Parakkal Deepak

Ferroptosis is an iron-dependent type of cell death caused by excessive membrane lipid peroxidation. It remains a challenge to detect ferroptotic cells, especially in in vivo settings, hindering translational studies. Here we discover that a reducing reagent-resistant (3R) dimer of the transferrin receptor 1 (TfR1) is a highly specific indicator for lipid peroxidation. The 3R dimer is elevated in cells when ferroptosis is induced, either by pharmacological agents or by genetic perturbations. Furthermore, the 3R dimer can be used to detect disease-associated ferroptosis in tissue and in extracellular vesicles isolated from mouse or patient plasma. Given the near-ubiquitous expression of TfR1, we posit that the 3R dimer may function as a ferroptosis marker with widespread potential utility for basic and translational studies.

Background and Aims: Isolated perianal fistulizing Crohn’s disease (IPFCD) is an uncommon presentation of Crohn’s disease with an uncertain natural history. We aimed to characterize contemporary diagnostic strategies, management approaches, and long-term outcomes, including progression to luminal Crohn’s disease. Methods: We conducted a retrospective multicenter cohort study across 25 centers within the ECCO-CONFER network. Adult patients with IPFCD and no evidence of luminal Crohn’s disease at baseline were included. The primary outcome was progression to luminal Crohn’s disease. Secondary outcomes included clinical and radiological fistula response and patterns of medical and surgical management. Time-to-event analyses were performed using Kaplan–Meier methods. Results: A total of 121 patients were included with a median follow-up of 76 months (IQR 46-118). Diagnostic pathways were heterogeneous, with most patients undergoing colonoscopy (91.7%) and pelvic magnetic resonance imaging (63.6%), alongside variable use of additional modalities. Management was intensive, with 76.9% receiving biologic therapies and 85.1% undergoing combined medical–surgical treatment. Complete clinical remission was achieved in 57% of patients, while radiological healing was observed in 46.4%. During follow-up, 42 (34.7%) patients developed luminal Crohn’s disease. Median progression-free survival was 145.6 months, with a median time to luminal diagnosis of 110 months (IQR 40-152). No consistent predictors of progression were identified. Conclusions: Approximately one-third of patients with IPFCD developed luminal Crohn’s disease over long-term follow-up, typically after several years. However, many patients remain free of intestinal involvement, reflecting a heterogenous disease course and highlighting the need for standardized evaluation and improved risk stratification.

Obesity is increasingly prevalent among patients with inflammatory bowel diseases (IBD), with more than half of individuals with Crohns disease (CD) or ulcerative colitis (UC) classified as overweight or obese at diagnosis. Beyond body mass index (BMI), visceral adipose tissue (VAT) is emerging as a critical determinant of adverse IBD outcomes, including increased disease activity, reduced therapeutic response, higher surgical risk, and postoperative recurrence. Obesity and excess VAT also amplify cardiometabolic comorbidities commonly observed in IBD, such as metabolic dysfunction–associated steatotic liver disease (MASLD) and atherosclerotic cardiovascular disease (CVD), even in patients without traditional risk factors. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed obesity management and confer established CVD and metabolic benefits. Preclinical studies show that GLP-1 RAs reduce visceral adiposity, modulate gut microbiota, enhance intestinal barrier integrity, and attenuate proinflammatory signaling pathways relevant to IBD pathogenesis. Emerging human data suggest that therapy with GLP-1 RAs is safe in patients with IBD and is associated with lower rates of hospitalization and surgical risk, particularly among patients with obesity, although effects on disease activity remain unclear. Several ongoing randomized controlled trials are evaluating GLP-1 RAs as adjunctive therapy for IBD. Beyond intestinal inflammation, GLP-1 RAs may favorably impact IBD-associated comorbidities, including MASLD, CVD, neurologic disorders, chronic pain, and metabolic bone disease. Important considerations include gastrointestinal tolerability, procedural implications for endoscopy, and the risk of lean muscle mass loss, underscoring the need for multidisciplinary care. As obesity becomes increasingly common in IBD, GLP-1 RAs represent a promising therapeutic strategy warranting further prospective investigation.

BACKGROUND Large language models (LLMs) offer promise for systematic review data extraction, but performance in complex multidisciplinary domains and utility for clinical statement generation remain insufficiently described. OBJECTIVE To evaluate Google NotebookLM for AI-assisted data extraction and RAND/UCLA consensus statement generation in a systematic review of IBD, obesity, and cardiometabolic comorbidities. METHODS Studies were organized into domain-specific notebooks; structured prompts generated standardized evidence tables. Two independent reviewers validated outputs against full-text articles using a four-category error classification. Cell-level accuracy and critical accuracy (cells free of major factual errors) were the primary metrics; workflow time was compared against a published conventional extraction benchmark. Concordance between AI-generated and expert-finalized statements was assessed. RESULTS Across 57 articles, 1,710 data cells were extracted; 151 (8.83%) were flagged, yielding 91.17% cell-level accuracy. Major factual errors occurred in only 4 cells (0.23%), for a critical accuracy of 99.77%. Most errors were minor omissions (59.6%) or incomplete extractions (30.5%); domain error rates ranged from 7.08% to 11.33%. The pipeline required 17.7 versus a projected 165.1 person-hours (89.3% reduction). PICO-structured prompting generated 70 candidate statements; 58 of 112 finalized panel statements (51.8%) were AI-derived, and 85.7% were retained in the finalized set. CONCLUSIONS Google NotebookLM demonstrates feasibility as a primary extraction and synthesis tool in a multidisciplinary systematic review, with extractive incompleteness as the principal limitation and substantial time savings over conventional approaches. Its novel application to RAND/UCLA consensus statement generation extends AI-assisted evidence synthesis to clinical consensus generation workflow.

Infliximab (IFX) has traditionally been administered intravenously (IV) for the treatment of moderate-to-severe ulcerative colitis (UC) and Crohn’s disease (CD). Advances in biologic drug delivery and evolving patient preferences have led to the development of subcutaneous (SC) formulations that permit self-administration. Compared with IV dosing, SC IFX offers several potential advantages, including greater convenience and flexibility, reduced healthcare utilization, and more stable serum drug exposure. Evidence supporting SC IFX has emerged from pharmacokinetic studies, randomized controlled trials, real-world cohorts, and meta-analyses. These studies suggest that SC IFX is effective and generally well tolerated in selected patients with inflammatory bowel disease (IBD), particularly following successful IV induction therapy. Despite these data, uptake of SC IFX in routine clinical practice remains relatively limited. Potential barriers include prescriber familiarity with IV therapy, concerns regarding patient adherence, reimbursement structures, and limited awareness of SC formulations. In this review, we summarize the current evidence supporting SC IFX, critically examine pharmacokinetic and immunogenicity considerations, discuss practical implementation challenges, and highlight unresolved questions regarding patient selection, dose optimization, and long-term positioning of SC IFX within contemporary IBD management.

Background: Large language models (LLMs) offer promise for systematic review data extraction, but performance in complex multidisciplinary domains and utility for clinical statement generation remain insufficiently described. Objectives: To evaluate Google NotebookLM for AI-assisted data extraction and RAND/UCLA consensus statement generation in a systematic review of IBD, obesity, and cardiometabolic comorbidities. Methods: Studies were organized into domain-specific notebooks; structured prompts generated standardized evidence tables. Two independent reviewers validated outputs against full-text articles using a four-category error classification. Cell-level accuracy and critical accuracy (cells free of major factual errors) were the primary metrics; workflow time was compared against a published conventional extraction benchmark. Concordance between AI-generated and expert-finalized statements was assessed. Results: Across 57 articles, 1,710 data cells were extracted; 151 (8.83%) were flagged, yielding 91.17% cell-level accuracy. Major factual errors occurred in only 4 cells (0.23%), for a critical accuracy of 99.77%. Most errors were minor omissions (59.6%) or incomplete extractions (30.5%); domain error rates ranged from 7.08% to 11.33%. The pipeline required 17.7 versus a projected 165.1 person-hours (89.3% reduction). PICO-structured prompting generated 70 candidate statements; 58 of 112 finalized panel statements (51.8%) were AI-derived, and 85.7% were retained in the finalized set. Conclusion: Google NotebookLM demonstrates feasibility as a primary extraction and synthesis tool in a multidisciplinary systematic review, with extractive incompleteness as the principal limitation and substantial time savings over conventional approaches. Its novel application to RAND/UCLA consensus statement generation extends AI-assisted evidence synthesis to clinical consensus generation workflow.

Perianal fistulas are a common complication of Crohn's disease. Despite the current treatment options, fistula recurrence/treatment failure rates are high. The aim of this study was to assess healthcare resource utilization (HCRU) among patients with new, persistent, and recurrent Crohn's perianal fistulas (CPF) in the USA. A retrospective, multi-site medical chart review was conducted in patients with CPF. Data on HCRU were collected for ≥2 years after the index date (date of most-recent episode of CPF symptoms between January 2016 and December 2018). In total, 227 patients were included among whom there were 236 fistulas: new (n = 94, 39.8%), persistent (n = 108, 45.8%), and recurrent (n = 34, 14.4%). Mean (standard deviation [SD]) age was 47.7 (13.7) years, 81.5% were White, 50.7% were male. After index (mean follow-up 33.8 months), 67.0% of patients received medical treatments, 59.9% had surgical interventions, and 42.7% received both. The mean (SD) number of CPF-related and all-cause outpatient visits was 8.75 (8.20) and 18.27 (16.96), the mean (SD) number of CPF-related and all-cause emergency room visits was 0.06 (0.27) and 0.65 (1.55), and the mean (SD) number of CPF-related and all-cause inpatient visits was 0.30 (0.79) and 0.83 (1.81), respectively. Patients with new fistulas had more CPF-related and all-cause outpatient visits and fewer all-cause inpatient visits than patients with persistent/recurrent fistulas (p < 0.05). The use of biologics for underlying Crohn's disease before index was not captured. Furthermore, this study was subject to missing data and limited generalizability (most sites located in Midwest USA). There is a substantial HCRU burden among patients with CPF, likely owing to the requirement for multiple and repeated interventions, indicating an unmet need for effective management strategies that promote long-term fistula healing to ultimately support reduced patient burden and HCRU.

Due to increasingly nuanced Crohn disease therapy selection and disease evaluation, radiologic assessment of transmural healing, although aspirational, may be more complete than endoscopic assessment of mucosal healing, which is the current treatment target.

Introduction: Obesity and related cardiometabolic comorbidities, including hypertension, dyslipidaemia, diabetes, metabolic dysfunction-associated steatotic liver disease and atherosclerotic cardiovascular disease, are increasingly prevalent among individuals with inflammatory bowel disease (IBD). These conditions influence disease activity, therapeutic response, surgical outcomes and overall quality of life, yet evidence remains fragmented. The M odulate O besity and relate D metabolic compl I cations F or Y ielding improvements in IBD outcomes (MODIFY-IBD) initiative aims to synthesise evidence and generate consensus recommendations to guide practice and future research in this area. This study describes a protocol for a structured evidence synthesis and Research ANd Development/University of California, Los Angeles (RAND/UCLA) Appropriateness Method (RUAM) consensus process. Methods and analysis: We will conduct three systematic reviews and a structured evidence synthesis organised into three domains: (1) the impact of obesity on IBD outcomes, (2) the burden of cardiometabolic complications in IBD and (3) the management of overweight, obesity and cardiometabolic comorbidities in IBD. A multidisciplinary international panel of gastroenterologists, surgeons, endocrinologists, hepatologists, cardiologists and dietitians will assess each statement using the RAND/UCLA appropriateness method. Panellists will rate the appropriateness of each statement (only those that fall within their area of expertise) on a 1–9 scale (1–3=inappropriate, 4–6=uncertain and 7–9=appropriate), with medians rounded up (eg, 6.5=appropriate). Agreement will be assessed using the RAND Disagreement Index (DI<1.0=agreement). Ethics and dissemination: This study will not involve direct patient participation, as it is based on evidence synthesis and expert consensus; therefore, formal research ethics committee approval will not be required. Patient representatives will contribute to the consensus process to provide contextual perspectives but no identifiable data will be collected. Findings will be disseminated through publication in peer-reviewed journals, presentation at major gastroenterology and IBD conferences and communication with professional societies. A lay summary and patient-friendly infographic will also be developed to facilitate translation of recommendations into clinical practice. PROSPERO registration numbers: CRD420251178843: a systematic review of the impact of obesity on inflammatory bowel disease outcomes. CRD420251178799: a systematic review of cardiometabolic complications in inflammatory bowel disease. CRD420251174653: management of overweight, obesity and cardiometabolic comorbidities in inflammatory bowel disease: a systematic review.