Large language models: a primer and gastroenterology applications.

Over the past year, the emergence of state-of-the-art large language models (LLMs) in tools like ChatGPT has ushered in a rapid acceleration in artificial intelligence (AI) innovation. These powerful AI models can generate tailored and high-quality text responses to instructions and questions without the need for labor-intensive task-specific training data or complex software engineering. As the technology continues to mature, LLMs hold immense potential for transforming clinical workflows, enhancing patient outcomes, improving medical education, and optimizing medical research. In this review, we provide a practical discussion of LLMs, tailored to gastroenterologists. We highlight the technical foundations of LLMs, emphasizing their key strengths and limitations as well as how to interact with them safely and effectively. We discuss some potential LLM use cases for clinical gastroenterology practice, education, and research. Finally, we review critical barriers to implementation and ongoing work to address these issues. This review aims to equip gastroenterologists with a foundational understanding of LLMs to facilitate a more active clinician role in the development and implementation of this rapidly emerging technology.

Large language models in gastroenterology: a simplified overview for clinicians This text discusses the recent advancements in large language models (LLMs), like ChatGPT, which have significantly advanced artificial intelligence. These models can create specific, high-quality text responses without needing extensive training data or complex programming. They show great promise in transforming various aspects of clinical healthcare, particularly in improving patient care, medical education, and research. This article focuses on how LLMs can be applied in the field of gastroenterology. It explains the technical aspects of LLMs, their strengths and weaknesses, and how to use them effectively and safely. The text also explores how LLMs could be used in clinical practice, education, and research in gastroenterology. Finally, it discusses the challenges in implementing these models and the ongoing efforts to overcome them, aiming to provide gastroenterologists with the basic knowledge needed to engage more actively in the development and use of this emerging technology.

NSAIDs do not reduce severity among post-ERCP pancreatitis patients.

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most studied chemoprophylaxis for post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). While previous systematic reviews have shown NSAIDs reduce PEP, their impact on moderate to severe PEP (MSPEP) is unclear. We conducted a systematic review and meta-analysis to understand the impact of NSAIDs on MSPEP among patients who developed PEP. We later surveyed physicians' understanding of that impact. DESIGN: A systematic search for randomized trials using NSAIDs for PEP prevention was conducted. Pooled-prevalence and Odds-ratio of PEP, MSPEP were compared between treated vs. control groups. Analysis was performed using R software. Random-effects model was used for all variables. Physicians were surveyed via email before and after reviewing our results. RESULTS: 7688 patients in 25 trials were included. PEP was significantly reduced to 0.598 (95%CI, 0.47-0.76) in the NSAIDs group. Overall burden of MSPEP was reduced among all patients undergoing ERCP: OR 0.59 (95%CI, 0.42-0.83). However, NSAIDs didn't affect the proportion of MSPEP among those who developed PEP (p = 0.658). Rectal Indomethacin and diclofenac reduced PEP but not MSPEP. Efficacy didn't vary by risk, timing of administration, or bias-risk. Survey revealed a change in the impression of the effect of NSAIDs on MSPEP after reviewing our results. CONCLUSIONS: Rectal diclofenac or indomethacin before or after ERCP reduce the overall burden of MSPEP by reducing the pool of PEP from which it can arise. However, the proportion of MSPEP among patients who developed PEP is unaffected. Therefore, NSAIDs prevent initiation of PEP, but do not affect severity among those that develop PEP. Alternative modalities are needed to reduce MSPEP among patients who develop PEP.

Transarterial Chemoembolization-Induced Ischemic Colitis: A Rare Complication Due to Nontarget Embolization.

Nontarget embolization is a rare complication that may occur after a patient undergoes transarterial chemoembolization as a localized treatment of hepatocellular carcinoma. This phenomenon can occur because of variations in arterial blood supply to the liver and ultimately can lead to ischemic complications in unintended locations. We describe a case of nontarget embolization during transarterial chemoembolization causing ischemic colitis because of anatomic variation in the origin of the right hepatic artery. This case highlights the importance of recognizing rare side effects associated with this procedure and the need for comprehensive imaging to assess for anatomical variation to avoid poor outcomes.

Amphipathic Liponecrosis Impairs Bacterial Clearance and Causes Infection During Sterile Inflammation.

BACKGROUND & AIMS: Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition. METHODS: Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry. RESULTS: Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered ß-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid. CONCLUSIONS: Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.

Statin Use Reduces the Risk of Hepatocellular Carcinoma: An Updated Meta-Analysis and Systematic Review.

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver resulting in approximately 800,000 deaths annually. A growing body of research investigating statin use and HCC risk has shown conflicting results. We aim to evaluate the current evidence of statin impact on HCC risk. We performed a comprehensive literature search in PubMed, PubMed Central, Embase, and ScienceDirect databases from inception through May 2019 to identify all studies that evaluated the association between statin use and HCC. We included studies that presented an odds ratio (OR) with a 95% confidence interval (CI) or presented data sufficient to calculate the OR with a 95% CI. Statistical analysis was performed using the Comprehensive Meta-Analysis (CMA), Version 3 software, and a Forrest plot was generated. We assessed for publication bias using conventional techniques. Twenty studies (three randomized controlled trials, six cohorts, and 11 case-controls) with 2,668,497 patients including 24,341 cases of HCC were included in the meta-analysis. Our findings indicate a significant risk reduction of HCC among all statin users with a pooled odds ratio of 0.573 (95% CI: 0.491-0.668, I2= 86.57%) compared to non-users. No publication bias was found using Egger's regression test or on visual inspection of the generated Funnel plot. The results indicate that statin use was associated with a 43% lower risk of HCC compared to statin non-users. Further prospective randomized research is needed to confirm the association.

Factors associated with adjuvant systemic anti-cancer treatment discontinuation for early breast cancer during the COVID-19 pandemic.

OBJECTIVE: The Covid-19 pandemic led to challenging discussions between oncology clinicians and patients regarding additional risks posed by SARS-CoV-2 infection whilst receiving systemic anti-cancer therapies (SACT). We assess the potential factors affecting discontinuation of adjuvant early breast cancer treatment during the pandemic. METHODS: Data were collected on all patients with early breast cancer undergoing adjuvant SACT, between 16 March and 17 April 2020 at a single UK cancer centre. Univariate binary logistic regression analysis was performed on variables including age, recurrence risk, Index of Multiple Deprivation decile, presence of physical comorbidities, modality of treatment (neoadjuvant or adjuvant), type of treatment (cytotoxic chemotherapy or monoclonal antibodies), percentage of cycles completed and availability of alternative treatments, with a binary dependent variable on treatment discontinuation. RESULTS: Sixty-two patients with early breast cancer were identified: 18 receiving neoadjuvant and 44 adjuvant therapies. Median age was 57.5 years (range 31-75 years). Age (P = 0.02), percentage of treatment cycles completed (P = 0.014) and presence of alternative treatment options (P = 0.019) were significant factors for SACT discontinuation during the height of the Covid-19 pandemic. CONCLUSION: Factors affecting patients' decisions to discontinue SACT for early breast cancer during the Covid-19 pandemic were elucidated, which may help identify patients requiring additional support.

Evidence showing lipotoxicity worsens outcomes in covid-19 patients and insights about the underlying mechanisms.

We compared three hospitalized patient cohorts and conducted mechanistic studies to determine if lipotoxicity worsens COVID-19. Cohort-1 (n = 30) compared COVID-19 patients dismissed home to those requiring intensive-care unit (ICU) transfer. Cohort-2 (n = 116) compared critically ill ICU patients with and without COVID-19. Cohort-3 (n = 3969) studied hypoalbuminemia and hypocalcemia's impact on COVID-19 mortality. Patients requiring ICU transfer had higher serum albumin unbound linoleic acid (LA). Unbound fatty acids and LA were elevated in ICU transfers, COVID-19 ICU patients and ICU non-survivors. COVID-19 ICU patients (cohort-2) had greater serum lipase, damage-associated molecular patterns (DAMPs), cytokines, hypocalcemia, hypoalbuminemia, organ failure and thrombotic events. Hypocalcemia and hypoalbuminemia independently associated with COVID-19 mortality in cohort-3. Experimentally, LA reacted with albumin, calcium and induced hypocalcemia, hypoalbuminemia in mice. Endothelial cells took up unbound LA, which depolarized their mitochondria. In mice, unbound LA increased DAMPs, cytokines, causing endothelial injury, organ failure and thrombosis. Therefore, excessive unbound LA in the circulation may worsen COVID-19 outcomes.

Effects of Potential Micro- and Macro-nutrients in Combatting COVID-19.

PURPOSE OF REVIEW: Gain insight on the effect of some recently studied nutrients and nutritional markers on the COVID-19 disease course. RECENT FINDINGS: In vitro studies indicate that SCFAs do not interfere with SARS-CoV-2 infectivity. Observational studies indicate that eating processed or red meat three or more times per week had overall higher risk of pneumonia. Studies suggest that markers of regular outdoor physical activity (high HDL, lack of vitamin D deficiency, lack of obesity, etc.) prevent severe complications of COVID-19. SUMMARY: Although no definitive nutrients were found to significantly alter the COVID-19 disease course, some therapeutic candidates such as calcium, vitamin D, and albumin were surmised. Other nutrients that modulate serum lipid levels, cytokine levels, and albumin levels may hold promise for prevention of morbid or fatal outcomes related to COVID-19, as does the reduction of red or processed meat consumption.

Prognostic role of albumin level in heart failure: A systematic review and meta-analysis.

BACKGROUND: Hypoalbuminemia (HA) is common in HF, however, its pathophysiology and clinical implications are poorly understood. While multiple studies have been published in the past decade investigating the role of serum albumin in HF, there is still no consensus on the prognostic value of this widely available measure. The objective of this study is to assess the prognostic role of albumin in heart failure (HF) patient. METHODS: Unrestricted searches of MEDLINE, EMBASE, Cochrane databases were performed. The results were screened for relevance and eligibility criteria. Relevant data were extracted and analyzed using Comprehensive Meta-Analysis software. The Begg and Mazumdar rank correlation test was utilized to evaluate for publication bias. RESULTS: A total of 48 studies examining 44,048 patients with HF were analyzed. HA was found in 32% (95% confidence interval [CI] 28.4%-37.4%) HF patients with marked heterogeneity (I2 = 98%). In 10 studies evaluating acute HF, in-hospital mortality was almost 4 times more likely in HA with an odds ratios (OR) of 3.77 (95% CI 1.96-7.23). HA was also associated with a significant increase in long-term mortality (OR: 1.5; 95% CI: 1.36-1.64) especially at 1-year post-discharge (OR: 2.44; 95% CI: 2.05-2.91; I2 = 11%). Pooled area under the curve (AUC 0.73; 95% CI 0.67-0.78) was comparable to serum brain natriuretic peptide (BNP) in predicting mortality in HF patients. CONCLUSION: Our results suggest that HA is associated with significantly higher in-hospital mortality as well as long-term mortality with a predictive accuracy comparable to that reported for serum BNP. These findings suggest that serum albumin may be useful in determining high-risk patients.

Adipose saturation reduces lipotoxic systemic inflammation and explains the obesity paradox.

Obesity sometimes seems protective in disease. This obesity paradox is predominantly described in reports from the Western Hemisphere during acute illnesses. Since adipose triglyceride composition corresponds to long-term dietary patterns, we performed a meta-analysis modeling the effect of obesity on severity of acute pancreatitis, in the context of dietary patterns of the countries from which the studies originated. Increased severity was noted in leaner populations with a higher proportion of unsaturated fat intake. In mice, greater hydrolysis of unsaturated visceral triglyceride caused worse organ failure during pancreatitis, even when the mice were leaner than those having saturated triglyceride. Saturation interfered with triglyceride's interaction and lipolysis by pancreatic triglyceride lipase, which mediates organ failure. Unsaturation increased fatty acid monomers in vivo and aqueous media, resulting in greater lipotoxic cellular responses and organ failure. Therefore, visceral triglyceride saturation reduces the ensuing lipotoxicity despite higher adiposity, thus explaining the obesity paradox.

Oral vancomycin prophylaxis for the prevention of Clostridium difficile infection: A systematic review and meta-analysis.

OBJECTIVE: Recently, oral vancomycin prophylaxis (OVP) has been suggested for the prevention of Clostridium difficile infection (CDI). We conducted a systematic review and meta-analysis to investigate the efficacy and safety of this approach. DESIGN: Systematic review and meta-analysis. METHODS: We conducted a computerized search of MEDLINE, EMBASE, and Cochrane databases from inception to March 2019 for publications investigating OVP for CDI prevention. Results were screened for eligibility. Relevant data were extracted and analyzed. Publication bias was assessed using the Egger test. RESULTS: Ultimately, 8 retrospective studies and 1 prospective study examining 2174 patients, published between 2016 and 2019 were included in the review. OVP was associated with decreased CDI (odds ratio, 0.263; 95% confidence interval, 0.13-0.52) with considerable heterogeneity (I2 = 61%). Meta-regression showed that total daily dose of OVP correlated with CDI, explaining 100% of heterogeneity between studies. Furthermore, 3 studies evaluated the risk of vancomycin-resistant enterococci (VRE) infection after OVP and found no significant increase. CONCLUSION: Our results suggest that OVP might decrease CDI rates in at-risk populations, although this conclusion should be interpreted with caution. Higher daily doses of OVP might increase CDI. Although the use of OVP in high-risk patients may reduce CDI, this suggestion has yet to be validated by prospective blinded randomized controlled trials.

Thermodynamic interference with bile acid demicelleization reduces systemic entry and injury during cholestasis.

Bile acids (BA), with their large hydrophobic steroid nucleus and polar groups are amphipathic molecules. In bile, these exist as micelles above their critical micellar concentration (CMC). In blood at low concentrations, these exist as monomers, initiating cellular signals. This micellar to monomer transition may involve complex thermodynamic interactions between bile salts alone or with phospholipids, i.e. mixed micelles and the aqueous environment. We therefore went on to test if therapeutically relevant changes in temperature could influence micellar behavior of bile salts, and in turn whether this affected the biological responses in cells, and in vivo. Sodium taurocholate (STC) belongs to a major class of bile salts. STC has a CMC in the 5-8 mM range and its infusion into the pancreatic duct is commonly used to study pancreatitis. We thus studied micellar breakdown of STC using isothermal titration calorimetry (ITC), dynamic light scattering and cryogenic transmission electron microscopy. Under conditions relevant to the in vivo environment (pH 7.4, Na 0.15 M), ITC showed STC to have a U shaped reduction in micellar breakdown between 37 °C and 15 °C with a nadir at 25 °C approaching ≈90% inhibition. This temperature dependence paralleled pancreatic acinar injury induced by monomeric STC. Mixed micelles of STC and 1-palmitoyl, 2-oleyl phosphatidylcholine, a phospholipid present in high proportions in bile, behaved similarly, with ≈75% reduction in micellar breakdown at 25 °C compared to 37 °C. In vivo pancreatic cooling to 25 °C reduced the increase in circulating BAs after infusion of 120 mM (5%) STC into the pancreatic duct, and duct ligation. Lower BA levels were associated with improved cardiac function, reduced myocardial damage, shock, lung injury and improved survival independent of pancreatic injury. Thus micellar breakdown of bile salts is essential for their entry into the systemic circulation, and thermodynamic interference with this may reduce their systemic entry and consequent injury during cholestasis, such as from biliary pancreatitis.

Opioid use is associated with incomplete capsule endoscopy examinations: a systematic review and meta-analysis.

BACKGROUND: Capsule endoscopy (CE) is a non-invasive imaging modality designed to evaluate various small bowel pathologies. Failure to reach the cecum within the battery lifespan, termed incomplete examination, may result in inadequate testing and possibly delayed therapy. Several studies have attempted to evaluate the association between CE completion and opioid use. However, their results are conflicting. The aim of this meta-analysis is to evaluate the previously published literature on the association between opioid use and CE completion. METHODS: We performed a comprehensive literature search in PubMed, PubMed Central, Embase, and ScienceDirect databases from inception through June 1, 2018, to identify all studies that evaluated the association between CE completion and opioid use. We included studies that presented an odds ratio (OR) with a 95% confidence interval (CI) or presented the data sufficient to calculate the OR with a 95% CI. Statistical analysis was performed using the comprehensive meta-analysis (CMA), version 3 software. RESULTS: Five studies with a total of 1,614 patients undergoing CE in the inpatient (IP) and outpatient (OP) setting were included in this study, 349 of which had an incomplete CE (21.6%). The pooled OR for CE completion is 0.50 (95% CI: 0.38-0.66, I2=36.9%) in opioid users compared to non-users. No publication bias was found using Egger's regression test. CONCLUSIONS: Our results indicate that patients on opioids are significantly less likely to have a complete CE examination compared to non-users. To our knowledge, this study represents the first meta-analysis to assess this association.

Ringer's Lactate Prevents Early Organ Failure by Providing Extracellular Calcium.

OBJECTIVE: Ringer's lactate may improve early systemic inflammation during critical illnesses like severe acute pancreatitis, which are associated with hypocalcemia. Ringer's lactate is buffered and contains lactate and calcium. We, thus analyzed extracellular calcium or lactate's effects on the mechanisms, intermediary markers, and organ failure in models mimicking human disease with nonesterified fatty acid (NEFA) elevation. METHODS: Meta-analyses and experimental studies were performed. Experimentally, extracellular calcium and lactate were compared in their interaction with linoleic acid (LA; a NEFA increased in human severe pancreatitis), and its subsequent effects on mitochondrial depolarization and cytosolic calcium signaling resulting in cell injury. In vivo, the effect of LA was studied on organ failure, along with the effect of calcium or lactate (pH 7.4) on severe acute pancreatitis-associated organ failure. A meta-analysis of human randomized control trials comparing Ringer's lactate to normal saline was done, focusing on necrosis and organ failure. RESULTS: Calcium reacted ionically with LA and reduced lipotoxic necrosis. In vivo, LA induced organ failure and hypocalcemia. During severe pancreatitis, calcium supplementation in saline pH 7.4, unlike lactate, prevented hypocalcemia, increased NEFA saponification, reduced circulating NEFA and C-reactive protein , reduced pancreatic necrosis adjacent to fat necrosis, and normalized shock (carotid pulse distension) and blood urea nitrogen elevation on day 1. This, however, did not prevent the later increase in serum NEFA which caused delayed organ failure. Meta-analysis showed Ringer's lactate reduced necrosis, but not organ failure, compared with normal saline. CONCLUSION: Hypocalcemia occurs due to excess NEFA binding calcium during a critical illness. Ringer's lactate's early benefits in systemic inflammation are by the calcium it provides reacting ionically with NEFA. This, however, does not prevent later organ failure from sustained NEFA generation. Future studies comparing calcium supplemented saline resuscitation to Ringer's lactate may provide insights to this pathophysiology.

A Case of Black Esophagus.

Acute esophageal necrosis, commonly known as black esophagus, is a serious clinical condition that requires prompt diagnosis and management to improve morbidity and mortality. We present a 47-year-old woman who had this potentially lethal condition. The patient initially presented with hematemesis, and esophagogastroduodenoscopy at presentation showed diffuse esophageal ulcerations, erosions, and necrosis. During her admission, she required multiple blood transfusions for active bleeding, after which her clinical condition stabilized. Repeat esophagogastroduodenoscopy showed near-complete resolution of the earlier findings.

Factors That Affect Prevalence of Small Intestinal Bacterial Overgrowth in Chronic Pancreatitis: A Systematic Review, Meta-Analysis, and Meta-Regression.

OBJECTIVES: Small intestinal bacterial overgrowth (SIBO) can complicate chronic pancreatitis (CP) and interfere with management. Its predisposing factors in CP and treatment response are unknown. In this review, we evaluated factors affecting disease burden. METHODS: A computerized search of PubMed and EMBASE databases from inception through May 2019 was done for studies correlating SIBO with CP. Studies were screened, and relevant data were extracted and analyzed. Pooled prevalence, odds ratio (OR), and meta-regression were performed using the random effects model as classically described by Borenstein et al. (2009). SIBO's relation to diabetes mellitus (DM), pancreatic exocrine insufficiency (PEI), narcotic use, and proton-pump inhibitor use was investigated. Treatment response was pooled across studies. P value < 0.05 was considered significant. RESULTS: In 13 studies containing 518 patients with CP, SIBO prevalence was 38.6% (95% confidence interval [CI] 25.5-53.5). OR for SIBO in CP vs controls was 5.58 (95% CI 2.26-13.75). Meta-regression showed that PEI and the diagnostic test used were able to explain 54% and 43% of the variance in SIBO prevalence across studies, respectively. DM and PEI were associated with increased SIBO in CP with OR (2.1, 95% CI 1.2-3.5) and OR (2.5, 95% CI 1.3-4.8), respectively. Symptomatic improvement was reported in 76% of patients after SIBO treatment. DISCUSSION: SIBO complicates 38% of CP with OR of 5.58 indicating a predisposition for this condition. PEI correlates with SIBO in CP and might play a role in pathophysiology. DM and PEI are associated with increased SIBO in CP. Treatment of SIBO may lead to symptomatic improvement.