Proton Pump Research Articles

Ketosis-prone Diabetes Presenting with Acute Esophageal Necrosis or “Black Esophagus”: An Intriguing New Clinical Association

Background:: Ketosis-prone diabetes (KPD) is an intermediate subtype of diabetes mellitus, usually affecting Afro-American adults, presenting with diabetic ketoacidosis (DKA), without the classic phenotype of autoimmune type 1 diabetes. Patients require insulin therapy at onset for the acute decompensation, then usually remain insulin-free for prolonged periods with diet alone or with other antidiabetic drugs. DKA can be rarely complicated by upper gastrointestinal bleeding and mucosal necrosis, a severe complication named acute esophageal necrosis (AEN) burdened by high mortality. The association of KPD presenting with DKA complicated by AEN is here reported for the first time, to the knowledge of the authors, in the medical literature. Case Presentation:: Here we report an interesting case of middle-aged African woman, newly diagnosed with KPD, presenting with DKA hematemesis. The patient was first treated at Intensive Care Unit for the ketoacidosis with intravenous fluids combined with continuous insulin infusion, and then switched to subcutaneous regimen. At the same time, esophagogastroduodenoscopy (EGD) was performed to diagnose acute esophageal necrosis, which was promptly managed with proton pump inhibitors infusion, fasting, and parenteral nutrition. After the correct clinical evaluation, the patient was switched to oral antidiabetic and basal insulin at discharge and an EGD follow-up was scheduled. Conclusions:: KPD remains an under-recognized and under-diagnosed type of diabetes which can present as DKA. Since DKA could be a possible trigger of AEN, a rare but potentially lifethreatening condition, that clinicians should be aware of, in patients presenting with upper gastrointestinal bleeding and ketoacidosis. The prompt management and classification of DKA, combined with the EGD execution for early AEN diagnosis and follow-up, is essential.

Temporal trends in use of antisecretory agents among patients administered clopidogrel-based dual antiplatelet therapy after percutaneous coronary intervention.

Antisecretory drugs are commonly prescribed with clopidogrel-based dual antiplatelet therapy (DAPT) to prevent gastrointestinal bleeding in high-risk patients after percutaneous coronary intervention (PCI). However, omeprazole and esomeprazole (inhibiting proton pump inhibitors [PPIs]) may increase cardiovascular event rates on co-administration with clopidogrel. This study aimed to examine trends in the use of antisecretory agents in patients administered clopidogrel-based DAPT and the concomitant use of clopidogrel and inhibiting PPIs. We used National Inpatient Sample data compiled by the Health Insurance Review & Assessment Service from 2009 to 2020. Further, we identified patients who were prescribed clopidogrel-based DAPT after PCI and investigated the concomitant use of antisecretory agents with clopidogrel. To verify the annual trend of drug utilization, we used the Cochran-Armitage trend test. From 2009 to 2020, the percentage of H2 receptor antagonist users decreased steadily (from 82.5% in 2009 to 25.3% in 2020); instead, the percentage of PPI users increased (from 23.7% in 2009 to 82.0% in 2020). The use of inhibiting PPI also increased (from 4.2% in 2009 to 30.7% in 2020). Potassium competitive acid blockers (P-CABs) were rarely used before 2019; however, in 2020, it accounted for 7.8% of the antisecretory users. Our study demonstrates that the use of inhibiting PPIs increased steadily in patients administered clopidogrel-based DAPT therapy. This is a major concern since the concomitant use of inhibiting PPIs with clopidogrel could increase the risk of cardiovascular events.

Comparison of safety and efficacy between Nirmatrelvir-ritonavir and molnupiravir in the treatment of COVID-19 infection in patients with advanced kidney disease: a retrospective observational study

Nirmatrelvir-ritonavir is used in patients with coronavirus disease 2019 (COVID-19) with normal or mild renal impairment (eGFR ≥30ml/min per 1.73m2). There is limited data regarding its use in advanced kidney disease (eGFR <30ml/min per 1.73m2). We performed a retrospective territory-wide observational study evaluating the safety and efficacy of nirmatrelvir-ritonavir when compared with molnupiravir in the treatment of patients with COVID-19 with advanced kidney disease. We adopted target trial emulation using data from a territory-wide electronic health record database on eligible patients aged ≥18 years with advanced kidney disease (history of eGFR <30ml/min per 1.73m2) who were infected with COVID-19 and were prescribed with either molnupiravir or nirmatrelvir-ritonavir within five days of infection during the period from 16 March 2022 to 31 December 2022. A sequence trial approach and 1:4 propensity score matching was applied based on the baseline covariates including age, sex, number of COVID-19 vaccine doses received, Charlson comorbidity index (CCI), hospitalisation, eGFR, renal replacement therapy, comorbidities (cancer, respiratory disease, myocardial infarction, ischaemic stroke, diabetes, hypertension), and drug use (renin-angiotensin-system agents, beta blockers, calcium channel blockers, diuretics, nitrates, lipid lowering agents, insulins, oral antidiabetic drugs, antiplatelets, immuno-suppressants, corticosteroids, proton pump inhibitors, histamine H2 receptor antagonists, monoclonal antibody infusion) within past 90 days. Individuals were followed up from the index date until the earliest outcome occurrence, death, 90 days from index date or the end of data availability. Stratified Cox proportional hazards regression adjusted with baseline covariates was used to compare the risk of outcomes between nirmatrelvir-ritonavir recipients and molnupiravir recipients which include (i) all-cause mortality, (ii) intensive care unit (ICU) admission, (iii) ventilatory support, (iv) hospitalisation, (v) hepatic impairment, (vi) ischaemic stroke, and (vii) myocardial infarction. Subgroup analyses included age (<70; ≥70 years); sex, Charlson comorbidity index (≤5; >5), and number of COVID-19 vaccine doses received (0-1; ≥2 doses). A total of 4886 patients were included (nirmatrelvir-ritonavir: 1462; molnupiravir: 3424). There were 347 events of all-cause mortality (nirmatrelvir-ritonavir: 74, 5.06%; molnupiravir: 273, 7.97%), 10 events of ICU admission (nirmatrelvir-ritonavir: 4, 0.27%; molnupiravir: 6, 0.18%), 48 events of ventilatory support (nirmatrelvir-ritonavir: 13, 0.89%; molnupiravir: 35, 1.02%), 836 events of hospitalisation (nirmatrelvir-ritonavir: 218, 23.98%; molnupiravir: 618, 28.14%), 1 event of hepatic impairment (nirmatrelvir-ritonavir: 0, 0%; molnupiravir: 1, 0.03%), 8 events of ischaemic stroke (nirmatrelvir-ritonavir: 3, 0.22%; molnupiravir: 5, 0.16%) and 9 events of myocardial infarction (nirmatrelvir-ritonavir: 2, 0.15%; molnupiravir: 7, 0.22%). Nirmatrelvir-ritonavir users had lower rates of all-cause mortality (absolute risk reduction (ARR) at 90 days 2.91%, 95% CI: 1.47-4.36%) and hospitalisation (ARR at 90 days 4.16%, 95% CI: 0.81-7.51%) as compared with molnupiravir users. Similar rates of ICU admission (ARR at 90 days-0.09%, 95% CI:-0.4 to 0.2%), ventilatory support (ARR at 90 days 0.13%, 95% CI:-0.45 to 0.72%), hepatic impairment (ARR at 90 days 0.03%, 95% CI:-0.03 to 0.09%), ischaemic stroke (ARR at 90 days-0.06%, 95% CI:-0.35 to 0.22%), and myocardial infarction (ARR at 90 days 0.07%, 95% CI:-0.19 to 0.33%) were found between nirmatrelvir-ritonavir and molnupiravir users. Consistent results were observed in relative risk adjusted with baseline characteristics. Nirmatrelvir-ritonavir was associated with significantly reduced risk of all-cause mortality (HR: 0.624, 95% CI: 0.455-0.857) and hospitalisation (HR: 0.782, 95% CI: 0.64-0.954). Patients with COVID-19 with advanced kidney disease receiving nirmatrelvir-ritonavir had a lower rate of all-cause mortality and hospital admission when compared with molnupiravir. Other adverse clinical outcomes were similar in both treatment groups. Health and Medical Research Fund (COVID1903010), Health Bureau, The Government of the Hong Kong Special Administrative Region, China.

Use of Acid-Suppression Therapy and Odds of Migraine and Severe Headache in the National Health and Nutrition Examination Survey.

Headache is an adverse event associated with the use of proton pump inhibitors (PPIs). Recently, migraine has emerged more specifically as a potential adverse event with PPI use. The objectives of this work were to capitalize on existing data to evaluate the association between migraine and severe headache prevalence and use of acid-suppression therapy, including PPIs, H2 receptor antagonists (H2RAs), and generic antacids; to compare risk from PPIs vs H2RAs; and to assess for potential mitigation by a dietary factor affected by acid-suppression therapy. Data from adults in the 1999-2004 National Health and Nutrition Examination Survey were used for this cross-sectional analysis. Acid-suppression therapy use was identified from self-report confirmed by product packaging review. Respondents who endorsed migraine or severe headache in the past 3 months were classified in the migraine or severe headache group. Dietary intake of magnesium was determined using one 24-hour recall interview. Multivariable logistic regression models were generated to analyze the relationship between acid-suppression therapy use and migraine or severe headache, and an interaction test was conducted to evaluate whether migraine or severe headache prevalence differed in relation to nutritional magnesium intake across acid-suppression therapy users and nonusers. In 11,818 US adults, the use of acid-suppression therapy was associated with higher odds of migraine or severe headache for all types of acid-suppression therapy and use of any type, as compared with those who did not use acid-suppression therapy: use of PPIs (70% higher), H2RAs (40% higher), and generic antacids (30% higher). Differences between acid-suppression therapy were not significant. An interaction was observed for H2RA use and magnesium intake (p = 0.024). These observations in US adults agree with previous findings that migraine or severe headache is a potential adverse event of PPIs, the most efficacious and most frequently used type of acid suppressing medication, and further suggest that other classes of acid suppressing medications (H2RAs and generic antacids) may also be implicated for migraine and severe headache. Future prospective analyses are needed to investigate migraine risk associated with acid suppressing medications while current evidence is sufficient to evaluate patients with migraine in light of recent deprescribing advice for PPIs.

Detection of helicobacter pylori by urea breathe test in a Nigerian population with upper gastrointestinal symptoms

Background: Helicobacter Pylori, a class one carcinogen is common globally with about 50% of the world’s population affected. It causes severe symptoms and complications including peptic ulcer disease and gastric cancer in infected persons. This study therefore aimed to determine the prevalence of Helicobacter Pylori as well as the clinical profile of patients with upper gastrointestinal symptoms seen at the Rivers State University Teaching hospital. Methodology: One hundred consecutive patients with upper GI symptoms undergoing Urea Breath test who fulfilled the inclusion criteria constituted the study population. The data was analyzed using IBM-SPSS Statistics for Windows, Version 22.0. Results were presented as means ± standard deviation and percentages/number for quantitative and qualitative variables respectively, while Categorical variables were compared with Pearson’s Chi-square. Result: Of the one hundred patients studied, 35 (35%) were males and 65 (65%) were females with a mean age of 49.56 ±14. 68. The prevalence of Helicobacter pylori was 33% affecting more females than males. The most common symptoms in the patients at presentation were heartburn (51%), epigastric pain (47%) and dyspepsia (35%). There was an insignificant positive correlation between the detection of Helicobacter pylori and a prior exposure to proton pump inhibitors. Conclusion: There is a high prevalence of Helicobacter pylori among patients with upper gastrointestinal symptoms. This buttresses the need for testing and treatment among Nigerians who present with such symptoms.

Skeletal Kinetics Reduction for Astrophysical Reaction Networks

A novel methodology is developed to extract accurate skeletal reaction models for nuclear combustion. Local sensitivities of isotope mass fractions with respect to reaction rates are modeled based on the forced optimally time-dependent (f-OTD) scheme. These sensitivities are then analyzed temporally to generate skeletal models. The methodology is demonstrated by conducting skeletal reduction of constant density and temperature burning of carbon and oxygen relevant to Type Ia supernovae (SNe Ia). The 495-isotopes Torch model is chosen as the detailed reaction network. A map of maximum production of 56Ni in SNe Ia is produced for different temperatures, densities, and proton-to-neutron ratios. The f-OTD simulations and the sensitivity analyses are then performed with initial conditions from this map. A series of skeletal models are derived and their performances are assessed by comparison against currently existing skeletal models. Previous models have been constructed intuitively by assuming the dominance of α-chain reactions. The comparison of the newly generated skeletal models against previous models is based on the predicted energy release and 44Ti and 56Ni abundances by each model. The consequences of y e ≠ 0.5 in the initial composition are also explored where y e is the electron fraction. The simulated results show that 56Ni production decreases by decreasing y e as expected, and that the 43Sc is a key isotope in proton and neutron channels toward 56Ni production. It is shown that an f-OTD skeletal model with 150 isotopes can accurately predict the 56Ni abundance in SNe Ia for y e ≲ 0.5 initial conditions.

Two-Year Results of Sleeve Gastrectomy Combined with Posterior Fundoplication for Obesity Patients with Gastroesophageal Reflux Disease.

Currently, gastroesophageal reflux disease (GERD) is the main side effect after sleeve gastrectomy (SG), causing discomfort and potential long-term risks. Surgical techniques combining fundoplication with SG are being evaluated to limit postoperative GERD. This single-center retrospective study evaluated patients who underwent SG with posterior fundoplication in the context of GERD between 2018 and 2021, with postoperative follow-up up to 24 months. The results were compared to a control group (ratio 1 to 4) who had SG without fundoplication. Observed total weight loss (TWL) was compared to predicted TWL using the Sophia multinational study's machine learning-based calculator. The series included 22 patients (mean body mass index 44.4 kg/m2) with GERD conditions: GERD symptoms (n = 15), hiatal hernia (n = 6), esophagitis (n = 7), and Barrett's esophagus (n = 5). Two patients required reoperation, including one for valve perforation. At 2 years, GERD was present in three patients (13.6%), including two who regularly took proton pump inhibitors. Compared to the control group (n=88), the frequency of GERD persisting at 2 years was significantly reduced in the SG with fundoplication group (p=0.05). The TWL at 12 and 24 months was 27.7% and 26.1%, respectively, with no significant difference compared to the weight predicted by the model, nor compared to the control group. The combination of posterior fundoplication with SG can be proposed in patients with GERD who have a contraindication to Roux-en-Y gastric bypass. Specific morbidity may exist at the beginning of the experience.

Comparative Efficacy and Safety of Potassium-Competitive Acid Blockers vs. Proton Pump Inhibitors for Peptic Ulcer with or without Helicobacter pylori Infection: A Systematic Review and Network Meta-Analysis

Novel potassium-competitive acid blockers (P-CABs) have emerged as effective acid-suppressive drugs in recent years, replacing proton pump inhibitors (PPIs). We aim to compare the efficacy and safety of P-CABs versus PPIs in the treatment of peptic ulcers with or without Helicobacter pylori (H. pylori) infection. We searched in PubMed, Embase, WOS, Cochrane Library, ClinicalTrials.gov, CNKI, and Wanfang databases (all years up to January 2024). Efficacy and safety outcomes were evaluated using odds ratio (OR) and 95% confidence intervals (CI). The Surface Under the Cumulative Ranking (SUCRA) probabilities were used to rank each intervention. Among 14,056 studies screened, 56 studies involving 9792 participants were analyzed. Vonoprazan demonstrated the best efficacy in ulcer healing rate and H. pylori eradication rate (SUCRA = 86.4% and 90.7%, respectively). Keverprazan ranked second in ulcer healing rates (SUCRA = 76.0%) and was more effective in pain remission rates (SUCRA = 91.7%). The risk of adverse events was low for keverprazan (SUCRA = 11.8%) and tegoprazan (SUCRA = 12.9%), and moderate risk for vonoprazan (SUCRA = 44.3%) was demonstrated. Compared to lansoprazole, vonoprazan exhibited a higher risk of drug-related adverse events (OR: 2.15; 95% CI: 1.60–2.89) and serious adverse events (OR: 2.22; 95% CI: 1.11–4.42). Subgroup analysis on patients with H. pylori-positive peptic ulcers showed that vonoprazan was at the top of the SUCRA rankings, followed by keverprazan. Vonoprazan showed superior performance in peptic ulcers, especially for patients with H. pylori-positive peptic ulcers. However, the risk of adverse events associated with vonoprazan should be noted. Keverprazan has also shown good therapeutic outcomes and has performed better in terms of safety.

Tipifarnib physiologically-based pharmacokinetic modeling to assess drug-drug interaction, organ impairment, and biopharmaceutics in healthy subjects and cancer patients.

A physiologically-based pharmacokinetic (PBPK) model for tipifarnib, which included mechanistic absorption, was built and verified by integrating invitro data and several clinical data in healthy subjects and cancer patients. The final PBPK model was able to recover the clinically observed single and multiple-dose plasma concentrations of tipifarnib in healthy subjects and cancer patients under several dosing conditions, such as co-administration with a strong CYP3A4 inhibitor and inducer, an acid-reducing agent (proton pump inhibitor and H2 receptor antagonist), and with a high-fat meal. In addition, the model was able to accurately predict the effect of mild or moderate hepatic impairment on tipifarnib exposure. The appropriately verified model was applied to prospectively simulate the liability of tipifarnib as a victim of CYP3A4 enzyme-based drug-drug interactions (DDIs) with a moderate inhibitor and inducer as well as tipifarnib as a perpetrator of DDIs with sensitive substrates of CYP3A4, CYP2B6, CYP2D6, CYP2C9, and CYP2C19 in healthy subjects and cancer patients. The effect of a high-fat meal, acid-reducing agent, and formulation change at the therapeutic dose was simulated. Finally, the model was used to predict the effect of mild, moderate, or severe hepatic, and renal impairment on tipifarnib PK. This multipronged approach of combining the available clinical data with PBPK modeling-guided dosing recommendations for tipifarnib under several conditions. This example showcases the totality of the data approach to gain a more thorough understanding of clinical pharmacology and biopharmaceutic properties of oncology drugs in development.

Modulating the Electrolyte Microenvironment in Electrical Double Layer for Boosting Electrocatalytic Nitrate Reduction to Ammonia.

Electrochemical nitrate reduction reaction (NO3RR) is a promising approach to achieve remediation of nitrate-polluted wastewater and sustainable production of ammonia. However, it is still restricted by the low activity, selectivity and Faraday efficiency for ammonia synthesis. Herein, we propose an effective strategy to modulate the electrolyte microenvironment in electrical double layer (EDL) by mediating alkali metal cations in the electrolyte to enhance the NO3RR performance. Taking bulk Cu as a model catalyst, the experimental study reveals that the NO3--to-NH3 performance in different electrolytes follows the trend Li+ < Cs+ < Na+ < K+. Theoretical studies illustrate that the proton transport rate in NO3RR and the activity of the rate-determining step (NO3- to NO2-) increase in the order Li+ < Cs+ < Na+ < K+. The cation effects are also general for two typical nanostructured catalysts including copper/cuprous oxide and nickel phosphides, achieving near-100% Faradaic efficiency and over 99% conversion of NO3- to NH3. Furthermore, we demonstrate that NO3- can be converted to high-purity NH4Cl by copper/cuprous oxide catalyst in K+-containing electrolyte.

Effect of Operating Conditions on the Capacity of Vanadium Redox Flow Batteries

Abstract Vanadium redox flow batteries (VRFBs) present a viable solution to address the intermittent power output challenge associated with wind and solar energy generation. However, their development is impeded by their low energy density and high cost. To achieve the objective of cost reduction, it is crucial to optimize operating conditions, minimize capacity loss, and enhance battery performance. Through meticulous experimental analysis, this study thoroughly examines the impact of membrane thickness, current density, flow rate, and self-discharge on battery capacity. The experimental findings reveal that an increase in membrane thickness results in elevated resistance to proton transport, thereby weakening electrochemical reactions. Moreover, surpassing critical values for current density and flow rate also leads to a decrease in capacity. Prolonged shelving induces severe self-discharge reactions that accelerate deterioration of capacity fade. This research suggests that obtaining optimal operational parameters can effectively mitigate battery capacity fade.

Preparation and study on H–MoS2/SLS modified SPI@SPEEK blend proton exchange membrane with balanced proton conductivity and stability

Proton exchange membranes (PEMs) are the core components of fuel cells, and research has long focused on how to balance their proton conductivity and durability. In this work, a series of homogeneous blend of sulfonated polyimide (SPI) and sulfonated polyether ether ketone (SPEEK) hybrid membranes with were constructed refined with sulfonated MoS2 (H–MoS2) and sodium lignosulfonate (SLS). The results showed that the tensile strength of the films was enhanced by 39.4% (67.84 MPa) compared to the base film. The composite films incorporating 1 wt% H-MoS2 and 2 wt% SLS has excellent proton conductivity, which can reach 50.24 mS/cm at 80°C and 100% humidity. The embed hybrid structure constructed by H–MoS2 and SLS, which not only effectively solves the limitations of the proton transport channel of traditional polymer materials, but also provides abundant proton transport sites, which provides a new strategy for preparing high-performance PEM.

Systematic review and meta-analysis: proton pump inhibitors slightly decrease the severity of chronic cough

The Montreal consensus recognizes chronic cough as an extra-esophageal manifestation of gastroesophageal reflux disease. We performed a meta-analysis to assess the effects of acid-suppressive medications in adults with non-specific chronic cough. The protocol was registered on PROSPERO (CRD42022368769). Placebo-controlled randomized trials evaluating the impact of acid-suppressive medications on persistent cough were included. The systematic search was performed on the 1st of November 2022 in three databases. A random-effects model was used for the calculations. The effect size was the standardized mean difference (SMD) with 95% confidence interval (CI). A total number of 11 double-blinded placebo-controlled randomized trials were included in the meta-analysis. Data showed that compared to placebo, PPIs decreased the severity of cough (SMD 0.33; CI 0.05; 0.61). Therapeutic response was not different in patients with non-specific chronic cough only, compared to those with laryngopharyngeal reflux. Prolonged treatment durations did not result in greater symptomatic improvement, with SMD 0.33 (CI − 0.22; 0.88), 0.31 (CI − 1.74; 2.35), 0.32 (CI − 0.29; 0.93) and 0.34 (CI − 0.16; 0.85), following 4, 6, 8 and 12 weeks of treatment, respectively. The pooled analysis of the improvement in quality of life with PPIs found an SMD of 0.39 (CI − 0.51; 1.29). PPIs mildly decrease the severity of non-specific chronic cough, irrespective of treatment duration.

Clinical Characteristics and Outcomes of Pembrolizumab Induced Gastritis: A Systematic Review of the Literature.

Pembrolizumab is associated with the development of gastritis, but its clinical features have not been characterized. To explore the clinical features of pembrolizumab induced gastritis and provide reference for the prevention and treatment of gastritis. Case reports and case series related to pembrolizumab induced gastritis were retrospectively analyzed by searching the database from inception to September 30, 2023. Thirty-nine patients with gastritis entered the study with a median age of 63years (range 34, 81). The median time to gastritis was 11.1months (range 0.3, 60) and 7 cycles (range 1, 27) after administration. Epigastric pain (24 cases, 61.5%), nausea (17 cases, 43.6%), and vomiting (16 cases, 41.0%) were the most frequently complained symptoms. Esophagogastroduodenoscopy mainly showed erythematous (16 cases, 41.0%), hemorrhage (14 cases, 35.9%) and erosions (11 cases, 28.2%). Gastric mucosal biopsy shows chronic active gastritis with lymphocytic infiltration. These patients' symptoms and gastric mucosa improved or recovered after receiving systemic steroid and proton pump inhibitor therapy regardless of whether pembrolizumab was discontinued. These patients' symptoms and gastric mucosa improved or recovered after treatment with systemic steroids, proton pump inhibitors, and biological agents. Gastritis is an extremely rare adverse effect of pembrolizumab. When patients receiving pembrolizumab complain of abdominal symptoms, endoscopy, tissue biopsy, and immunohistochemical staining should be actively performed for early identification and diagnosis of gastritis.

Spatiotemporal dynamics of the proton motive force on single bacterial cells.

Electrochemical gradients across biological membranes are vital for cellular bioenergetics. In bacteria, the proton motive force (PMF) drives essential processes like adenosine triphosphate production and motility. Traditionally viewed as temporally and spatially stable, recent research reveals a dynamic PMF behavior at both single-cell and community levels. Moreover, the observed lateral segregation of respiratory complexes could suggest a spatial heterogeneity of the PMF. Using a light-activated proton pump and detecting the activity of the bacterial flagellar motor, we perturb and probe the PMF of single cells. Spatially homogeneous PMF perturbations reveal millisecond-scale temporal dynamics and an asymmetrical capacitive response. Localized perturbations show a rapid lateral PMF homogenization, faster than proton diffusion, akin to the electrotonic potential spread observed in passive neurons, explained by cable theory. These observations imply a global coupling between PMF sources and consumers along the membrane, precluding sustained PMF spatial heterogeneity but allowing for rapid temporal changes.

Impact of gender on the management and prognosis of oesophageal fistula after atrial fibrillation ablation - a subanalysis of the worldwide POTTER-AF study

Abstract Background Oesophageal fistula (OF) is a rare but devastating complication following atrial fibrillation (AF) ablation. The data regarding the impact of gender on the management and prognosis of OF are scarce. Methods The POTTER-AF study is a worldwide, multi-centre registry conducted under the auspices of the Working Group of Cardiac Electrophysiology of the German Cardiac Society (AGEP, DGK) which evaluated the incidence, management, and outcome of post-procedural OF following catheter ablation of AF. A total of 553 729 patients underwent ablation procedures for AF or atrial tachycardia (AT) in 214 electrophysiological centres from 35 countries between 1996 and 2022. Of them, 138 (0.025%) patients experienced postprocedural OF and data regarding the gender, management and prognosis were available in 117 patients. Herein we conducted a gender- based analysis of the patients exhibiting OF. Purpose To evaluate the impact of gender on the management and prognosis of OF. Results Females represented 47% of the study population, which is a notable finding considering that the female population represents only a minority of the patients receiving AF/AT ablation. They were less likely to have atrioesophageal fistula (90.9% vs. 100%; p=0.021). Oesophageal-pericardial fistula occurred solely in females (7.3% vs. 0%; p=0.046). Congestive heart failure was significantly less frequent in the female population (7.4% vs. 26.7%; p=0.012). No other difference was seen between genders regarding the baseline characteristics and comorbidities (Table1). The energy source, ablation technique and utilization of oesophageal temperature probes were similar for males and females. Significantly less women received proton pump inhibitors (PPI) postprocedural (64.8% vs. 84.7%; p=0.017). The median duration until onset of symptoms was 20 days for women and 16.5 days for men (p=0.14), while the median duration until OF diagnosis was 22.5 days and 19.5 days respectively (p=0.217). Significantly more women underwent echocardiography (36.4% vs. 15%; p=0.01) as diagnostic method. More women exhibited stroke (32.7% vs. 14.8%; p=0.040), while there was no significant difference regarding the incidence of septic shock, coma, cardiac arrest, cardiac tamponade, and gastro-intestinal bleeding. Significantly more women than men presented no complications other than OF (9.6% vs. 0%; p=0.026). The females were more likely to undergo endoscopic treatment (35.8% vs. 17.7%; p=0.034), but less likely to undergo direct surgical treatment, without stenting (28.3% vs. 51.6%; p=0.014) (Figure1). The mortality was 63.6% for women and 67.2% for men (p=0.70), with no difference in terms of major and minor sequelae. Conclusion Approximatively half of the patients exhibiting postprocedural OF are females. Women showed a higher rate of endoscopic treatment and a lower rate of direct surgical treatment. The survival, as well as the incidence of minor and major sequelae were similar between genders.

Long-term proton pump inhibitors therapy and prevalence of hyperprolactinemia. a cross-sectional study in outpatient gastroenterology clinics

Objective: To evaluate serum prolactin and macroprolactin levels in patients on long-term proton pump inhibitors therapy. Method: The cross-sectional study was conducted from January 2018 to November 2019 after approval from the ethics review committee of the Commission on Science and Technology for Sustainable Development in the South University, Abbottabad, Pakistan. And comprised patients from two gastroenterology outpatient clinics in the Khyber Pakhtunkhwa province using proton pump inhibitors for &gt;3 months either alone or in combination with either histamine receptor antagonists or prokinetics. Blood samples were collected from each patient for hormonal screening. Data was analysed using SPSS 25. Results: Of the 166 patients, 101(60.8%) were females and 65(39.2%) were males. The overall mean age was 42.5±14.2 years, and the median serum prolactin level was 23.2ng/ml (interquartile range: 14.0-38.0ng/ml). There were 96(58%) patients with normoprolactinemia and 70(42%) with hypreprolactinemia. There were 19(11.4%) patients using combination therapy, while the rest were on proton pump inhibitors monotherapy. There was a significant increase in serum prolactin level with combination therapy compared to monotherapy (p=0.001). Pateints having treatment duration 11-20 months (p=0.006) and &gt;40 months (p=0.001) were at high risk of developing hyperprolactinemia. Conclusion: Long-term use of proton pump inhibitors could increase serum prolactin levels, and appropriate evaluation is essential for clinical management. Key Words: Proton pump inhibitors, Long-term therapy, Hyperprolactinemia, Omeprazole, Prolactin.

Modeled Hepatic/Plasma Exposures of Omeprazole Prescribed Alone in Cytochrome P450 2C19 Poor Metabolizers Are Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database.

Omeprazole, a gastric acid pump inhibitor, is repeatedly administered and is oxidatively metabolized mainly by polymorphic cytochrome P450 2C19. The prescribed dosage of omeprazole was discontinued or reduced in 47 of the 135 patients who received omeprazole alone in this survey, as recorded in the Japanese Adverse Drug Event Report database. The days to onset of omeprazole-related disorders were 3-4 d (median) and 16 d for intravenous 20-40 mg and oral 20 mg daily doses, respectively, in 34 patients for whom relevant data were available. The maximum plasma concentration of omeprazole was pharmacokinetically modeled after a single oral 40-mg dose in P450 2C19-defective poor metabolizers and was 2.4-fold higher than that in extensive metabolizers. The modeled area under the hepatic concentration curves of omeprazole in P450 2C19 poor metabolizers after virtual daily 40-mg doses for 7 d was 5.2-fold higher than that in the extensive metabolizers. Omeprazole-induced P450 2C19 (approx. 2-fold), resulting in increased hepatic intrinsic clearance in repeated doses, was considered after the second day. Virtual plasma/hepatic exposure estimated using pharmacokinetic modeling in subjects with P450 2C19 poor metabolizers indicated that these exposure levels virtually estimated could be one of causal factors for unexpected hepatic disorders induced by prescribed omeprazole, such as those resulting from drug interactions with repeatedly co-administered medicines.

#1495 5 and 10 year kidney outcomes in acute interstitial nephritis: a retrospective single-centre cohort study

Abstract Background and Aims Acute interstitial nephritis (AIN) is a common cause of acute kidney injury (AKI), histologically characterized by an interstitial inflammatory cell infiltrate. Data regarding long term kidney outcomes is lacking. We performed a retrospective cohort study to evaluate the long-term kidney and mortality outcomes in patients with biopsy-proven AIN between 2011-2018. Method We serve as a tertiary referral centre and sole nephrology provider for a population of over 650,000 people. We identified biopsy-proven AIN cases from the years 2011-2018 from our pathology database. Demographic data, creatinine, eGFR (calculated using CKD-EPI 2021 formula), dialysis and mortality data were collected from our electronic medical record. Ethical approval was obtained. Results Between 2011 – 2018, 576 native kidney biopsies were performed in our centre. 66 (11.5%) cases had pathologically confirmed AIN as the primary kidney diagnosis. Long-term outcome data was available for 90.9% (60). The median age at time of biopsy was 52.5 years (IQR 41.5 - 68.3). 68% of patients were male. The aetiology of AIN was medication in 42%, autoimmune in 15% and infection-associated in 3%. Of the cases of drug-induced AIN the predominant culprits agents were non-steroidal anti-inflammatories 28%, proton pump inhibitors in 24%, antibiotics 20%, with other medications in 8%. The median eGFR at the time of biopsy was 13.6 (IQR 7.9 -25.4) mls/min/1.73 m2. The median eGFR at year 1 was 47.8 (IQR 30.7 - 72.7) mls/min/1.73 m2, 54.4 (IQR 31.2 -79.6) mls/min/1.73 m2 at year 5 and 69.4 (IQR 19.9 - 86.1) mls/min/1.73 m2 at year 10. See Table 1 for results. At one year 64.3% of cases had eGFR &amp;lt; 60 mls/min/1.73 m2 (CKD III or higher). Interestingly the rate of CKD was lower at years 5 and 10 (54.7% and 50% respectively). GFR &amp;lt;30 mls/min (CKD IV or higher) were present in 25% at year 1, 26% at year 5 and 37% at year 10. 23% (14/60) people had dialysis-requiring AKI at the time of biopsy. Of these 21.4% (3) remained dialysis dependent at one year. In this group, no additional cases of ESKD were seen between years 1 through 5, one additional case of ESKD occurred by year 10. A composite outcome of kidney failure (GFR &amp;lt;15, dialysis or kidney transplantation) occurred in 48.2% at year 1, 54.7% at year 5 and 56.2% at year 10. Mortality data was available on 58 patients. 18.9% (11) people had died at 10 years follow-up. 8 out of the 11 deaths were within 5 years, 2 of which were within 1 year of diagnosis. Conclusion In this single centre study, kidney failure occurred in 48% of people at 10 years of follow up. 78% of dialysis-requiring cases recover independent renal function.

#1460 Targeting cyst progression: evaluation of anthelmintic and proton pump inhibitor in a rodent PKD model

Abstract Background and Aims In polycystic kidney disease (PKD) cyst formation and growth leads to progressive kidney damage. Recognizing the need for effective cyst-inhibitory drugs, we previously performed high-content screening of approved, repurposable drugs in a zebrafish model and identified several compounds with cyst-inhibitory activity and low toxicity. Here, we further tested two of the identified compounds, an anthelmintic agent and proton pump inhibitor, in a rodent model of PKD (PCK rat) for their cyst inhibitory and GFR-preserving capacity in mammals. Method The identified compounds were administered to 3-week-old male and female PCK rats for a total of 10 weeks to evaluate early drug effects on kidney function. Untreated PCK rats fed a normal ROD16 diet served as controls. After 5 weeks of treatment, total kidney and cystic volume and number of cysts were assessed in vivo by ultrasound. Following 10 weeks of treatment, kidney function was assessed by transcutaneous measurement of FITC-Sinistrin. After perfusion fixation in the same week, the kidneys, liver, heart, and pancreas were harvested for subsequent histological and molecular biological analyses. Results In male rats, 5-week proton pump inhibitor treatment was associated with a 50% reduction in the number of cysts (p &amp;lt; 0.05) and a nominal 22% reduction of fractional cystic kidney volume (CKV). Females showed a 16% reduction in cyst count and a modest reduction in fractional CKV. Treatment with the anthelmintic tended to reduce fractional CKV and cyst count in female animals whereas fractional cyst volume in males increased. After 10 weeks of treatment, a trend towards better preservation of GFR was observed for both therapies. Conclusion In conclusion, our study demonstrates a potential therapeutic benefit of a proton pump inhibitor and an anthelmintic agent in attenuating the progression of polycystic kidney disease (PKD) in a PCK rat model. The observed reductions in fractional cystic kidney volume and cyst count, coupled with marginal improvements in renal function, document a potential therapeutic effect of these compounds. Our preliminary findings justify further exploration of novel treatment modalities targeting cyst progression and renal dysfunction in this challenging clinical condition.