Objective:To investigate the effect of CT-derived fractional flow reserve (CT-FFR) measurement sites on the values and the diagnostic performance, and to determine the optimal measurement site for CT-FFR using invasive FFR as the reference standard.Methods:This study was part of the CT-FFR CHINA clinical trial. Patients with suspected coronary artery disease who were scheduled for invasive coronary angiography (ICA) were prospectively recruited from five clinical centers across the country from November 2018 to March 2020. Each enrolled patient underwent coronary CT angiography (CCTA), CT-FFR, ICA, and invasive pressure wire-based FFR assessments sequentially within one week. Four groups of CT-FFR values were obtained on each enrolled target vessels according to different CT-FFR measurement locations: 1, 2, 3 cm distal to the target lesion, and terminal vessel groups. Spearman and Bland-Altman analyses were used to explore the correlation and consistency of CT-FFR values and FFR values at different measurement sites. The measurement deviation of CT-FFR was also compared. Diagnostic accuracy and performance of CT-FFR, including sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC), in discriminating myocardial ischemia were analyzed across all measurement site groups on a per-vessel level, using FFR as the reference standard.Results:A total of 289 patients with 345 target lesion vessels were included. According to CCTA, there were 51 target vessels (14.8%) with<50% stenosis, 106 vessels (30.7%) with 50%-69% stenosis, and 188 vessels (54.5%) with stenosis≥70%. At per-vessel level, CT-FFR and FFR values at each measurement position group were highly positively correlated: 1 cm distal to target lesion group, r=0.734 ( P<0.001); 2 cm distal to target lesion group, r=0.732 ( P<0.001); 3 cm distal to target lesion group, r=0.737 ( P<0.001); terminal vessel group was 0.719 ( P<0.001). At per-vessel level, CT-FFR and FFR values of all measurement sites were in good agreement (Bland-Altman analysis results): 1 cm distal to target lesion group, 0.014 (95% LoA 0.002-0.026); 2 cm distal to target lesion group, 0.026 (95% LoA 0.015-0.038); 3 cm distal to target lesion group, 0.040 (95% LoA 0.039-0.051); terminal vessel group, 0.075 (95% LoA 0.064-0.087). And at per-vessel level, the accuracy of diagnosing myocardial ischemia with CT-FFR at 1 cm was highest [84.6% (95% CI 80.4%-88.3%)], and the lowest accuracy in the terminal vessel group [67.0% (95% CI 61.7%-72.0%)]. However, there was no significant difference in the diagnostic accuracy of CT-FFR at 1 cm, 2 cm [80.6% (95% CI 76.1%-84.6%)] and 3 cm [77.5% (95% CI 72.6%-81.7%)]. AUC of CT-FFR at 1 cm distal to the lesion were both highest for global level and moderately stenosis (50%-69%) lesions [0.85 (95% CI 0.81-0.89), 0.84 (95% CI 0.77-0.90)]. And the differences were statistically significant among the four measurement location groups (all P<0.05). Conclusions:The deviation of CT-FFR increases with measurement site distance distal to target lesions. One centimeter distal to the target lesion is the optimal measurement site, and the CT-FFR value here shows the highest diagnostic performance for myocardial ischemic lesions, especially for moderate stenosis.

Recent studies have identified a missense mutation in the β1-receptor (ADRB1-A187V) that exerts a pronounced impact on human sleep, with a noted decrease in protein abundance in vivo. The administration of β-blockers is frequently associated with sleep disturbances in clinical settings. In this study, we assessed the influence of various β-blockers on sleep within mouse models. Our findings indicated that β-blockers could induce varying degrees of arousal, sleep disruption, and a decrease in REMS (rapid eye movement sleep). We examined the dose-dependent effects of metoprolol and nebivolol on both sleep and cardiac functionality in both wild-type and Adrb1-A187V mutant mice. Our data suggested that, in contrast to cardiac effects, higher doses of metoprolol are required to have noted impact on sleep. No genotype effect was observed with metoprolol in terms of sleep or cardiac function. In contrast, the mutant mice demonstrated increased sensitivity to nebivolol, which exacerbated sleep fragmentation and impeded the onset of REMS. This study is expected to provide some reference for minimizing the occurrence of sleep disorders and reducing the adverse reactions of drugs to the greatest extent.

Objective:To observe the effect of rehabilitative exercise on knee function after anterior cruciate ligament (ACL) reconstruction.Methods:Fifty-eight patients with a reconstructed ACL were divided at random into a control group of 28 and an experimental group of 30. In addition to conventional basic treatment, the control group received routine orthopedic rehabilitation training, while the experimental group underwent exercise-based rehabilitation training 6 days a week for 6 weeks. Before and after the treatment, the efficacy in both groups was evaluated using Lysholm knee scoring (LKSS), numerical pain scoring (NRS), maximum knee flexion angle, and a thigh muscle atrophy index.Results:Both groups had significantly higher LKSS scores, lower NRS scores, larger maximum knee flexion angles, and increased thigh muscle atrophy indices, on average, after their treatments. Compared with the control group, the experimental group tended to have significantly higher LKSS scores, larger maximum knee flexion angles, and lower thigh muscle atrophy indices after the treatment. There was, however, no significant difference between the groups in their average NRS scores.Conclusions:Exercise-based rehabilitation training significantly improves the knee function of patients after ACL reconstruction, and its efficacy is superior to conventional orthopedic rehabilitation training.

Objective:To investigate the effect of CT-derived fractional flow reserve (CT-FFR) measurement sites on the values and the diagnostic performance, and to determine the optimal measurement site for CT-FFR using invasive FFR as the reference standard.Methods:This study was part of the CT-FFR CHINA clinical trial. Patients with suspected coronary artery disease who were scheduled for invasive coronary angiography (ICA) were prospectively recruited from five clinical centers across the country from November 2018 to March 2020. Each enrolled patient underwent coronary CT angiography (CCTA), CT-FFR, ICA, and invasive pressure wire-based FFR assessments sequentially within one week. Four groups of CT-FFR values were obtained on each enrolled target vessels according to different CT-FFR measurement locations: 1, 2, 3 cm distal to the target lesion, and terminal vessel groups. Spearman and Bland-Altman analyses were used to explore the correlation and consistency of CT-FFR values and FFR values at different measurement sites. The measurement deviation of CT-FFR was also compared. Diagnostic accuracy and performance of CT-FFR, including sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC), in discriminating myocardial ischemia were analyzed across all measurement site groups on a per-vessel level, using FFR as the reference standard.Results:A total of 289 patients with 345 target lesion vessels were included. According to CCTA, there were 51 target vessels (14.8%) with<50% stenosis, 106 vessels (30.7%) with 50%-69% stenosis, and 188 vessels (54.5%) with stenosis≥70%. At per-vessel level, CT-FFR and FFR values at each measurement position group were highly positively correlated: 1 cm distal to target lesion group, r=0.734 ( P<0.001); 2 cm distal to target lesion group, r=0.732 ( P<0.001); 3 cm distal to target lesion group, r=0.737 ( P<0.001); terminal vessel group was 0.719 ( P<0.001). At per-vessel level, CT-FFR and FFR values of all measurement sites were in good agreement (Bland-Altman analysis results): 1 cm distal to target lesion group, 0.014 (95% LoA 0.002-0.026); 2 cm distal to target lesion group, 0.026 (95% LoA 0.015-0.038); 3 cm distal to target lesion group, 0.040 (95% LoA 0.039-0.051); terminal vessel group, 0.075 (95% LoA 0.064-0.087). And at per-vessel level, the accuracy of diagnosing myocardial ischemia with CT-FFR at 1 cm was highest [84.6% (95% CI 80.4%-88.3%)], and the lowest accuracy in the terminal vessel group [67.0% (95% CI 61.7%-72.0%)]. However, there was no significant difference in the diagnostic accuracy of CT-FFR at 1 cm, 2 cm [80.6% (95% CI 76.1%-84.6%)] and 3 cm [77.5% (95% CI 72.6%-81.7%)]. AUC of CT-FFR at 1 cm distal to the lesion were both highest for global level and moderately stenosis (50%-69%) lesions [0.85 (95% CI 0.81-0.89), 0.84 (95% CI 0.77-0.90)]. And the differences were statistically significant among the four measurement location groups (all P<0.05). Conclusions:The deviation of CT-FFR increases with measurement site distance distal to target lesions. One centimeter distal to the target lesion is the optimal measurement site, and the CT-FFR value here shows the highest diagnostic performance for myocardial ischemic lesions, especially for moderate stenosis.

Objective:To observe the effect of rehabilitative exercise on knee function after anterior cruciate ligament (ACL) reconstruction.Methods:Fifty-eight patients with a reconstructed ACL were divided at random into a control group of 28 and an experimental group of 30. In addition to conventional basic treatment, the control group received routine orthopedic rehabilitation training, while the experimental group underwent exercise-based rehabilitation training 6 days a week for 6 weeks. Before and after the treatment, the efficacy in both groups was evaluated using Lysholm knee scoring (LKSS), numerical pain scoring (NRS), maximum knee flexion angle, and a thigh muscle atrophy index.Results:Both groups had significantly higher LKSS scores, lower NRS scores, larger maximum knee flexion angles, and increased thigh muscle atrophy indices, on average, after their treatments. Compared with the control group, the experimental group tended to have significantly higher LKSS scores, larger maximum knee flexion angles, and lower thigh muscle atrophy indices after the treatment. There was, however, no significant difference between the groups in their average NRS scores.Conclusions:Exercise-based rehabilitation training significantly improves the knee function of patients after ACL reconstruction, and its efficacy is superior to conventional orthopedic rehabilitation training.

Anaplastic lymphoma kinase (ALK) is the most common fusion gene involved in non-small cell lung cancer (NSCLC), and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors (ALK-TKIs). However, the clinical efficacy is highly variable. Pre-existing intratumoral heterogeneity (ITH) has been proven to contribute to the poor treatment response and the resistance to targeted therapies. In this work, we investigated whether the variant allele frequencies (VAFs) of ALK fusions can help assess ITH and predict targeted therapy efficacy. Through the application of next-generation sequencing (NGS), 7.2% (326/4548) of patients were detected to be ALK positive. On the basis of the adjusted VAF (adjVAF, VAF normalization for tumor purity) of four different threshold values (adjVAF < 50%, 40%, 30%, or 20%), the association of ALK subclonality with crizotinib efficacy was assessed. Nonetheless, no statistical association was observed between median progression-free survival (PFS) and ALK subclonality assessed by adjVAF, and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib. Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Anaplastic Lymphoma Kinase/therapeutic use* ; Crizotinib/therapeutic use* ; Lung Neoplasms/pathology* ; Protein Kinase Inhibitors/pharmacology* ; Gene Frequency

Objective: To assess the effect of viral macrophage inflammatory protein (vMIP) -Ⅱ on the expression of apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) , and to explore the mechanisms. Methods: A recombinant plasmid pEGFP-N3-K4 (vMIP-Ⅱ plasmid group) and an empty plasmid pEGFP-N3 (empty plasmid group) were separately transfected into 293T cells, and quantitative PCR and Western blot analysis were performed to evaluate the effect of transfection with vMIP-Ⅱ gene on the APOBEC3G expression in 293T cells. Some 293T cells in the empty plasmid group and vMIP-Ⅱ plasmid group were treated with 1 000 IU/ml interferon (IFN) -α for 36 hours, and then Western blot analysis was conducted to determine the APOBEC3G expression in the empty plasmid group and vMIP-Ⅱ plasmid group with or without IFN-α treatment. Some 293T cells transfected with vMIP-Ⅱ plasmids were treated with 75 μmol/L AG490 (a JAK/STAT signaling pathway inhibitor) and 20 μmol/L U0126 (an ERK signaling pathway inhibitor) separately; after 24 hours, total protein was extracted from 293T cells, and Western blot analysis was conducted to determine the expression of APOBEC3G. A recombinant plasmid containing APOBEC3G promoter was constructed by using a luciferase reporter gene, and the promoter fragment included the full-length promoter sequence (POS) of APOBEC3G, sequences with the lengths of 1 560, 960, 720, 480, 420, 360, 330 and 240 bp, and the regulatory element-free region (NEG) of APOBEC3G, separately. Some 293T cells were co-transfected with the recombinant plasmid carrying luciferase reporter gene and vMIP-Ⅱ plasmid (experimental group), or the recombinant plasmid and empty plasmid (control group). Subsequently, the activity of the APOBEC3G promoter was evaluated, and the key promoter region through which the transcriptional activity of APOBEC3G was regulated by vMIP-Ⅱ was analyzed. Statistical analysis was carried out by using t test, one-way analysis of variance and least significant difference (LSD) -t test. Results: The mRNA and protein expression of APOBEC3G was significantly higher in the vMIP-Ⅱ plasmid group (2.500 ± 0.013, 1.472 ± 0.013 respectively) than in the control group (1, 0.364 ± 0.030 respectively; t = 6.22, 6.54 respectively, both P < 0.05) . The APOBEC3G expression significantly differed among the empty plasmid group, vMIP-Ⅱ plasmid group, empty plasmid + IFN-α group and vMIP-Ⅱ plasmid + IFN-α group (1, 2.030 ± 0.108, 2.700 ± 0.081 and 2.600 ± 0.099 respectively; F = 67.026, P < 0.001) , but there was no significant difference between the vMIP-Ⅱ plasmid group and empty plasmid + IFN-α group (t = 3.46, P > 0.05) . The APOBEC3G expression also significantly differed among the vMIP-Ⅱ plasmid group, vMIP-Ⅱ plasmid + AG490 group and vMIP-Ⅱ plasmid + U0126 group (0.617 ± 0.025, 0.179 ± 0.061, 0.359 ± 0.012 respectively; F = 70.019, P < 0.001) , and was significantly lower in the vMIP-Ⅱ plasmid + AG490 group and vMIP-Ⅱ plasmid + U0126 group than in the vMIP-Ⅱ plasmid group (t = 9.66, 11.836 respectively, both P < 0.01) . Luciferase activity assay showed that the promoter activity significantly differed among the vMIP-Ⅱ plasmid groups transfected with POS, 1 560-, 960-, 720-, 480-, 420-, 360-, 330-, 240-bp or NEG sequences (F = 81.092, P < 0.001) , and the APOBEC3G promoter activity decreased greatly from the 720-bp group to 480-bp group. Conclusion vMIP-Ⅱ upregulates the expression of APOBEC3G, likely through the JAK/STAT signaling pathway or the key promoter region regulating the transcriptional activity of APOBEC3G.

Objective To discuss the effect of body posture change on the catheter tip position of totally implantable venous access port (TIVAP).Methods Under ultrasound guidance,implantation of TIVAP was carried out through bedside puncturing of internal jugular vein or subclavian vein.After the implantation of TIVAP,X-ray chest films of both erect position and supine position were taken to check the catheter tip position.The distance from the upper edge of the first thoracic vertebra to the catheter tip was separately measured on the erect position and supine position chest films.The shift of the catheter tip position was judged by the difference in the distance measured on chest films as well as by the comparison with the bony anatomic marks.Results Successful implantation of TIVAP was accomplished in 86 patients.When the patients changed from erect position to supine position,the catheter tip of TIVAP moved caudally in 71 patients,with the mean displace distance being (12.29±7.48) mm;the catheter tip of TIVAP moved cephalad in 31 patients,with the mean displace distance being (5.00±3.79) mm;and the catheter tip of TIVAP remained in the same position in 2 patients.When the patients changed from erect position to supine position,the catheter tip of TIVAP had a tendency to move toward the foot side,the average displace distance was (-9.32±9.36) mm,the difference in catheter tip location between two photographic positions was statistically significant (P＜0.000 1).No statistically significant correlation existed between the changes of catheter tip position and the sex,age,height,weight as well as body mass index (P＞0.05).Conclusion After the implantation of TIVAP,the position of catheter tip will change with patient's body posture.When patient's posture changes from erect position to supine position the tip of the catheter tends to shift towards the atrium.

Objective: To study the relationship between morphological characteristics, grading, diagnosis and prognosis in phyllodes tumors (PT) of the breast. Methods: A retrospective study was carried out on 83 PTs diagnosed between 1999 and 2003 that were classified semi-quantitatively according to the WHO recommendation. Follow-up data was available for some cases, and Cox regression analysis was used to evaluate factors affecting metastasis and recurrence. Results: All cases were classified into the benign (57.8%), borderline (28.9%) and malignant (13.3%). The overall recurrence rate for the 72 cases with follow-up data was 20.8% (15/72), and was 17.5% (7/40) in benign, 22.7% (5/22) in borderline and 3/10 in malignant PT, respectively, with no significant difference (P>0.05). The median interval between the initial diagnosis and the first recurrence was 24 months. Lung or bone metastases occurred in 1/22 borderline and 3/10 malignant PT patients 5 years post-surgery. The mitotic count and the degree of stromal cell atypia were significantly correlated with recurrence (P=0.001 and P=0.006). Multivariate analysis showed that severe stromal cell atypia was an independent predictor of recurrence-free survival in PT [HR=6.40 (95% CI=1.378 to 29.732), P=0.018]. Conclusions Each parameter in the histological grading of PT may have different prognostic value, and markedly increased mitotic count and were predictive of relapse.

Ebolavirus can cause hemorrhagic fever in humans with a mortality rate of 50%-90%. Currently, no approved vaccines and antiviral therapies are available. Human TIM1 is considered as an attachment factor for EBOV, enhancing viral infection through interaction with PS located on the viral envelope. However, reasons underlying the preferable usage of hTIM-1, but not other PS binding receptors by filovirus, remain unknown. We firstly demonstrated a direct interaction between hTIM-1 and EBOV GP in vitro and determined the crystal structures of the Ig V domains of hTIM-1 and hTIM-4. The binding region in hTIM-1 to EBOV GP was mapped by chimeras and mutation assays, which were designed based on structural analysis. Pseudovirion infection assays performed using hTIM-1 and its homologs as well as point mutants verified the location of the GP binding site and the importance of EBOV GP-hTIM-1 interaction in EBOV cellular entry.
Ebolavirus ; metabolism ; Flow Cytometry ; Glycoproteins ; metabolism ; Hepatitis A Virus Cellular Receptor 1 ; Hepatitis A Virus Cellular Receptor 2 ; Humans ; Membrane Glycoproteins ; metabolism ; Membrane Proteins ; metabolism ; Protein Binding ; Receptors, Virus ; metabolism ; Surface Plasmon Resonance ; Viral Envelope Proteins ; metabolism ; Viral Proteins ; metabolism