Efficacy and safety of sovleplenib (HMPL-523) in adult patients with chronic primary immune thrombocytopenia in China (ESLIM-01): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Sovleplenib, a novel spleen tyrosine kinase (SYK) inhibitor, showed promising safety and activity in patients with primary immune thrombocytopenia in a phase 1b/2 trial. We aimed to evaluate the efficacy and safety of sovleplenib in patients with chronic primary immune thrombocytopenia. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial (ESLIM-01) was done in 34 clinical centres in China. Eligible patients, aged 18-75 years, had chronic primary immune thrombocytopenia, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and received one or more previous treatments. Patients were randomly assigned (2:1) to receive oral sovleplenib or placebo, 300 mg once daily, for 24 weeks. Randomisation was stratified by baseline platelet counts, previous splenectomy, and concomitant treatment for anti-immune thrombocytopenia at baseline. The primary endpoint was durable response rate (proportion of patients with a platelet count of ≥50 × 109/L on at least four of six scheduled visits between weeks 14 and 24, not affected by rescue treatment) assessed by intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT05029635, and the extension, open-label phase is ongoing. FINDINGS: Between Sept 29, 2021, and Dec 31, 2022, 188 patients were randomly assigned to receive sovleplenib (n=126) or placebo (n=62). 124 (66%) were female, 64 (34%) were male, and all were of Asian ethnicity. Median previous lines of immune thrombocytopenia therapy were 4·0, and 134 (71%) of 188 patients had received previous thrombopoietin or thrombopoietin receptor agonist. The primary endpoint was met; durable response rate was 48% (61/126) with sovleplenib compared with zero with placebo (difference 48% [95% CI 40-57]; p<0·0001). The median time to response was 8 days with sovleplenib compared with 30 days with placebo. 125 (99%) of 126 patients in the sovleplenib group and 53 (85%) of 62 in the placebo group reported treatment-emergent adverse events (TEAEs), and most events were mild or moderate. Frequent TEAEs of grade 3 or higher for sovleplenib versus placebo were platelet count decreased (7% [9/126] vs 10% [6/62]), neutrophil count decreased (3% [4/126] vs 0% [0/62]), and hypertension (3% [4/126] vs 0% [0/62]). Incidences of serious TEAEs were 21% (26/126) in the sovleplenib group and 18% (11/62) in the placebo group. There were no deaths in the study. INTERPRETATION: Sovleplenib showed a clinically meaningful sustained platelet response in patients with chronic primary immune thrombocytopenia, with a tolerable safety profile and improvement in quality of life. Sovleplenib could be a potential treatment option for patients with immune thrombocytopenia who received one or more previous therapy. FUNDING: HUTCHMED and Science and Technology Commission of Shanghai Municipality.

Correlation of TyG-BMI and TyG-WC with severity and short-term outcome in new-onset acute ischemic stroke.

Objectives: To research the connection between the indexes of the indexes of triglyceride-glucose (TyG) combined with obesity indices and the initial neurological severity and short-term outcome of new-onset acute ischemic stroke. Methods: Data of patients with acute ischemic stroke admitted to the Stroke Ward of the Affiliated Hospital of Beihua University from November 2021 to October 2023, were collected. The two indexes were calculated by combining TyG and obesity indices: TyG-body mass index (TyG-BMI) and TyG-waist circumference (TyG-WC). The National Institute of Health Stroke Scale (NIHSS) was used to assess and group patients with neurological deficits within 24 hours of admission: mild stroke (NIHSS ≤5) and moderate-severe stroke (NIHSS >5). Short-term prognosis was evaluated using the modified Rankin Scale (mRS) at discharge or 14 days after onset of the disease and grouped: good outcome (mRS ≤2) and poor outcome (mRS >2). According to the quartiles of TyG-BMI and TyG-WC, the patients were placed into four groups: Q1, Q2, Q3 and Q4. Multi-factor logistic regression analysis was utilized to evaluate the correlation of TyG-BMI and TyG-WC with the severity and short-term outcome. Results: The study included 456 patients. After adjusting for multiple variables, the results showed that compared with the quartile 1, patients in quartile 4 of TyG-BMI had a reduced risk of moderate-severe stroke [Q4: OR: 0.407, 95%CI (0.185-0.894), P = 0.025]; Patients in quartiles 2, 3 and 4 of TyG-BMI had sequentially lower risk of short-term adverse outcomes [Q2: OR: 0.394, 95%CI (0.215-0.722), P = 0.003; Q3: OR: 0.324, 95%CI (0.163-0.642), P = 0.001; Q4: OR: 0.158, 95%CI (0.027-0.349), P <0.001]; Patients in quartiles 3 and 4 of TyG-WC had sequentially lower risk of moderate-severe stroke [Q3: OR: 0.355, 95%CI (0.173-0.728), P = 0.005; Q4: OR: 0.140, 95%CI (0.056-0.351), P <0.001]; Patients in quartiles 3 and 4 of TyG-WC had sequentially lower risk of short-term adverse outcomes [Q3: OR: 0.350, 95%CI (0.175-0.700), P = 0.003; Q4: OR: 0.178, 95%CI (0.071-0.451), P <0.001]. Conclusions: TyG-WC and TyG-BMI were correlated with the severity and short-term outcome of new-onset acute ischemic stroke. As TyG-WC and TyG-BMI increased, stroke severity decreased and short-term outcome was better.

Activation of Notch Signaling Pathway is involved in Extracellular Matrix Degradation in human induced pluripotent stem cells chondrocytes induced by HT-2 toxin.

Notch signaling regulates cartilage formation and homeostasis. Kashin-Beck Disease (KBD), an endemic osteochondropathy, is characterized by severe cartilage degradation. The etiology of KBD is related to the exposure of HT-2 toxin, a mycotoxin and primary metabolite of T-2 toxin. This study aims to explore the role of HT-2 toxin in the Notch signaling regulation and extracellular matrix (ECM) metabolism of hiPSCs-Chondrocytes. Immunohistochemistry and qRT-PCR were employed to investigate the expression of Notch pathway molecules in KBD articular cartilage and primary chondrocytes. hiPSCs-Chondrocytes, derived from hiPSCs, were treated with 100 ng/mL HT-2 toxin and the γ-secretase inhibitor (DAPT) for 48h, respectively. The markers related to the Notch signaling pathway and ECM were assessed using qRT-PCR and Western blot. Notch pathway dysregulation was prominent in KBD cartilage. HT-2 toxin exposure caused cytotoxicity in hiPSCs-Chondrocytes, and activated Notch signaling by increasing the mRNA and protein levels of NOTCH1 and HES1. HT-2 toxin also upregulated ECM catabolic enzymes and downregulated ECM components (COL2A1 and ACAN), indicating ECM degradation. DAPT-mediated Notch signaling inhibition suppressed the mRNA and protein level of ADAMTS5 expression while enhancing ECM component expression in hiPSCs-Chondrocytes. This study suggests that HT-2 toxin may induce ECM degradation in hiPSCs-Chondrocytes through activating Notch signaling.

Involvement of Yes-Associated Protein 1 Activation in the Matrix Degradation of Human-Induced-Pluripotent-Stem-Cell-Derived Chondrocytes Induced by T-2 Toxin and Deoxynivalenol Alone and in Combination.

T-2 toxin and deoxynivalenol (DON) are two prevalent mycotoxins that cause cartilage damage in Kashin-Beck disease (KBD). Cartilage extracellular matrix (ECM) degradation in chondrocytes is a significant pathological feature of KBD. It has been shown that the Hippo pathway is involved in cartilage ECM degradation. This study aimed to examine the effect of YAP, a major regulator of the Hippo pathway, on the ECM degradation in the hiPS-derived chondrocytes (hiPS-Ch) model of KBD. The hiPS-Ch injury models were established via treatment with T-2 toxin/DON alone or in combination. We found that T-2 toxin and DON inhibited the proliferation of hiPS-Ch in a dose-dependent manner; significantly increased the levels of YAP, SOX9, and MMP13; and decreased the levels of COL2A1 and ACAN (all p values < 0.05). Immunofluorescence revealed that YAP was primarily located in the nuclei of hiPS-Ch, and its expression level increased with toxin concentrations. The inhibition of YAP resulted in the dysregulated expression of chondrogenic markers (all p values < 0.05). These findings suggest that T-2 toxin and DON may inhibit the proliferation of, and induce the ECM degradation, of hiPS-Ch mediated by YAP, providing further insight into the cellular and molecular mechanisms contributing to cartilage damage caused by toxins.

Comparison of the control effect of corneal refractive therapy with vision shaping treatment designed orthokeratology on corneal morphology myopia at low E-values / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To observe and analyze the effectiveness and safety of wearing corneal refractive therapy(CRT)and vision shaping treatment(VST)designed orthokeratology in controlling myopic progression in adolescents with low E-value corneal morphology.METHODS: This prospective study involved 100 cases(100 eyes)of adolescent myopia patients fitted with orthokeratology at our optometry clinic from January 2020 to December 2021. The data of right eye were collected for research, and they were divided into low myopia group(-1.00 to -3.00 D)and moderate myopia group(-3.25 to -5.00 D)according to spherical equivalent, with 50 cases in each group. Each group of patients was further randomly divided into the CRT group and the VST group, with 25 cases in each group. Uncorrected visual acuity, refractive error, axial length(AL), tear film break-up time(BUT), corneal endothelial cell density, corneal staining grading, lens decentration, and refractive power at 15°-30° were measured before and after wearing orthokeratology, with a follow-up duration of 1.5 a.RESULTS: The uncorrected visual acuity of CRT and VST subgroups in the low myopia group showed no statistical significance at any time point after wearing orthokeratology. However, in the moderate myopia group, CRT subgroup showed better uncorrected visual acuity than the VST subgroup, with significant differences at 1 d and 1 wk(t=-9.474, -12.067, both P&#x003C;0.01); no significant differences were noted at other time points. After wearing lens for 6 mo and 1.5 a, the AL growth for the CRT subgroup in low and moderate myopia was less than the VST subgroup, with no statistically significant differences. There were no statistically significant differences in binocular BUT and corneal endothelial cell density after wearing lens for 6 mo and 1.5 a. Corneal injury was lower in the CRT subgroup than that in the VST subgroup, but the difference was not statistically significant(Z=-1.803, P=0.071). Lens decentration was significantly better in the CRT subgroup than in the VST subgroup(Z=-4.629, P&#x003C;0.001). In the periphery of the retina at 15°-30°, there were no significant differences in the amount of myopic defocus between the two groups, while it was statistically significant at 1, 3, and 6 mo in the moderate myopia subgroup(t=-3.949, P=0.008; t=-5.833, P&#x003C;0.001; t=-6.231, P&#x003C;0.001), indicating that CRT subgroup could produce a greater amount of myopic defocus.CONCLUSION: For patients with low E-value corneal morphology, CRT, using the vector height at 8 mm on the cornea for fitting, is not limited to the corneal E-value. It shapes faster and improves uncorrected visual acuity after shaping, especially for moderate myopia, achieving better daytime vision. In terms of controlling myopia, CRT fitting elevates return zone depth(RZD), creating a small central optical zone to produce more peripheral myopic defocus. However, there was no significant difference between the two groups in controlling AL growth. Both groups showed minimal corneal damage, indicating consistent safety in myopia control.

Single-cell transcriptome and metagenome profiling reveals the genetic basis of rumen functions and convergent developmental patterns in ruminants.

The rumen undergoes developmental changes during maturation. To characterize this understudied dynamic process, we profiled single-cell transcriptomes of about 308,000 cells from the rumen tissues of sheep and goats at 17 time points. We built comprehensive transcriptome and metagenome atlases from early embryonic to rumination stages, and recapitulated histomorphometric and transcriptional features of the rumen, revealing key transitional signatures associated with the development of ruminal cells, microbiota, and core transcriptional regulatory networks. In addition, we identified and validated potential cross-talk between host cells and microbiomes and revealed their roles in modulating the spatiotemporal expression of key genes in ruminal cells. Cross-species analyses revealed convergent developmental patterns of cellular heterogeneity, gene expression, and cell-cell and microbiome-cell interactions. Finally, we uncovered how the interactions can act upon the symbiotic rumen system to modify the processes of fermentation, fiber digestion, and immune defense. These results significantly enhance understanding of the genetic basis of the unique roles of rumen.

Air versus Perfluoropropane Gas in Pars Plana Vitrectomy for Primary Rhegmatogenous Retinal Detachment: A 3-Year Retrospective Study.

INTRODUCTION: This study aimed to compare anatomical outcomes of air and perfluoropropane gas (C3F8) tamponade in pars plana vitrectomy for the treatment of rhegmatogenous retinal detachment (RRD). METHODS: In this retrospective study, data were gathered from 578 patients (578 eyes) with RRD. The follow-up records of all 578 patients that underwent primary vitrectomy for RRD with air or C3F8 were examined and analyzed. Surgical outcomes of the two groups were compared. RESULTS: A total of 342 eyes were treated with air and 236 with C3F8. The mean follow-up period was 37.65 ± 2.33 months. Baseline and preoperative clinical characteristics were similar between groups, but the period to intraocular bubble disappearance (p < 0.0001), intraocular pressure on the first postoperative day (p < 0.0001), number of cases with intraocular pressure >21 mm Hg within 3 days post-surgery (p < 0.0001), and the number with intraocular pressure >21 mm Hg during follow-up (p = 0.0002) differed significantly between groups. Primary reattachment rates for air and C3F8 groups were 95.03% and 95.34%, respectively. Clinical characteristics were similar in those with and without successful reattachment, and the frequency of new or unclosed breaks was similar between the two groups. There was no significant difference in two groups according to the presence or absence of inferior retinal breaks and inferior detached quadrants. Univariate and multivariate logistic regression identified no risk factor for surgical failure. CONCLUSIONS: Air showed equivalent effects to C3F8, with a shorter period to intraocular bubble disappearance, less risk of postoperative intraocular hypertension, and less expense.

Hypertriglyceridemic waist phenotype: Association with initial neurological severity and etiologic subtypes in patients with acute ischemic stroke.

Objective: To explore the relationship of hypertriglyceridemic waist phenotype (HTWP) with initial neurological severity and etiologic subtypes in patients with acute ischemic stroke. Methods: The data for this study were collected from hospitalized patients within 72 h of acute ischemic stroke onset at the Department of Neurology of the Affiliated Hospital of Beihua University from 1 July 2020 to 30 June 2022. The initial neurological severity was assessed by the National Institute of Health Stroke Scale (NIHSS) on the day of admission: NIHSS <6 was defined as mild stroke, and NIHSS ≥6 as moderate to severe stroke. HTWP was defined by fasting serum triglycerides ≥1.7 mmol/L and waist circumference ≥90 cm in men and ≥80 cm in women. Differentiation of etiologic subtypes was based on the method reported in the Trial of Org 10 172 in Acute Stroke Treatment. Multivariate logistic regression analysis was used to analyze the association of HTWP with initial neurological severity and etiologic subtypes. Results: The study included 431 patients. Compared with the normal waist-normal blood triglyceride group, patients with HTWP had reduced risks of moderate to severe stroke [odds ratio (OR): 0.384, 95% confidence interval (CI): 0.170-0.869; P = 0.022]. In addition, the risk of small-artery occlusion stroke was 2.318 times higher in the HTWP group than in the normal triglyceride-normal waist (NWNT) group (OR: 2.318, 95% CI: 1.244-4.319; P = 0.008). Conclusion: Initial neurological severity was less severe in patients with HTWP, and HTWP was associated with an increased risk of small-artery occlusion stroke.

Monoclonal gammopathy of undetermined significance (MGUS) characterized by refractory lower gastrointestinal postoperative bleeding with coagulopathy.

Bleeding is a common complication after lower gastrointestinal surgery, and cases due to coagulation dysfunction are rare. The current authors encountered a 54-year-old Chinese man with refractory bleeding after endoscopic rectal polypectomy, and multiple endoscopic and surgical interventions failed to control that bleeding. An APTT mixing test could not be corrected and there was no evidence of autoimmune-related disease, so the presence of nonspecific antibodies was considered. After empiric therapy with a cyclophosphamide and glucocorticoid, APTT was corrected and gastrointestinal bleeding stopped. Based on laboratory results and therapeutic results, the patient was ultimately diagnosed with prolonged APTT induced by monoclonal gammopathy of undetermined significance (MGUS). MGUS and coagulopathy characterized by a prolonged APTT has rarely been reported. Here, studies noting elevated monoclonal immunoglobulins and coagulopathy have been reviewed. If a prolonged APTT of undetermined significance cannot be corrected with an APTT mixing test and if autoimmune-related factors are excluded, then plasma cell-related diseases such as MGUS need to be considered.

Non-magnetic ion site disorder effects on the quantum magnetism of a spin-1/2 equilateral triangular lattice antiferromagnet.

With the motivation to study how non-magnetic ion site disorder affects the quantum magnetism of Ba3CoSb2O9, a spin-1/2 equilateral triangular lattice antiferromagnet, we performed DC and AC susceptibility, specific heat, elastic and inelastic neutron scattering measurements on single crystalline samples of Ba2.87Sr0.13CoSb2O9with Sr doping on non-magnetic Ba2+ion sites. The results show that Ba2.87Sr0.13CoSb2O9exhibits (i) a two-step magnetic transition at 2.7 K and 3.3 K, respectively; (ii) a possible canted 120 degree spin structure at zero field with reduced ordered moment as 1.24µB/Co; (iii) a series of spin state transitions for bothH∥ab-plane andH∥c-axis. ForH∥ab-plane, the magnetization plateau feature related to the up-up-down phase is significantly suppressed; (iv) an inelastic neutron scattering spectrum with only one gapped mode at zero field, which splits to one gapless and one gapped mode at 9 T. All these features are distinctly different from those observed for the parent compound Ba3CoSb2O9, which demonstrates that the non-magnetic ion site disorder (the Sr doping) plays a complex role on the magnetic properties beyond the conventionally expected randomization of the exchange interactions. We propose the additional effects including the enhancement of quantum spin fluctuations and introduction of a possible spatial anisotropy through the local structural distortions.

Abnormal Level of Manganese, Iron, Iodine, and Selenium in the Hair of Children Living in Kashin-Beck Disease Endemic Areas.

Biological geochemistry is a main suggested cause of Kashin-Beck disease (KBD), due to the absence or excess of elements in the environment. Initially, Se deficiency is regarded as the most key role in the etiology of KBD, and selenium supplementation effectively helps to prevent and control KBD. However, several elements are reported to be relevant to KBD or selenium in succession, which indicated selenium deficiency is not the original etiology of KBD. The study comprehensively analyzed the characteristics of the bio-element profile of KBD and further re-examined the unique role of selenium in etiology. The study measured 14 elements, including sodium, potassium, calcium, phosphorus, magnesium, copper, iron, zinc, selenium, iodine, manganese, lead, arsenic, and mercury, which were detected from hair samples collected from 150 boys. Research participants were separated based on whether they had received any preventative treatment (with and without selenium supplementation). From endemic areas, 30 KBD and 30 healthy children without any preventative treatment were selected alongside 30 KBD and 30 healthy children with selenium supplementation. The participants from endemic areas were then compared to 30 healthy children living in non-endemic areas. Compared to the non-endemic group, the levels of iron and manganese were all significantly higher in the endemic groups and were further elevated in KBD participants (p < 0.05). In contrast, selenium and iodine levels in endemic areas were much lower than those of the control group (p < 0.05). The proportions of selenium excess (p < 0.05) and iodine deficiency (p < 0.05) in endemic groups were significantly lower than participants from non-endemic areas. Meanwhile, excess levels of iron (p < 0.05) and manganese (p < 0.05) were higher in the endemic groups. Moreover, the proportions of Zn/Fe and Se/Mn were found to be significantly lower in endemic area participants than those in the control group (p < 0.05). Three pairs of elements had a correlation coefficient value of more than 0.6: 0.7423 for manganese and calcium, 0.6446 for potassium and sodium, and 0.6272 for manganese and iron. The ratios of Se/Mn and Zn/Fe were associated with a correlation coefficient value of 0.8055. Magnesium, sodium, copper, and iodine levels were meticulously examined using binary regression analysis. This was also used to determine the ratios of Ca/Mg, Ca/P, Zn/Fe, Se/Mn, and Se/I. Thus, the study largely revealed the vital role of manganese, iron, and iodine (in conjunction with selenium) in KBD etiology and pathogenesis. High manganese and iron levels with low selenium and iodine levels were identified as characteristic features of the bio-element profile of KBD. The different element ratios reflect the interaction between several elements. The most significant of these were the proportions of Se/Mn and Zn/Fe, which may be significant in the occurrence and development of KBD.

The first human induced pluripotent stem cell line of Kashin-Beck disease reveals involvement of heparan sulfate proteoglycan biosynthesis and PPAR pathway.

Kashin-Beck disease (KBD) is an endemic osteochondropathy. Due to a lack of suitable animal or cellular disease models, the research progress on KBD has been limited. Our goal was to establish the first disease-specific human induced pluripotent stem cell (hiPSC) cellular disease model of KBD, and to explore its etiology and pathogenesis exploiting transcriptome sequencing. HiPSCs were reprogrammed from dermal fibroblasts of two KBD and one healthy control donor via integration-free vectors. Subsequently, hiPSCs were differentiated into chondrocytes through three-week culture. Gene expression profiles in KBD, normal primary chondrocytes, and hiPSC-derived chondrocytes were defined by RNA sequencing. A Venn diagram was constructed to show the number of shared differentially expressed genes (DEGs) between KBD and normal. Gene oncology and Kyoto Encyclopedia of Genes and Genomes annotations were performed, and six DEGs were further validated in other individuals by RT-qPCR. KBD cellular disease models were successfully established by generation of hiPSC lines. Seventeen consistent and significant DEGs present in all compared groups (KBD and normal) were identified. RT-qPCR validation gave consistent results with the sequencing data. Glycosaminoglycan biosynthesis-heparan sulfate/heparin; PPAR signaling pathway; and cell adhesion molecules (CAMs) were identified to be significantly altered in KBD. Differentiated chondrocytes derived from KBD-origin hiPSCs provide the first cellular disease model for etiological studies of KBD. This study also provides new sights into the pathogenesis and etiology of KBD and is likely to inform the development of targeted therapeutics for its treatment.

Revisiting the Phylogenetic Relationship and Evolution of Gargarini with Mitochondrial Genome (Hemiptera: Membracidae: Centrotinae).

In this study, we newly sequenced and analyzed the complete mitochondrial genomes of five genera and six species in Gargarini: Antialcidas floripennae, Centrotoscelus davidi, Kotogargara minuta, Machaerotypus stigmosus, Tricentrus fulgidus, and Tricentrus gammamaculatus. The mitochondrial genomes contain 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and a control region. The lengths of the mitochondrial genomes are 15,253 bp to 15,812 bp, and the AT contents of the obtained mitogenomes indicate a strong AT bias, ranging from 75.8% to 78.5%. The start codons of all PCGs show that most start with a typical ATN (ATA/T/G/C) codon and less start with T/GTG; the stop codon TAA is frequently used, and TAG and a single T are less used. In Gargarini mitogenomes, all tRNA genes can be folded into the canonical cloverleaf secondary structure, except for trnaS1, which lacks a stable dihydrouridine (DHU) stem and is replaced by a simple loop. At the same time, the phylogenetic analysis of the tribe Gargarini based on sequence data of 13 PCGs from 18 treehopper species and four outgroups revealed that the 10 Gargarini species form a steady group with strong support and form a sister group with Leptocentrini, Hypsauchenini, Centrotini, and Leptobelini. Diversification within Gargarini is distinguished by a Later Cretaceous divergence that led to the rapid diversification of the species. Moreover, the ancestral state reconstructions analysis showed the absence of the suprahumeral horn, which was confirmed as the ancestor characteristic of the treehopper, which has evolved from simple to complex. Our results shed new light specifically on the molecular and phylogenetic evolution of the pronotum in Gargarini.

Early warning value of laboratory parameters in patients with severe hemorrhagic fever with renal syndrome / 中华传染病杂志

Objective:To explore the early warning value of laboratory parameters in patients with severe hemorrhagic fever with renal syndrome (HFRS).Methods:The clinical data of 101 patients with HFRS hospitalized in the Department of Infectious Diseases of the First Hospital of Changsha from December 2013 to December 2020 were collected and analyzed. The differences of clinical routine laboratory parameters between mild and severe HFRS patients were compared and analyzed. The statistical methods including independent sample t test, rank sum test, chi-square test, Spearman rank correlation analysis, logistic regression analysis and receiver operator characteristic curve were used. Results:Among 101 patients with HFRS, 38 cases were in severe group and 63 cases in mild group. White blood cell count, aspartate aminotransferase (AST), prothrombin time (PT), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), serum creatinine, urea nitrogen and D-dimer in severe group were higher than those in mild group, while platelet count and albumin were lower than those in mild group, and the differences were all statistically significant ( t=8.61, Z=-3.76, t=4.19, Z=-2.84, Z=-7.23, t=4.98, t=4.64, t=36.02, Z=-5.49 and t=4.14, respectively; all P<0.050). Severe HFRS was positively correlated with white blood cell count, AST, PT, activated partial thromboplastin time (APTT), CK-MB, serum creatinine, urea nitrogen and D-dimer ( r=0.629, 0.376, 0.549, 0.471, 0.723, 0.500, 0.341 and 0.588, respectively; all P<0.001). White blood cell count, albumin, PT and CK-MB were independent influencing factors for the progression of severe HFRS (odds ratio ( OR)=0.922, 1.374, 0.730 and 0.938, respectively; all P<0.050). The area under curve (AUC) of white blood cell count, albumin, PT and CK-MB for the early warning prediction of severe HFRS were 0.869, 0.739, 0.785 and 0.931, respectively, with the optimal thresholds for prediction of 26.38×10 9/L, 26.05 g/L, 15.95 s and 35.5 U/L, respectively.And the AUC of the combined detection of the above laboratory parameters was 0.950, with the sensitivity of 87.3% and the specificity of 94.7%. Conclusions:White blood cell count, albumin, PT and CK-MB could be used as independent influencing factors for early warning of severe HFRS. Combined detection is more helpful for early warning of severe HFRS than single detection.

Association Between Cardiometabolic Index and Stroke: A Population- based Cross-sectional Study.

BACKGROUND: Cardiometabolic Index (CMI) was associated with several risk factors for stroke; however, few studies assessed the role of CMI in stroke risk. OBJECTIVE: This study aimed to assess the association between CMI and stroke in a population- based cross-sectional study. METHODS: This study included 4445 general residents aged ≥40 years selected by multistage stratified random cluster sampling. CMI was calculated as the product of the ratio of waist circumference to height (WHtR) and the ratio of triglyceride levels to high-density lipoprotein cholesterol levels (TG/HDL-C). Participants were categorized according to CMI quartiles: quartile 1 (Q1), quartile 2 (Q2), quartile 3 (Q3), and quartile 4 (Q4). Multivariate logistic regression analysis and receiver operating characteristic (ROC) curves were used to assess the association between CMI and stroke. RESULTS: A total of 4052 participants were included in the study, with an overall stroke prevalence of 7.2%. The prevalence of stroke increased with CMI quartiles, ranging from 4.4% to 9.2% (p for trend <0.001). Compared with Q1, stroke risk for Q2, Q3, and Q4 were 1.550-, 1.693-, and 1.704- fold, respectively. The area under the ROC curve (AUC) (95% CI) was 0.574 (0.558-0.589) for CMI, 0.627 (0.612-0.642) for WHtR, 0.556 (0.540-0.571) for TG/HDL-C. CMI was inferior to WHtR (p=0.0024), but CMI had a marginal advantage over TG/HDL-C (p<0.0001) in terms of its stroke discrimination ability. CONCLUSION: Although there was a strong and independent association between CMI and stroke in the general population, CMI had limited discriminating ability for stroke. Thus, new parameters should be developed.

Identifying discriminative features for diagnosis of Kashin-Beck disease among adolescents.

INTRODUCTION: Diagnosing Kashin-Beck disease (KBD) involves damages to multiple joints and carries variable clinical symptoms, posing great challenge to the diagnosis of KBD for clinical practitioners. However, it is still unclear which clinical features of KBD are more informative for the diagnosis of Kashin-Beck disease among adolescent. METHODS: We first manually extracted 26 possible features including clinical manifestations, and pathological changes of X-ray images from 400 KBD and 400 non-KBD adolescents. With such features, we performed four classification methods, i.e., random forest algorithms (RFA), artificial neural networks (ANNs), support vector machines (SVMs) and linear regression (LR) with four feature selection methods, i.e., RFA, minimum redundancy maximum relevance (mRMR), support vector machine recursive feature elimination (SVM-RFE) and Relief. The performance of diagnosis of KBD with respect to different classification models were evaluated by sensitivity, specificity, accuracy, and the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: Our results demonstrated that the 10 out of 26 discriminative features were displayed more powerful performance, regardless of the chosen of classification models and feature selection methods. These ten discriminative features were distal end of phalanges alterations, metaphysis alterations and carpals alterations and clinical manifestations of ankle joint movement limitation, enlarged finger joints, flexion of the distal part of fingers, elbow joint movement limitation, squatting limitation, deformed finger joints, wrist joint movement limitation. CONCLUSIONS: The selected ten discriminative features could provide a fast, effective diagnostic standard for KBD adolescents.

Dysregulation of Cells Cycle and Apoptosis in Human Induced Pluripotent Stem Cells Chondrocytes Through p53 Pathway by HT-2 Toxin: An in vitro Study.

Kashin-Beck disease (KBD) mainly damages growth plate of adolescents and is susceptible to both gene and gene-environmental risk factors. HT-2 toxin, which is a primary metabolite of T-2 toxin, was regarded as one of the environmental risk factors of KBD. We used successfully generated KBD human induced pluripotent stem cells (hiPSCs) and control hiPSCs, which carry different genetic information. They have potential significance in exploring the effects of HT-2 toxin on hiPSC chondrocytes and interactive genes with HT-2 toxin for the purpose of providing a cellular disease model for KBD. In this study, we gave HT-2 toxin treatment to differentiating hiPSC chondrocytes in order to investigate the different responses of KBD hiPSC chondrocytes and control hiPSC chondrocytes to HT-2 toxin. The morphology of HT-2 toxin-treated hiPSC chondrocytes investigated by transmission electron microscope clearly showed that the ultrastructure of organelles was damaged and type II collagen expression in hiPSC chondrocytes was downregulated by HT-2 treatment. Moreover, dysregulation of cell cycle was observed; and p53, p21, and CKD6 gene expressions were dysregulated in hiPSC chondrocytes after T-2 toxin treatment. Flow cytometry also demonstrated that there were significantly increased amounts of late apoptotic cells in KBD hiPSC chondrocytes and that the mRNA expression level of Fas was upregulated. In addition, KBD hiPSC chondrocytes presented stronger responses to HT-2 toxin than control hiPSC chondrocytes. These findings confirmed that HT-2 is an environmental risk factor of KBD and that p53 pathway interacted with HT-2 toxin, causing damaged ultrastructure of organelles, accelerating cell cycle in G1 phase, and increasing late apoptosis in KBD hiPSC chondrocytes.

Etomidate Attenuates the Ferroptosis in Myocardial Ischemia/Reperfusion Rat Model via Nrf2/HO-1 Pathway.

BACKGROUND: Ferroptosis has been found to play an important role in myocardial ischemia reperfusion (MIR) injury (MIRI). This study aimed to explore whether the improvement effect of Etomidate (Eto) on MIRI was related to ferroptosis. METHODS: The MIRI rats were constructed using left anterior descending artery occlusion for 30 min followed by reperfusion for 3 h. The Eto post-conditioning was performed by Eto administration at the beginning of the reperfusion. For rescue experiments, MIRI rats were pretreated with ferroptosis inducer erastin or Nrf2 inhibitor ML385 intraperitoneally 1 h prior to MIR surgery. RESULTS: Eto mitigated cardiac dysfunction and myocardium damage, as well as the release of creatine kinase and lactate dehydrogenase caused by ischemia/reperfusion (IR). Additionally, Eto reduced the expression of myocardial fibrosis-related proteins (collagen II and α-smooth muscle actin) and the secretion of inflammatory factors (IL-6, IL-1ß, and TNF-α) in MIRI rats. Also, Eto inhibited IR-induced ferroptosis in myocardium, including reducing superoxide dismutase content, glutathione activity, and glutathione peroxidase 4 expression, while increasing the levels of malondialdehyde and iron and Acyl-CoA synthetase long-chain family member 4. Moreover, the inhibition of Eto on IR-induced myocardial fibrosis and inflammation could be eliminated by erastin. The up-regulation of Nrf2 and HO-1 protein expression, and the nuclear translocation of Nrf2 induced by Eto in the myocardial tissues of MIRI rats, could be prevented by erastin. Besides, ML385 eliminated the inhibition of Eto on ferroptosis induced by MIR. CONCLUSIONS: Eto attenuated the myocardial injury by inhibiting IR-induced ferroptosis via Nrf2 pathway, which may provide a new idea for clinical reperfusion therapy.

Efficacy and safety of regorafenib or fruquintinib plus camrelizumab in patients with microsatellite stable and/or proficient mismatch repair metastatic colorectal cancer: an observational pilot study.

This study was to investigate the efficacy and safety of regorafenib or fruquintinib combined with camrelizumab in patients with microsatellite stable (MSS) and/or proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC). Medical records of MSS/pMMR mCRC patients who received regorafenib (80 mg) or fruquintinib (3 mg) once a day (21 days on/7 days off) plus camrelizumab (200 mg) every three weeks in Yuhuangding Hospital between January 2020 and June 2020 were retrospectively collected. Follow-up data up to November 1st, 2020 was gathered. The primary endpoint was the objective response rate (ORR) and disease control rate (DCR). The safety profile was the secondary endpoint. A total of 16 patients were enrolled. The ORR was 25.0% (4/16) and the DCR was 62.5% (10/16). The main adverse events (AEs) included reactive cutaneous capillary endothelial proliferation (RCCEP) (81.3%), fatigue (43.8%), hypertension (37.5%), hand-foot skin reaction (25.0%), and thyroid dysfunction (25.0%). Most AEs were grade 1 or 2, with only 1 patient of grade 3 liver dysfunction. All the AEs were ameliorated by effective symptomatic treatment. Regorafenib or fruquintinib plus camrelizumab exhibited promising efficacy in patients with MSS/pMMR mCRC. The toxicity was moderate and manageable.