Background and Clinical Significance: Congenital tufting enteropathy (CTE), or autosomal recessive congenital diarrhea type 5 (DIAR5), is a rare intestinal epithelial disorder characterized by severe neonatal-onset watery diarrhea, failure to thrive, and intestinal failure. Most cases are caused by biallelic EPCAM variants. Case Presentation: A 53-day-old female infant presented with severe watery diarrhea and failure to thrive from the first days of life. She was born at term with a birth weight of 3.4 kg and had 10-20 watery stools daily. At admission, she was dehydrated, dystrophic, and below the third weight percentile. Diarrhea persisted despite an amino acid-based formula and cessation of enteral feeding. Duodenal biopsy showed disturbed villous-crypt architecture, variable lamina propria inflammation, absence of intraepithelial lymphocytosis, epithelial tufts, and regenerative epithelial changes, supporting CTE. Whole-exome sequencing identified compound heterozygous EPCAM variants: a maternally inherited likely pathogenic frameshift variant, c.687_688del, p.(Lys230Asnfs*23), and a paternally inherited missense variant, c.757G>A, p.(Asp253Asn), classified as a variant of uncertain significance. TPN was initiated for intestinal failure. Follow-up was complicated by catheter-related sepsis, cholelithiasis, and recurrent pancreatitis requiring laparoscopic cholecystectomy. She subsequently tolerated limited enteral feeding but did not achieve enteral autonomy and remained dependent on TPN, while maintaining normal growth with nutritional support. Conclusions: CTE should be considered in infants with severe neonatal-onset diarrhea. Histopathology combined with genetic testing is essential for diagnosis. Long-term TPN and multidisciplinary management are required.

Gallbladder cancer (GBC) is usually described as the end point of chronic cholelithiasis-associated inflammation, and yet this linear formulation does not explain why only a small fraction of people with gallstones develop cancer, why histologically similar precursor lesions follow different evolutionary routes, or why invasion preferentially advances through anatomically and immunologically distinct interfaces. We propose a spatiotemporal ecosystem model that links five domains: gallstones and reflux as precipitating conditions; bile as a chemically active habitat; resident or transient microorganisms as context-dependent modifiers; metaplastic, biliary intraepithelial and intracholecystic precursor lineages as alternative epithelial trajectories; and stromal-immune niches that select for invasive phenotypes. Evidence from epidemiology, pathology, genomics, organoid and animal models, single-cell sequencing, and spatial profiling is integrated while preserving distinctions between association, mechanism, and clinical prediction. The strongest causal chain currently links prolonged mechanical or reflux injury with cycles of epithelial loss and repair, metaplastic or dysplastic changes, and acquisition of driver alterations. Microbial findings are biologically plausible and increasingly supported by functional Salmonella studies, but most human biliary microbiome datasets remain small and vulnerable to low-biomass contamination and treatment-related confounding. Precursor studies substantiate the existence of both BilIN progression in affected areas and alternative polypoid or BilIN-independent routes, arguing against a single obligatory sequence. Recent single-cell and spatial studies have identified organized, region-specific interactions among malignant epithelial states, macrophages, exhausted CD8 T cells, neutrophils, endothelial cells, fibroblasts, hepatocytes, and nerves at invasive margins. Liver-facing, serosal, perineural, lymphovascular, and nodal interfaces should not be assumed to share one ecology. These data shift the central question from which mutation is present to where a clone resides, which neighboring cells sustain it, and when the niche becomes permissive. The model suggests testable priorities: longitudinal sampling of high-risk gallbladders, paired bile-mucosa profiling with rigorous controls, lineage-resolved multi-section spatial analysis, and boundary-aware biomarkers validated in prospective cohorts.

Background: Given the increasing prevalence of dyslipidemia and multimorbidity in the older patient population, the lack of safety data on combined statin-fenofibrate therapy in this age group represents a critical gap. The post hoc subgroup analysis of the POSE study addresses this issue. Materials and Methods: The POSE study was a 3-year, real-world, observational, comparative, non-interventional study conducted in Europe. Patients with mixed dyslipidemia treated either by a fixed-dose combination of pravastatin 40 mg/fenofibrate 160 mg or a moderate-intensity statin monotherapy were enrolled. Safety outcomes included the occurrence of renal or urinary disorders, musculoskeletal or connective tissue disorders, hepatobiliary disorders, cholelithiasis, thromboembolic events, pancreatitis, worsening diabetes mellitus, elevated blood homocysteine levels, interstitial pneumopathy, phototoxicity, and fatal or non-fatal cardiovascular events. Laboratory parameters related to lipid control and renal, muscular, and hepatic functions were additionally evaluated. The post hoc analysis focused on a subgroup of patients aged 75 years and older. Results: A total of 458 patients were included in the analysis. The majority had hypertension (79.3%) and diabetes mellitus (55.0%). Over the 3-year study period, the incidence rate of composite safety events was numerically higher with the combination, though this did not reach statistical significance (RR = 2.18 [95% CI = 0.99-4.81]). Renal and urinary disorders were more frequent with the combination (5.5% vs. 0.8%), whereas musculoskeletal disorders, aggravated diabetes mellitus, and cardiovascular events showed no significant difference between groups, as the 95% confidence interval included 1. Globally, there were no significant differences regarding evolution of the hepatic, muscle, and renal biological parameters. From baseline to Year 3, TG levels decreased by 44.3% with pravastatin/fenofibrate and by 10.7% with statin monotherapy, while HDL-C levels increased by 26.5% and 0.4%, respectively. Conclusions: This real-life observational post hoc subgroup analysis suggests that in patients aged 75 years and older with mixed dyslipidemia at high or very high CV risk, pravastatin 40 mg/fenofibrate 160 mg demonstrates an acceptable long-term safety profile. The combination offers additional TG lowering and HDL-C improvement beyond moderate-intensity statin monotherapy, without a significant increase in overall safety events over three years.

Benign disease of the gallbladder is common and frequently treated by surgical removal of the gallbladder. Today, cholecystectomy is the most common operation performed by general surgeons, and the majority are done via minimally invasive techniques. However, during the early history of the surgical management of gallbladder disease, cholecystectomy was seldom performed due to perceived risks. We present a historical review of the management of benign gallbladder disease, delineating 4 distinct phases of the surgical approach to the disease. The management of benign gallbladder disease has drastically changed over the last 50 years, and innovations in the care of gallbladder patients have influenced nearly all aspects of abdominal surgery. We argue that the introduction of laparoscopic cholecystectomy was a watershed moment in the history of surgery, serving as a gateway procedure for minimally invasive surgery innovations that have occurred since.

Wünderlich syndrome, or spontaneous non-traumatic renal hemorrhage, is a rare and potentially life-threatening condition. We report the case of a 52-year-old woman presenting with right upper quadrant pain radiating to the lumbar region, bilious vomiting, and positive Murphy's and Giordano's signs, initially suggesting acute biliary disease. Ultrasonography demonstrated cholelithiasis and suspected choledocholithiasis; however, computed tomography urography revealed a large right-sided subcapsular and perirenal hematoma associated with a renal pelvic calculus. Because of the hematoma volume and suspicion of malignancy, nephrectomy was performed. Histopathological examination demonstrated an organized subcapsular hematoma with chronic inflammatory changes and no evidence of neoplasia. This case highlights the diagnostic challenge posed by atypical presentations of Wünderlich syndrome and underscores the essential role of computed tomography in distinguishing spontaneous renal hemorrhage from more common causes of acute abdominal pain.

Gallbladder, biliary, and pancreatic disorders are nonneoplastic diseases marked by inflammation, epithelial injury, and fibrosis. Cathepsins are lysosomal proteases involved in inflammatory activation, immune regulation, extracellular matrix turnover, and pancreatic enzyme activation. Observational links between dysregulated cathepsins and hepatopancreatobiliary pathology could reflect confounding or reverse causation. This study used Mendelian randomization (MR) to assess whether circulating cathepsins causally influence gallbladder, biliary, and pancreatic diseases. We conducted a 2-sample MR analysis using genetic variants associated with circulating cathepsin levels from the INTERVAL genome-wide association studies (3301 European participants). Summary statistics for cholecystitis, cholelithiasis, primary biliary cholangitis (PBC), primary sclerosing cholangitis, acute pancreatitis, and chronic pancreatitis were extracted from European-ancestry genome-wide association studies consortia. Instrumental variables were selected at P < 5 × 10-6 with linkage disequilibrium r2 < 0.001 to maximize instrument availability while retaining independence. The inverse-variance weighted estimator was the primary model, complemented by weighted median, MR-Egger, and mode-based methods. Instrument strength, pleiotropy, and heterogeneity were evaluated via F statistics, MR-Egger intercept, MR Pleiotropy RESidual Sum and Outlier, and Cochran Q. Benjamini-Hochberg false discovery rate (FDR) correction accounted for multiple testing, and sensitivity analyses included leave-one-out tests and PhenoScanner filtering. Two cathepsin B associations remained significant after FDR correction. Higher genetically predicted cathepsin B was linked to lower PBC risk (odds ratio [OR] = 0.784; 95% confidence interval [CI]: 0.664-0.925; P = .004; FDR = 0.022) and higher cholecystitis risk (OR = 1.080; 95% CI: 1.022-1.141; P = .006; FDR = 0.018). Other nominal associations did not survive correction and should be interpreted cautiously: cathepsin O with cholelithiasis (OR = 1.001; 95% CI: 1.000-1.003; P = .033; FDR = 0.199), cathepsin L2 with acute pancreatitis (OR = 1.156; 95% CI: 1.008-1.327; P = .038; FDR = 0.227), and cathepsin H with chronic pancreatitis (OR = 0.922; 95% CI: 0.853-0.997; P = .043; FDR = 0.255). No heterogeneity, horizontal pleiotropy, or reverse causation was detected. Genetically predicted cathepsin B appears protective for PBC but increases cholecystitis risk, supporting distinct causal roles among circulating cathepsins in hepatopancreatobiliary diseases. Associations involving cathepsin O, L2, and H were nominal, warranting cautious interpretation, replication, and further functional studies.

Introduction During laparoscopic cholecystectomy, pneumoperitoneum is created to facilitate exposure of the operative site. It provides the surgeon with adequate visualization; however, it has been associated with postoperative shoulder tip pain. As an alternative, low-pressure pneumoperitoneum (8-10 mmHg) has been proposed. This study compared the postoperative shoulder tip pain between standard- and low-pressure pneumoperitoneum created during laparoscopic cholecystectomy. Methods This was a prospective comparative study conducted in the Department of General Surgery over 18 months, following approval from the institutional ethics committee. After sample size calculation, 80 patients were enrolled who underwent elective laparoscopic cholecystectomy for uncomplicated cholelithiasis. They were randomly allocated into two equal groups: Group A (standard-pressure pneumoperitoneum) and Group B (low-pressure pneumoperitoneum). Postoperative shoulder tip pain and abdominal pain were assessed using the Visual Analog Scale. Additionally, demographic variables, operative time, intraoperative complications, and hospital stay duration were recorded. Results The mean intra-abdominal pressure (IAP) was significantly higher in Group A (11.51 ± 0.28 mmHg) than in Group B (9.50 ± 0.27 mmHg, p = 0.001). There were no reported instances of postoperative shoulder tip pain. Postoperative abdominal pain was recorded at 6, 12, and 24 hours, but it was comparable between both groups with no statistically significant differences. No statistically significant difference was observed for operative time, intraoperative complications, hospital stay, and postoperative complications between both groups. Conclusions No significant difference was noted between postoperative shoulder tip or abdominal pain in low- and standard-pressure pneumoperitoneum in patients undergoing laparoscopic cholecystectomy. Our findings suggest that pressure selection in laparoscopic cholecystectomy may be guided by surgeon preference rather than by differences in postoperative pain.