Proton Pump Research Articles

Expert consensus on the multifaceted utility of alginates in addressing diverse manifestations of acid reflux

Gastroesophageal reflux disease (GERD) is one of the most frequent reasons for seeking outpatient gastroenterology consultations. Current professional guidelines advocate the use of proton pump inhibitors (PPIs) as the primary medical approach to manage GERD. However, PPIs may not be as effective, especially for certain patients like those with non-erosive reflux disease (NERD). An alternative strategy for addressing symptomatic GERD involves obstructing the flow of acidic refluxate. Alginate-based pharmaceutical formulations have proven effective in alleviating symptoms of acid reflux for many years and provide rapid relief of symptoms with a long duration of action. Alginic acid derivatives, or alginates, combat acid reflux through a unique mechanism: they create a physical barrier that displaces the post-prandial acid pocket. Alginates have recently garnered renewed interest for promoting symptomatic relief especially when employed alongside antacids or PPIs. Here, the role of alginates is reviewed in the treatment of various profiles of acid reflux, including post-prandial acid reflux, nocturnal GERD, refractory GERD, and GERD during pregnancy, along with the opinion of expert gastroenterologists on the same. The experts believed that not all alginate formulations are equivalent and raft strength is the most important physicochemical property to be considered while selecting the alginate-based product. The physicochemical properties of the rafts eventually impact their effectiveness in relieving symptoms in clinical settings.

Signature of Proton-Hole Transfer in Hydrogen-Bonded Solids at 10 K.

Although proton transport in water ice is well understood, proton-hole transfer (PHT) involving proton abstraction by anions remains less explored. This study investigates PHT in H2S and NH3 solids at low temperatures, aiming to determine whether these solids exhibit negative charge transport similar to that in ice. In H2S and NH3 solids at 10 K, surface HS- and NH2- anions in hydrogen-bonded systems trigger negative current flow, providing a clear signature of PHT. This negative current is controlled by electron flow and 193 nm ultraviolet irradiation, which generates HS- and NH2- anions on the solid surfaces. In bilayer H2S/H2O and NH3/H2O solids, a significant negative current is observed only in the NH3/H2O solid, which is attributed to the exothermic proton abstraction by NH2- from H2O at the bilayer interface, a process not available for H2S on ice. This study is the first to demonstrate PHT-induced electrochemical behavior in hydrogen-bonded solids other than ice.

Proton pump inhibitors reduce chemotherapeutic hepatotoxicity and enhance hepatic uptake and accumulation of drug-loaded extracellular vesicles.

Extracellular vesicles (EVs) are involved in the progression of various diseases. Tumor cell-derived EVs (TEVs) are a particular concern, as they can induce fatty liver by promoting liver macrophages to secrete tumor necrosis factor (TNF), thus enhancing the toxicity of chemotherapy. Therefore, reducing pathogenic EV production is a potential strategy for treating EV-related diseases. However, there are currently no effective clinical reagents to obtain this purpose. In addition, EVs are also natural and ideal drug-delivery vehicles. Improving the delivery efficiency of EVs remains a challenge. Proton pump inhibitors (PPIs) have been demonstrated to promote cell uptake of EVs by inducing micropinocytosis. Here, we show that PPIs can accelerate TEV clearance, reduce TEV uptake by liver macrophages and decrease the mRNA expression of TNF in liver macrophages of tumor-bearing mice. Correspondingly, the fatty liver phenotypes are alleviated, and the tolerance to chemotherapy is improved in these mice. Furthermore, our findings indicate that PPIs facilitate the uptake of red blood cell-derived EVs (RBC-EVs) loaded with antisense oligonucleotides of Trim21 (Trim21-ASOs) by the liver macrophages of obesity. Consequently, the inhibition of macrophage inflammatory responses in obese mice mediated by RBC-EVs/Trim21-ASOs was further enhanced by PPIs, resulting in a more profound improvement in obesity and related metabolic disorders. In conclusion, our findings demonstrated that PPIs can effectively clear pathogenic EVs and enhance the delivery efficacy of EV vehicles, making them a highly promising clinical prospect.

Validation of an interactive process mining methodology for clinical epidemiology through a cohort study on chronic kidney disease progression.

Process mining holds promise for analysing longitudinal data in clinical epidemiology, yet its application remains limited. The objective of this study was to propose and evaluate a methodology for applying process mining techniques in observational clinical epidemiology. We propose a methodology that integrates a cohort study design with data-driven process mining, with an eight-step approach, including data collection, data extraction and curation, event-log generation, process discovery, process abstraction, hypothesis generation, statistical testing, and prediction. These steps facilitate the discovery of disease progression patterns. We implemented our proposed methodology in a cohort study comparing new users of proton pump inhibitors (PPI) and H2 blockers (H2B). PPI usage was associated with a higher risk of disease progression compared to H2B usage, including a greater than 30% decline in estimated Glomerular Filtration Rate (eGFR) (Hazard Ratio [HR] 1.6, 95% Confidence Interval [CI] 1.4-1.8), as well as increased all-cause mortality (HR 3.0, 95% CI 2.1-4.4). Furthermore, we investigated the associations between each transition and covariates such as age, gender, and comorbidities, offering deeper insights into disease progression dynamics. Additionally, a risk prediction tool was developed to estimate the transition probability for an individual at a future time. The proposed methodology bridges the gap between process mining and epidemiological studies, providing a useful approach to investigating disease progression and risk factors. The synergy between these fields enhances the depth of study findings and fosters the discovery of new insights and ideas.

The Inhibitory Effect of Hedera helix and Coptidis Rhizome Mixture in the Pathogenesis of Laryngopharyngeal Reflux: Cleavage of E-Cadherin in Acid-Exposed Primary Human Pharyngeal Epithelial Cells

Laryngopharyngeal reflux disease (LPRD) is a prevalent upper airway disorder characterized by inflammation and epithelial damage due to the backflow of gastric contents. Current treatments, primarily proton pump inhibitors (PPIs), often show variable efficacy, necessitating the exploration of alternative or adjunctive therapies. This study investigates the therapeutic potential of a mixture of Hedera helix and Coptidis rhizome (HHCR) in mitigating the pathophysiological mechanisms of LPRD. Using an in vitro model of human pharyngeal epithelial cells exposed to acidic conditions, we observed that acid exposure significantly increased the expression of adenosine A3 receptor (adenosine A3) and matrix metalloproteinase-7 (MMP-7), leading to E-cadherin cleavage and compromised epithelial integrity. Treatment with the HHCR mixture effectively suppressed adenosine A3 expression and MMP-7 activity, thereby reducing E-cadherin cleavage and preserving cellular cohesion. These results highlight the HHCR mixture’s ability to modulate the adenosine A3–MMP-7–E-cadherin pathway, suggesting its potential as a valuable adjunctive therapy for LPRD, particularly for patients unresponsive to conventional PPI treatment. This study provides new insights into the molecular interactions involved in LPRD and supports further clinical evaluation of HHCR as a complementary treatment option.

Helicobacter pylori, esophageal precancerous lesions, and proton pump inhibitor overuse

This article reviews the cohort study published in the World Journal of Gastroenterology , which reported low rates of Helicobacter pylori (H. pylori ) infection among esophageal cancer (EC) patients, coupled with proton pump inhibitor (PPI) overuse. These findings suggest a potential protective role of H. pylori against EC and indicate a possible association between PPI use and increased cancer risk. In light of these findings, our article examines the complex relationship between H. pylori and esophageal precancerous lesions, exploring the potential underlying mechanisms. We also address growing concerns regarding PPI overuse, including its potential effects on cancer therapy efficacy and the risk of drug interactions. Ultimately, this article highlights the urgent need for further research to evaluate the safety and efficacy of PPIs in cancer patients and to better understand their broader implications.

Highly prevalent geriatric medications and their effect on β-amyloid fibril formation.

The unprecedented increase in the older population and ever-increasing incidence of dementia are leading to a "silver tsunami" in upcoming decades. To combat multimorbidity and maintain daily activities, elderly people face a high prevalence of polypharmacy. However, how these medications affect dementia-related pathology, such as Alzheimer's β-amyloid (Aβ) fibrils formation, remains unknown. In the present study, we aimed to analyze the medication profiles of Alzheimer's disease (AD; n = 124), mild cognitive impairment (MCI; n = 114), and non-demented (ND; n = 228) patients to identify highly prevalent drugs and to determine the effects of those drugs on Aβ fibrils formation. Study subjects (≥ 65 years) were recruited from an academic geriatric practice that heavily focuses on memory disorders. The disease state was defined based on the score of multiple cognitive assessments. Individual medications for each subject were listed and categorized into 10 major drug classes. Statistical analysis was performed to determine the frequency of individual and collective drug classes, which are expressed as percentages of the respective cohorts. 10 µM monomeric β-amyloid (Aβ) 42 and fibrillar Aβ (fAβ) were incubated for 6-48h in the presence of 25 µM drugs. fAβ was prepared with a 1:10 ratio of Aβ42 to Aβ40. The amount of Aβ fibrils was monitored using a thioflavin T (Th-T) assay. Neuronal cells (N2A and SHSY-5Y) were treated with 25 µM drugs, and cell death was measured using a lactose dehydrogenase (LDH) assay. We noticed a high prevalence (82-90%) of polypharmacy and diverse medication profiles including anti-inflammatory (65-77%), vitamin and mineral (64-72%), anti-cholesterol (33-41%), anti-hypersensitive (35-39%), proton pump inhibitor (23-34%), anti-thyroid (9-21%), anti-diabetic (5-13%), anti-constipation (9-11%), anti-coagulant (10-13%), and anti-insomnia (9-20%) drugs in the three cohorts. Our LDH assay with 18 highly prevalent drug components showed toxic effects of Norvasc, Tylenol, Colace, and Plavix on N2A cells, and of vitamin D and Novasc on SH-SY5Y cells. All these drugs except Colace significantly reduced the amount of Aβ fibril when incubated with Aβ42 for a short period (6h). However, Lipitor, vitamin D, Levothyroxine, Prilosec, Flomax, and Norvasc prominently reduce the amount of fibrils when incubated with monomeric Aβ42 for a longer period (48h). Furthermore, our disaggregation study with fAβ showed consistent results for cholecalciferol (vitamin D), omeprazole (Prilosec), clopidogrel hydrogensulfate (Flomax), levothyroxine, and amlodipine (Norvasc). The chemical structures of these four efficient molecules contain polyphenol components, a characteristic feature of the structures of polyphenolic inhibitors of Aβ fibrillation. A higher polypharmacy incidence was observed in an elderly population of 228 ND, 114 MCI, and 124 AD patients. We found that several highly recommended drug components, including vitamin D3, Levothyroxine, Prilosec, Flomax, and Norvasc, efficiently reduce the amount of fibrils formed by monomeric Aβ42 and existing preformed Aβ fibrils in vitro. However, only Levothyroxine was able to prevent Aβ-mediated toxicity to SH-SY5Y cells. Our study suggested that these drugs likely function as polyphenolic inhibitors of Aβ.

Effects of Medication Period and Gastrin Levels on Endoscopic Gastric Mucosal Changes in Long-Term Proton Pump Inhibitor Users

Background/Objectives: Proton pump inhibitor (PPI) use has increased worldwide, including in continuous and longer-term users. Recent reports highlight PPI-related endoscopic gastric mucosal changes, including fundic gland polyps, hyperplastic polyps, multiple white and flat elevated lesions, cracked and cobblestone-like mucosa (CCLM), and black spots. PPI use elevates gastrin levels because of acid inhibition, and hypergastrinemia might be relevant to these findings. In this cross-sectional study, we retrospectively examined gastric mucosal changes in long-term PPI users, focusing on medication period and gastrin levels. Methods: We enrolled 57 patients who received a PPI (>1 year) at two clinics between January 2021 and March 2022. Participants were classified according to medication period: 1 < 5, 5–10, and ≥10 years. Gastrin levels were categorized as low, middle, and high (<250, 250–500, and ≥500 pg/mL, respectively). Odds ratios (OR) were estimated to assess the risk of endoscopic findings. Results: Of the 57 patients, 6 (10.5%), 25 (43.9%), and 26 (45.6%) were PPI users of 1 < 5, 5–10, and ≥10 years, respectively. There were no significant differences in the incidence of endoscopic findings among the medication periods. Low, middle, and high gastrin groups included 21 (36.8%), 21 (36.8%), and 15 (26.3%) patients, respectively. CCLM incidence was significantly elevated in higher gastrin level groups: middle (OR, 6.60; 95% confidence interval [CI], 1.46–29.75; p = 0.014) and high (OR, 9.00; 95% CI, 1.79–45.23; p = 0.0008) (p-trend = 0.0171). No significant differences were observed for other findings. Conclusions: No elevated risk of PPI-related gastric epithelial changes in long-term PPI users was observed time-dependently. Notably, higher gastrin levels were positively associated with CCLM development, irrespective of the medication period.

BN SO55 - Rare case of Ectopic pancreatitis in stomach and its Surgical Management

Abstract Background This presentation covers the case of Mr. D, a 38-year-old male who presented with upper abdominal pain and vomiting, initially treated as gastritis but later developing more complex symptoms. This case highlights the diagnostic challenges and management of ectopic pancreatitis, a rare condition characterized by pancreatic tissue located outside its usual anatomical position.Mr. D, a personal trainer with a history of asthma and Meckel's diverticulum excision, experienced recurring epigastric pain, bloating, and early satiety. His pain was particularly related to eating, fasting and often disrupted his sleep. Despite treatment with proton pump inhibitors (PPIs), his symptoms persisted, prompting further investigation Method Initial investigations including ultrasound, chest X-ray, and ECG showed no significant abnormalities. However, subsequent gastroscopy and CT scans suggested a gastrointestinal stromal tumor (GIST), leading to referral for endoscopic ultrasound (EUS) and biopsy. The findings indicated a highly vascular, mixed echogenic lesion in the submucosa, likely a GIST, but initial biopsies were inconclusive Results Following conservative treatment, Mr. D's inflammation significantly reduced, though he experienced recurrent pain necessitating surgical intervention. Diagnostic laparoscopy and gastroscopy revealed extensive adhesions and an inflammatory mass. The patient underwent a pyloric-preserving sleeve gastrectomy, with histology confirming pancreatic heterotopia with inflammation and cystic degeneration. Post-operatively, Mr. D initially struggled with dietary intake but improved over time, tolerating a solid diet by the last follow-up. Conclusion This case underscores the complexity of diagnosing and managing rare conditions like ectopic pancreatitis. It highlights the importance of a multidisciplinary approach and the potential need for surgical intervention when conservative management fails. The presentation aims to provide valuable insights into the diagnostic process, the role of MDT discussions, and the therapeutic challenges associated with ectopic pancreatitis.

Clostridioides difficile infection increases in-hospital mortality, length of stay, and hospital cost but not 30-day mortality in cirrhotic patients.

Clostridioides difficile infection (CDI) is a leading cause of nosocomial infection and is associated with both higher morbidity and mortality. Cirrhotic patients are more susceptible to CDI because of impaired gut immune response, use of proton pump inhibitor, and frequent hospitalization. We aim to investigate the impact of CDI on cirrhotic patients' in-hospital and 30-day mortality, length of stay, and hospital cost. Potentially eligible studies were identified from Embase, Medline, and Web of Sciences databases. A total of 2320 articles were identified. After reviewing, nine studies reporting in-hospital mortality and three reporting 30-day mortality of cirrhotic patients with CDI versus those without CDI were included. The meta-analysis of nine studies, consisting of 7 746 126 patients, revealed a significant association between CDI and in-hospital mortality in cirrhotic patients with the pooled OR of 1.68 (95% CI 1.29-1.85, I2 94%). Length of stay and hospital cost were also higher in the CDI group (pooled MD of 6.56days [95% CI 5.75-7.36, I2 94%] and 27.85 (×$1000) [95% CI 10.41-45.29, I2 100%], respectively). The funnel plots for the meta-analysis of the association between CDI and in-hospital mortality, length of stay, and hospitalization cost were not suggestive of publication bias. From three studies consisting of 3694 patients, we found that CDI was not associated with 30-day mortality in cirrhotic patients (pooled OR 1.20, 95% CI 0.75-2.24, I2 74%). CDI is associated with increased in-hospital mortality, length of stay, and hospital costs, but not with 30-day mortality in cirrhotic patients.

BN SO47 - Can Peroral Endoscopic Myotomy (POEM) be the new gold standard for Achalasia? – as it is safe and effective

Abstract Background Laparoscopic Heller’s cardiomyotomy is the gold standard for treatment of achalasia. POEM has emerged as a revolutionary minimal invasive procedure in the management of achalasia and related oesophageal motility disorders. POEM effectively utilises an endoscopic approach by creating a submucosal tunnel to perform a myotomy at the lower oesophageal sphincter (LES) , achieving symptomatic relief. Being firstly introduced in 2008, POEM offers an excellent alternative option to surgical intervention and conservative approaches. The aim of this study is to evaluate the clinical efficacy and safety of POEM since its introduction in our unit. Method POEM procedures performed in adult patients are recruited prospectively from May 2020 to January 2024 and data are collected using electronic trust records. Eckardt score (a commonly used scoring system to characterise severity of achalasia) is recorded before and after the procedure. A total of 46 patients are identified however three patients are excluded in this study due to unavailable clinical information. This study presents a cohort of patients with median age of 60 and an equal gender distribution. Results Out of 43 patients, 69.8% were treatment naïve and 30.2% had previous treatments. Mean Eckardt score pre-procedure was 8.2. The average length of hospital stay was 1.7 days and immediate post treatment complications were 6.9% (2.3% mucosotomy, 2.3% oesophageal leak, 2.3% infection). No mortality was recorded within 30 days post-procedure. A 93% clinical success rate (Eckardt score ≤3) was achieved in the initial follow-up period (three to six months) with a mean Eckardt score of 1.1. 41.9% of patients experienced reflux symptoms which require proton pump inhibitor use within four weeks post-procedure. 18.4% of patients had recurrent achalasia symptoms over their follow-up period. Conclusion The clinical success rate (Eckardt score ≤3) and recurrence rate post POEM in this study are comparable with the international cohort quoted in literature. Post POEM reflux rate is prevalent, which is a well-known complication. The substantial improvement in clinical outcomes, evidenced by the Eckardt score reduction and the low incidence of post-operative complications, underscores the procedure’s efficacy and safety. Overall, POEM represents a significant advancement in the treatment of oesophageal motility disorders, especially achalasia. This study presents POEM as a safer and less invasive treatment alternative compared to Heller’s cardiomyotomy.

Emerging Long-Term Risks of the Use of Proton Pump Inhibitors and Potassium-Competitive Acid Blockers.

Acid-related disorders represent a significant global health burden. Pharmacological treatment of these conditions has at times been challenged and limited by incomplete effectiveness, antibiotic resistance, adverse medication effects and/or interactions, and disease recurrence. Since the early 1990s, the mainstay of treatment has been proton pump inhibitors (PPIs). Recently, the US Food and Drug Administration issued a clearance for vonoprazan, a potassium-competitive acid blocker (PCAB). PCABs are a new class of acid-suppressing agents that may overcome some of these challenges. The aim of this review is to evaluate and compare the emerging long-term risks of PPI and PCAB therapies.

EGS SO04 - Gastrodoudenal Artery Pseudoaneurysm Secondary to blunt abdominal trauma: A rare case report

Abstract Background Visceral artery pseudoaneurysms (VAPAs) are rare, potentially life-threatning aneurysms found in the celiac, superior, or inferior mesenteric arteries. They are most common in the splenic artery (60-70%), followed by hepatic arteries (20%) and celiac or mesenteric arteries (10%). Usually asymptomatic, VAPAs are often discovered incidentally during abdominal imaging. They pose a high risk of rupture and haemorrhage. Risk factors include iatrogenic injury and abdominal trauma. Traumatic VAPAs are extremely rare with unclear management guidelines. Treatment options vary from observation to endovascular therapy or surgical repair. This report presents a case of a gastoduodenal artery psuedoaneurysm due to blunt abdominal trauma. Method A case report: a 68-year-old male with a high BMI and atrial fibrillation managed with edoxaban, presented with severe upper abdominal pain following a fall. Initial examination and laboratory results suggested acute pancreatitis or cholecystitis, but a CT angiography revealed a GDA pseudoaneurysm with active extravasation. The patient was referred for urgent therapeutic embolization; however, the pseudoaneurysm had spontaneously thrombosed, precluding the need for embolization. The patient was managed conservatively, with close monitoring in the high dependency unit (HDU), analgesics, proton pump inhibitors, and mechanical venous thromboembolism prophylaxis. He remained hemodynamically stable and was discharged with instructions for follow-up care. Results GDA pseudoaneurysms are rare, accounting for 0.01-1% of all visceral artery aneurysms, with trauma being an exceptionally infrequent cause. The management of VAPAs, particularly in hemodynamically stable patients, can range from conservative observation to endovascular interventions. This case underscores the importance of a multidisciplinary approach involving surgery, interventional radiology, and vascular teams for optimal management. Conclusion Gastroduodenal artery pseudoaneurysms secondary to blunt abdominal trauma can be effectively managed conservatively in stable patients. Comprehensive history-taking, appropriate imaging, and multidisciplinary discussions are crucial for successful outcomes. Continued monitoring is essential to ensure patient safety and address potential complications.

BN O03 - Pooled two-year results of the novel RefluxStop implantable device in management of gastroesophageal reflux disease in Germany: Retrospective analysis

Abstract Background The most common gastrointestinal disorder globally is gastroesophageal reflux disease (GERD). Standard-of-care treatments for GERD are medical therapy, via proton pump inhibitors (PPIs), and traditional antireflux surgery (i.e., Nissen fundoplication). Unfortunately, PPI therapy is associated with medication irresponsiveness in up to 40% of cases and Nissen fundoplication results in significant rates of postoperative adverse events (AEs), such as postoperative dysphagia. Notably, patients with large hiatal hernia (>3 cm) are exceedingly difficult to treat with antireflux surgery. This report presents the clinical results of patients treated with an emerging technology, the RefluxStop device, in Germany at our two centers. Method Between July of 2021 and November of 2023, 158 patients were operated on with RefluxStop surgery. This procedure entails correction of a defunct antireflux barrier through cruroplasty (with hiatal hernia reduction, if necessary), limited (90-120°) esophagogastroplication to recreate the acute angle of His and gastroesophageal flap valve, and regional stabilization of newly constructed anatomy with implantation of the RefluxStop device in a fully invaginated fundic pouch. Clinical outcomes included GERD Health-Related Quality of Life (GERD-HRQL) score, PPI use, and perioperative AEs. Results Patients of mean age 49±13.3 years and male (51.3%) had hiatal hernia >3 cm (22.2%). At 20±7-month follow-up, the median (IQR) GERD-HRQL score improved by 90.9% to 2 (0-2) from a baseline of 22 (19-31.5) (p<.001). PPI use decreased by 96.3%. Preoperative dysphagia (n=18) resolved in all patients with five cases (3.2%) of new-onset dysphagia occurring, but none requiring postoperative dilation. Hiatal hernia recurred in two patients (1.3%) and was treated with device repositioning. Device migration presented in two patients (1.3%) from excessively tight suturing of the fundic pouch. One of these patients was converted to Toupet fundoplication. Conclusion This study shows that RefluxStop provides excellent effectiveness and safety outcomes. Quality-of-life improvements were particularly appreciated with a 90.9% reduction in GERD-HRQL score. With the added context of 22.2% of this pooled cohort composed of difficult-to-treat patients (i.e., hiatal hernia >3 cm), RefluxStop surgery provides favorable efficacy in real-world settings with such patients. As with any novel surgical procedure, training is paramount to optimizing surgical outcomes and minimizing unwanted AEs. Further study is required to bolster the evidence supporting this emerging technology.

The 2-week wait pathway for suspected head and neck cancers in patients with throat and voice symptoms: referral patterns, common clinical practice and diagnostic efficacy of NICE guidelines.

The 2-week wait (2ww) referral pathway has been introduced into UK clinical practice to increase the early detection of cancer and improve survivals. The efficiency of this system for head and neck (H&N) cancers has been questioned over the years because of evidence of low pick-up rates. H&N cancers present with a wide variety of non-specific symptoms, particularly throat and voice symptoms. These symptoms need to be accurately interpreted together with risk factors if they are to be addressed adequately and overload of cancer facilities avoided. One of the most common outcomes of H&N 2ww referrals is laryngopharyngeal reflux (LPR), a common condition that could be diagnosed and managed in the primary care setting with a prescription of proton pump inhibitors (PPI) trials. We retrospectively analysed a cohort of consecutive patients referred on the 2ww pathway for throat and voice symptoms at University College London Hospital H&N cancer clinic during two months in 2019. A total of 101 patients (43.6% men, mean age 53.3 years) were included. Throat and voice symptoms were described as intermittent in 52.5% and non-lateralised in 88.1%. Diagnosis of LPR was made in 59.4% of the referrals. A PPI trial was prescribed by general practitioners (GPs) in only 7.9% of cases. The cancer pick-up rate in our cohort is 2.9%. An improved awareness of the symptoms of LPR could guide GPs to prescribe trials of PPIs in low-risk patients before rushing into a referral on a cancer pathway. This would improve the 2ww process on many levels, reduce the burden on the National Health Service and avoid patients' psychological distress.

Inhibition mechanism of potential antituberculosis compound lansoprazole sulfide

Tuberculosis is one of the most common causes of death worldwide, with a rapid emergence of multi-drug-resistant strains underscoring the need for new antituberculosis drugs. Recent studies indicate that lansoprazole-a known gastric proton pump inhibitor and its intracellular metabolite, lansoprazole sulfide (LPZS)-are potential antituberculosis compounds. Yet, their inhibitory mechanism and site of action still remain unknown. Here, we combine biochemical, computational, and structural approaches to probe the interaction of LPZS with the respiratory chain supercomplex III2IV2 of Mycobacterium smegmatis, a close homolog of Mycobacterium tuberculosis supercomplex. We show that LPZS binds to the Qo cavity of the mycobacterial supercomplex, inhibiting the quinol substrate oxidation process and the activity of the enzyme. We solve high-resolution (2.6 Å) cryo-electron microscopy (cryo-EM) structures of the supercomplex with bound LPZS that together with microsecond molecular dynamics simulations, directed mutagenesis, and functional assays reveal key interactions that stabilize the inhibitor, but also how mutations can lead to the emergence of drug resistance. Our combined findings reveal an inhibitory mechanism of LPZS and provide a structural basis for drug development against tuberculosis.

Abstract 4136743: Current Oral Anticoagulation Use Among Patients With Atrial Fibrillation and Risk Factors Associated With Inadequate Treatments: A Report From a UK Population Cohort Study

Background: The worldwide prevalence of atrial fibrillation (AF) continues to grow with approximately 60 million cases each year. Aim: To understand demographic and clinical attributes of patients receiving adequate DOAC (direct oral anticoagulant) treatment, DOAC undertreatments, or no OAC (oral anticoagulant) treatments, thus providing valuable perspectives into the current landscape of stroke prevention in AF within the UK. Methods: We used the Clinical Practice Research Datalink (CPRD) Aurum database from January 2020 to March 2021 for this retrospective observational study. Patients’ characteristics from various cohorts (standard dose [SD], low dose [LD] per label, LD inconsistent per label prescribing, and untreated) were evaluated based on OAC treatment. Duration of index OAC treatment, time to discontinuation and incidence rates across OAC treated cohorts were assessed. A machine learning method (Elastic Net) identified factors associated with being undertreated or untreated. Results: The final sample included 13,341 patients (mean age 78.5 and female 47%). Within a 180-day timeframe post-diagnosis, 76% of patients received OAC treatment, while 24% did not receive any OAC therapy. Among those treated with DOAC (n=9947), 74% were administered SD (n=7238), 18% received LD per labels (n=1756) and 10% were inappropriately prescribed LD of DOACs (n=953). Both LD cohorts tended to have shorter duration of OAC therapy (figure) and higher discontinuation rates (per 100 person-years; LD per label: 42.97; LD not per label: 39.11) compared to the SD cohort (SD: 31.67). Patients who were untreated were associated with elevated bleeding risk factors such as renal disease and prior bleeding history; patients who received inappropriate LD were associated with age above 75, renal disease, GI conditions with PPI (proton pump inhibitor) concomitant treatments when compared to SD cohort. Conclusions: In our study, a considerable proportion of AF patients remained untreated/undertreated and were associated with bleeding risk factors, highlighting the unmet needs within this population. Exploring potential alternative treatment options with enhanced safety profiles could offer substantial benefits to patients in need.

Long-Range Proton Channels Constructed via Hierarchical Peptide Self-Assembly.

The quest to understand and mimic proton translocation mechanisms in natural channels has driven the development of peptide-based artificial channels facilitating efficient proton transport across nanometric membranes. It is demonstrated here that hierarchical peptide self-assembly can form micrometers-long proton nanochannels. The fourfold symmetrical peptide design leverages intermolecular aromatic interactions to align self-assembled cyclic peptide nanotubes, creating hydrophilic nanochannels between them. Titratable amino acid sidechains are positioned adjacent to each other within the channels, enabling the formation of hydrogen-bonded chains upon hydration, and facilitating efficient proton transport. Moreover, these chains are enriched with protons and water molecules by interacting with immobile counter ions introduced into the channels, increasing proton flow density and rate. This system maintains proton transfer rates closely resembling those in natural protein channels over micrometer distances. The functional behavior of these inherently recyclable and biocompatible systems opens the door for their exploitation in diverse applications in energy storage and conversion, biomedicine, and bioelectronics.

Comparison Between Simple Batch and Fed-Batch Bioreactor Cultivation of Recombinant BCG

Background/Objectives: Tuberculosis continues to be a significant global health concern, causing 1.3 million deaths in 2022, particularly affecting children under 5 years old. The Bacillus Calmette-Guérin (BCG) vaccine, developed in 1921, remains the primary defense against tuberculosis but requires modernized production methods. The recombinant BCG-pertussis strain shows potential in providing dual protection against tuberculosis and whooping cough, especially for vulnerable newborns, and enhanced efficacy against bladder cancer. Implementing submerged cultivation techniques for rBCG-pertussis production can offer increased productivity and standardization. Methods: This study explores a fed-batch cultivation strategy with pH-stat control to feed L-glutamic acid through the acid pump into 1 L bioreactor. Three pH values were evaluated for fed-batch and a simple batch without pH control was done for comparison. The viable cell concentration was compared before and after freeze-drying samples harvested during the cultures. Results: L-glutamic acid was identified as the preferred substrate for rBCG-pertussis. While the fed-batch strategy did not enhance the maximum specific growth rate compared to simple batch cultivation, it did improve the specific growth rate after day 4 in the pH 7.4-controlled fed-batch cultures, thereby reducing the cultivation time. Fed-batch cultures controlled at three pH levels exhibited lower optical density than the simple batch, although the viable cell counts were similar. Notably, samples harvested after day 8 from the simple batch cultures showed a reduction in CFU/mL after freeze-drying, whereas all fed-batch samples exhibited high recovery of viable cell counts post lyophilization. Conclusions: The additional glutamate supplied to the fed-batch cultures may have protected the cells during the lyophilization process.

Proton pump inhibitors in inpatients: Are we getting it right? A retrospective analysis

Background: Proton pump inhibitors (PPIs) are commonly prescribed to hospitalized patients, but many of these prescriptions may not be based on evidence-based indications. It’s important to understand that inappropriate prescribing of PPIs can lead to unnecessary medications and financial burdens. Unfortunately, there are not many recent studies exploring how often PPIs are prescribed and if they are being prescribed appropriately. Objective: The study aimed to assess the appropriateness of PPIs use among hospitalized patients. It evaluated the indications for PPIs use and determined whether the use of PPIs in hospitalized patients is justified or not. Setting: The study was conducted at Hamad General Hospital, a tertiary academic healthcare center in the state of Qatar. Methods: A retrospective observational study with 201 subjects, was conducted in general internal medicine wards at a tertiary hospital. Physician documentation and inpatient and outpatient medication prescriptions were analyzed for PPIs exposure. Main outcome measures: The appropriateness of exposure to PPIs is determined based on international recommendations. Results: Of 533 hospitalized patients who were not critically ill, 201 (37.7%) were prescribed PPIs. The study found that 65.2% of the patients had no valid indication for PPIs exposure. Furthermore, 18% of patients were inappropriately prescribed stress ulcer prophylaxis with PPIs even though they had a low risk for the development of ulcer disease. After discharge, 82.6% of patients were prescribed PPIs, with the most common indication (43%) being gastrointestinal ulcer prophylaxis. Conclusion: This study sheds light on the issue of overutilization of PPIs, specifically in non-critically ill hospitalized patients. It highlights the unnecessary continuation of PPI prescriptions at discharge and emphasizes the importance of physicians reevaluating PPI prescriptions periodically to ensure they are still necessary and discontinuing them when possible to avoid unwanted consequences.