Insights into non-crossover recombination from long-read sperm sequencing.

Meiotic recombination is a fundamental process that generates genetic diversity by creating new combinations of existing alleles. Although human crossovers have been studied at the pedigree, population and single-cell level, the more frequent non-crossover events that lead to gene conversion are harder to study, particularly at the individual level. Here we show that single high-fidelity long sequencing reads from sperm can capture both crossovers and non-crossovers, allowing effectively arbitrary sample sizes for analysis from one male. Using fifteen sperm samples from thirteen donors we demonstrate variation between and within donors for the rates of different types of recombination. Intriguingly, we observe a tendency for non-crossover gene conversions to occur upstream of nearby PRDM9 binding sites, whereas crossover locations have a slight downstream bias. We further provide evidence for two distinct non-crossover processes. One gives rise to the vast majority of non-crossovers with mean conversion tract length under 50bp, which we suggest is an outcome of standard PRDM9-induced meiotic recombination. In contrast ~2% of non-crossovers have much longer mean tract length, and potentially originate from the same process as complex events with more than two haplotype switches, which is not associated with PRDM9 binding sites and is also seen in somatic cells.

In Situ Phase Separation-Induced Self-Healing Catalyst for Efficient Direct Seawater Electrolysis.

Direct seawater electrolysis technology for sustainable hydrogen production has garnered significant attention, owing to its abundant resource supply and economic potential. However, the complex composition and high chloride concentration of seawater have hindered its practical implementation. In this study, we report an in situ-synthesized dual-phase electrocatalyst (HPS-NiMo), comprising an amorphous phosphide protective outer phase and a crystalline alloy inner phase with supplementary sulfur active sites, to improve the kinetics of direct seawater electrolysis. The HPS-NiMo exhibits long-term stability, remaining stable for periods exceeding 120 h at 200 mA cm-2; moreover, it lowers the required operating voltage to ∼1.8 V in natural seawater. The chlorine chemistry, corrosion during direct natural seawater electrolysis, and mechanism behind the high-performing catalysts are discussed. We also investigated the possibility of recovering the anode precipitates, which inevitably occurs during seawater electrolysis.

Digital histological staining of tissue slide images from optical coherence microscopy.

The convergence of staining-free optical imaging and digital staining technologies has become a central focus in digital pathology, presenting significant advantages in streamlining specimen preparation and expediting the rapid acquisition of histopathological information. Despite the inherent merits of optical coherence microscopy (OCM) as a staining-free technique, its widespread application in observing histopathological slides has been constrained. This study introduces a novel approach by combining wide-field OCM with digital staining technology for the imaging of histopathological slides. Through the optimization of the histology slide production process satisfying the ground growth for digital staining as well as pronounced contrast for OCM imaging, successful imaging of various mouse tissues was achieved. Comparative analyses with conventional staining-based bright field images were executed to evaluate the proposed methodology's efficacy. Moreover, the study investigates the generalization of digital staining color appearance to ensure consistent histopathology, considering tissue-specific and thickness-dependent variations.

Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/ß, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.

Correction: Understanding the Role of Growth Factors in Modulating Stem Cell Tenogenesis.

[This corrects the article DOI: 10.1371/journal.pone.0083734.].

Geographic information system-based determination of priority monitoring areas for hazardous air pollutants in an industrial city.

Industrial cities are hotspots for many hazardous air pollutants (HAPs), which are detrimental to human health. We devised an identification method to determine priority HAP monitoring areas using a comprehensive approach involving monitoring, modeling, and demographics. The methodology to identify the priority HAP monitoring area consists of two parts: (1) mapping the spatial distribution of selected categories relevant to the target pollutant and (2) integrating the distribution maps of various categories and subsequent scoring. The identification method was applied in Ulsan, the largest industrial city in South Korea, to identify priority HAP monitoring areas. Four categories related to HAPs were used in the method: (1) concentrations of HAPs, (2) amount of HAP emissions, (3) the contribution of industrial activities, and (4) population density in the city. This method can be used to select priority HAP monitoring areas for intensive monitoring campaigns, cohort studies, and epidemiological studies.

Severity of sleep apnea as a prognostic factor for mortality in patients with multiple system atrophy.

BACKGROUND: We determined whether the severity of sleep apnea increases the risk of mortality in patients with multiple system atrophy (MSA) with and without stridor. MethodsThis retrospective study included patients who underwent polysomnography within one year after diagnosis of probable MSA. Stridor, sleep apnea, and arousal from sleep were determined using full-night polysomnography. Disease severity was measured using the Unified MSA Rating Scale (UMSARS). Survival data were collected and analyzed using Cox regression analysis. RESULTS: Sixty-four patients with MSA were included. During a median follow-up of 34.5 months, 49 (76.6 %) patients died. Stridor was present in 56.3 % of patients. Patients with stridor had more severe sleep apnea and shorter sleep time than those without, but the hazard ratio (HR) for death did not differ between patients with and without stridor. Among patients without stridor, apnea-hypopnea index ≥30/h (HR, 6.850; 95 % confidence interval [CI], 1.983-23.664; p = 0.002) and a score of UMSARS I + II (HR, 1.080; 95 % CI, 1.040-1.121; p < 0.001) were independently associated with death. In contrast, among patients with stridor, frequent arousals from sleep (HR, 0.254; 95 % CI, 0.089-0.729; p = 0.011) were a significant factor associated with longer survival, while MSA-cerebellar type tended to be associated with poor survival (HR, 2.195; 95 % CI, 0.941-5.120; p = 0.069). CONCLUSION: The severity of sleep apnea might be a significant predictor of shorter survival in MSA patients without stridor, whereas frequent arousals from sleep might be a significant predictor for longer survival in MSA patients with stridor.

Detection of EGFR exon 20 insertion mutations in non-small cell lung cancer: implications for consistent nomenclature in precision medicine.

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (E20ins) are the third most frequent mutations observed in non-small cell lung cancer, accounting for approximately 1-10% of all EGFR mutations. In the era of precision medicine and targeted therapies, consistent naming of genetic alterations is crucial to avoid confusion and errors. However, the annotation of EGFR E20ins mutations has been inconsistent, leading to confusion in the scientific literature and product documentation. In this study, our primary objective was to investigate the usage of different annotation related to EGFR E20ins in independent studies. Additionally, we assessed the distribution of EGFR E20ins mutations and estimated the detection coverage expected from each available EGFR E20ins detection assay. A total of 1,418 EGFR E20ins mutations were collected from six studies (FoundationInsights, Geneseeq Technology Inc, mobocertinib phase I/II trial, poziotinib phase II trial, sunvozertinib phase I trial, and Samsung Medical Center) and reorganised according to Human Genome Variation Society (HGVS) nomenclature. Our analysis revealed that the majority of EGFR E20ins mutations requiring correction were 'insertion' or 'deletion-insertion', which should be appropriately designated as 'duplication'. Additionally, duplicated variants were reported using different annotations in each study, and furthermore, even identical variant sequences were annotated differently within the same study. In all six studies, p.A767_V769dup and p.S768_D770dup were the most frequently observed EGFR E20ins. The Oncomine Dx Target Test showed the highest patient coverage at 77.2%, followed by the Droplex EGFR Mutation Test v2 with a patient coverage of 70.5% for EGFR E20ins patients. To ensure comprehensive coverage in real-world settings, it is essential to standardise the annotations for each variant, for example using the HGVS nomenclature. The accurate classification and analysis of drug responsiveness in EGFR E20ins necessitate consideration of the nomenclature, particularly with respect to the locations where the actual mutations occur.

Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations.

Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, particularly in women. EGFR mutations and anaplastic lymphoma kinase (ALK) fusions are major genetic alterations observed in NSLA, and NSLA with these alterations have been well studied and can be treated with targeted therapies. To provide insights into the molecular profile of NSLA without EGFR and ALK alterations (NENA), we selected 141 NSLA tissues and performed proteogenomic characterization, including whole genome sequencing (WGS), transcriptomic, methylation EPIC array, total proteomic, and phosphoproteomic analyses. Forty patients with NSLA harboring EGFR and ALK alterations and seven patients with NENA with microsatellite instability were excluded. Genome analysis revealed that TP53 (25%), KRAS (22%), and SETD2 (11%) mutations and ROS1 fusions (14%) were the most frequent genetic alterations in NENA patients. Proteogenomic impact analysis revealed that STK11 and ERBB2 somatic mutations had broad effects on cancer-associated genes in NENA. DNA copy number alteration analysis identified 22 prognostic proteins that influenced transcriptomic and proteomic changes. Gene set enrichment analysis revealed estrogen signaling as the key pathway activated in NENA. Increased estrogen signaling was associated with proteogenomic alterations, such as copy number deletions in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14. Finally, saracatinib, an Src inhibitor, was identified as a potential drug for targeting activated estrogen signaling in NENA and was experimentally validated in vitro. Collectively, this study enhanced our understanding of NENA NSLA by elucidating the proteogenomic landscape and proposed saracatinib as a potential treatment for this patient population that lacks effective targeted therapies. SIGNIFICANCE: The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.

Prmt7 regulates the JAK/STAT/Socs3 signaling pathway in postmenopausal cardiomyopathy.

Protein arginine methyltransferases (PRMTs) modulate diverse cellular processes, including stress responses. The present study explored the role of Prmt7 in protecting against menopause-associated cardiomyopathy. Mice with cardiac-specific Prmt7 ablation (cKO) exhibited sex-specific cardiomyopathy. Male cKO mice exhibited impaired cardiac function, myocardial hypertrophy, and interstitial fibrosis associated with increased oxidative stress. Interestingly, female cKO mice predominantly exhibited comparable phenotypes only after menopause or ovariectomy (OVX). Prmt7 inhibition in cardiomyocytes exacerbated doxorubicin (DOX)-induced oxidative stress and DNA double-strand breaks, along with apoptosis-related protein expression. Treatment with 17ß-estradiol (E2) attenuated the DOX-induced decrease in Prmt7 expression in cardiomyocytes, and Prmt7 depletion abrogated the protective effect of E2 against DOX-induced cardiotoxicity. Transcriptome analysis of ovariectomized wild-type (WT) or cKO hearts and mechanical analysis of Prmt7-deficient cardiomyocytes demonstrated that Prmt7 is required for the control of the JAK/STAT signaling pathway by regulating the expression of suppressor of cytokine signaling 3 (Socs3), which is a negative feedback inhibitor of the JAK/STAT signaling pathway. These data indicate that Prmt7 has a sex-specific cardioprotective effect by regulating the JAK/STAT signaling pathway and, ultimately, may be a potential therapeutic tool for heart failure treatment depending on sex.

Mapping the spatial distribution of primary and secondary PM2.5 in a multi-industrial city by combining monitoring and modeling results.

Industrial cities are strongly influenced by primary emissions of PM2.5 from local industries. In addition, gaseous precursors, such as sulfur oxides (SOX), nitrogen oxides (NOX), and volatile organic compounds (VOCs), emitted from industrial sources, undergo conversion into secondary inorganic and organic aerosols (SIAs and SOAs). In this study, the spatial distributions of primary and secondary PM2.5 in Ulsan, the largest industrial city in South Korea, were visualized. PM2.5 components (ions, carbons, and metals) and PM2.5 precursors (SO2, NO2, NH3, and VOCs) were measured to estimate the concentrations of secondary inorganic ions (SO42-, NO3-, and NH4+) and secondary organic aerosol formation potential (SOAFP). The spatial distributions of SIAs and SOAs were then plotted by combining atmospheric dispersion modeling, receptor modeling, and monitoring data. Spatial distribution maps of primary and secondary PM2.5 provide fundamental insights for formulating management policies in different districts of Ulsan. For instance, among the five districts in Ulsan, Nam-gu exhibited the highest levels of primary PM2.5 and secondary nitrate. Consequently, controlling both PM2.5 and NO2 emissions becomes essential in this district. The methodology developed in this study successfully identified areas with dominant contributions from both primary emissions and secondary formation. This approach can be further applied to prioritize control measures during periods of elevated PM levels in other industrial cities.

Mapping nationwide concentrations of sulfate and nitrate in ambient PM2.5 in South Korea using machine learning with ground observation data.

Particulate matter (PM) is a major air pollutant in Northeast Asia, with frequent high PM episodes. To investigate the nationwide spatial distribution maps of PM2.5 and secondary inorganic aerosols in South Korea, prediction models for mapping SO42- and NO3- concentrations in PM2.5 were developed using machine learning with ground-based observation data. Specifically, the random forest algorithm was used in this study to predict the SO42- and NO3- concentrations at 548 air quality monitoring stations located within the representative radii of eight intensive air quality monitoring stations. The average concentrations of PM2.5, SO42-, and NO3- across the entire nation were 17.2 ± 2.8, 3.0 ± 0.6, and 3.4 ± 1.2 µg/m3, respectively. The spatial distributions of SO42- and NO3- concentrations in 2021 revealed elevated concentrations in both the western and central regions of South Korea. This result suggests that SO42- concentrations were primarily influenced by industrial activities rather than vehicle emissions, whereas NO3- concentrations were more associated with vehicle emissions. During a high PM2.5 event (November 19-21, 2021), the concentration of SO42- was primarily influenced by SOX emissions from China, while the concentration of NO3- was affected by NOX emissions from both China and Korea. The methodology developed in this study can be used to explore the chemical characteristics of PM2.5 with high spatiotemporal resolution. It can also provide valuable insights for the nationwide mitigation of secondary PM2.5 pollution.

Dual Higgs modes entangled into a soliton lattice in CuTe.

Recently discovered Higgs particle is a key element in the standard model of elementary particles and its analogue in materials, massive Higgs mode, has elucidated intriguing collective phenomena in a wide range of materials with spontaneous symmetry breaking such as antiferromagnets, cold atoms, superconductors, superfluids, and charge density waves (CDW). As a straightforward extension beyond the standard model, multiple Higgs particles have been considered theoretically but not yet for Higgs modes. Here, we report the real-space observations, which suggest two Higgs modes coupled together with a soliton lattice in a solid. Our scanning tunneling microscopy reveals the 1D CDW state of an anisotropic transition metal monochalcogenide crystal CuTe is composed of two distinct but degenerate CDW structures by the layer inversion symmetry broken. More importantly, the amplitudes of each CDW structure oscillate in an out-of-phase fashion to result in a regular array of alternating domains with repeating phase-shift domain walls. This unusual finding is explained by the extra degeneracy in CDWs within the standard Landau theory of the free energy. The multiple and entangled Higgs modes demonstrate how novel collective modes can emerge in systems with distinct symmetries broken simultaneously.

Superaerophobic/Superhydrophilic Multidimensional Electrode System for High-Current-Density Water Electrolysis.

Water electrolysis is emerging as a promising renewable-energy technology for the green production of hydrogen, which is a representative and reliable clean energy source. From economical and industrial perspectives, the development of earth-abundant non-noble metal-based and bifunctional catalysts, which can simultaneously exhibit high catalytic activities and stabilities for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER), is critical; however, to date, these types of catalysts have not been constructed, particularly, for high-current-density water electrolysis at the industrial level. This study developed a heterostructured zero-dimensional (0D)-one-dimensional (1D) PrBa0.5Sr0.5Co1.5Fe0.5O5+δ (PBSCF)-Ni3S2 as a self-supported catalytic electrode via interface and morphology engineering. This unique heterodimensional nanostructure of the PBSCF-Ni3S2 system demonstrates superaerophobic/superhydrophilic features and maximizes the exposure of the highly active heterointerface, endowing the PBSCF-Ni3S2 electrode with outstanding electrocatalytic performances in both HER and OER and exceptional operational stability during the overall water electrolysis at high current densities (500 h at 500 mA cm-2). This study provides important insights into the development of catalytic electrodes for efficient and stable large-scale hydrogen production systems.

Social participation mediates the relationship between self-efficacy and loneliness among people with stroke during COVID-19: a cross-sectional study.

BACKGROUND: People post-stroke experience increased loneliness, compared to their healthy peers and loneliness may have increased during COVID due to social distancing. How social distancing affected loneliness among people after stroke is unknown. Bandura's self-efficacy theory suggests that self-efficacy may be a critical component affecting individuals' emotions, behaviors, attitudes, and interpretation of everyday situations. Additionally, previous studies indicate that self-efficacy is associated with both loneliness and social participation. This study investigates relationships among self-efficacy, social participation, and loneliness in people with stroke. OBJECTIVES: Determine how social participation affects the relationship between self-efficacy and loneliness in people with stroke during the COVID-19 pandemic. METHODS: 44 participants were community-dwelling individuals, ≥ 6 months post-stroke who participated in a 2-hour phone interview. A regression-based mediation analysis was conducted using these measures: Participation Strategies Self-Efficacy Scale, Activity Card Sort for social participation, and UCLA Loneliness Scale for loneliness. RESULTS: The total effect of self-efficacy on loneliness was significant (b = -0.36, p = .01). However, social participation fully mediated the relationship between self-efficacy and loneliness (indirect effect, b = -0.11, 95% CI [-0.24, -0.01]; direct effect, b = -0.25, 95% CI [-0.03, 0]). CONCLUSIONS: Self-efficacy is associated with both social participation and loneliness in people with stroke in this cross-sectional study. Mediation analysis findings suggest that interventions focused on increasing social participation may prevent or potentially alleviate loneliness in people with stroke who have low self-efficacy.

Implementation of a portable diffraction phase microscope for digital histopathology.

Quantitative phase imaging (QPI) has a significant advantage in histopathology as it helps in differentiating biological tissue structures and cells without the need for staining. To make this capability more accessible, it is crucial to develop compact and portable systems. In this study, we introduce a portable diffraction phase microscopy (DPM) system that allows the acquisition of phase map images from various organs in mice using a low-NA objective lens. Our findings indicate that the cell and tissue structures observed in portable DPM images are similar to those seen in conventional histology microscope images. We confirmed that the developed system's performance is comparable to the benchtop DPM system. Additionally, we investigate the potential utility of digital histopathology by applying deep learning technology to create virtual staining of DPM images.

Direct and Indirect Chimeric Antigen Receptor T-Cell Imaging with PET/MRI in a Tumor Xenograft Model.

Background Chimeric antigen receptor (CAR) T cells are a promising cancer therapy; however, reliable and repeatable methods for tracking and monitoring CAR T cells in vivo remain underexplored. Purpose To investigate direct and indirect imaging strategies for tracking the biodistribution of CAR T cells and monitoring their therapeutic effect in target tumors. Materials and Methods CAR T cells co-expressing a tumor-targeting gene (anti-CD19 CAR) and a human somatostatin receptor subtype 2 (hSSTr2) reporter gene were generated from human peripheral blood mononuclear cells. After direct labeling with zirconium 89 (89Zr)-p-isothiocyanatobenzyl-desferrioxamine (DFO), CAR T cells were intravenously injected into immunodeficient mice with a CD19-positive and CD19-negative human tumor xenograft on the left and right flank, respectively. PET/MRI was used for direct in vivo imaging of 89Zr-DFO-labeled CAR T cells on days 0, 1, 3, and 7 and for indirect cell imaging with the radiolabeled somatostatin receptor-targeted ligand gallium 68 (68Ga)-DOTA-Tyr3-octreotide (DOTATOC) on days 6, 9, and 13. On day 13, mice were euthanized, and tissues and tumors were excised. Results The 89Zr-DFO-labeled CAR T cells were observed on PET/MRI scans in the liver and lungs of mice (n = 4) at all time points assessed. However, they were not visualized in CD19-positive or CD19-negative tumors, even on day 7. Serial 68Ga-DOTATOC PET/MRI showed CAR T cell accumulation in CD19-positive tumors but not in CD19-negative tumors from days 6 to 13. Notably, 68Ga-DOTATOC accumulation in CD19-positive tumors was highest on day 9 (mean percentage injected dose [%ID], 3.7% ± 1.0 [SD]) and decreased on day 13 (mean %ID, 2.6% ± 0.7) in parallel with a decrease in tumor volume (day 9: mean, 195 mm3 ± 27; day 13: mean, 127 mm3 ± 43) in the group with tumor growth inhibition. Enhanced immunohistochemistry staining of cluster of differentiation 3 (CD3) and hSSTr2 was also observed in excised CD19-positive tumor tissues. Conclusion Direct and indirect cell imaging with PET/MRI enabled in vivo tracking and monitoring of CAR T cells in an animal model. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bulte in this issue.

4-1BB immunotherapy: advances and hurdles.

Since its initial description 35 years ago as an inducible molecule expressed in cytotoxic and helper T cells, 4-1BB has emerged as a crucial receptor in T-cell-mediated immune functions. Numerous studies have demonstrated the involvement of 4-1BB in infection and tumor immunity. However, the clinical development of 4-1BB agonist antibodies has been impeded by the occurrence of strong adverse events, notably hepatotoxicity, even though these antibodies have exhibited tremendous promise in in vivo tumor models. Efforts are currently underway to develop a new generation of agonist antibodies and recombinant proteins with modified effector functions that can harness the potent T-cell modulation properties of 4-1BB while mitigating adverse effects. In this review, we briefly examine the role of 4-1BB in T-cell biology, explore its clinical applications, and discuss future prospects in the field of 4-1BB agonist immunotherapy.

The impact of Renin-Angiotensin System Inhibitors on bone fracture risk: a nationwide nested case-control study.

BACKGROUND: The therapeutic efficacy of renin-angiotensin system inhibitors (RASi) in elderly patients with hypertension and at risk of fractures has been in the limelight because of accumulating evidence that localized RAS activation in bone tissue leads to osteoclastic bone resorption, resulting in osteoporosis. This study set out to investigate the association between RASi use and fracture incidence in a large cohort. METHODS: We employed a nested case-control design to investigate the association between RASi use and newly developed fractures. A case was defined as a patient newly diagnosed with a fracture between January 2004 and December 2015. We selected 1,049 cases and controls using 1:1 propensity score matching. Conditional logistic regression analysis was conducted to estimate the association between RASi exposure and fracture incidence. RESULTS: Overall, RASi usage was significantly associated with lower odds for fracture incidence (ever-users vs never-users: OR, 0.73; 95% CI, 0.59-0.91). We found that ARB-only users experienced fewer fractures than RASi-never users (OR, 0.65; 95% CI, 0.49-0.86), whereas ACEi-only users or ARB/ACEi-ever users did not. In subgroup analysis, RASi-ever users without cerebrovascular disease, those with a BMI exceeding 23, and statin exposure had significantly lower ORs. CONCLUSIONS: The present study established a significant association between RASi use and reduced fracture incidence, thus highlighting the potential clinical utility of RASi use as a preventive strategy in elderly patients at risk for osteoporotic fractures.