Journal of Cellular and Molecular Medicine

Background: Lumbar disc herniation, with or without concomitant disc degeneration, is a major cause of lumbar radiculopathy and low back pain, which also a key public musculoskeletal disorder without an exact pathophysiology. Studies have suggested that inflammatory cells and biochemical markers of inflammation also play an important role in lumbar radiculopathy in addition to nerve compression. The aim of the present study was to assess the association of selected circulatory inflammatory markers (CRP, hs-CRP and E-selectin) in patients with lumbar disc herniation without radiological degeneration (LDH) and lumbar disc herniation with radiological degeneration (LDHD). Materials & methods: This case-control study included 208 participants, comprising 104 patients with lumbar disc pathology and 104 controls. Patients were further stratified into LDH (n=67) and LDHD (n=37). Serum CRP, hs-CRP and E-selectin concentrations were measured. Results: Among the patients, 35.6 % presented with LDHD while 64.4 % had only LDH. Significantly increased median hs-CRP (p<0.001) and CRP (p<0.001) were observed in patients groups compared to controls, while CRP showing a consistent independent association across the combined disease (OR=1.68, 95% CI=1.33-2.14, p<0.001), LDHD (OR=1.62, 95% CI=1.16-2.20, p=0.005) and LDH (OR=1.69, 95% CI=1.30-2.20, p<0.001) multivariable models. No significant difference was observed in serum E-selectin between the study groups. Multivariable models incorporating inflammatory and clinical variables demonstrated substantially greater discriminatory performance than individual biomarkers alone. Conclusion: Elevated circulating CRP and hs-CRP concentrations were associated with lumbar disc pathology, with CRP showing a consistent independent association across the combined disease, LDH and LDHD multivariable models, whereas E-selectin showed no significant association. Multivariable models incorporating inflammatory and clinical variables demonstrated greater discriminatory performance than individual biomarkers. These findings support a potential systemic inflammatory component in lumbar disc pathology, although the cross-sectional nature of the measurements does not establish causality or a local inflammatory response within the disc.

Background: Patients receiving anti-TNF treatment for chronic inflammatory disease display impaired antibody responses, but it remains unclear how immune memory formation is affected. We evaluated antibody responses and memory B cells (Bmem) after COVID-19 booster vaccination in inflammatory bowel disease (IBD) patients receiving anti-TNF treatment. Methodology: Blood was sampled at baseline, 1, and 6 months after WH1/BA.5 bivalent or XBB.1.5 monovalent vaccination from 27 IBD patients receiving intravenous anti-TNF and 44 controls. Neutralizing antibodies were measured using an infectious virus assay. SARS-CoV-2 spike receptor binding domain (RBD)-specific serum IgG was quantified by ELISA, and RBD-specific Bmem were immunophenotyped by flow cytometry using recombinant proteins from ancestral, Omicron BA.1, BA.5, XBB.1.5, and JN.1 variants. Results: Serum IgG to vaccine RBD and neutralizing antibodies in patients increased pre to 1 month post-vaccination, but were lower than controls. Ancestral-, BA.5- and XBB.1.5-specific Bmem increased after vaccination but were significantly lower in patients than controls. Within RBD-specific Bmem, frequencies of recently activated CD21lo cells were increased after vaccination, and were higher in patients than controls. Fewer antigen-specific Bmem in patients expressed IgG4, and more expressed IgG3 or IgD following vaccination. Following vaccination, more RBD-specific Bmem recognized multiple viral variants. However, patients had fewer Bmem that could bind to subvariants than controls. Conclusion: Antibody and Bmem responses to COVID-19 booster vaccination in anti-TNF-treated IBD patients displayed reduced capacity, durability and cross-reactivity, suggesting impaired immune memory for protection against breakthrough infection. This supports the recommendation for annual booster vaccination to prevent severe disease and viral spread.

Background: Severe aortic stenosis is associated with systemic and splanchnic hemodynamic disturbances that may alter gut microbial metabolism and host inflammatory responses. Objectives: We aimed to determine whether TAVI remodels the gut microbiome-derived metabolome and whether post-procedural SCFA dynamics are associated with the inflammatory cytokine response. Methods: We conducted a prospective paired single-center study of patients undergoing elective TAVI at Bern University Hospital. Stool and blood samples were collected before and three months after the procedure. Gut microbial composition was profiled by full-length 16S rRNA sequencing, circulating short-chain fatty acids (SCFAs) by targeted metabolomics, and inflammatory mediators by multiplex cytokine analysis, and integrated with hemodynamic and clinical data. Results: Forty patients were enrolled. Following TAVI, microbial richness declined without significant restructuring of overall community composition. In contrast, circulating SCFA profiles were significantly remodeled, driven by selective reductions in butyrate and isovalerate. A greater decline in circulating butyrate was inversely associated with IL-18 elevation (rho=0.668, p<0.001, n=36), independent of aortic valve calcification burden, hemodynamic improvement, and cardiovascular medications. Baseline isovalerate was nominally associated with 1-month adjudicated adverse events (AUC 0.77; exploratory). Conclusions: TAVI is associated with selective changes in gut microbiome-derived metabolic output rather than broad alterations in microbial community structure. Declining circulating butyrate identifies a gut-metabolite-immune axis linked to IL-18 dynamics and represents a potential biomarker of inflammatory recovery following valve intervention.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease characterized by progressive medial degeneration, impaired mechanical integrity, and extracellular matrix (ECM) degradation. However, no pharmacological therapy has been proven to halt aneurysm progression or prevent dissection or rupture. Vascular smooth muscle cells (VSMCs) are vital for maintaining medial architecture by sensing and remodeling the surrounding ECM; however, the mechanism by which abnormal ECM mechanics are transmitted to nuclear transcriptional programs that disrupt aortic wall matrix homeostasis remains incompletely understood. Integrative transcriptomic screening of Lysyl oxidase (LOX)-deficient and ?-aminopropionitrile (BAPN)-induced TAAD models identified vestigial-like family member 4 (VGLL4) as a mechanosensitive transcriptional regulator of TAAD. VGLL4 was enriched in VSMCs and markedly increased in aortas from patients with TAAD and BAPN-induced TAAD mice. VSMC specific deletion of Vgll4 protected mice from BAPN-induced aortic dilation, dissection, rupture-associated mortality, vascular stiffening, ECM degradation, and medial destruction. Mechanistically, pathological matrix remodeling and mechanical stress induced VGLL4 expression in VSMCs, where VGLL4 cooperated with specificity protein 1 (SP1) to activate Wisp1 transcription. In vivo, VSMC-enriched Wnt-inducible signaling pathway protein (WISP1) overexpression exacerbated TAAD progression, whereas Wisp1 knockdown protected against BAPN-induced TAAD and mitigated the severe aortic phenotype driven by VGLL4 overexpression. Secreted WISP1 bound Tissue Inhibitor of Metalloproteinases 3 (TIMP3) through its C-terminal domain and impaired TIMP3-mediated MMP9 inhibition, thereby increasing MMP9 proteolytic activity and accelerating ECM degradation. Consistently, in vivo Wisp1 knockdown protected against BAPN-induced TAAD. Together, these findings define the VGLL4-WISP1-TIMP3/MMP9 axis, which couples pathological ECM mechanics to nuclear transcriptional activation and protease-dependent matrix degradation in VSMCs. This pathway promotes medial structural failure, aortic mechanical stability loss, and TAAD progression, identifying WISP1 as a potential therapeutic target for preserving aortic wall matrix homeostasis.

Background: Transplant arterial injury is an underlying feature of acute organ transplant rejection and is a main cause of late heart transplant failure. The role of the gut microbiota, and especially specific microbial components of this community, in controlling immune responses that cause this aspect of rejection is poorly understood. Methods: We utilized a murine aortic interposition model of transplant arterial injury to investigate the role of the gut commensal bacteria, Akkermansia muciniphila, in controlling immune responses in transplant arteries. Results: Early life treatment of female mice with broad spectrum antibiotics, which delayed colonization of the intestinal tract with bacteria until after weaning, led to the development of dysbiosis in adults that was characterized by the absence of A. muciniphila. This was related to an elevation in systemic levels of CCL2 and a reduction in the immunomodulatory short-chain fatty acid, propionate. When transplant arterial injury was examined, there was more arterial injury indicative of acute rejection and increased intimal thickening reflective of transplant arteriosclerosis in grafts from dysbiotic mice compared to controls. Dysbiosis also increased macrophage accumulation early after transplantation in dysbiotic mice. Notably, restoring A. muciniphila in the gut microbiota of dysbiotic mice through voluntary oral administration in infants ameliorated macrophage-mediated transplant arterial injury. Conclusions: A. muciniphila is an immunomodulatory component of the gut microbiota that protects against vascular injury and pathology in organ transplantation.

Background: Cardiometabolic diseases frequently involve concurrent cardiovascular and hepatic dysfunction, yet the conserved molecular mechanisms underlying these systemic responses remain poorly defined. Objectives: To identify conserved molecular responses across complementary manifestations of cardiometabolic stress and determine whether integrated multi-organ analyses reveal therapeutically actionable targets for heart failure. Methods: Cardiac functional phenotyping, hepatic injury profiling, and bulk RNA sequencing were performed across three complementary mouse models representing distinct manifestations of cardiometabolic stress: high-fat diet plus L-NAME (HFD+LN)-induced heart failure with preserved ejection fraction (HFpEF; cardiovascular disease), Western diet (WD)-induced obesity (systemic metabolic stress), and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced steatotic liver disease (hepatic metabolic stress). Comparative transcriptomic analyses distinguished organ-specific responses from conserved molecular signatures. Results: Each model produced distinct systemic, hepatic, and cardiac phenotypes accompanied by divergent transcriptional responses within individual organs. Cross-model and cross-organ integration identified a limited set of conserved molecular responses to cardiometabolic stress, with Serpine1, encoding plasminogen activator inhibitor-1 (PAI-1), emerging as a highly conserved candidate that exhibited preferential induction in the heart. Pharmacologic inhibition of PAI-1 significantly improved cardiac function and attenuated adverse remodeling in established HFpEF, whereas hepatic pathology was comparatively less affected, indicating differential organ-specific dependence on this pathway. Conclusions: Integrated analyses across complementary manifestations of cardiometabolic stress identified conserved molecular signatures that transcend individual disease models and organs. These findings establish a comparative framework for discovering cardiovascular therapeutic targets and identify PAI-1 as a promising mediator of cardiac remodeling in cardiometabolic disease.

Orthodontic tooth movement relies on a tightly regulated pro-inflammatory and pro resorptive mechanoresponse of local periodontal ligament fibroblasts (PdLFs). Dysregulation is linked to complications such as root resorption and tooth loss. Hyperlipidemic conditions promote excessive PdL mechanoresponses, with growth differentiation factor 15 (GDF15) acting as potential regulator. This study examined the contribution of the inflammasome/pyroptosis pathway as underlying mechanism for dysregulated mechanoresponses. Human PdLFs were treated with palmitic acid (PA) or oleic acid (OA) for six days before 24 hours of compressive loading. PA increased CASP1, CASP4, and CASP3 activity, secretion of IL-1{beta}, IL-18, and HMGB1, and LDH release. Pharmacological blockade and siRNA-mediated knockdown of inflammasome- and pyroptosis-related targets revealed that NLRP3, CASP1, CASP4, and GSDMD partially contributed to monocyte and osteoclast overactivation. Silencing PA-increased GDF15, partially normalized the phenotype, at least in part by inflammasome/pyroptosis regulation. GDF15 acted through extracellular, and a nuclear signaling route, each accounting partially to this phenotype. Together, GDF15 partially regulates the PA-induced, pyroptosis-associated overactivated mechanoresponse alongside pyroptosis-independent mechanisms suggesting it as an interesting target for potential clinical interventions.

Hepatocellular carcinoma (HCC) is particularly aggressive and difficult to treat. Due to the lack of early clinical diagnosis and the unsatisfactory clinical treatment effect, it is particularly important to identify novel markers that can predict tumor behavior in HCC. biogenesis of ribosomes BRX1 (BRIX1) is abundant in various tissues of the human body. However, the regulatory mechanisms and its role in various tissues are not fully understood. Here, we analyzed the expression pattern of BRIX1 in HCC from public gene expression databases and tissue samples from clinical HCC. We confirmed that BRIX1 was upregulated in both HCC cell lines and HCC paraffin section samples. BRIX1 depletion significantly dicreased the capacity of cells to grow and migrate in vitro, and knockdown BRIX1 suppressed tumor growth in xenograft tumor model. Mechanistically, BRIX1 depletion suppressed the MAPK/ERK pathway, as reflected by reduced phosphorylated ERK (p-ERK) levels. In summary, we provide a rational clue for the further investigation of BRIX1 as an invaluable biological marker for diagnosing and predicting prognosis of patients with HCC.

Abstract Calcific deposits in the arterial media have been associated with a number of metabolic and genetic disorders including diabetes, chronic kidney disease and generalized arterial calcification of infancy. While medial calcification and physiologic hard tissue mineralization in the skeleton are both regulated by several common determinants, emerging data suggest that there might be fundamental differences in the mechanisms underlying these two processes. Objective: We previously demonstrated that elastin haploinsufficiency delays medial calcification in MGP-deficient mice. Here, using mice in which a human ELN transgene rescues mouse elastin deficiency, we investigated whether the origin and abundance of arterial elastin differentially affect the initiation and progression of medial calcification. Approach and Results: We pursued a transgenic approach to alter the arterial elastin scaffold in MGP-deficient mice. Our analyses of a humanized MGP-deficient model with 40% reduction of medial elastin content showed a complete absence of the early-stage vascular calcification. Additionally, we showed that mouse and human elastin orthologues affect vascular calcification in a comparable manner. Conclusion: Arterial elastin abundance, rather than orthologue origin, modulates the initiation and progression of medial calcification in MGP-deficient mice. A further reduction in arterial elastin beyond that achieved by elastin haploinsufficiency profoundly delays mineral deposition and maturation, whereas restoration of elastin abundance through transgenic human ELN expression restores arterial calcification.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by high metastatic dissemination, therapy resistance, and poor clinical outcome. Inhibitor of differentiation 1 or ID1, is frequently overexpressed in PDAC and is associated with tumour progression and adverse clinical outcome. However, the mechanisms governing its post-transcriptional regulation remain insufficiently characterized. Here, we identify tumour-suppressive miR-615-5p as a regulator of ID1 expression in PDAC. Integrative in-silico target prediction prioritized miR-615-5p based on seed complementarity and thermodynamic stability with the ID1 3' -UTR. Expression analysis of available PDAC clinical datasets revealed reduced miR-615-5p expression associated with increased ID1 expression. Direct association was validated using luciferase reporter assays, where miR-615-5p suppressed 3' -UTR reporter activity of ID1 in a sequence dependent manner, while mutation of the predicted binding site attenuated this effect. Further biotinylated-RIP and AGO2-RIP assays demonstrated the co-enrichment of ID1 transcripts and miR-615-5p with AGO2 associated RISC complexes, while AntimiR mediated inhibition of miR-615-5p perturbs association between miR/ID1 to AGO2, supporting interaction specificity. Functionally, modulation of miR-615-5p altered ID1 expression and impacted PDAC cell migration in vitro. Mechanistic analyses further indicated that the miR-615-5p/ID1 axis influences autophagic flux where miR-615-5p mediated inhibition of autophagy suppresses ID1 dependent cellular migration. Collectively, these findings define a previously uncharacterized miRNA-dependent regulation of ID1 expression and link this axis to autophagy-associated migratory responses in PDAC cells. The study expands the post-transcriptional regulatory landscape of ID1 and provides a possible mechanism where suppression of miR-615-5p leads to ID1 overexpression and subsequent poor clinical outcome in PDAC cells.

Background VEXAS syndrome is a late onset autoinflammatory disease caused by somatic UBA1 mutations and characterized by heterogeneous systemic and hematologic manifestations. We aimed to describe all identified Belgian cases through a national multicenter cohort. Methods We conducted a retrospective study across four Belgian tertiary centers. Clinical, biological, genetic, therapeutic, and outcome data were collected using standardized anonymized case report forms. Analyses were descriptive. Results Twenty-one male patients were identified between January 2018 and May 2025. General symptoms such as Fatigue, weight loss and sweating occurred in 95% of cases. The most frequent manifestations were cutaneous (85.7%), hematologic (76.2%), articular (66.7%), thromboembolic (57.1%), chondritis (42.9%), ophthalmologic (38.1%), pulmonary (38.1%). Other manifestations also included vasculitis (61.9%). At diagnosis, 95% had anemia, macrocytic in 57%, and 28.6% had thrombocytopenia. Corticosteroids were the main first line therapy. Second line treatments included anti IL 6 agents (46.7%), JAK inhibitors (20%), and azacitidine (14.3%). Complete remission occurred in 50% of patients receiving anti IL 6 therapy and in 33% treated with either JAK inhibitors or azacitidine. Two patients underwent allogeneic stem cell transplantation, one died from infectious complications. Twenty six infectious episodes were recorded, including opportunistic infections. Six patients (28.6%) died during follow-up, four from infectious complications. Conclusion This first Belgian national cohort confirms the clinical heterogeneity of VEXAS syndrome and highlights substantial infectious morbidity and mortality. Access to targeted second-line therapies, particularly anti IL-6 agents and JAK inhibitors, remains challenging despite apparent clinical benefit.

Liver metastases (LM) remain a major cause of death from different cancer types, in particular malignancies of the gastrointestinal tract. Liver metastases predict a poor response to immunotherapy due, among others, to the immunotolerant microenvironment (ME) of the liver and loss of local and systemic cytotoxic T cells. Thus, strategies that can reprogram the immune ME of the liver and restore cytotoxic T cell reactivity are being sought. We previously reported that estrogen signaling blockade impedes the growth of LM by reducing MDSC accumulation and monocyte/macrophage polarization. The aim of this study was to elucidate the underlying mechanism(s) and assess whether estrogen signaling in the myeloid lineage was driving the immunotolerant ME of LM. To this end, we generated mice with conditional myeloid cell-specific deletions of estrogen receptors (ER) or ER{beta} and analyzed in these mice the effect of ER loss on the liver immune ME and the outgrowth of LM. In mice with ER, but not with ER{beta} deletion, we observed a marked reduction in the growth of murine colon carcinoma MC-38 liver metastases as compared to their respective controls. Flow cytometry and immunohistochemistry revealed a decrease in macrophages that were polarized to the pro-tumorigenic M2-like phenotype and a concomitant increase in activated CD8+ T and NK cells relative to controls. Bulk RNAseq analysis performed on hepatic immune cells infiltrating the liver revealed changes in the expression of key cytokines/chemokines mediating immune cell recruitment, activation and polarization, including Ccl5 (upregulated) and Csf1 (downregulated). Taken together, the data suggest that ER signaling in myeloid-derived cells programs the immune landscape and contributes to an immunosuppressive and metastases-growth permissive ME in the liver.

Background: Sleeve gastrectomy is the most frequently performed bariatric procedure worldwide but is associated with the development of de novo gastroesophageal reflux disease (GERD). Hiatal hernia has been identified as a relevant anatomical factor in postoperative reflux, although most studies evaluate it dichotomously without analyzing whether its size influences GERD risk. The aim was to evaluate the association between preoperative hiatal hernia size and de novo GERD after sleeve gastrectomy. Methods: Retrospective, single - center, observational study of patients undergoing sleeve gastrectomy at Hospital Central Norte de Petroleos Mexicanos (2018 - 2025). Demographic and clinical characteristics, endoscopic classification of hiatal hernia size (small <2 cm, medium 2.1 - 4 cm, large >4 cm), and evidence of de novo GERD were analyzed using descriptive statistics, Fisher's exact test, odds ratio (=R) estimation with 95% confidence intervals (CI), and binary logistic regression. Statistical significance was set at p<0.05. Results: Fiftysix patients were included (mean age 48.3 {+/-} 8.1 years; 67.9% male). Hiatal hernia classification was conclusive in 46 patients (82.1%): 63.0% no hernia, 4.3% small, 30.4% medium, and 2.2% large. De novo GERD occurred in 14.0% of patients without preexisting GERD (6/43). No significant association was found between hiatal hernia size and de novo GERD (Fisher p=0.515). In the reduced logistic model, neither hiatal hernia (medium/large vs. absent/small; OR 3.47; 95% CI 0.50 - 29.43; p=0.207) nor age (OR 1.02; 95% CI 0.90 - 1.13; p=0.754) was significantly associated. No evaluated factor (sex, smoking, alcohol, age) reached significance. Conclusions: In this cohort, no statistically significant association was demonstrated between preoperative hiatal hernia size and de novo GERD after sleeve gastrectomy; however, the low number of events limits the ability to exclude a clinically relevant association. These findings are compatible with a multifactorial mechanism rather than with the isolated presence of this finding. Prospective studies with larger sample sizes and standardized reflux assessment instruments are required to confirm these results.

Recurrent urinary tract infection represents a substantial unmet public health in women. Local administration of estradiol has been shown to reduce recurrence, however in vitro models of the female urinary tract remain limited and the mechanisms underlying the effects of estradiol are incompletely understood. Here, we describe a novel iPSC organoid differentiation protocol and its application to establish a multilayered transwell barrier culture model. Estradiol treatment resulted in reduced expression of innate antimicrobial peptides and cytokines, together with increased expression of demannosylation pathways. Treatment of transwell cultures with a combination of female sex hormones reduced endogenous CXCL8 signaling, independently of a 24-hour uropathogenic Escherichia coli (UPEC) challenge. To our knowledge, this is the first iPSC organoid-derived model of the urinary tract, which provides a platform for investigating interactions between the urothelium, urobiome and hormonal environment.

We identified Sleep Bursts (SBs), as a novel phenomenon of brief (1-2 sec), often periodic bursts in cranial forces occurring during human sleep. Our goal was to characterize SBs in normal subjects, then compare SB in a cohort of subjects with neurodegenerative disease (NDD). We recorded 32 cognitively healthy subjects (23 -87 years) and 13 subjects with NDD (51 - 84 years). SBs occurred in all 45 subjects. SBs occurred at 0.57 SB/min (once per 105 seconds) in controls and 0.40 SB/min (once per 150 seconds) in NDD (p = 0.0043). SB occurred with equal rates across all sleep stages in both groups. When occurring periodically, SBs had modal intervals (3.75 bursts/min (0.0625 Hz) - 2.67 bursts/min (0.044 Hz)). EEG power increased in the delta range 1-2 seconds before and following the SB. EEG delta power during a SB was significantly lower in all NDD subjects across sleep stages compared to controls. The relatively low frequency of SB events and synchronization with EEG power has no parallel in human sleep; we hypothesize that SBs may represent a brain-generated pulsatile component of brain glymphatic drainage.

Background Limited heart rate rise contributes to reduced exercise tolerance for people who have heart failure with reduced ejection fraction (HFrEF), yet rate-adaptive pacing does not improve functional capacity due to an attenuated force-frequency relationship (FFR). How the FFR relates to total peripheral resistance and sympathetic tone in HFrEF is unknown. Methods In a prospective, observational study, participants with HFrEF and controls underwent an incremental pacing protocol, during which heart rate was increased from 50 to 140 beats per minute. At each heart rate increment LV contractility was measured by echocardiography to determine the FFR, as well as continuous beat-to-beat measurement of systolic and diastolic blood pressures with a plethysmography device to determine cardiac output, total peripheral resistance and blood pressure variability (BPV). A microneurography study was then conducted to measure muscle sympathetic nerve activity (MSNA) during incremental pacing. Results A total of 157 participants with HFrEF and 55 controls (mean age 71.1{+/-}1.4 years, 172 (81.1%) male) underwent the pacing protocol. We observed single units in seven of 11 participants who participated in the microneurography study. In both groups, LV contractility and cardiac output increased until the peak of the FFR, after which these declined. We observed a reduction in total peripheral resistance, blood pressure variability, MSNA frequency and incidence coinciding with the peak of the FFR, beyond which these increased. Whilst these relationships were present in both groups, they were more evident in participants with HFrEF. Conclusions For people with HFrEF there is a bidirectional relationship between heart rate and sympathetic activation, with a nadir of sympathetic tone occurring at the peak of the FFR. Both excessively low and high heart rates are accompanied by greater sympathetic activation. Taken together, these data suggest that optimal heart rate targets for HFrEF are likely to be individual.

Objective: To determine whether the most cited and the most publicly discussed benign prostatic hyperplasia (BPH) literature describe the same body of work, and whether clinicians and patients read different evidence. Methods: Four Boolean Web of Science searches and four matched Altmetric Explorer searches were run in February 2024, restricted to literature indexed with urologic terminology, and screened in duplicate. Two arms were assembled: the 50 most-cited articles (citation census May 2024) and the 50 with the highest Altmetric Attention Scores. Funding source and intervention focus were hand-coded from the full text of all 100 articles; open-access status came from Unpaywall. Arms were compared with Mann-Whitney U and Fisher exact tests Results: Eight of 50 articles (16%) appeared in both arms. Citation selected articles were older (median 2008 versus 2018, p<0.001), more often randomized trials (58% versus 22%, p<0.001), and more often published in urology-specific journals (96% versus 66%, p<0.001). Industry funded 50% versus 18% of articles (p=0.001) and non-industry sources 8% versus 36% (p=0.001). Only 10% of citation-selected articles were open access versus 56% (p<0.001). Attention data were recoverable for only 13 citation-selected articles (median score 9 versus 17). The two arms were cited in the 2026 AUA BPH Guideline at indistinguishable rates (22% versus 20%, p=1.00). Conclusions: These are largely distinct bodies of work, separated most decisively by whether they can be read without a subscription, yet both inform guideline development equally. Patients arrive with evidence systematically different from, and no less guideline-relevant than, that underpinning their urologist's training.

Objectives To validate two computational fluid dynamics (CFD) models derived from computed tomography angiography (CTA) for estimating trans-stenotic pressure gradients, using invasive intra-arterial pressure measurements as the reference standard in patients with renal artery stenosis (RAS). Background We assessed whether non-invasive assessment of the pressure gradient using CFD could be a reliable alternative to intra-arterial measurements for identifying hemodynamically significant RAS. Methods We performed intra-arterial measurements at rest and during dopamine-induced hyperemia to assess the trans-stenotic pressure gradient in 28 patients with RAS. A pre-intervention CTA scan was used to simulate the pressure gradient with a CFD model using a strategy based on Murray's law (CFD-Mu) and cortical volume (CFD-C). The agreement between the simulated and measured pressure gradients was assessed using intraclass correlation coefficients (ICC), Bland-Altman analysis and diagnostic agreement on the presence of a hemodynamically significant stenosis. Results In 20 patients, successful measurements and simulations were obtained. The ICC between measured pressure gradient and the CFD pressure gradient was 0.78 and 0.94 during baseline and 0.86 and 0.72 during hyperemia, for CFD-Mu and CFD-C, respectively. The sensitivity of CFD-Mu and CFD-C was 70% for both models at rest and 100% compared to the hyperemic measurements, whereas the specificity was 90% and 70% at rest and 79% and 72% during hyperemia, respectively. Conclusions The results support the use of individualized CFD simulations for hemodynamic assessment of RAS using CTA as input. The CFD models demonstrated high accuracy for the identification of a hemodynamically significant stenosis.

Introduction: C3 glomerulopathy (C3G) is driven by fluid-phase alternative complement pathway dysregulation, with emerging evidence linking glomerular neutrophil infiltration to disease severity. Neutrophil extracellular traps (NETs) are implicated in other forms of glomerulonephritis. However, their participation in the pathogenesis of C3G remains undefined. Methods: Kidney biopsies from 33 patients with C3G (15 with dense deposit disease [DDD] and 18 with C3 glomerulonephritis [C3GN]) were compared with 15 anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) biopsies as a neutrophil-rich disease control in this retrospective cross-sectional study. Glomerular neutrophils and NETs were identified using immunofluorescence, staining for myeloperoxidase, citrullinated histone H3, peptidyl arginine deiminase-4, and DNA. Supervised machine learning was used to quantify glomerular NET formation, and the data were correlated with kidney function at time of biopsy using linear regression. Results: Intraglomerular NETs were abundant and detected in the majority of glomeruli in C3G biopsies. Compared with AAV, C3G showed a significantly higher fraction of neutrophils forming NETs, despite similar neutrophil counts per glomerulus. NET abundance was similar in DDD and C3GN. In exploratory analyses, a greater proportion of glomeruli containing NETs was associated with lower kidney function (estimated glomerular filtration rate) at biopsy, and this association remained significant after adjustment for age, C3G subtype, and interstitial fibrosis. Conclusions: These observations demonstrate that intraglomerular NETs are a common and prominent observation in C3G and are associated with reduced kidney function at biopsy. These findings raise the possibility that NET deposition in glomeruli is a previously unrecognized driver of glomerular injury in C3G.

Objective: Chronic atrial and intestinal dysrhythmia (CAID) syndrome is a rare autosomal recessive cohesinopathy classically defined by sick sinus syndrome and chronic intestinal pseudo-obstruction; however, emerging evidence suggests an association with cerebral small vessel disease (CSVD). We aimed to characterize the neurological and neuroimaging spectrum of CSVD in CAID syndrome. Methods: We conducted a cross-sectional, retrospective study of 16 French-Canadians with genetically confirmed CAID syndrome. All patients underwent comprehensive neurological assessment. Brain MRI was performed in 14 patients, with CSVD markers evaluated by an expert neuroradiologist according to the STRIVE-2 criteria. Results: The median age at last evaluation was 34 years (range, 19-60); 62.5% were women. Neurological manifestations included migraines (44.4%), mild cerebellar signs (16.7%), and ischemic or hemorrhagic cerebrovascular events (12.5%). MRI showed white matter hyperintensities (92.9%), lacunes (50%) and cerebral microbleeds (85.7%), affecting deep, lobar, and infratentorial regions, with marked cerebellar predominance (11/12; 91.7%); five patients exhibited innumerable microbleeds. Despite the young cohort, moderate-to-severe CSVD was common (median SVD score 1.5, IQR 0-4). Patients with countless microbleeds were older than those with discrete lesions (46.2 vs. 31.2 years; p=0.043). Management of atrial fibrillation required individualized strategies, including left atrial appendage closure, balancing ischemic and hemorrhagic risks. Interpretation: CAID syndrome represents a novel monogenic cause of CSVD, characterized by early, extensive cerebral microbleeds with mixed distribution and distinctive cerebellar predominance. Coexisting congenital cardiac disease and arrhythmias place patients at dual ischemic and hemorrhagic risk. Systematic neurological evaluation and MRI are warranted, particularly prior to antithrombotic therapy.