Introduction

Acute-on-chronic liver failure (ACLF) is a severe complication in patients with liver cirrhosis, often escalating rapidly and requiring urgent interventions. Meropenem, an important antibiotic for treating severe infections, necessitates accurate dosing to be effective and safe.

Aims & Methods

In this study aims the impact of implementing therapeutic drug monitoring (TDM) for meropenem in ACLF patients in an intensive care unit (ICU) with an innovative interprofessional approach was assessed. An interprofessional team of physicians, hospital pharmacists, and staff nurses collaborated to optimize meropenem therapy through TDM. Meropenem was administered via continuous infusion following an initial loading dose, with serum levels monitored twice weekly using high-performance liquid chromatography (HPLC). The evaluation metrics included serum meropenem concentrations, compliance with the interprofessional team's recommendations, and total consumption of the antibiotic.

Results

The initial TDM results showed a mean meropenem serum concentration of 20.9 ± 9.6 mg/L. Of note, only 16.0% of the patients had serum concentrations within the designated target range, while 84.0% exceeded it. Follow-up measurements in Week 2 and Week 3 showed improved targeting, with average concentrations of 15.2 ± 5.7 mg/L and 11.9 ± 2.3 mg/L, respectively. By Week 2, 41.7% of patients were within the target range, and by Week 3, this increased to 50%. The advice of the interprofessional team was fully implemented. Furthermore, there was a notable reduction in meropenem usage: from 42.1 RDD/100 patient days in the preceding period to 37.9 RDD/100 patient days during the study, marking a 10.0% decrease in application density.

Conclusion

The introduction of an interprofessional TDM approach for meropenem in patients with ACLF significantly improved dosing of carbapenems. Our innovative interprofessional approach brought serum levels within desired ranges more effectively and managed to reduce overall meropenem consumption. The study underscores the value of innovative collaborative, interprofessional efforts in optimizing drug therapy, particularly in complex ICU settings, enhancing patient safety and treatment efficacy.

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms, such as gastrointestinal symptoms. Emerging evidence suggests that gut permeability and inflammation play a role in PD pathophysiology via the gut-brain axis. According to Braak’s theory, the pathological degeneration associated with PD may originate from the gut and subsequently develop in the brain through the vagus nerve.

Aims & Methods

The aims were to assess the relationship between gut permeability and neuroinflammation in a cohort of patients with PD and REM behavior disorder (RBD), a condition that often precedes the onset of PD. The study prospectively included 28 PD patients and 18 RBD patients both complaining of GI symptoms. No serious organic diseases or therapies potentially affecting GI motility were reported. Relevant demographic and clinical data were collected for all patients. There was the inclusion of 14 healthy controls (HCs). A serum ELISA assay of tumor necrosis factor (TNF), caspase-1, and lipopolysaccharide-binding protein (LBP) was performed in all participants to investigate systemic inflammatory status and gut permeability, respectively. In a total of 10 PD patients, 4 RBD patients and 9 HCs, multiple colic biopsies were obtained to assay tissue expression of inflammation markers by both western blot (WB) (i.e. caspase-1 and procaspase-1) and immunofluorescence (IF) (i.e. ASC and CD68). Data were expressed as mean ± SD, and ANOVA and Dunnett's tests were used to compare the three groups.

Results

All three groups were comparable in age and sex. Serum assays showed significantly increased LBP, in patients with PD (35.0 ± 0.25; p = 0.002) and RBD (32.2 ± 1.1; p = 0.009) compared with HCs. TNF (0.1 ± 0.02; p = 0.03) and caspase-1 (16.9 ± 9.4; p = 0.04) were significantly raised only in the PD group in comparison with HCs (Table 1). WB analysis showed significant differences in the expression of procaspase-1 (157.3 ± 17.8; p = 0.02) and caspase-1 (168.3 ± 23.3; p = 0.03) only in PD patients compared with HCs. IF showed a qualitative increase in both CD68+ macrophage infiltration and ASC expression in PD and RBD groups compared with HCs.

	PD	RBD	HCs	P-value
LBP (ng/ml)	35.0 ± 0.25	32.2 ± 1.1	23.1 ± 2.1	0.009 (RBD vs HCs) 0.002 (PD vs HCs)
Caspasi-1 (ng/ml)	16.9 ± 9.4	11.4 ± 2.1	9.9 ± 2.7	0.04 (PD vs HCs)
TNF (pg/ml)	0.1 ± 0.02	0.05 ± 0.02	0.04 ± 0.02	0.03 (PD vs HCs)

Conclusion

Our results show a bowel activation of NLRP3 inflammasome in PD, as demonstrated both by the levels of procaspase-1 and caspase-1 on WB analysis and by the increase of CD68+ macrophages and ASC in the lamina propria of colonic mucosa. Only a qualitative increase in NLRP3 activation at IF could be observed in RBD patients. However, findings from colonic biopsies, if related to elevated serum levels of TNF and caspase-1 in PD patients, and LBP in PD and RBD patients, suggest that bowel inflammation, sustained by increased gut permeability, may represent an early stage in the develop of RBD and PD.

Introduction

The detection of cancer within large non-pedunculated colorectal polyps (LNPCPs) is suboptimal in non-expert settings. Identification of 6 macroscopic (Blink) features (6BF) of deep submucosal invasive cancer (SMI) has shown significant improvement in the sensitivity of cancer detection by inexperienced endoscopists at the expense of decreased specificity. This study investigates the impact of endoscopic resection scars, which can resemble deep SMI, on the accuracy of non-expert endoscopists using the 6BF evaluation system known as Blink Impression.

Aims & Methods

An online survey was disseminated containing 20 overview images of LNPCPs (1 image/polyp). Images (randomized) were shown before, and after a 2-minute educational video (the intervention) introducing the 6BF - fold deformation, extra redness, depression, chicken skin mucosa, ulceration and spontaneous bleeding. Before and after the intervention participant Blink Impression was elicited (cancer/no cancer) and only after, the presence of the 6BF. Responses were analysed relative to histopathology (no vs superficial vs deep SMI) and expert opinion on the presence of the 6BF and endoscopic resection scars.

Results

7/20 LNPCPs contained cancer (3 superficial, 4 deep SMI), 3 contained scars. 191 participants from 21 countries completed 3,755 observations. 129/191 (67.5%) participants were inexperienced. Expert-identified scarred LNPCPs contained median 1.0 (IQR 2.0) BF vs 1.0 (IQR 2.0) for no cancer, 2.0 (IQR 2.0) for superficial SMI and 3.0 (IQR 2.0) for deep SMI (all P<.001). Presence of ≥2 BF therefore reliably identifies cancer within LNPCPs but not scars. Fold deformation was the only BF identified more commonly amongst scarred LNPCPs (44.6%) vs no cancer (22.5%, P<.001) and vs superficial SMI (33.0%, P<.001), but similar to deep SMI (44.6%, P=1.000). Depression, chicken skin mucosa and spontaneous bleeding were less commonly identified in scarred polyps (12.3%, 7.6% and 1.8%) than both no cancer (33.1%, 14.4% and 8.6%, all P<.001), superficially invasive (68.6%, 14.3% and 5.8%, all P<.001) or deeply invasive polyps (45.9%, 19.6% and 40.5%, all P<.001). Extra redness and ulceration were identified with similar frequency to no cancer in scars (26.4% vs 26.8%, P=0.891 and 10.2% vs 9%, P=0.441 respectively), but less commonly than superficial (64.2%, P<.001 and 15.7%, P<.001) or deep SMI (60.2%, P<.001 and 24.7%, P<.001) (Table 1).

Conclusion

The presence of ≥2BF reliably discriminates LNPCPs with cancer from non-cancer even in the presence of scarred lesions amongst non-expert endoscopists. Scarred LNPCPs exhibit fold deformation at a similar rate to LNPCPs with deep SMI but other BF are not present.

References

Debels LK, Smeets S, Poortmans PJ, Argenziano ME, Desomer L, Anderson J, Valori R, David J Tate. Identification of 6 key features of colorectal polyps increases the sensitivity of cancer detection and ability to discriminate deep submucosal invasion The basis of the Blink (first) impression? United European Gastroenterology Journal 2023; Vol.11

Introduction

Ulcerative colitis, a type of inflammatory bowel disease, is characterised by chronic colonic inflammation often resulting in uncontrolled crypt lengthening and the development of colitis-associated colorectal cancer (CA-CRC). Orally administered Emu Oil, derived from Emu adipose tissue, has demonstrated protective and reparative properties in preclinical models of bowel disease, including CA-CRC. However, its long-term potential to reduce colonocyte proliferation and inhibit CA-CRC progression remains undetermined. Protein Ki-67 has been used widely as a proliferation marker for human tumour cells and may serve as a potential predictive biomarker for cancer progression.

Aims & Methods

We hypothesized that orally administered Emu Oil would reduce colonocyte proliferation, evidenced by decreased Ki-67 expression, in a mouse model of CA-CRC. Female C57BL/6 mice were injected with saline or azoxymethane (7.4mg/kg; intraperitoneal), followed by ad libitum access to either water or three dextran sulphate sodium (DSS)/water cycles (each cycle comprising seven days DSS [2%w/v] and 14 days water). Mice (n=9/group) were orally administered either water (80μL) or Emu Oil (low 80μL or high 160μL dose) thrice weekly for nine weeks. Proximal and distal colonic sections were stained with haematoxylin and eosin for crypt depth, cell count and size measurements and stained immunohistochemically to detect and quantify the proliferation marker Ki-67 in upper and lower colonocyte crypt zones. p<0.05 was considered statistically significant.

Results

In the proximal colon, numbers of Ki-67-positive cells in the upper and lower crypt regions of CA-CRC mice were increased by up to 100% compared with normal controls; low dose Emu Oil significantly decreased numbers of Ki-67-positive cells by 47% (p<0.05) compared with CA-CRC controls. Numbers of Ki-67-positive cells in the distal colon increased only in the upper crypt region in CA-CRC controls compared with normal mice (157%), with no further impact following Emu Oil administration (p>0.05). The overall percentage of Ki-67-positive cells remained unchanged in proximal and distal colonic crypts across treatment groups (p>0.05). Proximal and distal colonic crypt depth increased in mice with CA-CRC (20% and 37%, respectively; p<0.01), with greater distal colonocyte count, compared with normal controls (37%; p<0.05). Emu Oil did not impact proximal and distal colonic crypt depth nor cell counts in normal or CA-CRC mice (p>0.05). Furthermore, proximal colonocyte count, proximal and distal colonic cell diameter, and number of cells per 100μm remained unchanged among treatment groups (p>0.05).

Conclusion

Crypt lengthening in CA-CRC was primarily attributed to crypt cell hyperplasia, determined by increased cell numbers with no change in cell size. Low-dose Emu Oil administration in mice with CA-CRC resulted in attenuation of proximal colonic crypt cell proliferation, with no impact on crypt depth or cell size. Importantly, crypt depth and proliferation in normal mice remained unchanged following Emu Oil treatment, supporting its safety for long-term use to treat intestinal disorders. Future studies would benefit from an assessment of Emu Oil and its impact on expression of the oncogene Kras, tumour suppressor genes p53 and Apc, and inflammatory cytokines, including interleukin- 6, tumor necrosis factor-alpha and interferon-gamma, which are implicated in colorectal cancer progression.

Introduction

Peroxisome proliferator-activated receptor delta (PPARδ) agonists, such as seladelpar, emerged as potential therapies for PBC and other cholestatic diseases. PPARδs are nuclear receptors widely expressed in hepatocytes, cholangiocytes, Kupffer cells, and hepatic stellate cells. Activation of this receptor may modify the progression of PBC, particularly through its bile acid retention mechanism and antifibrotic and anti-inflammatory effects, inducing biochemical and clinical improvement in PBC patients.

Aims & Methods

We aimed to compare the efficacy and safety of seladelpar vs placebo for treating patients with primary biliary cholangitis (PBC) and inadequate response or intolerance to ursodeoxycholic acid (UDCA). We systematically searched MEDLINE, Embase, and Cochrane databases from inception to March 12, 2024. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were employed for dichotomous and continuous outcomes, respectively, using a random-effects model. We used Review Manager 5.4.1 for statistical analyses.

Results

We included 3 randomized clinical trials (395 patients). The results of the pooled analyses are shown in Table 1. Compared with placebo, seladelpar increased the probability of achieving composite biochemical response both at week 4 (RR 6.7; 95% CI 4.0 to 11.1) and at week 12 (RR 6.1; 95% CI 3.7 to 9.9), decreased alkaline phosphatase levels both at week 4 (MD -34.3%; 95% CI -39.6 to -29.0%) and at week 12 (MD -40.8%; 95% CI -47.9 to -33.6), increased the probability of achieving alkaline phosphatase normalization at week 12 (RR 18.6; 95% CI 3.8 to 90.4), and decreased pruritus scores at week 12 in both the overall population (MD -0.6; 95% CI -1.1 to -0.2) and the population with baseline pruritus score ≥4 (MD -1.2; 95% CI -2.0 to -0.4). Additionally, there was a non-significant difference between seladelpar and placebo in the risk of any adverse event (RR 1.0; 95% CI 0.9 to 1.1), any serious adverse event (RR 0.9; 95% CI 0.3 to 2.4), or any adverse event leading to treatment discontinuation (RR 0.7; 95% CI 0.2 to 2.0).

Table 1. Results from the pooled analyses

Conclusion

Seladelpar may be an effective and safe treatment option for patients with PBC and inadequate response or intolerance to UDCA. However, new large RCTs assessing long-term efficacy and safety outcomes are necessary to better evaluate its place in PBC management.

References

1. Hirschfield GM, Shiffman ML, Gulamhusein A, et al. Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study. Hepatology 2023;78:397–415.
2. Hirschfield GM, Bowlus CL, Mayo MJ, et al. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis. N Engl J Med 2024;390:783–794.
3. Jones D, Boudes PF, Swain MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. The Lancet Gastroenterology & Hepatology 2017;2:716–726.

Disclosure

The authors have no ​conflict of interest

Introduction

Helicobacter pylori (H. pylori) is a bacterium which inhabits the gastric epithelium and has been associated as a causative agent for dyspepsia, chronic gastritis, peptic and duodenal ulceration and gastric cancer. Testing for this pathogen is by Urea Breath Test (UBT) or OGD, and treatment varies according to local sensitivities and guidelines. H. pylori rates in developed countries have been falling in recent years as have those of associated conditions including gastric cancer, however increases in antimicrobial resistance recently has slowed this trend.
The current burden of disease either in asymptomatic population or symptomatic in Ireland is unknown, as are the rates of reinfection and recrudescence. Having up-to-date data on local epidemiology could have an effect on our strategy to detect and manage this class 1 carcinogen..

Aims & Methods

All UBTs performed in a tertiary hospital since 2016 were retrospectively assessed.
Demographic data & test results were taken from the UBT computer database and electronic patient record. All patients returning positive tests were offered appropriate antimicrobial therapy based on up to date local guidelines, and follow-up post-eradication testing by repeat UBT.

Results

From 2016-2023, 6716 UBTs were performed. 32 were excluded due to incomplete data. N=6684. 2752 (41.16%) were male, mean age was 43. Overall, 1589 (23.77%) tests were positive. There was no significant difference in positivity by gender (p=0.321). However there was a slight positive correlation with increasing age (AUC=0.5178 p=0.035). The positivity rate in our cohort reduced by roughly 2% per annum from 2016-22 (30%-18.5%).
Data on UBT type (Diagnostic vs Post-Eradication) was available from 2020-2023 when 3496 tests were performed and 2570 (73.5%) were diagnostic tests: 1060 (41.2%) male, mean age 41 years, 48 (19%) were positive. Positivity between genders was similar (p=0.3771). Conversely, in the post-eradication group n=926 (412, 44.5% Male), 259 (28%) were positive, females were more likely to remain positive post-therapy (32% vs 23%, X2=8.031, p=0.0046).
Over the 8 years, 747 patients returned positive tests (306 (41%) male). All were offered follow up testing. Males were significantly less likely to attend follow-up testing (140/306, 46% vs 254/441, 58%, p=0.0017)
In all 83 (2.4%) patients were re-tested for H. pylori after returning negative UBT tests due to persistent symptoms. Mean time to re-testing was 270 days, 34 (40%) were positive, representing 0.97% of the cohort.. Both genders were equally likely to have had a false negative UBT, male 10/30 versus 24/77 women, p=0.8214)

Conclusion

The overall positivity rate for diagnostic tests over the past 8 years was (19%) and is falling year on year.
The high positivity rate for post-eradication tests (28%) reflects rising antibiotic resistance.
The overall attendance rates for post-eradication tests after positive results were disappointing
Finally, the false negative rate in patients with persistent symptoms was high, 40% retested remained positive, raising the possibility of residual infection in our asymptomatic cohort.

References

1. Chen, Y.C., et al., Global Prevalence of Helicobacter pylori Infection and Incidence of Gastric Cancer Between 1980 and 2022. Gastroenterology, 2024. 166 (4): p. 605-619.
2. Warren, J.R. and B. Marshall, Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet, 1983. 1 (8336): p. 1273-5.
3. Marshall, B.J. and J.R. Warren, Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet, 1984. 1 (8390): p. 1311-5.
4. Zullo, A., et al., Gastric MALT lymphoma: old and new insights. Ann Gastroenterol, 2014. 27 (1): p. 27-33.
5. Mulder, D.T., et al., Prevalence of Gastric Precursor Lesions in Countries With Differential Gastric Cancer Burden: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol, 2024.
6. Malfertheiner, P., et al., Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut, 2022.

Introduction

Endoscopic ultrasound (EUS) has broadened its diagnostic and therapeutic scopes, as it is able to target lesions <3mm. High-frequency radial EUS-miniprobes exhibit procedural time reduction, improving image quality and maneuverability. EndoSound Vision System (EndoSound, Oregon, USA) is a new EUS (N-EUS) portable device that fastens onto a standard gastroscope, enabling a free working channel. It is an affordable alternative to conventional-EUS devices; and a promising opportunity to shorten the difficult EUS learning curve.

Aims & Methods

We aim to determine the feasibility and effectiveness of N-EUS in terms of anatomical structures appropriate identification in comparison with conventional-EUS. This prospective study included patients ≥18 years-old undergoing EUS evaluation in June-November 2023 by eight endoscopists from different institutions from South and North America. Patients underwent two consecutive procedures: First, a conventional EUS with a linear-array echoendoscope (Pentax EG38-J1OUT, Pentax Medical, Germany). Then, a different endoscopist performed EUS using the N-EUS coupled to a video gastroscope with therapeutic access (EG29-i10, Pentax Medical, USA). A post-procedure ad-hoc survey was completed by the second endoscopist, to assess N-EUS acceptability in terms of endoscopists’ experience using this device.

Results

Thirty-one patients underwent conventional EUS and N-EUS: 16/31 performed by first-time N-EUS users, 15/31 by endoscopists with prior N-EUS exposure, with median procedural times of 30 and 15 minutes, respectively (p=.04). Main EUS indication was chronic dyspepsia (35.5%). Identified structures during N-EUS were the liver/gallbladder/common bile duct (30/31, 96.8%), full pancreas (29/31, 93.5%), kidneys/left kidney (24/31, 77%; 13/15 endoscopists with prior exposure vs 11/16 first-time N-EUS users; p<.001), left adrenal gland (20/31, 64.5%). Gallbladder (GB) was unobserved in 8 cases, 7/8 had prior cholecystectomy. Evaluation position was 54.8% supine; 3/31 switched to left lateral. All procedures were completed with 100% clinical and technical success, requiring navigation changes in 51.6%, mainly in first-time N-EUS users (p=.001). FNB tissue sampling was achieved in 100% cases. Endoscopists’ experience was predominantly described as “meeting clinical expectations”. The ad-hoc survey showed high psychometrics, with homogeneity among surveyed endoscopists, without redundancy (Cronbach’s alpha of .91), and a good construct validity (Kaiser-Meyer-Olkin Criterion of .728 and Barlett´s test p-value =.0005). When comparing both procedures, appropriate identification of GB or lack of, full pancreas, left/both kidneys and left adrenal gland was 31/31 vs 30/31, 31/31 vs 29/31, 31/31 vs 24/31 (p=.0233), and 29/31 vs 20/31 (p=.0158), respectively. Considering conventional EUS as a gold standard, the observed agreement of N-EUS to identify these structures were 96.8%, 93.5%, 77.4% and 64.5%, correspondingly. Observed agreement for kidneys and left adrenal gland increased when sub-analyzing the cases assessed by endoscopists with prior N-EUS exposure: 81.2% and 76.9%, respectively.

Conclusion

N-EUS is a safe, effective, and feasible tool for EUS evaluation, with high acceptability by endoscopists. Prior ex-vivo training may be warranted for first-time N-EUS users.

References

1. LeBlanc JK. An overview of endoscopic ultrasound equipment. Minerva Gastroenterol Dietol. 2008 Jun;54(2):177-87. PMID: 18319690 .
2. Varas Lorenzo, M.J., Abad Belando, R. and Sánchez-Vizcaíno Mengual, E. (2018), Miniprobe Endoscopic Sonography for Gastrointestinal Tract Assessment: A Case Series of 1451 Procedures. J Ultrasound Med, 37: 293-303. https://doi.org/10.1002/jum.14330
3. Deprez PH. Choice of endosonographic equipment and normal endosonographic anatomy. Best Pract Res Clin Gastroenterol. 2009;23(5):623-37. doi: 10.1016/j.bpg.2009.07.001 . PMID: 19744628 .

Disclosure

Carlos Robles-Medranda is a key opinion leader and consultant for Pentax Medical, Boston Scientific, Steris, Medtronic, Motus, Micro-tech, G-Tech Medical Supply, CREO Medical, EndoSound, and mdconsgroup. All other authors declare no conflicts of interest.