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Abstract Background and Aims Fibroblast–neutrophil interactions are implicated in ulcerative colitis (UC) treatment resistance, but whether fibroblasts modify neutrophil inflammatory activity remains unclear. We investigated responses to fibroblast exposure, stromal depletion, and α5β1-directed treatment. Methods We integrated human and mouse colonic single-cell RNA sequencing (scRNA-seq), spatial protein profiling (CODEX), fibroblast–neutrophil coculture, and dextran sulfate sodium (DSS) mouse colitis with fibroblast activation protein (FAP) ablation or α5β1-directed treatment. Readouts included cellular representation and protein fluorescence via flow cytometry, neutrophil extracellular trap (NET)-associated elastase activity, RNA programs and epithelial responses using scRNA-seq. Results Inflamed UC tissue contained higher fractions of inflammatory fibroblasts and oncostatin M (OSM)- and CXCR4-associated neutrophils. Inflammatory fibroblasts had higher FAP–α5β1 module scores, and proximity to FAP-high fibroblasts was associated with higher neutrophil OSM and CXCR4 fluorescence. UC fibroblasts increased neutrophil OSM, CXCR4 and myeloperoxidase (MPO) fluorescence and NET-associated elastase activity relative to control fibroblasts, while α5β1-directed treatment attenuated these responses. Both mouse FAP ablation and α5β1 blockade in DSS colitis reduced histologic inflammation and overall neutrophil frequency. Ablation broadly reduced recovered neutrophil representation, whereas blockade increased OSM-positive and PADI4-positive percentages within neutrophils despite lower MPO fluorescence within these subsets. Both interventions were associated with lower epithelial chemokine scores but distinct absorptive and mucus/secretory responses. Conclusions Fibroblast exposure modifies neutrophil inflammatory phenotype and effector-associated activity, identifying candidate therapeutic pathways in UC. Evaluating these responses alongside neutrophil representation and tissue inflammation could inform pharmacodynamic assessment of stromal-directed therapies. Graphical Abstract What You Need to Know Background and Context Fibroblast–neutrophil interactions are associated with treatment resistance in ulcerative colitis. Whether fibroblast exposure modifies neutrophil inflammatory phenotype and effector activity, beyond its established recruitment role, remains unclear. New Findings UC fibroblasts increased neutrophil inflammatory proteins and NET-associated elastase activity; α5β1-directed treatment attenuated these responses. FAP ablation and α5β1-directed treatment reduced colitis and overall neutrophil frequency. α5β1-directed treatment lowered MPO within OSM-positive and PADI4-positive neutrophils despite higher marker-positive percentages. Epithelial single-cell RNA sequencing revealed reduced chemokine programs with both interventions but distinct barrier-associated and regenerative expression patterns. Limitations Cellular drug targets remain unresolved. Spatial associations and elastase activity do not establish direct contact, NET formation, or clinical efficacy. Clinical Research Relevance Fibroblast-associated pathways offer candidate therapeutic opportunities to modify neutrophil inflammatory phenotype and effector activity in UC. Coculture responses were pharmacologically modifiable, and stromal interventions reduced experimental colitis. Measuring neutrophil frequency, subset proteins, and effector activity alongside tissue inflammation could guide pharmacodynamic assessment. Clinical efficacy and treatment-selection utility require validation. Basic Research Relevance Human coculture provides experimental evidence that fibroblast exposure modifies neutrophil inflammatory proteins and NET-associated elastase activity. FAP+ stromal ablation and α5β1-directed treatment produced distinct patterns of neutrophil representation and subset proteins in colitis. Epithelial single-cell RNA sequencing revealed reduced chemokine programs with both interventions but differing barrier-associated and regenerative expression patterns. Together, these findings motivate mechanistic studies of how stromal recruitment cues, soluble signals, and matrix-associated interactions regulate neutrophil responses, and whether these changes contribute to reduced epithelial inflammation and tissue repair. Lay Summary Fibroblasts, support cells in the intestine, increased inflammatory activity in immune cells called neutrophils. Blocking a pathway involved in cell attachment reduced these responses in cultures. Targeting fibroblast-associated pathways also reduced experimental colitis, with changes in intestinal lining gene activity related to inflammation, barrier function, and repair. These findings suggest potential approaches to treating ulcerative colitis.

Objective: The aim of this study was to evaluate outcomes of fenestrated-branched endovascular aortic repair (FB-EVAR) of thoracoabdominal aortic aneurysms (TAAAs) and complex abdominal aortic aneurysms (CAAAs) in patients actively smoking at the time of repair compared with previous smokers and non-smokers. Methods: Single-center retrospective review of elective FB-EVARs for TAAA and CAAAs between 2007 and 2023 was conducted. Demographics, comorbidities, aneurysm extent/ morphology, technical details, and peri-operative outcomes were collected. Patients were grouped into 1 of 3 groups: active smokers, prior smokers, and never smokers. Patients who stopped smoking within 6 weeks to surgery were considered active smokers. Rupture and symptomatic aneurysms were excluded. Endpoints included early (<30 days) mortality and major adverse events (MAEs). Results: There were 676 patients (73% male, mean age 74 ± 7.8). There were 141 (21%) active smokers, 455 (67%) prior smokers, and 80 (12%) never smokers. Active smokers were significantly younger than prior or never smokers (71 ± 6.7, 75 ± 6.9, and 76 ± 12, respectively; P < .001). Cardiovascular risk factors were similar, except active smokers were significantly more likely to have chronic obstructive pulmonary disease (60% vs 42% vs 6.2%, P < .001) and peripheral arterial disease (31% vs 24% vs 10%, P = .002) when compared to prior and never smokers, respectively. Patients who never smoked had significantly more extent II aneurysms (34%) than prior (18%) and active (15%) smokers, P = .001. Univariable and multivariable logistic regression analyses showed no statistically significant associations between smoking status and any specific peri-operative adverse events following surgery. Conclusion: Active smoking status does not appear to affect peri-operative outcomes after FB-EVAR for complex aortic aneurysms. Although smoking cessation must be strongly encouraged, repair should not be delayed due to active smoking status. Clinical Impact These data suggest that active smoking, in isolation, should not be considered a contraindication to elective FB-EVAR when anatomy is suitable and patients are otherswise optimized. This is particularly relevant for high-risk patients who may have limited alternative treatment options. Proceeding with FB-EVAR in active smokers does not appear to compromise early safety or procedural efficacy.

Chimeric antigen receptor (CAR) T-cell therapy is a transformative modality for refractory hematologic malignancies; however, its adoption in Latin America and the Caribbean (LAC) is severely constrained by prohibitive manufacturing costs, limited specialized infrastructure, and fragmented regulatory frameworks. To address this translational gap, we propose a pragmatic, cost-adapted model for establishing Good Manufacturing Practice (GMP) laboratories tailored to the socioeconomic realities of LAC. This model advocates for decentralized, modular cleanroom facilities that integrate fully closed automated manufacturing platforms with risk-based quality management systems. Furthermore, we emphasize the strategic implementation of artificial intelligence (AI) and digital health tools—such as electronic batch records and predictive analytics—to optimize resource utilization and ensure stringent regulatory compliance. Essential to this framework is the cultivation of a specialized local workforce and the promotion of regional regulatory harmonization through initiatives like PAHO’s Red PARF. Ultimately, this scalable approach provides a realistic roadmap to democratize CAR T-cell therapy in LAC, fostering regional biomanufacturing autonomy and promoting equitable patient access.

Abstract Objectives To systematically evaluate the certainty of evidence for treatment strategies across age groups and mood phases in bipolar disorder, and develop an open access web platform to facilitate shared decision making. Design Living umbrella review, evaluation, analysis, and communication hub (U-REACH) project. Data sources PubMed, PsycInfo, and Cochrane library databases, from inception to 19 November 2024. Eligibility criteria for selecting studies Systematic reviews with network or pairwise meta-analyses of randomised controlled trials of pharmacological, nutraceutical, psychosocial, brain stimulation, or circadian rhythm based treatments, administered as monotherapy (without concurrent interventions), augmentation treatment (interventions added to an ongoing treatment regimen), or combination treatment (simultaneous initiation of two different interventions), examining any age group, bipolar disorder phase (ie, acute bipolar depression, mania or mixed episodes, or maintenance), treatment, control, or outcome. Results 77 studies met the inclusion criteria (21 network meta-analyses and 56 pairwise meta-analyses), including 116 unique pharmacological (n=74), brain stimulation (n=18), nutraceutical (n=13), psychosocial (n=8), and circadian rhythm based (n=3) treatments as monotherapy, augmentation, or combination therapy, along with five control interventions. These studies covered 133 unique outcomes (45 efficacy outcomes and 88 safety outcomes) resulting in 2510 meta-analyses with Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) ratings of the certainty of the evidence as high (n=236), moderate (n=827), low (n=986), and very low (n=461). A communication hub, the Evidence Based Interventions for Bipolar Disorder (EBI-BD) platform, was developed and the full results are freely available ( https://ebibd-database.org ), including the preference based tool (12 interventions and 17 safety outcomes). Interventions effective across outcomes varied by phases. For bipolar depression, effective interventions in adults were cariprazine, divalproex or valproate, fluoxetine, ketamine (augmentation), lamotrigine, lumateperone, lurasidone, olanzapine, olanzapine with fluoxetine, and quetiapine, whereas effective interventions in children and adolescents were lurasidone and olanzapine with fluoxetine. For mania episodes, effective interventions in adults were aripiprazole, asenapine, carbamazepine, cariprazine, divalproex or valproate, haloperidol, lithium, olanzapine, paliperidone, quetiapine (also augmentation), risperidone (also as augmentation), tamoxifen, and ziprasidone, whereas effective interventions in children and adolescents were aripiprazole, asenapine, olanzapine, quetiapine, and risperidone. For maintenance, interventions effective across outcomes in adults were aripiprazole (also the long acting injectable formulation), asenapine, divalproex or valproate, lithium, olanzapine, group psychoeducation (augmentation), quetiapine, and risperidone long acting injectable formulation. Interventions effective across phases were aripiprazole (also as augmentation and as a long acting injectable formulation), asenapine, cariprazine, cognitive behavioural therapy (augmentation), divalproex or valproate, lamotrigine, lithium, olanzapine (also as augmentation), paliperidone, quetiapine (also as augmentation), and risperidone (also as augmentation and the long acting injectable formulation) (adults). Treatment effects by neuroscience based nomenclature classes are also reported. Conclusions The EBI-BD tool can help clinicians make evidence based, personalised treatment decisions for bipolar disorder. This resource can inform clinical guidelines and provides a foundation for continuously improving bipolar disorder care as new evidence emerges. Trial registration Open Science Framework https://osf.io/pjmvn/ Readers’ note This is a living systematic review and may be updated in the next two years if additional evidence emerges.

SUMMARY OBJECTIVE: The aim of this study was to estimate the prevalence of isthmocele using transvaginal ultrasound, magnetic resonance imaging and diagnostic hysteroscopy. METHODS: A cross-sectional study conducted from 2020 to 2022 in tertiary academic hospital with ninety non-pregnant women with a history of cesarean section. Transvaginal ultrasound (n=90), magnetic resonance imaging (n=65) and office diagnostic hysteroscopy (n=81) were performed within a short interval for each patient. RESULTS: The women had a mean age of 34.8±6.3 years, mean number of 2.0±1.1 cesarean sections and mean duration of 40 months since their last cesarean. The prevalence of isthmocele with 95%CIs was 11.3% (5.5–19.7%) on transvaginal ultrasound, 66.1% (53.3–77.4%) on magnetic resonance imaging, and 43.2% (32.2–54.6%) on diagnostic hysteroscopy. When transvaginal ultrasound was considered reference, accuracy for diagnostic hysteroscopy was 57.89% (44.1%; 70.6%) and magnetic resonance imaging, 43.86% (30.9; 57.5%); when magnetic resonance imaging was reference, accuracy for diagnostic hysteroscopy was 54.39% (40.75; 67.43%). Agreement analysis (kappa) among the methods showed low scores between diagnostic hysteroscopy and magnetic resonance imaging regarding transvaginal ultrasound (0.126, p<0.001 and 0.103, p<0.001, respectively) and between diagnostic hysteroscopy and magnetic resonance imaging (0.206, p=0.014). CONCLUSION: The prevalence of isthmocele was lower in transvaginal ultrasound and higher in magnetic resonance imaging. Accuracy varied from 43 to 58% among the three methods and agreement between tests for diagnosing isthmocele was low.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

Abstract In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject‐matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence‐synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment‐specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.

Background The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. Methods We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC‐PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation‐free survival across the new PH clusters. We quantify metabolites of the arginine‐nitric oxide pathway and D‐dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. Results Clustering analysis identify 3 clear clusters in CC ‐ PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation‐free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D‐dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. Conclusions We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.