Plasma extrachromosomal circular DNA is a pathophysiological hallmark of short-term intensive insulin therapy for type 2 diabetes.

BACKGROUND: Extrachromosomal circular DNA (eccDNA) has emerged as a promising biomarker for disease diagnosis and prognosis prediction. However, its role in type 2 diabetes remains unexplored. OBJECTIVE: To investigate the characteristics and dynamics of circulating eccDNAs in newly diagnosed type 2 diabetes mellitus (T2DM) patients undergoing short-term intensive insulin therapy (SIIT), a highly effective treatment for inducing long-term glycemic remission. METHODS: We conducted Circle-Seq analysis on plasma samples from 35 T2DM patients at three time points: pre-SIIT, post-SIIT, and 1-year post-SIIT. Our analysis encompassed the characterization of eccDNA features, including GC content, eccDNA length distribution, genomic distribution, and the genes in eccDNAs. RESULTS: Following SIIT, we observed an increase in plasma eccDNA load, suggesting metabolic alterations during therapy. Notably, a correlation was identified between eccDNA profiles and glycemia in T2DM, both quantitatively and genetically. Our analysis also revealed the frequent presence of metabolism-related genes within T2DM plasma eccDNAs, some of which spanned gene exons and/or fractions. CONCLUSION: This study represents the first report of cell-free eccDNA in T2DM and underscores a compelling association between cell-free eccDNA and profound glycemic changes. These findings highlight the potential of eccDNAs as crucial players in the context of T2DM and glycemic control.

Imaging findings and clinical relevance of 68Ga-Pentixafor PET in atherosclerosis: a systematic review.

OBJECTIVE: We aimed to perform a qualitative synthesis of evidence on the role of 68Ga-Pentixafor PET in atherosclerosis. METHODS: A systematic search of the PubMed and Embase databases for studies reporting the evaluation of atherosclerotic lesions by 68Ga-Pentixafor PET was performed with a search time frame from database creation to 2022-12-26. The diagnostic test evaluation tool QUADAS-2 was used to evaluate the quality of the included literature and to perform descriptive analyses of relevant outcome indicators. RESULTS: A total of 6 studies with 280 patients were included. One study reported only imaging outcome metrics, while the other five studies reported imaging outcome metrics and clinical correlation metrics. For imaging outcomes, three studies reported imaging results for 68Ga-Pentixafor PET only, and the other three studies reported imaging results for comparative analysis of 68Ga-Pentixafor PET with 18F-FDG PET. For clinical correlation, three studies reported the correlation between tracer uptake and cardiovascular risk factors, one study reported the correlation between tracer uptake and plaque calcification, and one study reported the correlation between all three: tracer uptake, cardiovascular risk factors, and plaque calcification. CONCLUSION: 68Ga-Pentixafor PET has a good imaging effect on atherosclerotic lesions, and it is a promising imaging modality that may replace 18F-FDG PET for atherosclerosis imaging in the future. In patients with atherosclerosis, there is a clear clinical correlation between cardiovascular risk factors, tracer uptake, and plaque calcification.

Comparison of 68 Ga-DOTATATE PET/CT and 68 Ga-Pentixiafor PET/CT Imaging in a Case of Merkel Cell Carcinoma.

ABSTRACT: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma with a high rate of metastasis and mortality. We present 68 Ga-DOTATATE PET/CT and 68 Ga-pentixiafor PET/CT findings of MCC in a 62-year-old man. Both 68 Ga-DOTATATE PET/CT and 68 Ga-pentixiafor PET/CT revealed increased radioactive uptake of lesions in the scan range. Compared with 68 Ga-DOTATATE PET/CT, the lesions showed higher uptake in 68 Ga-pentixiafor PET/CT. Our case showed that 68 Ga-pentixiafor might be a promising radiotracer in the evaluation of MCC.

How local outbreak of COVID-19 affect the risk of internet public opinion: A Chinese social media case study.

Motivated by the realistic demand of controlling the Internet public opinion risk caused by the local outbreak of COVID-19, this paper creatively proposes a COVID-19 local outbreak Internet public opinion risk grading research framework. The SMAA-FAHPSort II method combining Analytic Hierarchy Process Sort II (AHPSort II) method with Stochastic Multicriteria Acceptability Analysis (SMAA-2) method is introduced into this framework, to evaluate the Internet public opinion risk level of social media during the local outbreak of COVID-19. In addition, this framework is applied to a case of Internet public opinion risk evaluation on Microblog platform of China. According to the number of new cases per day in mainland China, this paper divides the period from May 7, 2020 to September 3, 2021 into seven stages. A total of more than 10,000 Microblog hot topics were collected, after screening and preprocessing, 5422 related topics are remained to help complete the Internet public opinion risk evaluation. The case study analysis results show that the number of days classified as moderate risk and above has reached more than 280. This proves that the local outbreak of COVID-19 will indeed increase the risk of Internet public opinion, and correlation analysis confirms that the level of public opinion risk is positively correlated with the severity of the epidemic in the real world. Furthermore, the effectiveness and advantages of the proposed method are verified by comparative analysis and sensitivity analysis. Finally, some effective public opinion management suggestions have been put forward. This paper can provide reference for the government to formulate or improve relevant strategies, and also has great significance for reducing the risk of Internet public opinion in social media.

Digital economy, energy efficiency, and carbon emissions: Evidence from provincial panel data in China.

Improving energy efficiency and lowering carbon emissions are of great importance to realize the "dual carbon" goal of carbon peak and carbon neutrality. Digital economy is a new engine of economic development, but whether or how it affects energy efficiency and carbon emissions are unclear. Utilizing panel data of China's 30 provinces from 2012 to 2019, this study empirically explores the relationships among digital economy, energy efficiency, and carbon emissions. Meanwhile, from the perspective of energy efficiency, applying mediation models and panel threshold model, it analyzes the direct, indirect, and nonlinear influencing mechanisms of digital economy on carbon emissions. The results reflect that the development of digital economy in China intensifies carbon emissions. Energy efficiency serves as a vital partial mediator between the two. The enhancement of energy efficiency can lower carbon emissions. However, the development of digital economy is not conducive to improving energy efficiency, thereby, indirectly increasing carbon emissions. The mediating effect of energy efficiency accounts for 30.58 % of the total effect of digital economy on carbon emissions. Meanwhile, taking energy efficiency into account, the impact of digital economy on carbon emissions has a significant double-threshold effect and presents an N-shaped trend. [0.824, 0.912] is the optimal range of energy efficiency, within which the growth of the digital economy can empower carbon emission abatement to some extent. In addition, the expansion of population size, the coal-based energy consumption structure, and the industrial structure significantly increase carbon emissions. The improvements in living standards and environmental regulations can help to decrease carbon emissions, but the emission abatement effects are not significant. Those conclusions reveal the importance of optimizing the level and quality of digital economy and adopting differentiated digital economy development policies based on energy efficiency to achieve carbon emission reduction.

Evaluation of p16/Ki-67 dual-stain as triage test for high-risk HPV-positive women: A hospital-based cross-sectional study.

BACKGROUND: Most human papillomavirus (HPV)-positive women recover from infections and do not develop cervical intraepithelial neoplasia (CIN) and cervical cancer. Additional triage approaches are needed to reduce unnecessary colposcopy referrals. The aim of this study is to determine the high-risk HPV prevalence in a hospital-based population and to evaluate the performance of p16/Ki-67 dual-stain test for the triage of high-risk HPV-positive women to detect precursor lesions and cervical cancer compared with the ThinPrep cytologic test (TCT). METHODS: In a hospital-based population, 100,801 women were provided with a primary HPV DNA test and only women with high-risk HPV infections were triaged using TCT and p16/Ki-67 dual-stain test. CIN2 or worse (≥CIN2) or CIN3 or worse (≥CIN3) were defined as the clinical end points. RESULTS: The p16/Ki-67 dual-stain indicated a statistically significant higher sensitivity (82.8% vs. 66.7%%), specificity (51.6% vs. 44.4%), positive predictive value (33.2% vs. 25.8%), negative predictive value (91.2% vs. 82.1%), and accuracy (58.6% vs. 49.4%) compared with TCT examination within ≥CIN2 cases. Similar patterns were observed for the ≥CIN3 end point. CONCLUSIONS: Our study demonstrated that p16/Ki-67 dual-stain test could achieve better performance compared with TCT examination for ≥CIN2 or ≥ CIN3 detection, representing a promising approach as a specific and efficient triage strategy for high-risk HPV-positive women.

Identification of Novel Compound Heterozygous Variants of the PNPLA6 Gene in Boucher-Neuhäuser Syndrome.

Background: Boucher-Neuhäuser syndrome (BNS, MIM 215470) is a rare autosomal recessive syndrome caused by mutations in the PNPLA6 gene. Few BNS cases have been reported for functional validation at the RNA level. Herein, we report on the family of a 17-year-old girl with clinical characteristics of BNS, genetic validation, and a systematic review of PNPLA6 variants related to BNS. Methods: Clinical data and blood samples were collected from the patient and their parents, and whole-exome sequencing was performed and confirmed by Sanger sequencing. RNA-sequencing (RNA-Seq) and quantitative RT-PCR (qRT-PCR) were performed, and the three-dimensional protein structures of the variants were predicted. Results: We report a 17-year-old female with progressive night blindness since the age of four, primary amenorrhea, and non-development of secondary sexual characteristics. Her impaired vision was diagnosed as retinal pigmentary degeneration of the retina. She had congenital hypogonadotropic hypogonadism (CHH) but no cerebellar ataxia at present. Two novel compound heterozygous variants (c.2241del/p.Met748TrpfsTer65 and c.2986A>G/p.Thr996Ala) of the PNPLA6 gene (NM_006702.4) were identified by whole-exome sequencing. The former variant was carried from her healthy father and has not been reported previously. The latter was inherited from her healthy mother and was noted in a report without functional studies. The RT-PCR results showed that the mRNA expression of PNPLA6 was lower in this patient and her father than in the control group. She was diagnosed with BNS. Both variants (c.2241del and c.2986A>G) were likely pathogenic according to the ACMG criteria. The novel variants in the PNPLA6 gene related to Boucher-Neuhäuser syndrome were summarized in this article. Conclusion: The possibility of Boucher-Neuhäuser syndrome should be considered when patients present with night blindness, impaired vision, and hypogonadotropic hypogonadism. Gene sequencing is currently the primary diagnostic method. Herein, novel compound heterozygous variants of PNPLA6 were identified in a BNS patient, and its function was verified at the RNA level. The PNPLA6 c.2241del variant is novel and potentially pathogenic, expanding the mutation spectrum in PNPLA6.

The effect of short-term intensive insulin therapy on inflammatory cytokines in patients with newly diagnosed type 2 diabetes.

BACKGROUND: Diabetes mellitus was a chronic low-grade inflammatory disease and had increased circulating inflammatory cytokines and acute phase proteins. We aimed to identify the changes of inflammatory cytokines in newly diagnosed type 2 diabetic patients after short-term intensive insulin therapy using continuous subcutaneous insulin infusion (CSII). METHODS: Thirty-three newly diagnosed type 2 diabetic patients were enrolled between September 2020 to December 2020. Expression of 40 inflammatory cytokines of the patients were tested with RayBiotech antibody array before and after 1 week of intensive insulin therapy of CSII. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to explore the signaling pathway involved in the therapy. RESULTS: Five inflammatory cytokines were downregulated significantly after 1 week of CSII therapy. They were interleukin-6 receptor (IL-6R), regulated upon activation normal T-cell expressed and secreted (RANTES), intercellular adhesion molecule-1 (ICAM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and platelet-derived growth factor type BB (PDGF-BB) (p < 0.05 and foldchange <0.83). Among patients with baseline glycated hemoglobin (HbA1c) < 10%, three proinflammatory cytokines were decreased significantly after therapy: IL-6R, RANTES, and ICAM-1. As for the patients with baseline HbA1c ≥ 10%, eight inflammatory cytokines were inhibited significantly after the treatment, including ICAM-1, IL-6R, RANTES, TIMP-1, TIMP-2, macrophage inflammatory protein-1 beta (MIP-1ß), PDGF-BB, and tumor necrosis factor receptor type II (TNF RII). No matter which subgroup of baseline HbA1c level was considered, the decreased cytokines after CSII therapy were significantly involved in TNF signaling pathway. Nuclear factor-kappa B (NF-κB) signaling pathway was mainly enriched in patients with baseline HbA1c ≥ 10%. CONCLUSIONS: A panel of 40 inflammatory cytokines, measured by protein microarray, were evaluated for 1 week of CSII treatment in newly diagnosed type 2 diabetic patients. After treatment, many proinflammatory cytokines decreased. In the higher baseline HbA1c subgroup, more proinflammatory cytokines improved. No matter which subgroup of HbA1c level was considered, IL-6R, RANTES, and ICAM-1, which were involved in TNF signaling pathway, decreased significantly after CSII therapy. This was the first report showing that the cytokines of IL-6R, TIMP-2, PDGF-BB, and TNF RII decreased after the CSII therapy.

Multi-stage Internet public opinion risk grading analysis of public health emergencies: An empirical study on Microblog in COVID-19.

In the period of Corona Virus Disease 2019 (COVID-19), millions of people participate in the discussion of COVID-19 on the Internet, which can easily trigger public opinion and threaten social stability. This paper creatively proposes a multi-stage risk grading model of Internet public opinion for public health emergencies. On the basis of general public opinion risk grading analysis, the model continuously pays attention to the risk level of Internet public opinion based on the time scale of regular or major information updates. This model combines Analytic Hierarchy Process Sort II (AHPSort II) and Swing Weighting (SW) methods and proposes a new Multi-Criteria Decision Making (MCDM) method - AHPSort II-SW. Intuitionistic fuzzy number and linguistic fuzzy number are introduced into the model to evaluate the criteria that cannot be quantified. The multi-stage model is tested using more than 2,000 textual data about COVID-19 collected from Microblog, a leading social media platform in China. Seven public opinion risk assessments were conducted from January 23 to April 8, 2020. The empirical results show that in the early COVID-19 outbreak, the risk of public opinion is more serious on macroscopic view. In details, the risk of public opinion decreases slowly with time, but the emergence of important events may still increase the risk of public opinion. The analysis results are in line with the actual situation and verify the effectiveness of the method. Comparative analysis indicates the improved method is proved to be superior and effective, sensitivity analysis confirms its stability. Finally, management suggestions was provided, this study contributes to the literature on public opinion risk assessment and provides implications for practice.

Genetic Profiles and Three-year Follow-up Study of Chinese Males With Congenital Hypogonadotropic Hypogonadism.

BACKGROUND: The correlation between long-term treatment outcomes with genotypes in congenital hypogonadotropic hypogonadism (CHH) males is rarely reported. AIM: To investigate the correlations among genotypes, phenotypes, and treatment outcomes for CHH male patients. METHODS: Whole exome sequencing was performed for 73 Chinese CHH males from one academic center. Patients self-selected one of the 4 treatments: pulsatile Gonadorelin pump (PGP), cyclical gonadotropins therapy (CGT), human menopausal gonadotropin monotherapy, or testosterone replacement treatment. Clinical assessments were performed every 3 months for 3 years. OUTCOMES: The pathogenicity of variants was determined. Baseline clinical features, spermatogenesis outcomes were analysed. RESULTS: 62 variants were identified in 51 patients (69.9%), 17 of which were novel. Among these mutations, variants on FGFR1, PROKR2, CHD7, ANOS1 and NSMF gene were 16.1%, 16.1%, 11.3%, 8.1% and 8.1% respectively. 11 patients followed the oligogenic pattern (21.6%). All CHD7 patients had hearing impairment or structural deformities of external/inner ear, and were diagnosed as CHARGE syndrome. 24.7% of CHH patients manifested with ear/hearing anomalies. KS patients had higher rates of cryptorchidism history and ear/hearing anomalies than normosmic CHH subjects. Male patients with PROKR2 mutations showed relatively better testicular development, less dental deformity when compared with FGFR1 mutations. About 30% normosmic patients defined by simple olfactory assessment showed olfactory nerve center (ONC) dysplasia under nasal sinus MRI examination. Among the CHH males treated with CGT or PGP, 70.2% reached spermatogenesis within 3 years of treatment. CLINICAL IMPLICATIONS: No direct correlation was observed between certain responsible genes and spermatogenic outcomes. When CHH patients were identified with CHD7 variants, ear/hearing evaluation should be carefully performed. The precise assessment of ONC development was advised for normosmic CHH subjects. STRENGTHS & LIMITATIONS: This study provided informative long-term treatment data of CHH male patients screened with whole exome sequencing. The limitations included small number of subgroups with multifaceted gene variants, clinical heterogeneity, and uncontrolled sperm-inducing treatment method. The seventeen novel mutations worth experimental validation in the future. CONCLUSION: The clinical severity is partially related with specific gene variants, and detailed individualized data and outcomes were provided. Ear/hearing anomalies were closely connected with CHD7 variants, and were common problems for CHH patients. Simple olfactory assessment underestimated the true olfactory deficit. L. Zhang, Y. Gao, Q. Du, et al. Genetic Profiles and Three-year Follow-up Study of Chinese Males With Congenital Hypogonadotropic Hypogonadism. J Sex Med 2021;18:1500-1510.

Association between uric acid lowering and renal function progression: a longitudinal study.

BACKGROUND: This study aimed to explore the association between uric acid lowering and renal function. MATERIALS AND METHODS: We conducted a population-based cohort study with 1,534 subjects for 4 years from 2012 to 2016. The population was divided into four groups according to the interquartile range of changes in serum uric acid with quartile 1 representing lower quarter. Renal function decline was defined as eGFR decreased more than 10% from baseline in 2016. Renal function improvement was defined as eGFR increased more than 10% from baseline in 2016. Cox regression analysis was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: In the adjusted Cox regression models, compared to quartile 4, quartile 1 (HR = 0.64, 95% CI [0.49-0.85]), quartile 2 (HR = 0.65, 95% CI [0.50-0.84]) and quartile 3 (HR = 0.75, 95% CI [0.58-0.96]) have reduced risk of renal function decline. An increasing hazard ratio of renal function improvement was shown in quartile 1 (HR = 2.27, 95% CI [1.45-3.57]) and quartile 2 (HR = 1.78, 95% CI [1.17-2.69]) compared with quartile 4. CONCLUSIONS: Uric acid lowering is associated with changes in renal function. The management of serum uric acid should receive attention in clinical practice and is supposed to be part of the treatment of chronic kidney disease.

Serum inhibin B for differentiating between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty: a systematic review and meta-analysis.

PURPOSE: The distinction between congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) in patients with delayed puberty is difficult to distinguish, but important for timely treatment. The aim of this study is to perform a systematic review and meta-analysis to determine the diagnostic performance of serum inhibin B (INHB) levels for differentiating CHH and CDGP. METHODS: PubMed, EMBASE, and Cochrane Library databases were systematically searched from the date of database inception to November 10, 2019 for studies examining the use of serum INHB to discriminate between CHH and CDGP. Pooled odds ratios (OR), sensitivity, specificity, and 95% confidence intervals (CI) were calculated. The Quality Assessment of Diagnostic Studies-2 (QUADAS-2) was used to assess the quality of the included studies. Sub-analyses were performed including that based on testicular volume (TV) and study design. RESULTS: Seven studies, comprising of 349 patients (96 CHH and 253 CDGP), were included in the meta-analysis. For differentiating between CHH and CDGP, INHB level exhibited good diagnostic accuracy with a pooled sensitivity of 92% (95% confidence interval [CI]: 0.86-0.96, I2 = 0.4%, p = 0.4343), specificity of 92% (95% CI: 0.88-0.94, I2 = 68.1%, p = 0.0009), and pooled area under the receiver operating characteristic curve (AUC) of 0.9619. The cut-off values of INHB for boys were 56, 66, 80, 96, 94.7, 111, and 113 pg/ml (assay method standardized to Gen II ELISA). Sub-analyses showed that testicular volume and study design could be a source of statistically significant heterogeneity in specificity. In boys with a testicular volume of ≤3 ml, INHB performed well with a sensitivity of 92%, specificity of 98%, and AUC of 0.9956. CONCLUSION: INHB exhibits excellent diagnostic efficiency in distinguishing CHH from CDGP, especially in boys with severe puberty deficiency (TV ≤ 3 ml).

Endothelial cell-derived small extracellular vesicles suppress cutaneous wound healing through regulating fibroblasts autophagy.

Diabetic foot ulcer is a life-threatening clinical problem in diabetic patients. Endothelial cell-derived small extracellular vesicles (sEVs) are important mediators of intercellular communication in the pathogenesis of several diseases. However, the exact mechanisms of wound healing mediated by endothelial cell-derived sEVs remain unclear. sEVs were isolated from human umbilical vein endothelial cells (HUVECs) pretreated with or without advanced glycation end products (AGEs). The roles of HUVEC-derived sEVs on the biological characteristics of skin fibroblasts were investigated both in vitro and in vivo We demonstrate that sEVs derived from AGEs-pretreated HUVECs (AGEs-sEVs) could inhibit collagen synthesis by activating autophagy of human skin fibroblasts. Additionally, treatment with AGEs-sEVs could delay the wound healing process in Sprague-Dawley (SD) rats. Further analysis indicated that miR-106b-5p was up-regulated in AGEs-sEVs and importantly, in exudate-derived sEVs from patients with diabetic foot ulcer. Consequently, sEV-mediated uptake of miR-106b-5p in recipient fibroblasts reduces expression of extracellular signal-regulated kinase 1/2 (ERK1/2), resulting in fibroblasts autophagy activation and subsequent collagen degradation. Collectively, our data demonstrate that miR-106b-5p could be enriched in AGEs-sEVs, then decreases collagen synthesis and delays cutaneous wound healing by triggering fibroblasts autophagy through reducing ERK1/2 expression.

Establishment of trimester-specific thyroid stimulating hormone and free thyroxine reference interval in pregnant Chinese women using the Beckman Coulter UniCel™ DxI 600.

BACKGROUND: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals are essential for screening and diagnosing thyroid dysfunction during pregnancy. The aim of this study was to establish method- and trimester-specific TSH and FT4 reference intervals in pregnant Chinese women using the Beckman Coulter UniCel™ DxI 600. METHODS: A cross-sectional dataset analysis was performed. A total of 3507 participants were recruited, and 2743 were eligible for analysis to set reference intervals. TSH, FT4, and thyroid peroxidase antibody (TPOAb) levels were analyzed with the Beckman Coulter UniCel™ DxI 600 Access® immunoassay system. Ranges between the 2.5th and 97.5th percentiles were defined as reference intervals for TSH and FT4. RESULTS: The calculated reference intervals for the first, second, and third trimesters were TSH: 0.06-3.13, 0.07-4.13 and 0.15-5.02 mIU/L, respectively, and FT4: 8.72-15.22, 7.10-13.55 and 6.16-12.03 pmol/L, respectively. CONCLUSIONS: Our reference intervals for TSH and FT4 are distinct from the ranges reported in the DxI 600 instruction manual and previously reported data, confirming the importance of method-specific reference intervals.