Citations

Abstract This study delineates a novel multisystem caliber-persistent arteriopathy syndrome, fundamentally redefining the classical Dieulafoy's lesion from a localized gastrointestinal anomaly to a systemic congenital vasculopathy. Through integrated histopathological and genomic analysis of a forensic autopsy case, we identified pervasive arterial remodeling across seven organ systems— characterized by absent physiological tapering— indicating developmental angiogenic dysregulation. Whole-genome sequencing uncovered pathogenic variants in PDE8B , LRCH1 , and ADA genes, with functional enrichment analyses implicating dysregulated purine–cAMP signaling and cytoskeletal organization as core pathogenic mechanisms. These findings establish a genetic basis for the observed pan-vascular phenotype and highlight the necessity of systematic vascular screening in cases of unexplained multiorgan hemorrhage. This work provides a foundational framework for diagnosing and investigating congenital vascular malformations with hemorrhagic risk, urging a paradigm shift in clinical evaluation and etiological assessment.

Traditional solvents face limitations in environmental friendliness, biocompatibility, and functional tunability, which restrict their use in pharmaceuticals, biocatalysis, and biosensing.

ABSTRACT Stroke remains one of the most devastating complications following transcatheter aortic valve implantation (TAVI). Although cerebral embolic protection devices (CEPDs) have emerged to mitigate patients' risks, their impact on stroke risk, as well as other clinical and neurocognitive outcomes after TAVI, remains uncertain. We aimed to assess whether CEPDs alleviate stroke risks and neurocognitive outcomes after TAVI. We systematically searched MEDLINE, Scopus, Web of Science (WOS), and the Cochrane CENTRAL from inception until May 2025. We included randomized controlled trials (RCTs) that assessed the effectiveness of CEPD compared to the control group (no CEPD) in adult patients (> 18 years) undergoing TAVI. The primary endpoint was the incidence of all‐cause stroke. In contrast, the secondary endpoints included disabling stroke, systemic bleeding, transient ischemic attack (TIA), and major adverse cardiovascular and cerebrovascular events (MACCE). Additionally, we assessed neurological outcomes, including changes in the Montreal Cognitive Assessment (MoCA) score, the National Institutes of Health Stroke Scale (NIHSS) score, and the presence of new ischemic lesions. Nine RCTs comprising 11,696 patients were included in the final analysis. The use of CEPDs showed no statistical difference in reducing all‐cause stroke compared to the control group (OR = 0.91, 95% CI [0.73–1.15], p = 0.44). Additionally, there was no significant difference in other studies' secondary outcomes, including disabling stroke, MACCE, systemic bleeding, or neurological outcomes, such as worsening NISSS, decline in MoCA score, and the presence of new ischemic lesions. The use of CEPD during TAVI showed no benefit in reducing the risks of all‐cause stroke and other neurological outcomes studied.

Abstract Regulation of gene expression is central to the development of immune cells and their ability to respond to infection. As part of a clinical evaluation, we identified two sisters with recurrent infections, hypogammaglobulinemia, and memory B cell deficiency, diagnosed as common variable immunodeficiency. Whole exome sequencing identified a heterozygous variant (Leu50Ser, L50S) in a conserved region of EZH2, the catalytic subunit of the epigenetic gene repressor Polycomb Repressive Complex 2 (PRC2). EZH2-catalyzed histone H3 lysine 27 methylation (H3K27me) in bulk was not overall significantly disrupted by this variant, in patient samples or cell lines expressing EZH2-L50S. EZH2-L50S protein is expressed similar to wild-type and can form PRC2. However, we find that specific genomic regions that normally have high wild-type levels of H3K27me3 are deficient in the L50S context, particularly around gene promoters. EZH2-L50S is still recruited to these sites, but is not as active. Using recombinant purified PRC2, we determine that L50S affects methylation of nucleosomes and disrupts allosteric stimulation that normally amplifies H3K27me3, consistent with the location of L50 in the allosteric regulatory region of PRC2. Thus, variation of EZH2 L50, occurring at low frequency in the population may interfere with normal B cell gene expression patterns, contributing to immunodeficiency. This study has implications for genetic variation in PRC2 in the general population.

Abstract Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e−4). At disease progression, multiple myeloma cells upregulated cancer–testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune–tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune–tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.

BACKGROUND Among antiretroviral therapy–suppressed (ART-suppressed) people with HIV (PWH), women have higher levels of some inflammatory markers than men, but the effect of sex on the inflammatory proteome, and whether age modifies these differences, remain unclear. METHODS Plasma inflammatory protein levels were assessed in ART-suppressed PWH from the Center for AIDS Research Network of Integrated Clinical Systems. The relationship between sex and plasma proteins — including 22 interferon-α response pathway proteins — was assessed, adjusting for confounders and assessing interactions by age. RESULTS Of 922 participants, 162 (18%) were female. The median age was 47, above which the majority of women had undetectable plasma anti-Müllerian hormone levels, a biomarker of ovarian reserve. Age modified the influence of sex on the inflammatory proteome. Older age (>47) was associated with greater increases among women than men in 194 proteins. Interferon-α response proteins were higher in men in those ≤ 47 but higher in women in those > 47 (interaction P < 0.001). Among the 131 proteins associated with mortality risk ( q < 0.05), only 5 differed by sex among those ≤ 47, while 79 differed by sex in those > 47, with nearly all being higher in women. Women had decreased mortality than men ≤ 47 ( P < 0.001) but had similar mortality > 47 ( P = 0.84). CONCLUSION The menopausal transition appears to increase systemic type I interferon responses and inflammation in women with HIV, which may contribute to a loss of female advantage in mortality. FUNDING NIH National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute of Allergy and Infectious Diseases.

Key Points The kidney microvasculature was quantified reliably in human autosomal dominant polycystic kidney disease early on, using super-resolution ultrasound localization microscopy. Microvascular parameters correlated with structural and functional indices, constituting promising biomarkers to evaluate noncystic parenchyma. Microvascular parameters may serve to assess disease severity and monitor progression from the early stages of the disease. Background In vitro studies in individuals with autosomal dominant polycystic kidney disease (ADPKD) have shown extensive intrarenal microvascular remodeling. However, analyses have been limited to the time of kidney failure because of the invasive nature of current methodologies to assess the intrarenal microvasculature. We hypothesized that super-resolution ultrasound microvascular imaging, known as ultrasound localization microscopy, enabled by high-framerate ultrasound imaging and microbubble localization and tracking postprocessing techniques, would safely, reliably, and reproducibly assess the intrarenal microvasculature in individuals with ADPKD at an early stage of the disease. Methods We prospectively enrolled young (<40 years of age), well-characterized, early-stage (eGFR >90 ml/min per 1.73 m 2 ) individuals with ADPKD, and sex–age 1:1 matched controls ( n =17 each) and assessed the intrarenal microvasculature using ultrasound localization microscopy. We determined the intersonographer reliability, intraobserver repeatability, and interobserver reproducibility of microvascular parameters in both groups, and the day-to-day variability in the control group. Microvascular parameters were correlated with structural (total kidney volume) and functional (eGFR) markers in individuals with ADPKD. Results Ultrasound localization microscopy provided a super-resolved map of the intrarenal microvasculature in ADPKD and matched controls. Intrarenal microvascular parameters ( e.g ., vessel density) were quantified in a safe, reliable (intraclass correlation coefficients, 0.96; 95% confidence interval, 0.91 to 0.98), reproducible (intraclass correlation coefficient, 0.96; 95% confidence interval, 0.93 to 0.98), and repeatable (coefficient of variations, 3.6%) manner. In control individuals, the day-to-day variability of most parameters was low, with coefficient of variation ranging from 1.8% to 10.7%. Microvascular parameters differed in individuals with ADPKD compared with controls, despite preserved eGFR. Interestingly, cortical vessel density and its derived perfusion correlated directly with eGFR, whereas tortuosity indices presented an inverse correlation. Conclusions Ultrasound localization microscopy provided a safe and reliable in vivo assessment of the human intrarenal microvasculature.