA).
Exclusion included; surveillance for IBD and elective ESD.

Results

In total, 15 proceduralist (11 gastroenterologists, 4 surgeons) performed 39, 206 elective colonoscopies from 2012 to 2022. The baseline characteristics of patients, year and procedure sessions are similarly distributed between the early and late groups.
Multivariant analysis found significant associations between late procedures and lower adenoma detection rates, polyp detection rates and SSL detection rates. After adjusting for age, gender, proceduralist, year, morning or afternoon procedure, and bowel preparation quality, PDR, ADR and SDR remain 20-28% lower in late colonoscopies compared with early ones. We also found that age, gender, proceduralist, year and bowel preparation independently affected ADR in multivariant analysis. However, morning or afternoon ADRs did not significantly differ after adjusting for other variables. Proceduralist were found to be the only additional significant variable for SDR in multivariant analysis. There was no significant association between timing of procedures and major adverse events.

Conclusion

This is the largest single-centre study on operator fatigue and its effect on colonoscopy quality. Although the minimum standards for ADR was achieved, ‘late procedures’ have statistically significant lower ADR, PDR and SSLDR compared to ‘early procedures’. There was no difference in the complication rates between ‘early procedures’ and ‘late procedures’.
This study highlights the detrimental effect of fatigue in later procedures affecting the quality of colonoscopies and may be applicable in principal to other procedural based clinical work. Importantly, this may or perhaps will or is having an impact on patient safety, satisfaction, outcomes and clinical KPI’s for the operators and hospital administrators.

Disclosure

None