Epitope editing enables targeted immunotherapy of acute myeloid leukaemia.

Despite the considerable efficacy observed when targeting a dispensable lineage antigen, such as CD19 in B cell acute lymphoblastic leukaemia1,2, the broader applicability of adoptive immunotherapies is hampered by the absence of tumour-restricted antigens3-5. Acute myeloid leukaemia immunotherapies target genes expressed by haematopoietic stem/progenitor cells (HSPCs) or differentiated myeloid cells, resulting in intolerable on-target/off-tumour toxicity. Here we show that epitope engineering of donor HSPCs used for bone marrow transplantation endows haematopoietic lineages with selective resistance to chimeric antigen receptor (CAR) T cells or monoclonal antibodies, without affecting protein function or regulation. This strategy enables the targeting of genes that are essential for leukaemia survival regardless of shared expression on HSPCs, reducing the risk of tumour immune escape. By performing epitope mapping and library screenings, we identified amino acid changes that abrogate the binding of therapeutic monoclonal antibodies targeting FLT3, CD123 and KIT, and optimized a base-editing approach to introduce them into CD34+ HSPCs, which retain long-term engraftment and multilineage differentiation ability. After CAR T cell treatment, we confirmed resistance of epitope-edited haematopoiesis and concomitant eradication of patient-derived acute myeloid leukaemia xenografts. Furthermore, we show that multiplex epitope engineering of HSPCs is feasible and enables more effective immunotherapies against multiple targets without incurring overlapping off-tumour toxicities. We envision that this approach will provide opportunities to treat relapsed/refractory acute myeloid leukaemia and enable safer non-genotoxic conditioning.

Correction: FoQDE2-dependent milRNA promotes Fusarium oxysporum f. sp. cubense virulence by silencing a glycosyl hydrolase coding gene expression.

[This corrects the article DOI: 10.1371/journal.ppat.1010157.].

Histone H3K27 Demethylase SlJMJ3 Modulates Fruit Ripening in Tomato.

The histone lysine (K) demethylase 4 (KDM4/JHDM3) subfamily of jumonji domain-containing demethylases (JMJs) has been implicated in various aspects of plant development. However, their involvement in regulating the ripening of fleshy fruits remains unclear. Here, we identified SlJMJ3, a member of the KDM4/JHDM3 family, as a H3K27me3 demethylase in tomato (Solanum lycopersicum) that plays an important role in fruit ripening regulation. Overexpression of SlJMJ3 led to accelerated fruit ripening, whereas loss-of-function of SlJMJ3 delayed this process. Furthermore, we determined that SlJMJ3 exerts its regulatory function by modulating the expression of multiple ripening-related genes involved in ethylene biosynthesis and response, carotenoid metabolism, cell wall modification, transcriptional control, and DNA methylation modification. SlJMJ3 bound directly to the promoters of ripening-related genes harboring the CTCTGYTY motif and activates their expression. Additionally, SlJMJ3 reduced the levels of H3K27me3 at its target genes, thereby up-regulating their expression. In summary, our findings highlight the role of SlJMJ3 in the regulation of fruit ripening in tomato. By removing the methyl group from trimethylated histone H3 lysine 27 at ripening-related genes, SlJMJ3 acts as an epigenetic regulator that orchestrates the complex molecular processes underlying fruit ripening.

Rupture process of the 2021 M7.4 Maduo earthquake and implication for deformation mode of the Songpan-Ganzi terrane in Tibetan Plateau.

The deformation mode of the Tibetan Plateau is of crucial importance for understanding its construction and extrusion processes, as well as for the assessment of regional earthquake potential. Block motion and viscous flow models have been proposed to describe the deformation field but are not fully supported by modern geophysical observations. The 2021 Mw 7.4 Maduo earthquake, which occurred inside the Songpan-Ganzi terrane (SGT) in central-east Tibet, provides a chance to evaluate the associated deformation mode of the region. We conduct a joint inversion for this earthquake and resolve a bilateral rupture process, which is characterized by super- and subshear rupture velocities, respectively. We interpret this distinct rupture behavior to be the result of the respective slip concentration depths of the two ruptured segments. We analyze geological, seismic, and geodetic evidence and find that the SGT upper crust shows distributed shear deformation and distinct transverse anisotropy, which are associated with folded structures originating from compression of the paleo-Tethys ocean accretional prism realigned by following shear deformation. The SGT receives lateral shear loading from its NS boundary and accommodates a right-step sinistral motion across the terrane boundary faults. The unique tectonic setting of the SGT defines locations and behaviors of internal faulting and strong earthquakes such as the 2021 Maduo earthquake, with the latter occurring on slow-moving faults at intervals of several thousands of years.

Adult epithelioid glioblastoma exhibits an extremely poor prognosis and high frequency of SWI/SNF complex mutation: Insights from a retrospective study.

Epithelioid glioblastoma (eGBM) is a rare subtype of GBM. Given the update of the definition of GBM, the understanding of the molecular characteristics and prognosis of "true" adult eGBM remains limited. Herein, we retrospectively analyzed the clinicopathological data of 39 adult eGBM cases. Adult eGBM primarily affected females, with a male-to-female ratio of 1:2.3. The average age of diagnosis was 53 years, and the tumor affected the temporal lobe in 41% of cases (16/39, 41%). Microscopically, the tumors consisted mainly or entirely of epithelioid cells. Perivascular infiltration (10/39, 25.6%) and leptomeningeal dissemination (7/39, 17.9%) were not uncommon. BRAF V600E mutation was detected in 40.9% of cases (n = 9/22). Next-generation sequencing revealed that CDKN2A/B homogeneous deletion was the most frequently mutated gene (8/10, 80%), followed by TERT promoter mutation (7/10, 70%), Cyclin-dependent kinases 4 or 6 (CDK4/6) amplification (5/10, 50%) and BRAF V600E mutation (50%, 5/10). Notably, the incidence of ARID1B mutation in eGBM was 50% (5/10), representing the first report of such a mutation in this subtype of GBM. ARID1B was known to be a subunit of the SWI/SNF chromatin remodeler. Chromosome analysis showed a 7+/10- signature in 90% (9/10) cases. Adult eGBM carried a dismal prognosis compared to GBM with IDH and H3 wild-type (typical GBM) (OS: 13.89 vs 24.30 months; P = .003) and even typical GBM without MGMT promoter methylation (OS: 13.89 vs 22.08 months; P = .036). Based on these findings, it can be concluded that adult eGBM harbors a high frequency of the 7+/10- signature and alterations in the MAPK pathway, SWI/SNF complex and cyclin-related genes and portends an extremely poor prognosis.

Therapeutic vaccine-induced plasma cell differentiation is defective in the presence of persistently high HBsAg levels.

BACKGROUND & AIMS: Mechanisms behind the impaired response of antigen-specific B cells to therapeutic vaccination in chronic hepatitis B virus (HBV) infection remain unclear. The development of vaccines or strategies to overcome this obstacle is vital for advancing the management of chronic hepatitis B. METHODS: A mouse model, denominated as E6F6-B, was engineered to feature a knock-in of a B-cell receptor (BCR) that specifically recognizes HBsAg. This model served as a valuable tool for investigating the temporal and spatial dynamics of humoral responses following therapeutic vaccination under continuous antigen exposure. Using a suite of immunological techniques, we elucidated the differentiation trajectory of HBsAg-specific B cells post-therapeutic vaccination in HBV carrier mice. RESULTS: Utilizing the E6F6-B transfer model, we observed a marked decline in antibody-secreting cells 2 weeks after vaccination. A dysfunctional and atypical pre-plasma cell population (BLIMP-1+ IRF4+ CD40- CD138- BCMA-) emerged, manifested by sustained BCR signaling. By deploying an antibody to purge persistent HBsAg, we effectively prompted the therapeutic vaccine to provoke conventional plasma cell differentiation. This resulted in an enhanced anti-HBs antibody response and facilitated HBsAg clearance. CONCLUSIONS: Sustained high levels of HBsAg limit the ability of therapeutic hepatitis B vaccines to induce the canonical plasma cell differentiation necessary for anti-HBs antibody production. Employing a strategy combining antibodies with vaccines can surmount this altered humoral response associated with atypical pre-plasma cells, leading to improved therapeutic efficacy in HBV carrier mice. IMPACT AND IMPLICATIONS: Therapeutic vaccines aimed at combatting HBV encounter suboptimal humoral responses in clinical settings, and the mechanisms impeding their effectiveness have remained obscure. Our research, utilizing the innovative E6F6-B mouse transfer model, reveals that the persistence of HBsAg can lead to the emergence of an atypical pre-plasma cell population, which proves to be relevant to the potency of therapeutic HBV vaccines. Targeting the aberrant differentiation process of these atypical pre-plasma cells stands out as a critical strategy to amplify the humoral response elicited by HBV therapeutic vaccines in carrier mouse models. This discovery suggests a compelling avenue for further study in the context of human chronic hepatitis B. Encouragingly, our findings indicate that synergistic therapy combining HBV-specific antibodies with vaccines offers a promising approach that could significantly advance the pursuit of a functional cure for HBV.

FoQDE2-dependent milRNA promotes Fusarium oxysporum f. sp. cubense virulence by silencing a glycosyl hydrolase coding gene expression.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate protein-coding gene expression primarily found in plants and animals. Fungi produce microRNA-like RNAs (milRNAs) that are structurally similar to miRNAs and functionally important in various biological processes. The fungus Fusarium oxysporum f. sp. cubense (Foc) is the causal agent of Banana Fusarium vascular wilt that threatens global banana production. It remains uncharacterized about the biosynthesis and functions of milRNAs in Foc. In this study, we investigated the biological function of milRNAs contributing to Foc pathogenesis. Within 24 hours post infecting the host, the Argonaute coding gene FoQDE2, and two Dicer coding genes FoDCL1 and FoDCL2, all of which are involved in milRNA biosynthesis, were significantly induced. FoQDE2 deletion mutant exhibited decreased virulence, suggesting the involvement of milRNA biosynthesis in the Foc pathogenesis. By small RNA sequencing, we identified 364 small RNA-producing loci in the Foc genome, 25 of which were significantly down-regulated in the FoQDE2 deletion mutant, from which milR-87 was verified as a FoQDE2-depedent milRNA based on qRT-PCR and Northern blot analysis. Compared to the wild-type, the deletion mutant of milR-87 was significantly reduced in virulence, while overexpression of milR-87 enhanced disease severity, confirming that milR-87 is crucial for Foc virulence in the infection process. We furthermore identified FOIG_15013 (a glycosyl hydrolase-coding gene) as the direct target of milR-87 based on the expression of FOIG_15013-GFP fusion protein. The FOIG_15013 deletion mutant displayed similar phenotypes as the overexpression of milR-87, with a dramatic increase in the growth, conidiation and virulence. Transient expression of FOIG_15013 in Nicotiana benthamiana leaves activates the host defense responses. Collectively, this study documents the involvement of milRNAs in the manifestation of the devastating fungal disease in banana, and demonstrates the importance of milRNAs in the pathogenesis and other biological processes. Further analyses of the biosynthesis and expression regulation of fungal milRNAs may offer a novel strategy to combat devastating fungal diseases.

The Dynamic Role of Endoplasmic Reticulum Stress in Chronic Liver Disease.

Chronic liver disease (CLD) is a major worldwide public health threat, with an estimated prevalence of 1.5 billion individuals with CLD in 2020. Chronic activation of endoplasmic reticulum (ER) stress-related pathways is recognized as substantially contributing to the pathologic progression of CLD. The ER is an intracellular organelle that folds proteins into their correct three-dimensional shapes. ER-associated enzymes and chaperone proteins highly regulate this process. Perturbations in protein folding lead to misfolded or unfolded protein accumulation in the ER lumen, resulting in ER stress and concomitant activation of the unfolded protein response (UPR). The adaptive UPR is a set of signal transduction pathways evolved in mammalian cells that attempts to reestablish ER protein homeostasis by reducing protein load and increasing ER-associated degradation. However, maladaptive UPR responses in CLD occur due to prolonged UPR activation, leading to concomitant inflammation and cell death. This review assesses the current understanding of the cellular and molecular mechanisms that regulate ER stress and the UPR in the progression of various liver diseases and the potential pharmacologic and biological interventions that target the UPR.

Analysis of factors influencing the risk of secondary infection in patients colonized or infected with multidrug-resistant Gram-negative bacteria following hospitalization.

We seek to investigate the multifaceted factors influencing secondary infections in patients with multidrug-resistant Gram-negative bacteria (MDR-GNB) colonization or infection post-hospitalization. A total of 100 patients with MDR-GNB colonization or infection were retrospectively reviewed, encompassing those admitted to both the general ward and intensive care unit of our hospital from August 2021 to December 2022. Patients were categorized into the control group (non-nosocomial infection, n = 56) and the observation group (nosocomial infection, n = 44) based on the occurrence of nosocomial infection during hospitalization. Clinical data were compared between the two groups, including the distribution and antibiotic sensitivity of MDR-GNB before nosocomial infection. Significant differences were observed between the two groups in terms of age, underlying diseases, immune status, length of stay, and invasive medical procedures (P < 0.05). The observation group also had fewer patients practicing optimized hygiene, strict isolation, and antibiotic control than the control group (P < 0.05). Factors influencing the risk of secondary infection after hospitalization in patients colonized or infected with MDR-GNB included patient age, underlying diseases, immune status, length of hospitalization, medical invasive procedures, optimized hygiene, strict isolation, and antibiotic control (P < 0.05). The length of hospitalization and treatment cost in the observation group were higher than those in the control group (P < 0.05). This study comprehensively analyzes the intricate mechanisms of secondary infections in patients with MDR-GNB infections post-hospitalization. Key factors influencing infection risk include patient age, underlying diseases, immune status, length of hospitalization, medical invasive procedures, optimized hygiene, strict isolation, and antibiotic control.

Ex vivo culture resting time impacts transplantation outcomes of genome-edited human hematopoietic stem and progenitor cells in xenograft mouse models.

Ex vivo resting culture is a standard procedure following genome editing in hematopoietic stem and progenitor cells (HSPCs). However, prolonged culture may critically affect cell viability and stem cell function. We investigated whether varying durations of culture resting times impact the engraftment efficiency of human CD34+ HSPCs edited at the BCL11A enhancer, a key regulator in the expression of fetal hemoglobin. We employed electroporation to introduce CRISPR-Cas9 components for BCL11A enhancer editing and compared outcomes with nonelectroporated (NEP) and electroporated-only (EP) control groups. Post-electroporation, we monitored cell viability, death rates, and the frequency of enriched hematopoietic stem cell (HSC) fractions (CD34+CD90+CD45RA- cells) over a 48-hour period. Our findings reveal that while the NEP group showed an increase in cell numbers 24 hours post-electroporation, both EP and BCL11A-edited groups experienced significant cell loss. Although CD34+ cell frequency remained high in all groups for up to 48 hours post-electroporation, the frequency of the HSC-enriched fraction was significantly lower in the EP and edited groups compared to the NEP group. In NBSGW xenograft mouse models, both conditioned with busulfan and nonconditioned, we found that immediate transplantation post-electroporation led to enhanced engraftment without compromising editing efficiency. Human glycophorin A+ (GPA+) red blood cells (RBCs) sorted from bone marrow of all BCL11A edited mice exhibited similar levels of γ-globin expression, regardless of infusion time. Our findings underscore the critical importance of optimizing the culture duration between genome editing and transplantation. Minimizing this interval may significantly enhance engraftment success and minimize cell loss without compromising editing efficiency. These insights offer a pathway to improve the success rates of genome editing in HSPCs, particularly for conditions like sickle cell disease.

Assessing the Role of BN-Embedding Position in B2N2-Perylenes.

Incorporating heteroatoms can effectively modulate the molecular optoelectronic properties. However, the fundamental understanding of BN doping effects in BN-embedded polycyclic aromatic hydrocarbons (PAHs) is underexplored, lacking rational guidelines to modulate the electronic structures through BN units for advanced materials. Herein, a concise synthesis of novel B2N2-perylenes with BN doped at the bay area is achieved to systematically explore the doping effect of BN position on the photophysical properties of PAHs. The shift of BN position in B2N2-perylenes alters the π electron conjugation, aromaticity and molecular rigidness significantly, achieving substantially higher electron transition abilities than those with BN doped in the nodal plane. It is further clarified that BN position dominates the photophysical properties over BN orientation. The revealed guideline here may apply generally to novel BN-PAHs, and aid the advancement of BN-PAHs with highly-emissive performance.

Global, regional and national burdens of Nasopharynx cancer in the adolescents and young adults from 1990 to 2019 and its predictions.

PURPOSE: To use data from the Global Burden of Disease (GBD) Study 2019 to report the global, regional and national rates and trends of deaths incidence, prevalence, disability-adjusted life years (DALYs) for Nasopharynx cancer (NPC) in adolescents and young adults (AYAs). METHODS: Data from the GBD 2019 were used to analyze deaths incidence, prevalence and DALYs due to NPC at global, regional, and national levels. Joinpoint regression analysis was used to calculate the average annual percentage changes (AAPC). The association between incidence, prevalence and DALYs and socioeconomic development was analyzed using the GBD Socio-demographic Index (SDI). Finally, projections were made until 2030 and calculated in Nordpred. RESULTS: The incidence, prevalence, death and DALYs rates (95%UI) due to NPC 0.96 (0.85-1.09, 6.31 (5.54-7.20),0.20 (0.19-0.22), and 12.23(11.27-13.29) in 2019, respectively. From 1990 to 2019, the incidence and prevalence rates increased by 1.79 (95% CI 1.03 to 2.55) and 2.97(95% CI 2.13 to 3.82) respectively while the deaths and DALYs rates declined by 1.64(95%CI 1.78 to 1.49) and 1.6(95%CI 1.75 to 1.4) respectively. Deaths and DALYs rates in South Asia, East Asia, North Africa and Middle East decreased with SDI. Incidence and prevalence rates in East Asia increased with SDI. At the national level, the incidence and prevalence rates are high in China, Taiwan(China), Singapore, Malaysia, Brunel Darussalam, Algeria, Tunisia, Libya and Malta. Meanwhile, the deaths and DALYs rates are still high in Malaysia, Brunel Darussalam, Greenland and Taiwan(Province of China). The deaths and DALYs rates are low in Honduras, Finland and Norway. From the 2020 to 2030, ASIR、ASPR and ASDR in most regions are predicted to stable, but DALYs tends to decline. CONCLUSION: NPC in AYAs is a significant global public problem. The incidence, prevalence, and DALYs rates vary widely by region and country. Therefore different regions and countries should be targeted to improve the disease burden of NPC.

Predicting the Metal Mixture Toxicity with a Toxicokinetic-Toxicodynamic Model Considering the Time-Dependent Adverse Outcome Pathways.

Chemicals mainly exist in ecosystems as mixtures, and understanding and predicting their effects are major challenges in ecotoxicology. While the adverse outcome pathway (AOP) and toxicokinetic-toxicodynamic (TK-TD) models show promise as mechanistic approaches in chemical risk assessment, there is still a lack of methodology to incorporate the AOP into a TK-TD model. Here, we describe a novel approach that integrates the AOP and TK-TD models to predict mixture toxicity using metal mixtures (specifically Cd-Cu) as a case study. We preliminarily constructed an AOP of the metal mixture through temporal transcriptome analysis together with confirmatory bioassays. The AOP revealed that prolonged exposure time activated more key events and adverse outcomes, indicating different modes of action over time. We selected a potential key event as a proxy for damage and used it as a measurable parameter to replace the theoretical parameter (scaled damage) in the TK-TD model. This refined model, which connects molecular responses to organism outcomes, effectively predicts Cd-Cu mixture toxicity over time and can be extended to other metal mixtures and even multicomponent mixtures. Overall, our results contribute to a better understanding of metal mixture toxicity and provide insights for integrating the AOP and TK-TD models to improve risk assessment for chemical mixtures.

Association between thymic hyperplasia and serum calcium level in Graves' disease.

BACKGROUND: Graves' disease increases bone resorption in hyperthyroidism, leading to elevated serum calcium levels and a negative bone balance. Thymic hyperplasia is observed in some Graves' disease patients. What's more, there have been a few reports of increased serum calcium and severe osteoporosis induced by Graves' disease with thymic hyperplasia. It remains unclear whether Graves' disease with thymic hyperplasia is associated with higher serum calcium levels. Our study aimed to investigate the possibility of elevated serum calcium levels and aggravated bone mobilization in Graves' disease patients with thymic hyperplasia. METHODS: Newly diagnosed and untreated patients with Graves' disease (n = 96) were enrolled. They were divided into two groups based on the incidental detection of thymic hyperplasia during imaging. Albumin, alkaline phosphatase, calcium, free triiodothyronine, free thyroxine, thyroid-stimulating hormone, and thyrotrophin receptor antibody (TRAb) were measured, and a computerized tomography of the chest was obtained. RESULTS: Patients with Graves' disease who had thymic hyperplasia were notably younger (P=0.018) and exhibited higher serum calcium levels (P=0.001) compared to those with Graves' disease without thymic hyperplasia. In the multiple regression analysis, thymic hyperplasia, TRAb, and female gender were significant variables associated with elevated serum calcium levels in patients with Graves' disease, collectively accounting for 31.7% of the variation in serum calcium. CONCLUSIONS: Graves' disease patients with thymic hyperplasia showed higher serum calcium levels. thymic hyperplasia, TRAb, and female gender were found to be correlated with increased serum calcium levels in Graves' disease, suggesting a potential association between thymic hyperplasia and bone mobilization in Graves' disease.

Recent development of VEGFR small molecule inhibitors as anticancer agents: A patent review (2021-2023).

VEGFR, a receptor tyrosine kinase inhibitor (TKI), is an important regulatory factor that promotes angiogenesis and vascular permeability. It plays a significant role in processes such as tumor angiogenesis, tumor cell invasion, and metastasis. VEGFR is mainly composed of three subtypes: VEGFR-1, VEGFR-2, and VEGFR-3. Among them, VEGFR-2 is the crucial signaling receptor for VEGF, which is involved in various pathological and physiological functions. At present, VEGFR-2 is closely related to a variety of cancers, such as non-small cell lung cancer (NSCLC), Hepatocellular carcinoma, Renal cell carcinoma, breast cancer, gastric cancer, glioma, etc. Consequently, VEGFR-2 serves as a crucial target for various cancer treatments. An increasing number of VEGFR inhibitors have been discovered to treat cancer, and they have achieved tremendous success in the clinic. Nevertheless, VEGFR inhibitors often exhibit severe cytotoxicity, resistance, and limitations in indications, which weaken the clinical therapeutic effect. In recent years, many small molecule inhibitors targeting VEGFR have been identified with anti-drug resistance, lower cytotoxicity, and better affinity. Here, we provide an overview of the structure and physiological functions of VEGFR, as well as some VEGFR inhibitors currently in clinical use. Also, we summarize the in vivo and in vitro activities, selectivity, structure-activity relationship, and therapeutic or preventive use of VEGFR small molecule inhibitors reported in patents in the past three years (2021-2023), thereby presenting the prospects and insights for the future development of targeted VEGFR inhibitors.

Developmental dyslexia genes are selectively targeted by diverse environmental pollutants.

BACKGROUND: Developmental dyslexia, a complex neurodevelopmental disorder, not only affects children's academic performance but is also associated with increased healthcare costs, lower employment rates, and reduced productivity. The pathogenesis of dyslexia remains unclear and it is generally considered to be caused by the overlap of genetic and environmental factors. Systematically exploring the close relationship between exposure to environmental compounds and susceptibility genes in the development of dyslexia is currently lacking but high necessary. METHODS: In this study, we systematically compiled 131 publicly reported susceptibility genes for dyslexia sourced from DisGeNET, OMIM, and GeneCards databases. Comparative Toxicogenomics Database database was used to explore the overlap between susceptibility genes and 95 environmental compounds, including metals, persistent organic pollutants, polycyclic aromatic hydrocarbons, and pesticides. Chemical bias towards the dyslexia risk genes was taken into account in the observation/expectation ratios > 1 and the corresponding P value obtained by hypergeometric probability test. RESULTS: Our study found that the number of dyslexia risk genes targeted by each chemical varied from 1 to 109. A total of 35 chemicals were involved in chemical reactions with dyslexia-associated genes, with significant enrichment values (observed/expected dyslexia risk genes) ranging from 1.147 (Atrazine) to 66.901 (Dibenzo(a, h)pyrene). CONCLUSION: The results indicated that dyslexia-associated genes were implicated in certain chemical reactions. However, these findings are exploratory, and further research involving animal or cellular experiments is needed.

Triglyceride-Glucose Index as a Predictor of Lower Extremity Arterial Disease in Patients with Diabetes: A Hospitalized Population Retrospective Study.

BACKGROUND: The triglyceride-glucose (TyG) index is a new, simple, and inexpensive marker of insulin resistance that is becoming increasingly important as a promising predictor of diseases such as atherosclerosis. Atherosclerosis is the main cause of lower extremity arterial disease (LEAD). In this study, we investigated the relationship between TyG index values and LEAD risk in patients with diabetes. METHODS: Patients with diabetes hospitalized at the Endocrinology Department of our hospital from June 1, 2021, to May 31, 2022, were retrospectively included. Baseline data, biochemical indicators, and ankle-brachial index values were collected. Statistical methods were used to assess the relationship between TyG index values and the risk of LEAD. RESULTS: A total of 1,040 hospitalized patients with diabetes were included, they were divided into the LEAD group with 168 patients and the no LEAD group with 872 patients. TyG index values in the LEAD group were higher than those in the no LEAD group (9.94 ± 0.78 vs. 9.36 ± 0.70, P < 0.001). TyG index values were independently correlated with LEAD risk in patients with diabetes (odds ratio = 3.92, 95% confidence interval (CI): 2.92-5.26, P < 0.001) in multivariate logistic regression analysis after adjusting for different risk factors (all P < 0.05). The area under the receiver operating characteristic curve was 0.72 (95% CI: 0.68-0.76) when TyG index values were used to diagnose LEAD in patients with diabetes. When Youden's index reached the maximum value of 0.34, the optimal TyG index threshold for predicting the onset of diabetic LEAD was 9.56, sensitivity was 71.1%, and specificity was 63.0%. CONCLUSIONS: Increases in TyG index values were associated with the risk of LEAD in patients with diabetes and, thus, may be used as a predictor of LEAD in this patient population, especially in primary care institutions with relatively few resources.

Age-adjusted Charlson comorbidity index is associated with the risk of osteoporosis in older fall-prone men: a retrospective cohort study.

BACKGROUND: There is growing evidence linking the age-adjusted Charlson comorbidity index (aCCI), an assessment tool for multimorbidity, to fragility fracture and fracture-related postoperative complications. However, the role of multimorbidity in osteoporosis has not yet been thoroughly evaluated. We aimed to investigate the association between aCCI and the risk of osteoporosis in older adults at moderate to high risk of falling. METHODS: A total of 947 men were included from January 2015 to August 2022 in a hospital in Beijing, China. The aCCI was calculated by counting age and each comorbidity according to their weighted scores, and the participants were stratified into two groups by aCCI: low (aCCI < 5), and high (aCCI ≥5). The Kaplan Meier method was used to assess the cumulative incidence of osteoporosis by different levels of aCCI. The Cox proportional hazards regression model was used to estimate the association of aCCI with the risk of osteoporosis. Receiver operating characteristic (ROC) curve was adapted to assess the performance for aCCI in osteoporosis screening. RESULTS: At baseline, the mean age of all patients was 75.7 years, the mean BMI was 24.8 kg/m2, and 531 (56.1%) patients had high aCCI while 416 (43.9%) were having low aCCI. During a median follow-up of 6.6 years, 296 participants developed osteoporosis. Kaplan-Meier survival curves showed that participants with high aCCI had significantly higher cumulative incidence of osteoporosis compared with those had low aCCI (log-rank test: P < 0.001). When aCCI was examined as a continuous variable, the multivariable-adjusted model showed that the osteoporosis risk increased by 12.1% (HR = 1.121, 95% CI 1.041-1.206, P = 0.002) as aCCI increased by one unit. When aCCI was changed to a categorical variable, the multivariable-adjusted hazard ratios associated with different levels of aCCI [low (reference group) and high] were 1.00 and 1.557 (95% CI 1.223-1.983) for osteoporosis (P <  0.001), respectively. The aCCI (cutoff ≥5) revealed an area under ROC curve (AUC) of 0.566 (95%CI 0.527-0.605, P = 0.001) in identifying osteoporosis in older fall-prone men, with sensitivity of 64.9% and specificity of 47.9%. CONCLUSIONS: The current study indicated an association of higher aCCI with an increased risk of osteoporosis among older fall-prone men, supporting the possibility of aCCI as a marker of long-term skeletal-related adverse clinical outcomes.

Development and internal validation of a clinical prediction model for osteopenia in Chinese middle-aged and elderly men: a prospective cohort study.

BACKGROUND: Early identification of patients at risk of osteopenia is an essential step in reducing the population at risk for fractures. We aimed to develop and validate a prediction model for osteopenia in Chinese middle-aged and elderly men that provides individualized risk estimates. METHODS: In this prospective cohort study, 1109 patients who attend regular physical examinations in the Second Medical Centre of Chinese PLA General Hospital were enrolled from 2015.03 to 2015.09. The baseline risk factors included dietary habits, exercise habits, medical histories and medication records. Osteopenia during follow-up were collected from Electronic Health Records (EHRs) and telephone interviews. Internal validation was conducted using bootstrapping to correct the optimism. The independent sample T-test analysis, Mann_Whitney U test, Chi-Square Test and multivariable Cox regression analysis were utilized to identify predictive factors for osteopenia in Chinese middle-aged and elderly men. A nomogram based on the seven variables was built for clinical use. Concordance index (C-index), receiver operating characteristic curve (ROC), decision curve analysis (DCA) and calibration curve were used to evaluate the efficiency of the nomogram. RESULTS: The risk factors included in the prediction model were bone mineral density at left femoral neck (LNBMD), hemoglobin (Hb), serum albumin (ALB), postprandial blood glucose (PBG), fatty liver disease (FLD), smoking and tea consumption. The C-index for the risk nomogram was 0.773 in the prediction model, which presented good refinement. The AUC of the risk nomogram at different time points ranged from 0.785 to 0.817, exhibiting good predictive ability and performance. In addition, the DCA showed that the nomogram had a good clinical application value. The nomogram calibration curve indicated that the prediction model was consistent. CONCLUSIONS: Our study provides a novel nomogram and a web calculator that can effectively predict the 7-year incidence risk of osteopenia in Chinese middle-aged and elderly men. It is convenient for clinicians to prevent fragility fractures in the male population.

Characteristics and Influencing Factors of Coagulation Dysfunction Caused by Cefoperazone/Sulbactam.

Objective: To evaluate associations between patient characteristics and cefoperazone/sulbactam-associated coagulation dysfunction. Methods: Retrospective analysis was performed on 821 cases of bacterial infection treated with cefoperazone/sulbactam for more than three days in the Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, from January 2018 to June 2022. The patients were divided into normal coagulation function group (NCFG) (781 cases) and abnormal coagulation function group (ACFG) (40 cases) according to their coagulation function. Univariate and multivariate logistic regression analysis used the general data of the two groups of patients to investigate the risk factors of abnormal coagulation function caused by cefoperazone/sulbactam. Results: The incidence of abnormal coagulation function caused by cefoperazone/sulbactam was 4.87% (40/821). There was no significant difference in gender, body mass index (BMI), marriage, educational background, and concurrent medical conditions between the two groups (all P > .05). The patients in ACFG were older, the dosage and duration of cefoperazone/sulbactam were more prolonged, and the liver and kidney functions were more abnormal than those in NCFG, with significant differences (all P < .05). Univariate and multivariate logistic regression analysis showed that age (≥ 65 years old) (OR=1.293, 95%CI:0.897-1.287), duration of therapy (>10d) (OR=1.765, 95%CI:1.052-3.761), daily dosage (>6g) (OR=3.291, 95%CI:1.732-6.871), aspartate aminotransferase (AST) (≥ 23.98U/L) (OR=3.281, 95%CI:1.009-6.981), alanine aminotransferase (ALT) (≥ 24.03U/L) (OR=2.109, 95%CI:1.276-3.298), and serum creatinine (SCR) (>107 µ mol/L) (OR=2.716, 95%CI:1.023-4.398), prothrombin time (PT) (≥ 13.9U/L) (OR=1.571, 95%CI:1.287-1.945) were the risk factors (P < .05). Conclusion: Elderly patients, time of use, daily dose of use, liver and kidney function, and PT are the risk factors of cefoperazone/sulbactam leading to abnormal coagulation function.