Evaluating mAbs binding abilities to Omicron subvariant RBDs: implications for selecting effective mAb therapies.

The ongoing evolution of the Omicron lineage of SARS-CoV-2 has led to the emergence of subvariants that pose challenges to antibody neutralization. Understanding the binding dynamics between the receptor-binding domains (RBD) of these subvariants spike and monoclonal antibodies (mAbs) is pivotal for elucidating the mechanisms of immune escape and for advancing the development of therapeutic antibodies. This study focused on the RBD regions of Omicron subvariants BA.2, BA.5, BF.7, and XBB.1.5, employing molecular dynamics simulations to unravel their binding mechanisms with a panel of six mAbs, and subsequently analyzing the origins of immune escape from energetic and structural perspectives. Our results indicated that the antibody LY-COV1404 maintained binding affinities across all studied systems, suggesting the resilience of certain antibodies against variant-induced immune escape, as seen with the mAb 1D1-Fab. The newly identified mAb 002-S21F2 showed a similar efficacy profile to LY-COV1404, though with a slightly reduced binding to BF.7. In parallel, mAb REGN-10933 emerged as a potential therapeutic candidate against BF.7 and XBB.1.5, reflecting the importance of identifying variant-specific antibody interactions, akin to the binding optimization observed in BA.4/5 and XBB.1.5. And key residues that facilitate RBD-mAb binding were identified (T345, L441, K444, V445, and T500), alongside residues that hinder protein-protein interactions (D420, L455, K440, and S446). Particularly noteworthy was the inhibited binding of V445 and R509 with mAbs in the presence of mAb 002-S21F2, suggesting a mechanism for immune escape, especially through the reduction of V445 hydrophobicity. These findings enhance our comprehension of the binding interactions between mAbs and RBDs, contributing to the understanding of immune escape mechanisms. They also lay the groundwork for the design and optimization of antiviral drugs and have significant implications for the development of treatments against current and future coronaviruses.

A Porphyrin-Based 3D Metal-Organic Framework Featuring [Cu8Cl6]10+ Cluster Secondary Building Units: Synthesis, Structure Elucidation, Anion Exchange, and Peroxidase-Like Activity.

Herein, we report a rare example of cationic three-dimensional (3D) metal-organic framework (MOF) of [Cu5Cl3(TMPP)]Cl5 ⋅ xSol (denoted as Cu-TMPP; H2TMPP=meso-tetrakis (6-methylpyridin-3-yl) porphyrin; xSol=encapsulated solvates) supported by [Cu8Cl6]10+ cluster secondary building units (SBUs) wherein the eight faces of the Cl--based octahedron are capped by eight Cu2+. Surface-area analysis indicated that Cu-TMPP features a mesoporous structure and its solvate-like Cl- counterions can be exchanged by BF4 -, PF6 -, and NO3 -. The polyvinylpyrrolidone (PVP) coated Cu-TMPP (denoted as Cu-TMPP-PVP) demonstrated good ROS generating ability, producing ⋅OH in the absence of light (peroxidase-like activity) and 1O2 on light irradiation (650 nm; 25 mW cm-2). This work highlights the potential of Cu-TMPP as a functional carrier of anionic guests such as drugs, for the combination therapy of cancer and other diseases.

Computational analysis of PD-L1 dimerization mechanism induced by small molecules and potential dynamical properties.

The design of small molecule inhibitors that target the programmed death ligand-1 (PD-L1) is a forefront issue in immune checkpoint blocking therapy. Small-molecule inhibitors have been shown to exert therapeutic effects by inducing dimerization of the PD-L1 protein, however, the specific mechanisms underlying this dimerization process remain largely unexplored. Furthermore, there is a notable lack of comparative studies examining the binding modes of structurally diverse inhibitors. In view of the research gaps, this work employed molecular dynamics simulations to meticulously examine the interactions between two distinct types of inhibitors and PD-L1 in both monomeric and dimeric forms, and predicted the dimerization mechanism. The results revealed that inhibitors initially bind to a PD-L1 monomer, subsequently attracting another monomer to form a dimer. Notably, symmetric inhibitors observed superior binding efficiency compared to other inhibitors. Key residues, including Ile54, Tyr56, Met115 and Tyr123 played a leading role in binding. Structurally, symmetric inhibitors were capable of thoroughly engaging the binding pocket, promoting a more symmetrical formation of PD-L1 dimers. Furthermore, symmetric inhibitors formed more extensive hydrophobic interactions with protein residues. The insights garnered from this research are expected to significantly contribute to the rational design and optimization of small molecule inhibitors targeting PD-L1.

Advanced molecular mechanisms of modified DRV compounds in targeting HIV-1 protease mutations and interrupting monomer dimerization.

HIV-1 protease (PR) plays a crucial role in the treatment of HIV as a key target. The global issue of emerging drug resistance is escalating, and PR mutations pose a substantial challenge to the effectiveness of inhibitors. HIV-1 PR is an ideal model for studying drug resistance to inhibitors. The inhibitor, darunavir (DRV), exhibits a high genetic barrier to viral resistance, but with mutations of residues in the PR, there is also some resistance to DRV. Inhibitors can impede PR in two ways: one involves binding to the active site of the dimerization protease, and the other involves binding to the PR monomer, thereby preventing dimerization. In this study, we aimed to investigate the inhibitory effect of DRV with a modified inhibitor on PR, comparing the differences between wild-type and mutated PR, using molecular dynamics simulations. The inhibitory effect of the inhibitors on PR monomers was subsequently investigated. And molecular mechanics Poisson-Boltzmann surface area evaluated the binding free energy. The energy contribution of individual residues in the complex was accurately calculated by the alanine scanning binding interaction entropy method. The results showed that these inhibitors had strong inhibitory effects against PR mutations, with GRL-142 exhibiting potent inhibition of both the PR monomer and dimer. Improved inhibitors could strengthen hydrogen bonds and interactions with PR, thereby boosting inhibition efficacy. The binding of the inhibitor and mutation of the PR affected the distance between D25 and I50, preventing their dimerization and the development of drug resistance. This study could accelerate research targeting HIV-1 PR inhibitors and help to further facilitate drug design targeting both mechanisms.

Exosome-delivered miR-410-3p reverses epithelial-mesenchymal transition, migration and invasion of trophoblasts in spontaneous abortion.

Current studies have indicated that insufficient trophoblast epithelial-mesenchymal transition (EMT), migration and invasion are crucial for spontaneous abortion (SA) occurrence and development. Exosomal miRNAs play significant roles in embryonic development and cellular communication. Hereon, we explored the roles of serum exosomes derived from SA patients on trophoblast EMT, migration and invasion. Exosomes were isolated from normal control (NC) patients with abortion for unplanned pregnancy and SA patients, then characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting. Exosomal miRNA profiles were identified by miRNA sequencing. The effects of serum exosomes on trophoblast migration and invasion were detected by scratch wound healing and transwell assays, and other potential mechanisms were revealed by quantitative real-time PCR (RT-PCR), western blotting and dual-luciferase reporter assay. Finally, animal experiments were used to explore the effects of exosomal miR-410-3p on embryo absorption in mice. The serum exosomes from SA patients inhibited trophoblast EMT and reduced their migration and invasion ability in vitro. The miRNA sequencing showed that miR-410-3p was upregulated in SA serum exosomes. The functional experiments showed that SA serum exosomes restrained trophoblast EMT, migration and invasion by releasing miR-410-3p. Mechanistically, SA serum exosomal miR-410-3p inhibited trophoblast cell EMT, migration and invasion by targeting TNF receptor-associated factor 6 (TRAF6) at the post-transcriptional level. Besides, SA serum exosomal miR-410-3p inhibited the p38 MAPK signalling pathway by targeting TRAF6 in trophoblasts. Moreover, milk exosomes loaded with miR-410-3p mimic reached the maternal-fetal interface and aggravated embryo absorption in female mice. Clinically, miR-410-3p and TRAF6 expression were abnormal and negatively correlated in the placental villi of SA patients. Our findings indicated that exosome-derived miR-410-3p plays an important role between SA serum and trophoblasts in intercellular communication, suggesting a novel mechanism by which serum exosomal miRNA regulates trophoblasts in SA patients.

Multiparametric Cardiovascular Magnetic Resonance in Nonhospitalized COVID-19 Infection Subjects: An Intraindividual Comparison Study.

PURPOSE: To investigate intraindividual cardiac structural and functional changes before and after COVID-19 infection in a previously healthy population with a 3T cardiac magnetic resonance (CMR). MATERIALS AND METHODS: A total of 39 unhospitalized patients with COVID-19 were recruited. They participated in our previous study as non-COVID-19 healthy volunteers undergoing baseline CMR examination and were recruited to perform a repeated CMR examination after confirmed COVID-19 infection in December 2022. The CMR parameters were measured and compared between before and after COVID-19 infection with paired t tests. The laboratory measures including myocardial enzymes and inflammatory indicators were also collected when performing repeated CMR. RESULTS: The median duration was 393 days from the first to second CMR and 26 days from clinical symptoms onset to the second CMR. Four patients (10.3%, 4/39) had the same late gadolinium enhancement pattern at baseline and repeated CMR and 5 female patients (12.8%, 5/39) had myocardial T2 ratio >2 (2.07 to 2.27) but with normal T2 value in post-COVID-19 CMR. All other CMR parameters were in normal ranges before and after COVID-19 infection. Between before and after the COVID-19 infection, there were no significant differences in cardiac structure, function, and tissue characterization, no matter with or without symptoms (fatigue, chest discomfort, palpitations, shortness of breath, and insomnia/sleep disorders) (all P >0.05). The laboratory measures at repeated CMR were in normal ranges in all participants. CONCLUSIONS: These intraindividual CMR studies showed unhospitalized patients with COVID-19 with normal myocardial enzymes had no measurable CMR abnormalities, which can help alleviate wide social concerns about COVID-19-related myocarditis.

Gut microbiota and risk of polycystic ovary syndrome: Insights from Mendelian randomization.

Background: Polycystic ovary syndrome (PCOS) is a multifaceted endocrine and metabolic syndrome with complex origins and pathogenesis that has not yet been fully elucidated. Recently, the interconnection between gut microbiota and metabolic diseases has gained prominence in research, generating new insights into the correlation between PCOS and gut microbiota composition. However, the causal link between PCOS and gut microbiota remains relatively unexplored, indicating a crucial gap in current research. Methods: We conducted a two-sample Mendelian randomization analysis using summary statistics obtained from the MiBioGen Consortium's extensive genome-wide association studies (GWAS) meta-analysis, focusing on the gut microbiota. Summary statistics for PCOS were acquired from the FinnGen Consortium R7 release data. Various statistical approaches, including inverse variance weighted, MR-Egger, maximum likelihood, weighted model, and weighted median, have been employed to investigate the causal association between the gut microbiota and PCOS. Additionally, we performed a reverse causal analysis. Cochran's Q statistic was used to assess the heterogeneity of the instrumental variables. Regarding the relationships between PCOS and specific genera within the gut microbiota, a significance level of P < 0.05 was observed, but only when q ≥ 0.1. Results: Our analysis revealed that specific microbial genera, namely Bilophila (P = 4.62 × 10-3), Blautia (P = 0.02), and Holdemania (P = 0.04), displayed a protective effect against PCOS. Conversely, the presence of the Lachnospiraceae family of bacteria was associated with a detrimental effect on PCOS (P = 0.04). Furthermore, reverse Mendelian randomization analysis confirmed the significant influence of Lachnospiraceae on PCOS. No significant variations in instrumental variables or evidence of horizontal pleiotropy were observed. Conclusions: The results revealed a definitive causal link between PCOS and the presence of Bilophila, Blautia, Holdemania, and Lachnospiraceae in the gut microbiota. This discovery could provide pivotal insights, leading to novel preventive and therapeutic approaches for PCOS.

Explore the pharmacological basis of ShengJiYiSui decoction in the treatment of amyotrophic lateral sclerosis based on network pharmacology and molecular docking technology.

Neurodegenerative illnesses have long been handled clinically by traditional Chinese medicine. This study is the first time to explore the pharmacological basis of application in amyotrophic lateral sclerosis (ALS) through network pharmacology and molecular docking techniques. In the present investigation, the TCMSP database and HIT2 database were examined for 9 TCM constituents of Sheng Ji Yu Sui Decoction (SJYSD), and the desired sites for the components were searched in the Drugbank database. and the Sjysd-target network was constructed. Associated targets for Amyotrophic lateral sclerosis (ALS) were then retrieved and collected in the OMIM, TTD, Genecards and DisGeNET databases. Protein-protein interaction and enrichment analysis were performed for the common targets of drugs and diseases, and molecular anchoring for the chosen core targets and related molecules was carried out. The results showed that SJYSD had 100 active compounds corresponding to 598 targets. ALS has a total of 5,325 genes. SJYSD and ALS share 163 genes, and these targets involve PI3K-AKT signaling, p53 signaling and IL-17 signaling, etc. The core components of luteolin and quercetin were discovered and may be used to treat ALS by regulating PI3K-AKT signaling pathway by HSP90AB1 protein.

Lead exposure induces neuronal apoptosis via NFκB p65/RBBP4/Survivin signaling pathway.

Lead (Pb), as a heavy metal that is easily exposed in daily life, can cause damage to various systems of body. Apoptosis is an autonomous cell death process regulated by genes in order to maintain the stability of internal environment, which plays an important role in the development of nervous system. RB binding protein 4 (RBBP4) is one of the core histone binding subunits and is closely related to the apoptosis process of nervous system cells. However, it is not known whether RBBP4 can regulate neuronal apoptosis in lead-exposed environments. We exposed PC12 cells to 0 µM (control group), 1 µM, and 100 µM PbAc for 24 h to obtain cell samples. The female rats ingested drinking water containing 0, 0.5 g/L, and 2.0 g/L PbAc from the first day of pregnancy to three weeks after delivery to obtain hippocampal tissue samples from mammary rats. The results of TUNEL showed that lead exposure promoted the onset of apoptosis in cells and hippocampus. The mRNA and protein levels of the apoptosis-related protein Survivin were significantly reduced in the lead-exposed group compared to the control group. In addition, we found that lead exposure reduces the mRNA and protein levels of RBBP4 in PC12 cells and hippocampus, and increases the mRNA and protein levels of NFκB p65. Moreover, inhibiting NFκB p65 can reverse the decrease in RBBP4 expression in the lead exposure model. Overexpression of RBBP4 increased Survivin expression and reduced apoptosis induced by lead exposure. This suggests that lead exposure induces apoptosis through the NFκB p65/RBBP4/Survivin signaling pathway.

Defining Biventricular Abnormalities by Cardiac Magnetic Resonance in Pre-Dialysis Patients with Chronic Kidney Disease.

Introduction: The aim of the study was to investigate biventricular structural and functional abnormalities in pre-dialysis patients across stages of chronic kidney disease (CKD) by cardiac magnetic resonance (CMR). Methods: Fifty-one CKD patients with CMR exams were retrospectively analyzed. Patients were divided into three groups according to estimated glomerular filtration rate (eGFR): CKD 1 group (patients with normal eGFR≥90 mL/min/1.73 m2, n = 20), CKD 2-3 group (patients with eGFR< 90 to ≥30 mL/min/1.73 m2, n = 14), and CKD 4-5 group (patients with eGFR<30 mL/min/1.73 m2, n = 17). Twenty-one age- and sex-matched healthy controls (HC) were recruited. CMR-derived left ventricular (LV) and right ventricular (RV) structural and functional measures were compared. Association between CMR parameters and clinical measures was assessed. Results: There was an increasing trend in RV mass index (RVMi) and LV mass index (LVMi) with the occurrence and development of CKD from HC group to CKD 4-5 group although no significant difference was observed between CKD 1 group and HC group. LV global radial strain and LV global circumferential strain dropped and native T1 value elevated significantly in CKD 4-5 group compared with the other three groups (all p < 0.05), while RV strain measures, RV ejection fraction, and LV ejection fraction showed no significant difference among 4 groups (all p > 0.05). Elevated LV end-diastolic volume index (ß = 0.356, p = 0.016) and RV end-systolic volume index (ß = 0.488, p = 0.001) were independently associated with RVMi. Increased systolic blood pressure (ß = 0.309, p = 0.004), LV end-systolic volume index (ß = 0.633, p < 0.001), and uric acid (ß = 0.261, p = 0.013) were independently associated with LVMi. Meanwhile, serum phosphorus (ß = 0.519, p = 0.001) was independently associated with native T1 value. Conclusion: In pre-dialysis CKD patients, left and right ventricular remolding has occurred. RVMi and LVMi were the first changed CMR indexes in the development of CKD when eGFR began to drop. Because fluid volume overload was the independent risk factor for RVMi and LVMi increase, reasonable controlling fluid volume overload may slow down the progression of biventricular remolding and may reduce related cardiovascular disease risk.

Entropy driven cooperativity effect in multi-site drug optimization targeting SARS-CoV-2 papain-like protease.

Papain-like protease (PLpro), a non-structural protein encoded by SARS-CoV-2, is an important therapeutic target. Regions 1 and 5 of an existing drug, GRL0617, can be optimized to produce cooperativity with PLpro binding, resulting in stronger binding affinity. This work investigated the origin of the cooperativity using molecular dynamics simulations combined with the interaction entropy (IE) method. The regions' improvement exhibits cooperativity by calculating the binding free energies between the complex of PLpro-inhibitor. The thermodynamic integration method further verified the cooperativity generated in the drug improvement. To further determine the specific source of cooperativity, enthalpy and entropy in the complexes were calculated using molecular mechanics/generalized Born surface area and IE. The results show that the entropic change is an important contributor to the cooperativity. Our study also identified residues P248, Q269, and T301 that play a significant role in cooperativity. The optimization of the inhibitor stabilizes these residues and minimizes the entropic loss, and the cooperativity observed in the binding free energy can be attributed to the change in the entropic contribution of these residues. Based on our research, the application of cooperativity can facilitate drug optimization, and provide theoretical ideas for drug development that leverage cooperativity by reducing the contribution of entropy through multi-locus binding.

Comprehensive analysis unveils altered binding kinetics of 5-/6-methylCytosine/adenine modifications in R2R3-DNA system.

Recent studies have shown that DNA methylation is an important epigenetic marker. Two prominent forms are methylation of the C5 position of cytosine and methylation of the C6 position of adenine. Given the vital significance of DNA methylation, investigating the mechanisms that influence protein binding remains a compelling pursuit. This study used molecular dynamics simulations to investigate the binding patterns of R2R3 protein and four differentially methylated DNAs. The alanine scanning combined with interaction entropy method was used to identify key residues that respond to different methylation patterns. The order of protein binding ability to DNA is as follows: unmethylated DNA > A11 methylation (5'-A6mAC-3') (6m2A system) > A10 methylation (5'-6mAAC-3') (6m1A system) > both A10 and A11 methylation (5'-6mA6mAC-3') (6mAA system) > C12 methylation (5'-AA5mC-3') (5mC system). All methylation systems lead to the sixth α helix (H6) (residues D105 to L116) moving away from the binding interface, and in the 5mC and 6m1A systems, the third α helix (H3) (residues G54 to L65) exhibits a similar trend. When the positively charged amino acids in H3 and H6 move away from the binding interface, their electrostatic and van der Waals interactions with the negatively charged DNA are weakened. Structural changes induced by methylation contributed to the destabilization of the hydrogen bond network near the original binding site, except for the 6m2A system. Moreover, there is a positive correlation between the number of methylated sites and the probability of distorting the DNA structure. Our study explores how different methylation patterns affect binding and structural adaptability, and have implications for drug discovery and understanding diseases related to abnormal methylation.

Quantitative investigation of the effects of DNA modifications and protein mutations on MeCP2-MBD-DNA interactions.

DNA methylation as an important epigenetic marker, has gained attention for the significance of three oxidative modifications (hydroxymethyl-C (hmC), formyl-C (fC), and carboxyl-C (caC)). Mutations occurring in the methyl-CpG-binding domain (MBD) of MeCP2 result in Rett. However, uncertainties persist regarding DNA modification and MBD mutation-induced interaction changes. Here, molecular dynamics simulations were used to investigate the underlying mechanisms behind changes due to different modifications of DNA and MBD mutations. Alanine scanning combined with the interaction entropy method was employed to accurately evaluate the binding free energy. The results show that MBD has the strongest binding ability for mCDNA, followed by caC, hmC, and fCDNA, with the weakest binding ability observed for CDNA. Further analysis revealed that mC modification induces DNA bending, causing residues R91 and R162 closer to the DNA. This proximity enhances van der Waals and electrostatic interactions. Conversely, the caC/hmC and fC modifications lead to two loop regions (near K112 and K130) closer to DNA, respectively. Furthermore, DNA modifications promote the formation of stable hydrogen bond networks, however mutations in the MBD significantly reduce the binding free energy. This study provides detailed insight into the effects of DNA modifications and MBD mutations on binding ability. It emphasizes the necessity for research and development of targeted Rett compounds that induce conformational compatibility between MBD and DNA, enhancing the stability and strength of their interactions.

Prevalence, clinical characteristics, and 3-dimensional radiographic analysis of supernumerary teeth in Guangzhou, China: a retrospective study.

OBJECTIVE: The aim was to investigate the prevalence and clinical and 3-dimensional (3D) radiographic characteristics of supernumerary teeth (ST) in a paediatric dental population. The factors associated with ST eruption potential were analysed, and the optimal extraction time for nonerupted ST was discussed. METHODS: A retrospective study was performed in a 13,336-participant baseline population aged 3-12 years for whom panoramic radiographs had been obtained in the hospital from 2019 to 2021. The medical records and radiographic data were reviewed to identify patients with ST. Both the demographic variables and ST characteristics were recorded and analysed . RESULTS: In total, 890 patients with 1,180 ST were screened from the 13,336 baseline population. The ratio of males (679) to females (211) was approximately 3.2:1. Generally, ST occurred singularly and were frequently found in the maxilla (98.1%). A total of 40.8% of ST were erupted, and the 6-year-old age group presented the highest eruption rate (57.8%). The eruption rate of ST was highly negatively correlated with age. A total of 598 patients additionally underwent cone- beam computed tomography (CBCT). According to the CBCT images, the majority of ST were conical, normally oriented, palatally situated, nonerupted and symptomatic. The most common ST-associated complication was failed eruption of adjacent teeth. In addition, symptomatic ST were more common in the 7- to 8- and 9- to 10-year-old age groups. The eruption rate of ST was 25.3% among the patients who had undergone CBCT. A normal orientation and the labial position were significant protective factors for ST eruption, with odds ratios (ORs) of 0.004 (0.000-0.046) and 0.086 (0.007-1.002), respectively. Age and the palatal position were significant risk factors, with ORs of 1.193 (1.065-1.337) and 2.352 (1.377-4.02), respectively. CONCLUSIONS: This study provides a detailed analysis of ST characteristics in 3-12 year old children. Age as well as the position and orientation of ST were reliable predictors of the ST eruption. An age of 6 years old may be the optimal time for extraction of nonerupted ST to maximize the utilization of eruption potential and reduce the incidence of ST-associated complications.

Organic Matter Transfer Caused by Concentration Difference Creates TC4 Surfaces with Switchable Wettability.

In this paper, low-cost electrochemical processing and heat treatment were adopted to fabricate titanium alloy surfaces with switchable wettability. Meanwhile, surface structure, roughness, and oxide content were regulated by electrochemical processing voltage. The effects of surface structure, roughness, oxide content, temperature, and time of heat treatment on switchable wettability were investigated. In addition to suitable structural conditions, surface chemistry is also crucial to preparing metal surfaces with switchable wettability. The surface chemistry of electrochemical processed surfaces was changed by organic matter transfer during heat treatment. In a certain voltage range, suitable surface structure, high roughness, and surface oxide content by high voltage contribute to the organic matter transfer. In a certain range of heating temperature and time, the concentration difference of organic matter is the premise of organic matter transfer. Concurrently, the higher the temperature, the faster the speed of organic matter transfer. Different from other relevant studies, the hypothesis that the concentration difference promotes organic matter transfer is proposed and verified by interesting experiments. The difference concentration of organic matter between the environment and the samples, as well as between the two samples, was created to promote organic matter transfer. Therefore, the electrochemical processed surfaces with switchable wettability were obtained by organic matter transfer in two ways.

Multiparametric cardiac magnetic resonance reveals persistent myocardial inflammation in patients with exertional heat illness.

OBJECTIVES: To explore the clinical potential of multiparametric cardiac magnetic resonance (CMR) in evaluating myocardial inflammation in patients with exertional heat illness (EHI). METHODS: This prospective study enrolled 28 males with EHI (18 patients with exertional heat exhaustion (EHE) and 10 with exertional heat stroke (EHS)) and 18 age-matched male healthy controls (HC). All subjects underwent multiparametric CMR, and 9 patients had follow-up CMR measurements 3 months after recovery from EHI. CMR-derived left ventricular geometry, function, strain, native T1, extracellular volume (ECV), T2, T2*, and late gadolinium enhancement (LGE) were obtained and compared among different groups. RESULTS: Compared with HC, EHI patients showed increased global ECV, T2, and T2* values (22.6% ± 4.1 vs. 19.7% ± 1.7; 46.8 ms ± 3.4 vs. 45.1 ms ± 1.2; 25.5 ms ± 2.2 vs. 23.8 ms ± 1.7; all p < 0.05). Subgroup analysis showed that ECV was higher in the EHS patients than those in EHE and HC groups (24.7% ± 4.9 vs. 21.4% ± 3.2, 24.7% ± 4.9 vs. 19.7% ± 1.7; both p < 0.05). Repeated CMR measurements at 3 months after baseline CMR showed persistently higher ECV than HC (p = 0.042). CONCLUSIONS: With multiparametric CMR, EHI patients demonstrated increased global ECV, T2, and persistent myocardial inflammation at 3-month follow-up after EHI episode. Therefore, multiparametric CMR might be an effective method in evaluating myocardial inflammation in patients with EHI. CLINICAL RELEVANCE STATEMENT: This study showed persistent myocardial inflammation after an exertional heat illness (EHI) episode demonstrated by multiparametric CMR, which is a potential promising method to evaluate the severity of myocardial inflammation and guide return to work, play, or duty in EHI patients. KEY POINTS: • EHI patients showed an increased global extracellular volume (ECV), late gadolinium enhancement, and T2 value, indicating myocardial edema and fibrosis. • ECV was higher in the exertional heat stroke patients than exertional heat exhaustion and healthy control groups (24.7% ± 4.9 vs. 21.4% ± 3.2, 24.7% ± 4.9 vs. 19.7% ± 1.7; both p < 0.05). • EHI patients showed persistent myocardial inflammation with higher ECV than healthy controls 3 months after index CMR (22.3% ± 2.4 vs. 19.7% ± 1.7, p = 0.042).

A clinical study of using ROC to compare the efficiency of ASL and BOLD in diagnosis of renal allograft function.

Background: This retrospective study aims to evaluate the effectiveness of renal transplantation function by comparing arterial spin labeling (ASL) and blood oxygen level dependent (BOLD) imaging with the receiver operating characteristic (ROC) curve. Methods: According to the estimated glomerular filtration rate (eGFR) values, 42 patients with normal kidney grafts (the normal kidney graft group, eGFR <60 mL/min/1.73 m2) and 93 patients with injured grafts (the kidney graft injury group, eGFR <60 mL/min/1.73 m2) were included in the present study. Renal blood flow (RBF) and the effective transverse relaxation rate (R2*) were calculated by comparing ASL and BOLD imaging. The ROC curve and the youden index were used to evaluate the diagnostic performance of ASL, BOLD, and the combination of them. Results: The results showed that all the clinical features of the patients, except for gender, differed significantly between the 2 groups (P<0.05). The mean RBF value of the renal transplant injury group (104.33±54.76 mL/100 g/min) was significantly lower than that of the normal group (191.84±63.96 mL/100 g/min, P<0.01). The mean medullary R2* value of the renal transplant injury group (27.91±3.35 1/s) was significantly higher than that of the normal group (25.22±2.94 1/s, P<0.01). Negative correlations were found between R2* and eGFR (r=-0.44), and RBF and R2* (r=-0.54; both P<0.01). The ROC analysis showed that both RBF and R2* reflected injured renal function [area under the curves (AUC) =0.86 and 0.72, respectively]. In addition, the AUC of RBF and R2* combined was 0.86, which was comparable to that of RBF alone (P=0.95), while combining R2* and RBF improved the diagnostic performance of R2* alone (AUC =0.86 versus 0.72, respectively; P<0.01). The youden index analysis showed that the diagnostic accuracy of ASL was 80.00%, better than 71.85% of BOLD; the sensitivity and specificity of ASL in diagnosing renal allograft dysfunction were 79.57% and 80.95%, superior to 77.42% and 59.52% of BOLD. Conclusions: Our results showed that the non-invasive assessment of ASL in clinical kidney transplant function is a more promising imaging technique than BOLD.

Long-term outcomes of arthroscopic synovectomy and core decompression through multiple small bone holes for early-stage avascular necrosis of the femoral head.

OBJECTIVE: This study described a minimally invasive approach for the management of early-stage avascular necrosis of the femoral head, which integrated arthroscopic intra-articular decompression and core decompression by drilling multiple small holes. METHOD: A total of 126 patients with 185 hip avascular necrosis were included between March 2005 and January 2008, and the hips were classified, based on the Association Research Circulation Osseous staging system, into stage I (n = 43), stage II (n = 114), and stage III (n = 28). Arthroscopic intra-articular inspection and debridement, along with drilling of multiple small holes for core decompression, were performed. The Modified Harris hip score system and radiographs were used to assess the pre- and post-surgery outcomes. RESULTS: One hundred and three patients (involving 153 hips) were followed up successfully for an average of 10.7 ± 3.4 years (range: 9-12 years). After surgery, the overall survival rate was 51.6% (79 hips), and the clinical survival rates were 79%, 72%, 52%, 32%, and 10% for patients with stage I, IIa, IIb, IIc, and III, respectively. The outcomes of patients with Association Research Circulation Osseous Stages I or IIA were better than those of other stages, while hips with a large necrotic area had poor results. This approach preserved the original biomechanical strength of the femoral head after core decompression and eliminated arthritis factors in the hip joint. CONCLUSION: The core decompression with multiple small-size holes is an effective method for treating early-stage avascular necrosis of the femoral head, particularly in those with pathological changes in the hip joint. LEVEL OF EVIDENCE: Therapeutic study, Level IV.