Respiratory pathogenic microbial infections: a narrative review.

Respiratory infectious diseases have long been recognised as a substantial global healthcare burden and are one of the leading causes of death worldwide, particularly in vulnerable individuals. In the post COVID-19 era, there has been a surge in the prevalence of influenza virus A and other multiple known viruses causing cold compared with during the same period in the previous three years, which coincided with countries easing COVID-19 restrictions worldwide. This article aims to review community-acquired respiratory illnesses covering a broad spectrum of viruses, bacteria, and atypical microorganisms and focuses on the cluster prevalence of multiple known respiratory pathogens in China, thereby providing effective prevention and control measures.

Biofunctional study on chemoresistance in esophageal squamous carcinoma cells induced by missense mutation of NOTCH1 p.E450K.

Background: Neoadjuvant chemotherapy (nCT) combined with surgery is one of the main strategies for the treatment of resectable locally advanced esophageal squamous cell carcinoma (ESCC). However, nearly 40% of patients did not benefit from nCT, and the detection rate of NOTCH1 missense mutation was significantly increased in patients who did not respond to chemotherapy, suggesting that the missense mutation may be related to tumor chemoresistance. We aim to explore the effect of a NOTCH1 missense mutation on cell phenotype, to interpret the biofunctional changes in cell lines with a NOTCH1 missense mutation and to analyze the effect of a NOTCH1 missense mutation on drug resistance in ESCC cell lines. Methods: Sanger sequencing was used to evaluate the exon mutations in the NOTCH1 ligand binding region of candidate ESCC cell lines. After screening, KYSE450 and KYSE140 cells were selected as the research objects, and point mutation cell lines [KYSE140-mutant-type (MT) and KYSE450-MT] were constructed by CRISPR/Cas9 technology. Then, functional experiments were performed with the four cell lines [KYSE450-MT/wild-type (WT) and KYSE140-MT/WT]. The drug resistance of ESCC cell lines was assessed with a drug sensitivity test, and the proliferation, invasion and migration of ESCC lines were evaluated by proliferation test, scratch test and Transwell test. The cell cycle status of ESCC cells was assessed using flow cytometry. Results: Drug sensitivity tests showed that the NOTCH1 p.E450K point mutation caused chemotherapy resistance in KYSE140 and KYSE450 ESCC cell lines. Cell proliferation, Wound scratch and Transwell assays showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, invasion and migration abilities of KYSE140 and KYSE450 cells. Flow cytometry analysis showed that the NOTCH1 p.E450K point mutation caused an increase in KYSE140 and KYSE450 cells in S phase. Conclusions: The NOTCH1 p.E450K point mutation causes chemotherapy resistance in KYSE140 and KYSE450 ESCC cells. Cell functional experiments showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, migration and invasion abilities of KYSE140 and KYSE450 cells and increased the number of cells in S phase.

Visual Analytics for Efficient Image Exploration and User-Guided Image Captioning.

Recent advancements in pre-trained language-image models have ushered in a new era of visual comprehension. Leveraging the power of these models, this paper tackles two issues within the realm of visual analytics: (1) the efficient exploration of large-scale image datasets and identification of data biases within them; (2) the evaluation of image captions and steering of their generation process. On the one hand, by visually examining the captions generated from language-image models for an image dataset, we gain deeper insights into the visual contents, unearthing data biases that may be entrenched within the dataset. On the other hand, by depicting the association between visual features and textual captions, we expose the weaknesses of pre-trained language-image models in their captioning capability and propose an interactive interface to steer caption generation. The two parts have been coalesced into a coordinated visual analytics system, fostering the mutual enrichment of visual and textual contents. We validate the effectiveness of the system with domain practitioners through concrete case studies with large-scale image datasets.

[Heavy Metal Content and Risk Assessment of Sediments and Soils in the Juma River Basin].

The sediment and soil in the Juma River channel pose a risk of pollution to the downstream ecological environment of Beijing and Xiong'an New Area. To address this issue, sediments and soil samples were collected along the river from the source to the Zhangfang outlet. The samples were further divided into three types:main stream sediment (29 samples), riverbank soil (27 samples), and farmland soil (26 samples). Enrichment factor analysis and the potential ecological risk index were employed to investigate the ecological risk. The results showed that the average concentrations of Cd, Hg, Pb, Zn, and Cu in the river sediment and soil in the study area were higher than those in the Baiyangdian Lake sediment and the surface soil of Hebei Province, whereas the concentrations of As, Cr, and Ni were relatively lower. The ranking of heavy metal pollution levels from high to low were Cd > Hg > Pb > Zn > Cu > Cr > Ni > As. The comprehensive ecological risk index showed that farmland soil and riverbank soil were mainly at a slight risk, followed by a moderate risk. The potential ecological risk of the main stream sediment was mainly moderate, severe, and extremely severe, accounting for 35.5%, 24.1%, and 24.1%, respectively, and the main contributing factors of the risk were Cd and Hg. The results of multivariate statistical analysis indicated that the main pollution sources of Cd, Pb, Zn, and Cu were industrial and mining activities. Cr, Ni, and As were mainly controlled by the weathering of the parent rock, and As was also influenced by agricultural activities. Hg was controlled by composite pollution sources such as industrial and mining activities, parent rock weathering, and atmospheric dust fall. Overall, the risk of heavy metal in the soil of the research area was generally at a slight level. However, there was a significant enrichment of Cd and other heavy metal in the sediment of the Taiyu-Sigezhuang-Pengtou River. This river section should be the focus of environmental monitoring, river dredging, and governance.

ATP Citrate Lyase is a General Tumour Biomarker and Contributes to the Development of Cutaneous Squamous Cell Carcinoma.

ATP citrate lyase, the first rate-limiting enzyme in de novo lipogenesis, plays a crucial role in tumour progression. This study explores ATP citrate lyase's potential as a tumour biomarker and its role in cutaneous squamous cell carcinoma. ATP citrate lyase expression patterns were analysed using TCGA and TIMER databases, and patient skin specimens were collected for immunohistochemistry to determine ATP citrate lyase levels. Cell proliferation, cell cycle, apoptosis, and c-Myc expression were assessed in A431 and SCL-1 cells. Stable cell lines with reduced ATP citrate lyase expression were obtained and subcutaneously implanted into nude mice to evaluate in vivo tumour growth. Ki67, c-Myc expression and TUNEL staining were analysed in subcutaneous tumours. ATP citrate lyase exhibited upregulation in various tumours, and showed significant associations with prognosis and immune infiltrate. Moreover, ATP citrate lyase was highly expressed in cutaneous squamous cell carcinoma. After ATP citrate lyase silencing, cutaneous squamous cell carcinoma cell growth decelerated, the cell cycle halted, cell apoptosis increased, and c-Myc expression decreased. Animal experiments revealed that, following ATP citrate lyase knockdown, tumour tissue growth slowed down, and there was a reduction in Ki-67 and c-Myc expression, accompanied by enhanced TUNEL staining. In conclusion, ATP citrate lyase may serve as a tumour biomarker. It is highly expressed in cutaneous squamous cell carcinoma and may serve as a therapeutic target.

Relationship between abnormal pelvic floor electromyography and obstetric factors in postpartum women: a cross-sectional study.

OBJECTIVE: To evaluate the surface electromyography (sEMG) of pelvic floor muscles (PFMs), compare between vaginal birth and cesarean section and correlate with maternity and obstetrics characteristics in primiparous 6-8 weeks postpartum. METHODS: PFMs surface electromyography screening data of primiparous postpartum women in our hospital at 6-8 weeks postpartum from 2018 to 2021 were selected and analyzed. The study collected data on delivery activities of 543 postpartum women totally. RESULTS: In general, the abnormal incidence of pelvic floor electromyography in postpartum women mainly occurred in slow muscle (type I fiber) stage and endurance testing stage. Compared to vaginal birth postpartum women, the incidence of abnormal pelvic floor electromyography in cesarean section postpartum women is lower. There were statistical differences in measurement values of pelvic floor electromyography in several different stages between cesarean section and vaginal birth (P < 0.005). Regarding the influence on pelvic floor electromyography, there were more influencing factors on vaginal birth postpartum women including age, height, weight, weight gain during pregnancy, gestational week, and first and second stage of labor than on cesarean section postpartum women whose influencing factors included age, weight gain during pregnancy, and newborn weight. CONCLUSION: Effects on surface electromyography (sEMG) of pelvic floor muscles (PFMs) at 6-8 weeks postpartum differed based on the different modes of delivery. The high-risk obstetric factors closely related to abnormal surface electromyography (sEMG) of pelvic floor muscles (PFMs) were maternal age, height, weight, and second stage of labor.

Effectiveness of a standardized quality control management procedure for COVID-19 RT-PCR testing: a large-scale diagnostic accuracy study in China.

BACKGROUND: The study aimed to construct a standardized quality control management procedure (QCMP) and access its accuracy in the quality control of COVID-19 reverse transcriptase-polymerase chain reaction (RT-PCR). METHODS: Considering the initial RT-PCR results without applying QCMP as the gold standard, a large-scale diagnostic accuracy study including 4,385,925 participants at three COVID-19 RT-PCR testing sites in China, Foshan (as a pilot test), Guangzhou and Shenyang (as validation sites), was conducted from May 21, 2021, to December 15, 2022. RESULTS: In the pilot test, the RT-PCR with QCMP had a high accuracy of 99.18% with 100% specificity, 100% positive predictive value (PPV), and 99.17% negative predictive value (NPV). The rate of retesting was reduced from 1.98% to 1.16%. Its accuracy was then consistently validated in Guangzhou and Shenyang. CONCLUSIONS: The RT-PCR with QCMP showed excellent accuracy in identifying true negative COVID-19 and relieved the labor and time spent on retesting.

Average lifespan variation among people with mental disorders in Denmark: a nationwide, register-based cohort study.

AIMS: Mortality associated with mental disorders has been estimated using metrics such as mortality rate ratios and life expectancy. However, the variation around the average life expectancy has never been quantified. The main aim of this study was to measure life disparity for people with mental disorders as a measure of inequality at the time of death. METHODS: Using data from Danish registries, average life disparity was introduced and calculated to measure the lifespan variation associated with major types of mental disorders. Average life expectancy is also reported for completeness. RESULTS: Compared with the general population, people with mental disorders not only had shorter average life expectancy, but experienced larger average life disparity. For those diagnosed with a mental disorder, average life expectancy increased between 1995 and 2021; however, average life disparity declined in women only, and did not change for men. In addition, the differences in both metrics between those with mental disorders and the general population were largest for substance use disorders and schizophrenia spectrum disorders. For these disorders, the differences even increased during the study period. CONCLUSIONS: Mortality rates for individuals with mental disorders have been declining in recent decades in Denmark; however, the increase in the average life disparity emphasizes the increasing heterogeneity and inequality in lifespans within this group, which requires measures to promote a longer and more equal life for those with mental disorders.

Development of ultra-thin poly(L-lactic acid)-based films integrating toughness, barrier properties, and gas selectivity: Towards gas-permeation controllable green food packaging.

High costs and low performance have constrained the application of bio-based materials in food packaging. Herein, a series of ultra-thin poly(L-lactic acid-iconic acid N-diol) (P(LA-NI)) copolymer films were developed using a "one-step" polycondensation process with integrated toughness, barrier properties, gas selectivity, and quality control features. The massive branched structure and gg conformers in P(LA-NI) act as "internal chain expansion" and "internal plasticization". Meanwhile, P(LA-NI) contains numerous polar groups and unique nanoscale microphase structures to realize excellent CO2, O2 barrier, CO2/O2 selectivity, anti-fogging, and UV shielding functions. The atmosphere within the package spontaneously achieves the desirable low O2 and high CO2 levels when packaging button mushrooms with high respiratory metabolism. Eventually, the shelf life of button mushrooms reached 24 days, >3-fold extended. This PLLA-based film meets "dual carbon" and "food safety" goals and has vast potential for fresh food preservation.

Theabrownin from Fu Brick tea ameliorates high-fat induced insulin resistance, hepatic steatosis, and inflammation in mice by altering the composition and metabolites of gut microbiota.

Fu Brick tea belongs to fermented dark tea, which is one of the six categories of tea. Fu Brick tea has been reported to reduce adiposity and has beneficial effects in the treatment of hypercholesterolemia and cardiovascular disease. Theabrownin (TB) is one of the pigments with the most abundant content in Fu Brick tea. TB has also been reported to have lipid-lowering effects, but its mechanism remains unclear. We found that TB could effectively reduce the insulin resistance and fat deposition induced by a high fat diet (HFD), decrease inflammation in the liver, improve intestinal integrity, and reduce endotoxins in circulation. Further studies showed that TB increased the abundance of Verrucomicrobiota and reduced the abundance of Firmicutes and Desulfobacterota in the intestinal tract of obese mice. The alteration of gut microbiota is closely linked to the metabolic phenotype after TB treatment through correlation analysis. Moreover, TB changed the gut microbial metabolites including L-ornithine, α-ketoglutarate, and glutamine, which have also been found to be upregulated in the liver after TB intervention. In vitro, L-ornithine, α-ketoglutarate, or glutamine significantly reduced lipopolysaccharide (LPS)-induced inflammation in macrophages. Therefore, our results suggest that TB can reduce adiposity, systemic insulin resistance, and liver inflammation induced by a HFD through altering gut microbiota and improving the intestinal tight junction integrity. The metabolites of gut microbiota might also play a role in ameliorating the HFD-induced phenotype by TB.

Major source categories of PM2.5 oxidative potential in wintertime Beijing and surroundings based on online dithiothreitol-based field measurements.

Fine particulate matter (PM2.5) causes millions of premature deaths each year worldwide. Oxidative potential (OP) has been proposed as a better metric for aerosol health effects than PM2.5 mass concentration alone. In this study, we report for the first time online measurements of PM2.5 OP in wintertime Beijing and surroundings based on a dithiothreitol (DTT) assay. These measurements were combined with co-located PM chemical composition measurements to identify the main source categories of aerosol OP. In addition, we highlight the influence of two distinct pollution events on aerosol OP (spring festival celebrations including fireworks and a severe regional dust storm). Source apportionment coupled with multilinear regression revealed that primary PM and oxygenated organic aerosol (OOA) were both important sources of OP, accounting for 41 ± 12 % and 39 ± 10 % of the OPvDTT (OP normalized by the sampled air volume), respectively. The small remainder was attributed to fireworks and dust, mainly resulting from the two distinct pollution events. During the 3.5-day spring festival period, OPvDTT spiked to 4.9 nmol min-1 m-3 with slightly more contribution from OOA (42 ± 11 %) and less from primary PM (31 ± 15 %). During the dust storm, hourly-averaged PM2.5 peaked at a very high value of 548 µg m-3 due to the dominant presence of dust-laden particles (88 % of total PM2.5). In contrast, only mildly elevated OPvDTT values (up to 1.5 nmol min-1 m-3) were observed during this dust event. This observation indicates that variations in OPvDTT cannot be fully explained using PM2.5 alone; one must also consider the chemical composition of PM2.5 when studying aerosol health effects. Our study highlights the need for continued pollution control strategies to reduce primary PM emissions, and more in-depth investigations into the source origins of OOA, to minimize the health risks associated with PM exposure in Beijing.

Correlation between standard sperm parameters and sperm DNA fragmentation from 11,339 samples.

Conventional semen parameters have long been considered fundamental in male fertility analyses. However, doubts have been raised regarding the clinical utility of the assessment of spermatozoa (sperm) DNA damage. In this retrospective study, we investigated the potential correlation between conventional semen parameters and semen DNA fragmentation (SDF) assessed as sperm DNA damage, in 11,339 semen samples collected between January 2019 and June 2022. We observed significant negative correlations between the DNA fragmentation index (DFI) and sperm viability (correlation coefficient [r] = -0.514) as well as progressive sperm motility (r = -0.512, p < 0.05). Samples were categorized into three groups according to DFI levels (Groups A, B, and C: ≤15%, 15 < DFI ≤30%, and >30%, respectively). Furthermore, the percentage of semen samples with normal sperm conventional parameters in Groups A, B, and C was 76.7% (4369/5697), 61.4% (2351/3827), and 39.7% (721/1815), respectively. Moreover, according to the reference values of conventional sperm parameters, the samples were divided into Groups F, G, and H with all normal, only one abnormal, and > two abnormal parameters, respectively. In addition, the proportions of samples with abnormal DFI values (>30) in Groups F, G, and H were 9.7% (721/7441), 23.1% (618/2676), and 39.0% (476/1222), respectively. Multivariate logistic regression models demonstrated that sperm vitality, progressive sperm motility, normal sperm form, total sperm count, semen volume, age, and some sperm kinematics collectively improved the area under the receiver operating characteristic curve (AUROC) to 0.861, surpassing the predictive value of a single predictor of pathologically damaged sperm DNA. Our study suggests that samples with abnormal sperm parameters may have a higher likelihood of high DNA fragmentation. Furthermore, certain semen parameters could be potential indicators of sperm DNA fragmentation, aiding sperm selection in assisted reproductive procedures.

The Impact of Home Cardiac Rehabilitation on Quality of Life and Psychological Well-Being in Patients with Coronary Heart Disease: A Randomized Controlled Study.

BACKGROUND Percutaneous coronary intervention (PCI), a therapeutic approach to coronary heart disease, significantly alleviates symptoms of coronary heart disease (CHD) and substantially improves quality of life. This study aimed to investigate the effect of home cardiac rehabilitation (HCR) on patients after PCI. MATERIAL AND METHODS We randomly divided 106 patients after PCI into an Intervention group (n=52) and a Control group (n=53). Left ventricular ejection fraction (LVEF), blood pressure, blood glucose, and low-density lipoprotein were measured in both groups before hospital discharge and after 3 months of engaging in the intervention. Patients were assessed using the short-form health survey (SF-12) scale and Hospital Anxiety and Depression Scale (HADS) scale. RESULTS After 3 months of HCR intervention, SF-12 scores of patients in the Intervention group were significantly higher compared to patients in the Control group (physical component summary (PCS): 47.46±9.86 vs 43.28±8.21; and Mental Component Summary (MCS): 50.68±9.82 vs 48.26±9.69) (P.

Exploration of the causality of frailty index on psoriasis: A Mendelian randomization study.

BACKGROUND: Frailty is associated with a variety of diseases, but the relationship between frailty and psoriasis remains unclear. METHODS: First, we conducted a two-sample Mendelian randomization based on genome-wide association studies (GWAS) to investigate genetic causality between frailty index and common diseases in dermatology. Inverse variance weighted was used to estimate causality. Second, expression quantitative trait locus (eQTLs) analysis was conducted to identify the genes affected by Single nucleotide polymorphisms (SNPs). Third, we performed function and pathway enrichment, transcriptome-wide association studies (TWAS) analysis based on eQTLs. RESULTS: It was shown that the rise of frailty index could increase the risk of psoriasis (IVW, beta = 0.916, OR = 2.500, 95%CI:1.418-4.408, p = 0.002) through Mendelian randomization (MR), and there was no heterogeneity and pleiotropy. There was no causality between the frailty index and other common diseases in dermatology. We found 31 eQTLs based on strongly correlated SNPs in the causality. TWAS analysis found that the expressions of four genes were closely related to psoriasis, including HLA-DQA1, HLA-DQA2, HLA-DRB1 and HLA-DQB1. CONCLUSION: It suggested that the frailty index had a significant positive causality on the risk of psoriasis, which was well documented by combined genomic, transcriptome, and proteome analyses.

Trends in application of fundus fluorescein angiography in fundus diseases during a recent ten-year period.

PURPOSE: To analyze the trends in the application of fundus fluorescein angiography (FFA) in fundus diseases over ten years. METHOD: It was a retrospective study. Patients who underwent FFA examinations between Jan 2012 and Dec 2021 in Eye Hospital of Wenzhou Medical University were included, excluding infants. Data included the fundus disease and examination time of FFA. RESULTS: A total of 37,038 cases underwent FFA examinations in our hospital in the past decade, and the number of each year was 3,628, 2,232, 2,230, 2,351, 3,546, 3,924, 5,325, 4,202, 4,432 and 5,168 from 2012 to 2021, respectively. The top three diseases were central serous chorioretinopathy (CSC), diabetic retinopathy (DR) and retinal vein occlusion (RVO) over the years from 2012 to 2021. The fourth to eighth ranked diseases were uveitis, age-related macular degeneration (AMD), choroidal neovascularization (CNV), optic neuropathy (ON) and polypoid choroidal vasculopathy (PCV) 9 years from 2012 to 2020; while retinal artery occlusion (RAO) ranked eighth and PCV fell out of the first eight in 2021. Tumor, Eale's disease, macular hemorrhage (MH), epiretinal retinal membrane (ERM) and Coat's disease had consistent proportions over the years. There was a significant statistical difference in the proportion of disease components over the years from 2012 to 2021(p = 0.000). CONCLUSION: Despite changes in annual distribution, CSC, DR, and RVO consistently ranked as the top three diseases requiring FFA examination. Changes might be related to the development of non-invasive fundus examination instruments and technologies. Indicated that FFA still hold its irreplaceable nature in diagnosing and understanding fundus diseases.

Extracellular vesicle-mediated pre-metastatic niche formation via altering host microenvironments.

The disordered growth, invasion and metastasis of cancer are mainly attributed to bidirectional cell-cell interactions. Extracellular vesicles (EVs) secreted by cancer cells are involved in orchestrating the formation of pre-metastatic niches (PMNs). Tumor-derived EVs mediate bidirectional communication between tumor and stromal cells in local and distant microenvironments. EVs carrying mRNAs, small RNAs, microRNAs, DNA fragments, proteins and metabolites determine metastatic organotropism, enhance angiogenesis, modulate stroma cell phenotypes, restructure the extracellular matrix, induce immunosuppression and modify the metabolic environment of organs. Evidence indicates that EVs educate stromal cells in secondary sites to establish metastasis-supportive microenvironments for seeding tumor cells. In this review, we provide a comprehensive overview of PMN formation and the underlying mechanisms mediated by EVs. Potential approaches to inhibit cancer metastasis by inhibiting the formation of PMNs are also presented.

Machine learning to optimize automated RH genotyping using whole-exome sequencing data.

Rh phenotype matching reduces but does not eliminate alloimmunization in patients with sickle cell disease (SCD) due to RH genetic diversity that is not distinguishable by serological typing. RH genotype matching can potentially mitigate Rh alloimmunization, but comprehensive and accessible genotyping methods are needed. We developed RHtyper as an automated algorithm to predict RH genotypes using whole-genome sequencing (WGS) data with high accuracy. Here, we adapted RHtyper for whole-exome sequencing (WES) data which are more affordable but challenged by uneven sequencing coverage and exacerbated sequencing read misalignment, resulting in uncertain prediction for 1) RHD zygosity and hybrid alleles, 2) RHCE*C versus RHCE*c alleles, 3) RHD c.1136C>T zygosity, and 4) RHCE c.48G>C zygosity. We optimized RHtyper to accurately predict RHD and RHCE genotypes using WES data by leveraging machine learning models and improved the concordance of WES with WGS predictions from 90.8% to 97.2% for RHD and 96.3 to 98.2% for RHCE among 396 patients in the Sickle Cell Clinical Research and Intervention Program (SCCRIP). In a second validation cohort with 3030 cancer survivors (15.2% Black or African Americans) from the St. Jude Lifetime Cohort Study (SJLIFE), the optimized RHtyper reached concordance rates between WES and WGS predications to 96.3% for RHD, and 94.6% for RHCE. In conclusion, machine learning improved the accuracy of RH predication from WES data. RHtyper has the potential, once implemented, to provide a precision medicine-based approach to facilitate RH genotype-matched transfusion and improve transfusion safety for patients with SCD.

Multi-modal molecular determinants of clinically relevant osteoporosis subtypes.

Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).