Citations

Abstract Background Alzheimer's disease (AD) is pathologically characterized by the presence of extracellular amyloid beta plaques and intracellular tau tangles. Related disorders share aspects of AD pathology including progressive supranuclear palsy (PSP), a tauopathy, and pathologic aging (PA) defined by presence of amyloid but not tau. We hypothesize that there are shared, and distinct, brain molecular changes associated with amyloid and tau protein levels in AD and related disorders and that identifying these will provide novel insights into disease pathogenesis. Methods We collected brain multiomics measures (genetic, transcriptomic, epigenomic, proteomic and metabolomic) from donors diagnosed with AD, PSP, PA and controls. Following quality control and normalization, omics measures were tested for association with disease diagnosis and amyloid and tau neuropathology using regression models adjusting for relevant covariates. Association with biochemical measures of core AD proteins were also assessed in a subset of AD cases. Gene sets were evaluated for enrichment of cellular pathways and cell type signatures. Results We found remarkably conserved transcriptomic changes associated with AD and PSP, and downregulation of myelination pathway genes in both diseases. Among PSP cases, we found divergent patterns of transcriptional associations with distinct tau lesions. In a cohort of AD cases, we found broad transcriptional and epigenetic dysregulation associated with levels of tau protein, but not amyloid beta. Conversely a genetic analysis implicated more variants associated with amyloid levels than tau. Conclusion Multi‐omics studies across various proteinopathies can identify convergent and divergent molecular signatures that are candidates for shared therapeutic targets and disease differentiating biomarkers.

Glioblastoma (GBM) remains one of the most lethal brain tumors, characterized by extensive immune evasion and a macrophage-dominated tumor microenvironment (TME). However, the molecular determinants governing tumor-associated macrophage (TAM) states and their immunoregulatory functions remain poorly understood. We integrated bulk- and single-cell transcriptomic datasets (TCGA, CGGA, Ivy GAP, and Brain Immune Atlas) to systematically characterize the expression, prognostic relevance, and immune contexture of the myeloid biomarker membrane-spanning 4-domain A6A, MS4A6A, in GBM. Differential expression, survival, and pathway enrichment analyses were performed. Single-cell mapping and CellChat modeling delineated MS4A6A-associated TAM subpopulations, intercellular communication networks, and ligand–receptor signaling dynamics. Spatial transcriptomic validation and pharmacogenomic modeling were conducted to assess anatomic enrichment and therapeutic vulnerabilities. High MS4A6A expression predicted unfavorable survival and correlated with increased stromal and immune infiltration. Single-cell analyses localized MS4A6A predominantly to TAMs, especially Regulatory- and Ribo-TAM states enriched for antigen presentation, T-cell regulation, and ribosomal biogenesis pathways. CellChat analysis revealed that MS4A6A-high TAMs exhibited markedly enhanced communication with CD4+ T cells and Tregs through upregulated PGE2–PTGER2/PTGER4, PECAM1–CD38, and THBS1–CD36 signaling axes, implicating MS4A6A in prostaglandin-driven immune suppression. Spatial profiling confirmed preferential localization of MS4A6A within perivascular and angiogenic niches. Pharmacogenomic prediction indicated that MS4A6A-high tumors were more sensitive to ERK, mTOR, and CDK4/6 inhibition. MS4A6A defines a macrophage-centered, immunosuppressive ecosystem in GBM, mediated by the activation of the PGE2 signaling axis. These findings position MS4A6A both as a prognostic biomarker and as a potential therapeutic node linking myeloid reprogramming to actionable pathway vulnerabilities in glioblastoma.

Objective: To examine the association of extent of otosclerotic plaque using high-resolution photon-counting computed tomography (PCCT) with hearing and surgical outcomes. Study design: Historical cohort. Setting: Large academic center. Patients: Patients with otosclerosis who completed PCCT imaging at time of initial evaluation. Interventions: Observation, surgery. Main outcome measures: Audiometric data. Results: A total of 53 ears were eligible for study. The mean age at PCCT was 51 years (SD: 14). The mean extent of oval window otosclerotic plaque measured in radial degrees was 112 (SD: 65) and the mean otosclerotic depth was 1.6mm (SD: 0.6). The mean air-bone gap pure-tone average was 18 dB (SD: 12) and the mean Carhart degree was 9 dB (SD: 10). The radial degrees of oval window extent were not significantly associated with air-bone gap (correlation coefficient: 0.14; P =0.3) or Carhart degree (correlation coefficient: 0.04; P =0.8). Likewise, otosclerotic plaque depth was not significantly associated with air-bone gap (correlation coefficient: −0.19; P =0.2) or Carhart degree (correlation coefficient: −0.08; P =0.6). After PCCT, 22 ears underwent surgery. In this subset, oval window extent and plaque depth were not significantly associated with the postoperative changes in air-bone gap or high-frequency thresholds. Conclusions: Despite enhanced visualization of subtle abnormalities with PCCT imaging, the extent of oval window otosclerotic plaque, measured in angular degrees and depth, was not associated with hearing loss at time of initial evaluation or postoperative audiologic changes in patients with otosclerosis.

Objective: To evaluate the impact of cochlear implantation (CI) and simultaneous endolymphatic sac decompression (ELSD) on vestibular and audiometric outcomes in patients with advanced Ménière disease (MD). Study design: Historical cohort. Setting: Tertiary academic medical center. Patients: Patients with medically refractory MD who underwent CI with or without simultaneous ELSD from 2000 through 2024. Interventions: CI with or without ELSD. Main outcome measures: Post-CI patient-reported changes in vertigo severity and frequency, Consonant-Nucleus-Consonant word (CNCw) scores, and AzBio sentences in quiet scores. Results: Ninety-nine patients with preoperative vertigo secondary to MD were eligible for study, including 17 (17%) who underwent simultaneous ELSD. In total, 15 (88%) and 2 (12%) of the 17 patients with simultaneous ELSD reported improvement and stability in vertigo severity, respectively; in comparison, 26 (32%), 40 (49%), and 16 (20%) of the 82 patients with CI alone reported improvement, stability, and worsening in vertigo severity, respectively ( P <0.001). Likewise, 15 (88%) and 2 (12%) of the patients with simultaneous ELSD reported improvement and stability in vertigo frequency, respectively, whereas 21 (26%), 43 (52%), and 18 (22%) of patients with CI alone reported improvement, stability, and worsening in vertigo frequency, respectively ( P <0.001). Post-CI speech recognition scores were not significantly different between the simultaneous ELSD and CI alone groups [median (IQR) CNCw 70 (38 to 82) vs. 72 (58 to 82) and median (IQR) AzBio quiet 87 (67 to 96) vs. 87 (73 to 94), respectively]. Conclusions: In patients with MD, CI with simultaneous ELSD provides improvement in vertigo symptoms and similar audiometric outcomes when compared with CI alone. In appropriately selected patients with both refractory vestibular symptoms and sensorineural hearing loss meeting criteria for implantation, CI with simultaneous ELSD offers improvement in severity and frequency of vertigo as well as successful auditory rehabilitation.

ABSTRACT Background Ehlers–Danlos syndrome (EDS) comprises inherited connective tissue disorders characterised by joint hypermobility, skin hyperextensibility and tissue fragility. It links to systemic comorbidities, including gastrointestinal (GI) disorders, but hitherto large‐scale data remain limited. We aimed to evaluate the prevalence of GI, systemic and psychological comorbidities in EDS patients versus propensity score‐matched controls, using a comprehensive research network database. Design This was a retrospective, propensity‐matched analysis (2005–2023) utilising the TriNetX network. We identified EDS patients (excluding Marfan's syndrome). Propensity score matching (1:1) generated balanced cohorts for age, sex and baseline characteristics. Comorbidities were analysed via prevalence rates and odds ratios (ORs) with 95% confidence intervals (CIs). Results Matched cohorts included 59,128 pairs. Among GI disorders, gastroesophageal reflux disease was most common in EDS (18.4%, OR 1.5, 95% CI 1.4–1.5, p < 0.001), followed by constipation (12.4%, OR 1.8, 95% CI 1.7–1.9, p < 0.001), irritable bowel syndrome (7.3%, OR 2.6, 95% CI 2.5–2.8, p < 0.001) and gastroparesis (4.7%, OR 8.2, 95% CI 7.3–9.2, p < 0.001). Psychiatric conditions showed heightened prevalence of anxiety (26.1%, OR 1.8, 95% CI 1.7–1.8, p < 0.001) and depression (18.7%, OR 1.3, 95% CI 1.2–1.3, p < 0.001). Systemic comorbidities included postural orthostatic tachycardia syndrome (13.2%, OR 899.7, 95% CI 483.8–1673.0, p < 0.001), chronic pain (7.9%, OR 7.0, 95% CI 6.4–7.6, p < 0.001), migraines (19.7%, OR 2.5, 95% CI 2.4–2.6, p < 0.001) and fibromyalgia (9.5%, OR 1.7, 95% CI 1.6–1.8, p < 0.001). Conclusion EDS patients exhibit heightened risk for GI, systemic and psychological comorbidities, highlighting the importance of multidisciplinary approaches for effective management.

Background This review evaluates the current evidence for the role of venoactive drugs (VADs) for venous origin chronic pelvic pain (VO-CPP) and provide insights to inform the design of an ideal randomized controlled trial (RCT) for future research. Methods A search was performed in the following databases: Ovid MEDLINE, Ovid EMBASE, Cochrane Library, and Scopus. Studies retrieved were screened for eligibility using Covidence software following PRISMA reviews’ methodology. The quality of RCTs and cross-over RCTs was assessed using the Cochrane review tools. Studies were reviewed by 3 physicians, with discrepancies resolved by consensus. A narrative review of the studies was conducted to identify and synthesize clinical outcomes and safety profile of VADs. Results Eleven studies (n = 748) were identified: 3 RCTs and 8 open-label prospective studies. Most participants were reproductive-age women with confirmed VO-CPP, diagnosed via imaging or laparoscopy. Micronized Purified Flavonoid Fraction (MPFF) was the most studied VAD. Pain assessment with VAS scores was the primary endpoint in all studies, with significant benefit in patients consistently demonstrated. Other endpoints included Pelvic Venous Clinical Severity Score (PVCSS) and Pelvic Varicose Vein Questionnaire (PVVQ), with improved symptoms and quality of life. Quantitative outcomes were also reported (reduced pelvic vein diameter; better venous hemodynamics). MPFF was safe, with few adverse events reported. Three RCTs had methodological limitations, with two judged high-risk for bias. Conclusions While many identified studies appear to be of low quality, the consistent beneficial effect on VO-CPP scores and the safety profile observed across all reviewed studies suggest that flavonoids have a positive role in the conservative management of pelvic venous disease (PeVD). Future well-designed RCTs are needed to confirm these findings. In the meantime, flavonoids should be considered a therapeutic option for symptomatic patients with PeVD who are not qualified for, not wishing, or are awaiting intervention.

Abstract Background Valve-sparing aortic root replacement has increasingly been performed in Marfan patients. However, there is ongoing debate on whether the non-aneurysmal sized aortic arch should be prophylactically replaced during the index operation. The aim of our retrospective single-centre study was to investigate the long-term status of the aortic arch in these patients. Methods Between 1993 and 2021, a total of 723 patients underwent valve-sparing aortic root replacement with a straight tube graft (David I reimplantation) at our institution; 119 patients had confirmed Marfan disease. Of these 119 Marfan patients, 67 patients had isolated aortic root aneurysm with no aortic arch pathology. These 67 patients underwent isolated David I procedure in an elective setting (only aortic root and ascending aortic replacement) without any concomitant procedures and were included in the present study. Results This study includes 67 patients with Marfan syndrome who underwent isolated elective valve-sparing aortic root replacement. The median age of patients was 30 years (20-41), and 47 were male (70%). The cardiopulmonary time was 157.5 (145.8-178.3) min, and aortic clamp time was 117.0 ± 19.8 min. The in-hospital mortality and stroke rates were both 0%. Follow-up was 100% complete. Survival at 1, 5, 10, 15, and 20 years were 100%, 100%, 93%, 89%, and 85%, respectively. Freedom from aortic arch reoperation due to aneurysm at 1, 5, 10, 15, and 20 years was 100%, 100%, 100%, 100%, and 95%, respectively. In follow-up, no patient required aortic arch replacement due to aortic arch aneurysm. A total of 3 patients underwent aortic arch replacement for type B aortic dissection. Of these 3 patients, 1 had chronic type B dissection with aortic aneurysm, and 2 had acute type B dissection. Conclusions The long-term results after valve-sparing aortic root replacement with a straight tube graft (David I procedure) in Marfan patients are excellent. Our study shows that the risk for future aortic arch intervention after elective valve sparing aortic root replacement in Marfan patients is extremely low. Hence, our study supports the idea that concomitant prophylactic aortic arch replacement during elective valve sparing aortic root replacement in Marfan patients with non-aneurysmal aortic arch is not necessary.