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Abstract Background Immunosuppression is a recognized risk factor for severe and disseminated coccidioidomycosis; however, data describing outcomes in patients with inflammatory bowel disease (IBD) receiving advanced therapy, including biologics and small molecules, remain limited. We aim to describe the prevalence, clinical presentation, treatment patterns, and outcomes of coccidioidomycosis in IBD patients receiving advanced therapy at an endemic tertiary care center. Methods We performed a retrospective observational study of adult patients with IBD at Mayo Clinic Arizona diagnosed with coccidioidomycosis between 2023 and 2026. Patients were included if IBD diagnosis preceded coccidioidomycosis diagnosis and advanced therapy had been active for at least 4 weeks before infection. Cases were classified as proven, probable, or possible based on microbiologic, clinical, radiographic, and serologic criteria. Clinical outcomes included antifungal treatment duration, hospitalization related to coccidioidomycosis or IBD, IBD treatment modification after diagnosis, re-emergence of coccidioidomycosis symptoms, and IBD-related surgery. Results A total of 48 patients met inclusion criteria. Among 1083 tested IBD patients receiving advanced therapy, coccidioidomycosis positivity prevalence was 4.4% when including all serologically positive patients and 1.9% when restricted to proven or probable cases. The median age at coccidioidomycosis diagnosis was 40 years (range 19-87 years), and 30 (62.5%) of 48 had Crohn’s disease. Proven or probable infection was identified in 21 (43.8%) of 48 patients, while 14 (29.2%) of 48 patients were classified as possible. Antifungal therapy was prescribed in 32 (66.7%) of 48 patients, including all proven cases, 15 (88.2%) of 17 probable cases, 9 (64.3%) of 14 possible cases, and 3 (25.0%) of 12 nondiagnostic cases. Among proven/probable/possible cases, the median antifungal treatment duration was 174 days (range 8-831 days). Advanced IBD therapy was continued in 3 (75.0%) of 4 proven cases, 9 (52.9%) of 17 probable cases, 12 (85.7%) of 14 possible cases, and all nondiagnostic cases. Hospitalization occurred in 6 (12.5%) of 48 of the cohort, all of which were proven/probable cases. Most patients remained on advanced therapy after diagnosis, although tumor necrosis factor α inhibitors were the most interrupted or discontinued agents. Conclusions In this endemic tertiary care cohort, management decisions varied according to diagnostic certainty. Patients with proven or probable coccidioidomycosis were more likely to receive antifungal therapy and undergo advanced IBD therapy modification, whereas most patients with possible or nondiagnostic serologic findings remained on advanced therapy without major IBD-related complications. Prolonged antifungal treatment was common, highlighting the complexity of managing coccidioidomycosis in immunosuppressed patients with IBD.

Eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) are immune-mediated disorders of the gastrointestinal (GI) tract that, despite involving different tissues, are increasingly recognized to coexist. Epidemiologic studies demonstrate a bidirectional association, with patients affected by one condition showing a higher-than-expected prevalence of the other, suggesting shared susceptibility rather than incidental overlap. Genetic and epigenetic data support partial convergence in immune regulatory pathways, while epithelial barrier dysfunction and antigen-driven immune activation emerge as common upstream features. Overlapping cytokine networks, including IL-4, IL-13, and IL-23 signaling, contribute to chronic inflammation in both diseases, although differences in tissue environment and immune dominance give rise to distinct inflammatory phenotypes and clinical behavior. Clinical outcomes in patients with dual diagnoses appear heterogeneous, with available data suggesting neither uniformly worsened nor clearly protective disease courses, underscoring the complexity of shared immune mechanisms operating within different anatomic contexts. Beyond inflammatory activity, coexistence of EoE and IBD poses important nutritional and quality-of-life challenges, as overlapping dietary restrictions and chronic symptoms increase the risk of malnutrition, micronutrient deficiencies, and psychosocial burden. Current therapies remain disease-specific, with strong evidence supporting proton pump inhibitors, swallowed topical steroids, dietary therapy, and dupilumab in EoE, and biologics and small molecules targeting TNF-α, IL-12/23, IL-23, integrins, and JAK–STAT signaling in IBD, while evidence guiding treatment in patients with dual diagnosis remains limited. Together, current evidence supports a framework of shared immune machinery with tissue-specific expression that explains coexistence while preserving the distinct identities of EoE and IBD. By integrating emerging genetic, immunologic, and clinical evidence, this review aims to provide a framework for understanding and managing patients with coexisting EoE and IBD.

Background: Perianal fistulizing Crohn’s disease (CD) is associated with significant morbidity and remains difficult to treat. Although advanced medical therapies are widely used, much of the available evidence derives from heterogeneous fistula populations or luminal CD trials, with limited perianal-specific synthesis and inconsistent outcome definitions. We conducted a systematic review focusing exclusively on perianal-specific clinical, radiologic, and composite outcomes in adults with perianal fistula (PAF) CD. Methods: We performed a systematic review in accordance with PRISMA 2020. Electronic databases were searched from inception through November 2025. We included randomized controlled trials and cohort studies enrolling adults with CD reporting outcomes specific to PAF. Interventions included biologics and small-molecule therapies, compared with placebo or other therapies. Due to substantial heterogeneity in outcome definitions and study designs, a meta-analysis was not performed. Risk of bias was assessed using Risk of Bias 2 (RoB 2) for randomized trials and the Newcastle–Ottawa Scale for observational studies. Results: Seven studies including >1200 participants with PAF-CD met inclusion criteria. Follow-up ranged from 24 weeks to 5 years. Across studies, outcome definitions and assessment modalities varied. Upadacitinib demonstrated significantly higher clinical fistula closure compared with placebo across multiple dose regimens at 52 weeks. In observational comparisons, ustekinumab and vedolizumab were associated with higher clinical closure rates than anti-TNF therapies. However, infliximab demonstrated higher closure rates than adalimumab as a first-line treatment. The definition for radiologic remission was less consistent across studies and often did not parallel clinical outcomes. Composite clinical–radiologic remission and response were reported in a limited number of studies, with filgotinib showing higher composite outcomes in comparison to placebo in a phase 2 trial. Surgical interventions, relapse outcomes, biomarkers [C-reactive protein (CRP)/fecal calprotectin (FCP)], and patient-reported outcomes were variably reported and not consistently significant across comparisons. Conclusions: Evidence for advanced therapies in PAF CD remains limited by heterogeneity in endpoint definitions, subjectivity in clinical observation, inconsistent radiologic reporting, and reliance on subgroup or observational comparisons. While anti-TNF therapy remains the most established option in guidelines, emerging data suggest significant benefits with ustekinumab, vedolizumab, and JAK inhibitors in selected patients. There is a need for PAF-specific, adequately powered randomized trials using standardized composite clinical and radiologic endpoints.

Acute severe ulcerative colitis (ASUC) is a medical emergency affecting up to 25% of patients with ulcerative colitis (UC), with colectomy required in approximately 25–30% of cases during the initial admission. Intravenous corticosteroids remain the first-line therapy, though one-third of patients do not respond, necessitating rescue with infliximab or calcineurin inhibitors, which are both supported by randomized trials and guideline recommendations. Comparative studies and meta-analyses have shown similar efficacy between these agents, while sequential use is associated with higher adverse event rates and should be restricted to specialized centers. Recent data have refined infliximab use, with the PREDICT-UC trial showing no superiority of intensified dosing over standard regimens. Emerging therapies are under investigation: vedolizumab has been used as maintenance following calcineurin induction; ustekinumab has shown benefits in retrospective UC cohorts, particularly after cyclosporine; and Janus kinase (JAK) inhibitors represent the most recent addition. The randomized TACOS trial and the prospective TRIUMPH study demonstrated an improved short-term response with tofacitinib in steroid-refractory ASUC, and real-world reports suggest promising outcomes with upadacitinib. While infliximab and cyclosporine remain as standard rescue therapies, ongoing trials with novel agents are likely to broaden treatment options. This review summarizes the clinical features, initial management, and the role of advanced therapies in ASUC.

Significant progress has been made in treating Coronavirus disease (COVID) – an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). An ominous turn in the pandemic is the evolving public health crisis emanating from persistent SARS-CoV-2 infection and its associated long-term impact. Long COVID or post–COVID syndrome describes protean symptoms that persist at least 3 months after the onset of acute illness and last for at least 2 months in individuals with a history of confirmed SARS-CoV-2 infection. Long COVID has become a public health concern. Millions of infected individuals are now facing chronic multi-organ failures, including neuropsychiatric, cardiovascular, pulmonary, and kidney complications. In general, the cause of long COVID syndrome is unclear but factors such as prolonged activation of immune responses, and viral persistence triggering transcription dysregulation of genes associated with normal thrombotic disease may play a role in cardiovascular complications. Although inflammatory biomarkers are reported in other disorders, it remains unclear whether similar biomarkers are associated with cardiovascular manifestations following COVID. Medications such as sulodexide directed at glycocalyx and coagulation have demonstrated benefits for long COVID in smaller studies. Here, we describe the outcomes of the symposium on the underlying cardiovascular mechanisms of the long COVID.

The evaluation, classification, and treatment of significant bone loss after total knee arthroplasty (TKA) continue to be a complex and debated topic in revision TKA (rTKA). Despite the introduction of new evidence and innovative technologies aimed at addressing the approach and care of severe bone loss in rTKA, there is no single document that systematically incorporates these newer surgical approaches. Therefore, a comprehensive review of the treatment of severe bone loss in rTKA is necessary. The Stavros Niarchos Foundation Complex Joint Reconstruction Center Hospital for Special Surgery, dedicated to clinical care and research primarily in revision hip and knee replacement, convened a Management of Bone Loss in Revision TKA symposium on June 24, 2022. At this meeting, the 42 international invited experts were divided into groups; each group was assigned to discuss questions related to 1 of the 4 topics: (1) assessing preoperative workup and imaging, anticipated bone loss, classification system, and implant surveillance; (2) achieving durable fixation in the setting of significant bone loss in revision TKA; (3) managing patellar bone loss and the extensor mechanism in cases of severe bone loss; and (4) considering the use of complex modular replacement systems: hinges, distal femoral, and proximal tibial replacements. Each group came to consensus, when possible, based on an extensive literature review and interactive discussion on their group topic. This document reviews each these 4 areas, the consensus of each group, and directions for future research.

Background Evidence-based international expert consensus regarding the impact of peripheral nerve block (PNB) use in total hip/knee arthroplasty surgery. Methods A systematic review and meta-analysis: randomized controlled and observational studies investigating the impact of PNB utilization on major complications, including mortality, cardiac, pulmonary, gastrointestinal, renal, thromboembolic, neurologic, infectious, and bleeding complications. Medline, PubMed, Embase, and Cochrane Library including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, were queried from 1946 to August 4, 2020. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess evidence quality and for the development of recommendations. Results Analysis of 122 studies revealed that PNB use (compared with no use) was associated with lower ORs for (OR with 95% CIs) for numerous complications (total hip and knee arthroplasties (THA/TKA), respectively): cognitive dysfunction (OR 0.30, 95% CI 0.17 to 0.53/OR 0.52, 95% CI 0.34 to 0.80), respiratory failure (OR 0.36, 95% CI 0.17 to 0.74/OR 0.37, 95% CI 0.18 to 0.75), cardiac complications (OR 0.84, 95% CI 0.76 to 0.93/OR 0.83, 95% CI 0.79 to 0.86), surgical site infections (OR 0.55 95% CI 0.47 to 0.64/OR 0.86 95% CI 0.80 to 0.91), thromboembolism (OR 0.74, 95% CI 0.58 to 0.96/OR 0.90, 95% CI 0.84 to 0.96) and blood transfusion (OR 0.84, 95% CI 0.83 to 0.86/OR 0.91, 95% CI 0.90 to 0.92). Conclusions Based on the current body of evidence, the consensus group recommends PNB use in THA/TKA for improved outcomes. Recommendation: PNB use is recommended for patients undergoing THA and TKA except when contraindications preclude their use. Furthermore, the alignment of provider skills and practice location resources needs to be ensured. Evidence level: moderate; recommendation: strong.

The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.

Introduction . The triglyceride and glucose (TyG) index has been described as a biochemical marker of insulin resistance (IR); however, its diagnostic accuracy remains uncertain. Objective . To summarize the evidence assessing the diagnostic accuracy of the TyG index regarding IR. Methods . A comprehensive search in MEDLINE, EMBASE, Web of Science, and Scopus was performed without any language restriction. Studies assessing the diagnostic accuracy of the TyG index against the hyperinsulinemic-euglycemic clamp (HIEC) or any other IR biochemical were assessed independently and in duplicate. Diagnostic accuracy measures (sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios) were extracted independently and in duplicate. The QUADAS-2 tool was used to assess the risk of bias of independent studies. Results . We identified 15 eligible studies with 69,922 participants and an overall quality of low to moderate. The TyG index was evaluated by HIEC and HOMA as reference tests. The highest achieved sensitivity was 96% using HIEC, and the highest specificity was of 99% using HOMA-IR, with a cutoff value of 4.68. AUC values varied from 0.59 to 0.88. Cutoff values for IR were variable between studies, limiting its comparability. Conclusion . In this systematic review, we found moderate-to-low quality evidence about the usefulness of the TyG index as a surrogate biochemical marker of IR. Due to the lack of a standardized IR definition and heterogeneity between studies, further validation and standardized cutoff values are needed to be used in clinical practice.

Background . Hypertriglyceridemia and hyperglycemia coexist in 30-60% of patients with diabetes. The impact of hypertriglyceridemia regarding HbA1c assay reliability remains uncertain. Therefore, we conducted a prospective in vivo controlled study with the aim of defining the association between triglyceride levels and HbA1c. Methods . A total of 44 patients with an index-hospital admission diagnosis of diabetic ketoacidosis or hypertriglyceridemia-induced pancreatitis, as a model for acute elevation of triglycerides, were recruited. Blood samples were drawn for the measurement of HbA1c, triglycerides, glucose, and hemoglobin at baseline and subsequently 24 and 48 hours after admission. HbA1c analysis was performed with high-performance liquid chromatography Bio-Rad D10 (NGSP approved). Results . All patients completed the study protocol. A difference between mean triglycerides from day 0 (baseline) to day 2 of 1567.2 mg/dL was observed. We found a difference between mean serum HbA1c from days 0 to 2 of 0.09% [1 mmol/mol] ( p = 0.004 ). Moreover, a weak correlation between the mean difference of HbA1c and triglycerides from baseline to day 2 was found to be statistically significant ( r = 0.256 , p = 0.015 ). None of these findings, however, are clinically significant. Conclusion . Triglycerides do not impair the interpretation of HbA1c assay. Patients and clinicians can now be confident that hypertriglyceridemia is not an important factor when interpreting HbA1c results.