Interferon stimulated immune profile changes in a humanized mouse model of HBV infection.

The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg and/or young ages, is still unresolved due to the lack of surrogate models. Here, we generate a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrate that human IFN stimulates gene expression profiles in huIFNAR peripheral blood mononuclear cells (PBMCs) are similar to those in human PBMCs, supporting the representativeness of this mouse model for functionally analyzing human IFN in vivo. Next, we reveal the tissue-specific gene expression atlas across multiple organs in response to human IFN treatment; this pattern has not been reported in healthy humans in vivo. Finally, by using the AAV-HBV model, we test the antiviral effects of human interferon. Fifteen weeks of human PEG-IFNα2 treatment significantly reduces HBsAg and HBeAg and even achieves HBsAg seroconversion. We observe that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon may be critical for HBsAg suppression. Our huIFNAR mouse can authentically respond to human interferon stimulation, providing a platform to study interferon function in vivo. PEG-IFNα2 treatment successfully suppresses intrahepatic HBV replication and achieves HBsAg seroconversion.

The value of conventional ultrasound combined with superb microvascular imaging and color Doppler flow imaging in the diagnosis of thyroid malignant nodules: a systematic review and meta-analysis.

Purpose: To evaluate and compare the value of conventional ultrasound-based superb microvascular imaging (SMI) and color Doppler flow imaging (CDFI) in the diagnosis of malignant thyroid nodule by meta-analysis. Methods: The literature included in the Cochrane Library, PubMed, and Embase were searched by using " superb microvascular imaging (SMI), color Doppler flow imaging (CDFI), ultrasound, thyroid nodules" as the keywords from inception through February 1, 2023. According to the inclusion and exclusion criteria, the clinical studies using SMI and CDFI to diagnose thyroid nodules were selected, and histopathology of thyroid nodules was used as reference standard. The diagnostic accuracy research quality assessment tool (QUADAS-2) was used to evaluate the quality of included literature, and the Review Manager 5.4 was used to make the quality evaluation chart. The heterogeneity test was performed on the literature that met the requirements, the combined sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were pooled, and a comprehensive ROC curve analysis was performed. Meta-DiSc version 1.4, StataSE 12, and Review Manager 5.4 software were used. Results: Finally, 13 studies were included in this meta-analysis. A total of 815 thyroid malignant nodules were assessed. All thyroid nodules were histologically confirmed after SMI or CDFI. The combined sensitivity, specificity, PLR, NLR, DOR, and area under the SROC curve of SMI for the diagnosis of malignant thyroid nodules were 0.80(95%CI: 0.77-0.83), 0.79(95%CI: 0.77-0.82), 4.37(95%CI: 3.0-6.36), 0.23(95%CI: 0.15-0.35), 22.29(95%CI: 12.18-40.78), and 0.8944, respectively; the corresponding values of CDFI were 0.62(95%CI: 0.57-0.67), 0.81(95%CI: 0.78-0.85), 3.33(95%CI: 2.18-5.07), 0.41(95%CI: 0.27-0.64), 8.93(95%CI: 3.96-20.16), and 0.8498. Deek funnel pattern showed no significant publication bias. Conclusion: The diagnostic efficiency of SMI for malignant thyroid nodules is better than CDFI, and SMI technology can provide significantly more information on vascularity, make up for the deficiency of CDFI, and has better clinical application value. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023402064.

Retrospective validation of ultrasound characteristics at 19-24 weeks as predictive tools for selective intrauterine growth restriction in monochorionic diamniotic twin pregnancies: a diagnostic study.

Background: Seeking an optimal time point for ultrasound examination is important for the diagnosis of late selective intrauterine growth restriction (sIUGR) at birth in monochorionic diamniotic (MCDA) twin pregnancies. We aimed to assess the role of ultrasound characteristics at 19-24 weeks as predictive tools for late sIUGR at birth in MCDA twin pregnancies. Methods: We retrospectively recruited 32 sIUGR and 56 normal patients with MCDA twin pregnancies. Ultrasound indexes of these included subjects at 19-24 weeks, including the middle cerebral artery peak systolic velocity (MCA-PSV), umbilical artery pulsatility index (UA-PI), middle cerebral artery pulsatility index (MCA-PI), and cerebroplacental ratio (CPR) were assessed. Receiver operating characteristic (ROC) curves were used to ascertain the predictive value of ultrasound characteristics discrepancy for such complications, and the relationship between the ultrasound characteristics and sIUGR was assessed by a logistic regression analysis. Results: Differences were found in the MCA-PI, UA-PI, and CPR discordances between the normal MCDA and sIUGR subjects. CPR discordance was the most effective characteristic for predicting sIUGR [area under the ROC curve (AUC) =0.883; 95% CI: 0.795-0.948], followed by UA-PI discordance (AUC =0.772; 95% CI: 0.685-0.829), and MCA-PI discordance (AUC =0.746; 95% CI: 0.681-0.823), respectively. Additionally, the optimal cutoff value of CPR discordance was 21.65, and the corresponding sensitivity and specificity were 0.750 and 0.929, respectively. The correlation analysis revealed that gestational age (GA) at ultrasound scan but not at delivery was significantly correlated with the MCA-PSV (r=0.55, P<0.01), UA-PI (r=0.55, P<0.01), MCA-PI (r=0.49, P<0.01), and CPR (r=0.55, P<0.01) in sIUGR, while GA at both ultrasound scan and birth was significantly correlated with MCA-PSV (r=0.65, P<0.01), UA-PI (r=0.49, P<0.01), MCA-PI (r=0.48, P<0.01), and CPR (r=0.63, P<0.01) in normal MCDA. Conclusions: Increased MCA-PI, UA-PI, and CPR discordances were found in fetuses with sIUGR. CPR discordance could serve as a predictive index for sIUGR. An early ultrasound examination may be more accurate than biochemical modality for sIUGR prediction.

Conventional ultrasonography and elastosonography in diagnosis of malignant thyroid nodules: A systematic review and meta-analysis.

Purpose: To evaluate the diagnostic value of conventional ultrasound and elastosonography in malignant thyroid nodules by meta-analysis. Methods: The literature included in the Cochrane Library, PubMed, and Embase were searched by using "elastosonography, ultrasonography, thyroid nodules" as the keywords. The clinical studies using elastosonography and conventional ultrasound to diagnose thyroid nodules were selected, and histopathology of thyroid nodules was used as reference standards. The quality evaluation and heterogeneity test were performed on the literature that met the requirements, the combined specificity and sensitivity were pooled, and a comprehensive ROC curve analysis was performed. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was utilized to evaluate the quality of each included study. Meta-DiSc version 1.4, StataSE 12 and Review Manager 5.4 were used. Results: A total of nine studies assessed 3066 thyroid nodules (2043 benign and 1023 malignant). The pooled sensitivity, specificity, PLR, NLR, and DOR of conventional ultrasound for the diagnose of malignant thyroid nodules were 0.833 (95% CI 0.809-0.855), 0.818 (95% CI 0.801-0.835), 4.85 (95% CI 4.36-5.39), 0.20 (95% CI 0.17-0.23), and 29.38 (95% CI 23.28-37.08), respectively, with an AUC of 0.9068. Also, the pooled sensitivity, specificity, PLR, NLR, and DOR of elastosonography were 0.774 (95% CI 0.741-0.804), 0.737 (95% CI 0.715-0.758), 3.14(95% CI 2.85-3.47), 0.29 (95% CI 0.25-0.34), and 9.35 (95% CI 7.63-11.46), respectively, with an AUC of 0.8801. Three studies provided data regarding the conventional ultrasound and elastosonography. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.902 (95% CI 0.870-0.928), 0.649 (95% CI 0.616-0.681), 2.72 (95% CI 2.46-3.00), 0.14 (95% CI 0.11-0.19), 25.51 (95%CI 17.11-38.03), and 0.9294. Conclusion: The existing evidence shows that elastosonography cannot completely replace conventional ultrasound in the diagnosis of malignant thyroid nodules, and the combination of elastosonography and conventional ultrasound gives a better diagnostic precision. Systematic review registration: www.crd.york.ac.uk, identifier PROSPERO CRD42022375808.

Retrospective validation of 11-13 weeks' gestation ultrasound characteristics as predictive tools for twin-twin transfusion syndrome and selective intrauterine growth restriction in monochorionic diamniotic twin pregnancies.

BACKGROUND: Twin to twin transfusion syndrome (TTTS) is a serious syndrome that can affect twin pregnancies involving a single placenta, impacts some of twin gestations with monochorionic diamniotic (MCDA) placentas. We validated the ultrasound characteristics of 11-13 weeks' gestation to predict TTTS and selective intrauterine growth restriction (sIUGR) in MCDA pregnancies. METHODS: We retrospectively included all of the MCDA twin pregnancies with ultrasound characteristics, including the crown-rump length (CRL), ductus venosus pulsatility index for veins (DV PIV), and nuchal translucency (NT) thickness, at 11-13 weeks' gestation, followed by mean difference and discordance comparison. Receiver operating characteristic (ROC) curves were constructed for the comparison of values of these predictive markers for identification of MCDA pregnancies with high-risk of adverse outcomes. RESULTS: A total of 98 MCDA pregnancies were included in this study. Among the 98, 34 (34.7%) developed sIUGR, whereas 10 (10.2%) expressed TTTS. Significant differences in NT discordance were found among the normal, sIUGR, and TTTS groups; moreover, a significant difference was found between pregnancies with normal outcomes and sIUGR (P<0.001), normal and TTTS (P<0.001), and sIUGR and TTTS (P<0.001). Difference in NT was determined to be the best predictive marker for sIUGR [area under the curve (AUC) =0.769; 95% confidence interval (CI): 0.591 to 0.992], and NT discordance was considered the best predictive marker for TTTS (AUC =0.802; 95% CI: 0.485 to 0.936). CONCLUSIONS: Significant differences in NT discordance were found between the normal, sIUGR, and TTTS groups, while NT difference and NT discordance were identified as predictive markers for sIUGR and TTTS, respectively.

JMJD3 acts in tandem with KLF4 to facilitate reprogramming to pluripotency.

The interplay between the Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and transcriptional/epigenetic co-regulators in somatic cell reprogramming is incompletely understood. Here, we demonstrate that the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3 plays conflicting roles in mouse reprogramming. On one side, JMJD3 induces the pro-senescence factor Ink4a and degrades the pluripotency regulator PHF20 in a reprogramming factor-independent manner. On the other side, JMJD3 is specifically recruited by KLF4 to reduce H3K27me3 at both enhancers and promoters of epithelial and pluripotency genes. JMJD3 also promotes enhancer-promoter looping through the cohesin loading factor NIPBL and ultimately transcriptional elongation. This competition of forces can be shifted towards improved reprogramming by using early passage fibroblasts or boosting JMJD3's catalytic activity with vitamin C. Our work, thus, establishes a multifaceted role for JMJD3, placing it as a key partner of KLF4 and a scaffold that assists chromatin interactions and activates gene transcription.