Fragmentation landscape of cell-free DNA revealed by deconvolutional analysis of end motifs.

Cell-free DNA (cfDNA) fragmentation is nonrandom, at least partially mediated by various DNA nucleases, forming characteristic cfDNA end motifs. However, there is a paucity of tools for deciphering the relative contributions of cfDNA cleavage patterns related to underlying fragmentation factors. In this study, through non-negative matrix factorization algorithm, we used 256 5' 4-mer end motifs to identify distinct types of cfDNA cleavage patterns, referred to as "founder" end-motif profiles (F-profiles). F-profiles were associated with different DNA nucleases based on whether such patterns were disrupted in nuclease-knockout mouse models. Contributions of individual F-profiles in a cfDNA sample could be determined by deconvolutional analysis. We analyzed 93 murine cfDNA samples of different nuclease-deficient mice and identified six types of F-profiles. F-profiles I, II, and III were linked to deoxyribonuclease 1 like 3 (DNASE1L3), deoxyribonuclease 1 (DNASE1), and DNA fragmentation factor subunit beta (DFFB), respectively. We revealed that 42.9% of plasma cfDNA molecules were attributed to DNASE1L3-mediated fragmentation, whereas 43.4% of urinary cfDNA molecules involved DNASE1-mediated fragmentation. We further demonstrated that the relative contributions of F-profiles were useful to inform pathological states, such as autoimmune disorders and cancer. Among the six F-profiles, the use of F-profile I could inform the human patients with systemic lupus erythematosus. F-profile VI could be used to detect individuals with hepatocellular carcinoma, with an area under the receiver operating characteristic curve of 0.97. F-profile VI was more prominent in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy. We proposed that this profile might be related to oxidative stress.

Epigenetic analysis of cell-free DNA by fragmentomic profiling.

Cell-free DNA (cfDNA) fragmentation patterns contain important molecular information linked to tissues of origin. We explored the possibility of using fragmentation patterns to predict cytosine-phosphate-guanine (CpG) methylation of cfDNA, obviating the use of bisulfite treatment and associated risks of DNA degradation. This study investigated the cfDNA cleavage profile surrounding a CpG (i.e., within an 11-nucleotide [nt] window) to analyze cfDNA methylation. The cfDNA cleavage proportion across positions within the window appeared nonrandom and exhibited correlation with methylation status. The mean cleavage proportion was ∼twofold higher at the cytosine of methylated CpGs than unmethylated ones in healthy controls. In contrast, the mean cleavage proportion rapidly decreased at the 1-nt position immediately preceding methylated CpGs. Such differential cleavages resulted in a characteristic change in relative presentations of CGN and NCG motifs at 5' ends, where N represented any nucleotide. CGN/NCG motif ratios were correlated with methylation levels at tissue-specific methylated CpGs (e.g., placenta or liver) (Pearson's absolute r > 0.86). cfDNA cleavage profiles were thus informative for cfDNA methylation and tissue-of-origin analyses. Using CG-containing end motifs, we achieved an area under a receiver operating characteristic curve (AUC) of 0.98 in differentiating patients with and without hepatocellular carcinoma and enhanced the positive predictive value of nasopharyngeal carcinoma screening (from 19.6 to 26.8%). Furthermore, we elucidated the feasibility of using cfDNA cleavage patterns to deduce CpG methylation at single CpG resolution using a deep learning algorithm and achieved an AUC of 0.93. FRAGmentomics-based Methylation Analysis (FRAGMA) presents many possibilities for noninvasive prenatal, cancer, and organ transplantation assessment.

Uptake of COVID-19 and influenza vaccines in relation to preexisting chronic conditions in the European countries.

BACKGROUND: The suboptimal uptake of COVID-19 and influenza vaccines among those with non-communicable chronic diseases is a public health concern, because it poses a higher risk of severe illness for individuals with underlying health conditions, emphasizing the need to address barriers to vaccination and ensure adequate protection for this vulnerable population. In the present study, we aimed to identify whether people with chronic illnesses are more likely to get vaccinated against COVID-19 and influenza in the European Union. METHODS: Cross-sectional data on 49,253 men (n = 20,569) and women (n = 28,684) were obtained from the ninth round of the Survey of Health, Ageing and Retirement in Europe (June - August, 2021). The outcome variables were self-reported COVID-19 and influenza vaccine uptake status. The association between the uptake of the vaccines and six preexisting conditions including high blood pressure, high blood cholesterol, chronic lung disease, diabetes, chronic bronchitis, and asthma was estimated using binary logistic regression methods. RESULTS: The vaccination coverage for COVID-19 ranged from close to 100% in Denmark (98.2%) and Malta (98.2%) to less than 50% in Bulgaria (19.1%) and Romania (32.7%). The countries with the highest percentage of participants with the influenza vaccine included Malta (66.7%), Spain (63.7%) and the Netherlands (62.5%), and those with the lowest percentage included Bulgaria (3.7%), Slovakia (5.8%) and Poland (9.2%). Participants with high blood pressure were 3% less likely [Risk difference (RD) = -0.03, 95% CI = -0.04, -0.03] to report taking COVID-19 and influenza [RD = -0.03, 95% CI= -0.04, -0.01] vaccine. Those with chronic lung disease were 4% less likely [RD = -0.04, 95% CI= -0.06, -0.03] to report taking COVID-19 and 2% less likely [RD= -0.02, 95% CI = -0.04, -0.01] to report taking influenza vaccine. Men and women with high blood pressure were 3% less likely to have reported taking both of the vaccines. CONCLUSIONS: Current findings indicate a suboptimal uptake of COVID-19 and influenza vaccines among adult men and women in the EU countries. Those with preexisting conditions, including high blood pressure and chronic lung disease are less likely to take the vaccines.

Cervical cancer screening aided by artificial intelligence, China.

Objective: To implement and evaluate a large-scale online cervical cancer screening programme in Hubei Province, China, supported by artificial intelligence and delivered by trained health workers. Methods: The screening programme, which started in 2017, used four types of health worker: sampling health workers, slide preparation technicians, diagnostic health workers and cytopathologists. Sampling health workers took samples from the women on site; slide preparation technicians prepared slides for liquid-based cytology; diagnostic health workers identified negative samples and classified positive samples based on the Bethesda System after cytological assessment using online artificial intelligence; and cytopathologists reviewed positive samples and signed reports of the results online. The programme used fully automated scanners, online artificial intelligence, an online screening management platform, and mobile telephone devices to provide screening services. We evaluated the sustainability, performance and cost of the programme. Results: From 2017 to 2021, 1 518 972 women in 16 cities in Hubei Province participated in the programme, of whom 1 474 788 (97.09%) had valid samples for the screening. Of the 86 648 women whose samples were positive, 30 486 required a biopsy but only 19 495 had one. The biopsy showed that 2785 women had precancerous lesions and 191 had invasive cancers. The cost of screening was 6.31 United States dollars (US$) per woman for the public payer: US$ 1.03 administrative costs and US$ 5.28 online screening costs. Conclusion: Cervical cancer screening using artificial intelligence in Hubei Province provided a low-cost, accessible and effective service, which will contribute to achieving universal cervical cancer screening coverage in China.

Opening KATP channels induces inflammatory tolerance and prevents chronic pain.

Current treatments for chronic pain are unsatisfactory, therefore, new therapeutics are urgently needed. Our previous study indicated that KATP channel openers have analgesic effects, but the underlying mechanism has not been elucidated. We speculated that KATP channel openers might increase suppressor of cytokine signaling (SOCS)-3 expression to induce inflammatory tolerance and attenuate chronic pain. Postoperative pain was induced by plantar incision to establish a chronic pain model. Growth arrest-specific 6 (Gas6)-/- and Axl-/- mice were used for signaling studies. The microglia cell line BV-2 was cultured for the in vitro experiments. The KATP channel opener significantly attenuated incision-induced mechanical allodynia in mice associated with the upregulated expression of SOCS3. Opening KATP channels induced the expression of SOCS3 in the Gas6/Axl signaling pathway in microglia, inhibited incision-induced mechanical allodynia by activating the Gas6/Axl-SOCS3 signaling pathway, and induced inflammatory tolerance to relieve neuroinflammation and postoperative pain. We demonstrated that opening of the KATP channel opening activated Gas6/Axl/SOCS3 signaling to induce inflammatory tolerance and relieve chronic pain. We explored a new target for anti-inflammatory and analgesic effects by regulating the innate immune system and provided a theoretical basis for clinical preemptive analgesia.

Platelet-rich Plasma Improves Radiotherapy-induced Emotional Disorder and Cognitive Dysfunction, Neuroinflammation in Aged Rats by Inhibiting the Activation of NLRP3 Inflammasomes.

Although radiotherapy (RT) is the preferred treatment for elderly patients with brain tumors, certain negative effects can't be ignored. Fortunately, platelet-rich plasma (PRP) presents with a promising potential for the treatment of neurological diseases. Therefore, this study aimed to explore the effect of PRP on neuroinflammation, emotional disorder and cognitive dysfunction induced by RT in aged rats. Firstly, whole brain RT (WBRT) model was established by whole brain irradiation with 10 Gy of 6-MeV electron beam in rats. Next, twenty 20-month-old female SD rats were divided into four groups (sham group, PRP group, WBRT group, and WBRT + PRP group) according different treatments. After that, the cognitive dysfunction and depression-like behavior of rats were examined by novel object recognition test (NORT), Morris water maze test (MWM), open field test (OFT) and elevated plus maze test (EPM). Besides, immunohistochemistry was used to detect the expression of microglial marker protein Iba-1 in rat hippocampus; enzyme linked immunosorbent assay (ELISA) to examine the levels of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 beta (IL-1ß), IL-18, and monocyte chemoattractant protein 1 (MCP-1) in rat hippocampus; real-time quantitative reverse transcription PCR (qRT-PCR) and western blot to measure the levels of neurotrophic factors brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B receptor (TrkB), and nerve growth factor (NGF) in rat hippocampus; and western blot also to observe the protein expression levels of NOD-like receptor protein 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), and IL-1ß in rat hippocampus. After experiments, some results obtained were shown as follows. PRP could significantly improve learning and memory ability and depression-like behavior, increase the level of neurotrophic factors, inhibit the activation of microglia and decrease the level of pro-inflammatory factors in WBRT rats. In addition, PRP significantly inhibited the activation of NLRP3 inflammasomes. To sum up, PRP can ameliorate neuroinflammation, emotional disorder and cognitive dysfunction induced by RT in aged rats, and the mechanism may be related to its inhibitory effect on NLRP3 inflammasome activation.

Identification and characterization of extrachromosomal circular DNA in maternal plasma.

We explored the presence of extrachromosomal circular DNA (eccDNA) in the plasma of pregnant women. Through sequencing following either restriction enzyme or Tn5 transposase treatment, we identified eccDNA molecules in the plasma of pregnant women. These eccDNA molecules showed bimodal size distributions peaking at ∼202 and ∼338 bp with distinct 10-bp periodicity observed throughout the size ranges within both peaks, suggestive of their nucleosomal origin. Also, the predominance of the 338-bp peak of eccDNA indicated that eccDNA had a larger size distribution than linear DNA in human plasma. Moreover, eccDNA of fetal origin were shorter than the maternal eccDNA. Genomic annotation of the overall population of eccDNA molecules revealed a preference of these molecules to be generated from 5'-untranslated regions (5'-UTRs), exonic regions, and CpG island regions. Two sets of trinucleotide repeat motifs flanking the junctional sites of eccDNA supported multiple possible models for eccDNA generation. This work highlights the topologic analysis of plasma DNA, which is an emerging direction for circulating nucleic acid research and applications.

Pachymic acid ameliorates bleomycin-induced pulmonary fibrosis through inhibiting endoplasmic reticulum stress in rats.

The effect of pachymic acid (PA) on pulmonary fibrosis in rats was expected to be investigated in this study. Firstly, bleomycin (BLM) was used to establish pulmonary fibrosis rat model, then PA (10, 20, or 40 mg/kg) was intragastrically administered to the rats for 14 days. Subsequently, a variety of tests was performed to observe changes in sample tissues after different treatments. Briefly, the degree of pulmonary edema in rats was assessed through dry/wet weight ratio. Hematoxylin and eosin (H&E) staining and Masson's trichrome staining were used to observe the pathological injury and fibrosis of lung tissue. Biochemical kits were applied to measure the levels of hydroxyproline (Hyp), transforming growth factor beta-1 (TGFß-1), malondialdehyde (MDA), reactive oxygen species (ROS), and adenosine triphosphate (ATP) and the activities of superoxide dismutase (SOD) and catalase (CAT) in rat lung tissues of each group. The mitochondrial DNA (mtDNA) copy number in rat lung tissue was tested using qRT-PCR. Additionally, the western blot was employed to detect the expression levels of pulmonary fibrosis-related proteins and endoplasmic reticulum (ER) stress-related proteins in each group of rat lung tissue. By virtue of experimental verification above, PA was discovered to alleviate BLM-induced pulmonary edema, pulmonary fibrosis and histopathological damage. On the one hand, PA treatment decreased Hyp and TGF-ß1 levels and down-regulated pulmonary fibrosis-related protein expression [collagen I, α-smooth muscle actin (α-SMA), and fibronectin] in the lung tissue of BLM rats. On the other hand, it significantly increased the levels of SOD, CAT and ATP while decreased the activities of MDA and ROS in BLM rat lung tissues. In addition, the expression levels of ER stress-related proteins [glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), Caspase 9, and activating transcription factor 4 (ATF4)] were significantly down-regulated in the lung tissue of BLM rats after PA treatment. Collectively, PA may ameliorate BLM-induced pulmonary fibrosis and histopathological damage in rats through inhibiting ER stress and improving mitochondrial function.

AMPK-autophagy-mediated inhibition of microRNA-30a-5p alleviates morphine tolerance via SOCS3-dependent neuroinflammation suppression.

BACKGROUND: The development of morphine tolerance is a clinical challenge for managing severe pain. Studies have shown that neuroinflammation is a critical aspect for the development of analgesic tolerance. We found that AMPK-autophagy activation could suppress neuroinflammation and improve morphine tolerance via the upregulation of suppressor of cytokine signaling 3 (SOCS3) by inhibiting the processing and maturation of microRNA-30a-5p. METHODS: CD-1 mice were utilized for the tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 was utilized to investigate the mechanism of AMPK-autophagy-mediated posttranscriptional regulation of SOCS3. Proinflammatory cytokines were measured by western blotting and real-time PCR. The levels of SOCS3 and miRNA-processing enzymes were evaluated by western blotting, real-time PCR and immunofluorescence staining. RESULTS: Based on experimental verification, miRNA-30a-5p could negatively regulate SOCS3. The AMPK activators AICAR, resveratrol and metformin downregulated miRNA-30a-5p. We found that AMPK activators specifically inhibited the processing and maturation of miRNA-30a-5p in microglia by degrading DICER and AGO2 via autophagy. Furthermore, a miRNA-30a-5p inhibitor significantly improved morphine tolerance via upregulation of SCOS3 in mice. It markedly increased the level of SOCS3 in the spinal cord of mice and subsequently inhibited morphine-induced phosphorylation of NF-κB p65. In addition, a miRNA-30a-5p inhibitor decreased the levels of IL-1ß and TNF-α caused by morphine in microglia. CONCLUSION: AMPK-autophagy activation suppresses neuroinflammation and improves morphine tolerance via the upregulation of SOCS3 by inhibiting miRNA-30a-5p.

The occurrence of COVID-19 is associated with air quality and relative humidity.

The association between meteorological factors and COVID-19 is important for the prevention and control of COVID-19. However, similar studies are relatively rare in China. This study aims to investigate the association between COVID-19 and meteorological factors, such as average temperature, relative humidity, and air quality index (AQI), and average wind speed. We collected the daily confirmed cases of COVID-19 and meteorological factors in Shanghai China from January 10, 2020 to March 31, 2020. A generalized additive model was fitted to quantify the associations between meteorological factors and COVID-19 during the study period. A negative association between average temperature and daily confirmed cases of COVID-19 was found on lag 13 days. In addition, we observed a significant positive correlation between meteorological factors (AQI, relative humidity) and daily confirmed cases of COVID-19. A 10 increase in AQI (lag1/7/8/9/10 days) was correlated with a 4.2%-9.0% increase in the daily confirmed cases of COVID-19. A 1% increase in relative humidity (lag1/4/7/8/9/10 days) was correlated with 1.7%-3.7% increase in the daily confirmed cases of COVID-19. However, the associations between average wind speed and the daily confirmed cases of COVID-19 is complex in different lag days. In summary, meteorological factors could affect the occurrence of COVID-19. Reducing the effects of meteorological factors on COVID-19 may be an important public health action for the prevention and control of COVID-19.

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers.

Hippo-YAP signaling pathway functions in early lineage differentiation of pluripotent stem cells, but the detailed mechanisms remain elusive. We found that knockout (KO) of Mst1 and Mst2, two key components of the Hippo signaling in mouse embryonic stem cells (ESCs), resulted in a disruption of differentiation into mesendoderm lineage. To further uncover the underlying regulatory mechanisms, we performed a series of ChIP-seq experiments with antibodies against YAP, ESC master transcription factors and some characterized histone modification markers as well as RNA-seq assays using wild type and Mst KO samples at ES and day 4 embryoid body stage respectively. We demonstrate that YAP is preferentially co-localized with super-enhancer (SE) markers such as Nanog, Sox2, Oct4 and H3K27ac in ESCs. The hyper-activation of nuclear YAP in Mst KO ESCs facilitates the binding of Nanog, Sox2 and Oct4 as well as H3K27ac modification at the loci where YAP binds. Moreover, Mst depletion results in novel SE formation and enhanced liquid-liquid phase-separated Med1 condensates on lineage associated genes, leading to the upregulation of these genes and the distortion of ESC differentiation. Our study reveals a novel mechanism on how Hippo-YAP signaling pathway dictates ESC lineage differentiation.

Capturing the interactome of newly transcribed RNA.

We combine the labeling of newly transcribed RNAs with 5-ethynyluridine with the characterization of bound proteins. This approach, named capture of the newly transcribed RNA interactome using click chemistry (RICK), systematically captures proteins bound to a wide range of RNAs, including nascent RNAs and traditionally neglected nonpolyadenylated RNAs. RICK has identified mitotic regulators amongst other novel RNA-binding proteins with preferential affinity for nonpolyadenylated RNAs, revealed a link between metabolic enzymes/factors and nascent RNAs, and expanded the known RNA-bound proteome of mouse embryonic stem cells. RICK will facilitate an in-depth interrogation of the total RNA-bound proteome in different cells and systems.

Characteristics of Fetal Extrachromosomal Circular DNA in Maternal Plasma: Methylation Status and Clearance.

BACKGROUND: Although the characterization of cell-free extrachromosomal circular DNA (eccDNA) has gained much research interest, the methylation status of these molecules is yet to be elucidated. We set out to compare the methylation densities of plasma eccDNA of maternal and fetal origins, and between small and large molecules. The clearance of fetal eccDNA from maternal circulation was also investigated. METHODS: We developed a sequencing protocol for eccDNA methylation analysis using tagmentation and enzymatic conversion approaches. A restriction enzyme-based approach was applied to verify the tagmentation results. The efficiency of cell-free fetal eccDNA clearance was investigated by fetal eccDNA fraction evaluations at various postpartum time points. RESULTS: The methylation densities of fetal eccDNA (median: 56.3%; range: 40.5-67.6%) were lower than the maternal eccDNA (median: 66.7%; range: 56.5-75.7%) (P = 0.02, paired t-test). In addition, eccDNA molecules from the smaller peak cluster (180-230 bp) were of lower methylation levels than those from the larger peak cluster (300-450 bp). Both of these findings were confirmed using the restriction enzyme approach. We also observed comparable methylation densities between linear and eccDNA of both maternal and fetal origins. The average half-lives of fetal linear and eccDNA in the maternal blood were 30.2 and 29.7 min, respectively. CONCLUSIONS: We found that fetal eccDNA in plasma was relatively hypomethylated compared to the maternal eccDNA. The methylation densities of eccDNA were positively correlated with their sizes. In addition, fetal eccDNA was found to be rapidly cleared from the maternal blood after delivery, similar to fetal linear DNA.

Single Cell and Plasma RNA Sequencing for RNA Liquid Biopsy for Hepatocellular Carcinoma.

BACKGROUND: Human plasma contains RNA transcripts released by multiple cell types within the body. Single-cell transcriptomic analysis allows the cellular origin of circulating RNA molecules to be elucidated at high resolution and has been successfully utilized in the pregnancy context. We explored the application of a similar approach to develop plasma RNA markers for cancer detection. METHODS: Single-cell RNA sequencing was performed to decipher transcriptomic profiles of single cells from hepatocellular carcinoma (HCC) samples. Cell-type-specific transcripts were identified and used for deducing the cell-type-specific gene signature (CELSIG) scores of plasma RNA from patients with and without HCC. RESULTS: Six major cell clusters were identified, including hepatocyte-like, cholangiocyte-like, myofibroblast, endothelial, lymphoid, and myeloid cell clusters based on 4 HCC tumor tissues as well as their paired adjacent nontumoral tissues. The CELSIG score of hepatocyte-like cells was significantly increased in preoperative plasma RNA samples of patients with HCC (n = 14) compared with non-HCC participants (n = 49). The CELSIG score of hepatocyte-like cells declined in plasma RNA samples of patients with HCC within 3 days after tumor resection. Compared with the discriminating power between patients with and without HCC using the abundance of ALB transcript in plasma [area under curve (AUC) 0.72)], an improved performance (AUC: 0.84) was observed using the CELSIG score. The hepatocyte-specific transcript markers in plasma RNA were further validated by ddPCR assays. The CELSIG scores of hepatocyte-like cell and cholangiocyte trended with patients' survival. CONCLUSIONS: The combination of single-cell transcriptomic analysis and plasma RNA sequencing represents an approach for the development of new noninvasive cancer markers.

Targeted Delivery of CXCL9 and OX40L by Mesenchymal Stem Cells Elicits Potent Antitumor Immunity.

Major obstacles in immunotherapies include toxicities associated with systemic administration of therapeutic agents, as well as low tumor lymphocyte infiltration that hampers the efficacies. In this study, we report a mesenchymal stem cell (MSC)-based immunotherapeutic strategy in which MSCs specifically deliver T/natural killer (NK) cell-targeting chemokine CXCL9 and immunostimulatory factor OX40 ligand (OX40L)/tumor necrosis factor superfamily member 4 (TNFSF4) to tumor sites in syngeneic subcutaneous and azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced spontaneous colon cancer mouse models. This approach generated potent local antitumor immunity by increasing the ratios of tumor-infiltrating CD8+ T and NK cells and production of antitumor cytokines and cytolytic proteins in the tumor microenvironment. Moreover, it improved the efficacy of programmed death-1 (PD-1) blockade in a syngeneic mouse model and significantly suppressed the growth of major histocompatibility complex class I (MHC class I)-deficient tumors. Our MSC-based immunotherapeutic strategy simultaneously recruits and activates immune effector cells at the tumor site, thus overcoming the problems with toxicities of systemic therapeutic agents and low lymphocyte infiltration of solid tumors.

Sequencing Analysis of Plasma Epstein-Barr Virus DNA Reveals Nasopharyngeal Carcinoma-Associated Single Nucleotide Variant Profiles.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. Plasma EBV DNA is a validated screening tool for NPC. In screening, there are some individuals who do not have NPC but carry EBV DNA in plasma. Currently it is not known from screening if there may be any genotypic differences in EBV isolates from NPC and non-NPC subjects. Also, low concentrations of EBV DNA in plasma could pose challenge to such EBV genotypic analysis through plasma DNA sequencing. METHODS: In a training dataset comprised of plasma DNA sequencing data of NPC and non-NPC subjects, we studied the difference in the EBV single nucleotide variant (SNV) profiles between the two groups. The most differentiating SNVs across the EBV genome were identified. We proposed an NPC risk score to be derived from the genotypic patterns over these SNV sites. We subsequently analyzed the NPC risk scores in a testing set. RESULTS: A total of 661 significant SNVs across the EBV genome were identified from the training set. In the testing set, NPC plasma samples were shown to have high NPC risk scores, which suggested the presence of NPC-associated EBV SNV profiles. Among the non-NPC samples, there was a wide range of NPC risk scores. These results support the presence of diverse SNV profiles of EBV isolates from non-NPC subjects. CONCLUSION: EBV genotypic analysis is feasible through plasma DNA sequencing. The NPC risk score may be used to inform the cancer risk based on the EBV genome-wide SNV profile.

The combination of symphysis-fundal height and abdominal circumference as a novel predictor of macrosomia in GDM and normal pregnancy.

BACKGROUND: Macrosomia is a major adverse pregnancy outcome of gestational diabetes mellitus (GDM). Although BMI, symphysis-fundal height (SFH) and abdominal circumference (AC) are associated with foetal weight, there are some limitations to their use, especially for the prediction of macrosomia. This study aimed to identify a novel predictive methodology to improve the prediction of high-risk macrosomia. METHODS: Clinical information was collected from 3730 patients. The association between the ISFHAC (index of the SFH algorithm multiplied by the square of AC) and foetal weight was determined and validated. A new index, the ISFHAC, was evaluated by area under the curve (AUC) analysis. RESULTS: A total of 1087 GDM and 657 normal singleton pregnancies were analysed. The ISFHAC was positively correlated with foetal weight in GDM pregnancies and normal pregnancies (NPs). The AUCs of the ISFHAC were 0.815 in the GDM group and 0.804 in the NP group, which were higher than those of BMI, SFH, AC and GA. The ISFHAC cut-off points were 41.7 and 37 in the GDM and NP groups, respectively. The sensitivity values for the prediction of macrosomia with high ISFHAC values were 75.9 and 81.3% in the GDM and NP groups, respectively, which were higher than those with BMI. Regarding the validation data, the sensitivity values for prediction with high ISFHAC values were 78.9% (559 GDM pregnancies) and 78.3% (1427 NPs). CONCLUSIONS: The ISFHAC can be regarded as a new predictor of and risk factor for macrosomia in GDM pregnancy and NP.

The migrating mediators and the interaction associated with the use of essential public health services: a cross-sectional study in Chinese older migrants.

BACKGROUND: Despite the incremental implementation of the essential public health services (EPHS) during the last decade, the goal of EPHS's equalization is impossible to cannot be achieved without appropriate policies targeting older migrants. Therefore, this study aims to examine whether the supply side meets the needs of older migrants and to explore the relationships among health status, the use of health services, and diverse factors. METHODS: The data were derived from a national cross-sectional dataset (N = 11,161) of the 2015 Chinese Migrant Dynamic Monitoring Survey. Mediating effects analysis and moderating effects analysis were conducted to explore the interactions between physical status and the use of EPHS in older migrants such as physical examination, health record, and follow-up services. RESULTS: The use of physical examination, health record, and follow-up services were correlated with each other. Household income, migrating for employment, and migrating for offspring were negatively associated with the use of EPHS. A positive association was observed between the use of EPHS and willingness for long-stay. The mediating effects of household income, migrating for employment, migrating for offspring, and willingness for long-stay were observed on the relationship between physical status and the use of EPHS. The moderating effects of household income and migrating for employment were discovered. CONCLUSION: Public health policies that may be worthy of consideration include further enhancing the delivery capacity of primary health institutions, integrating professional clinical resources into the primary health system, and launching the target policies to improve the accessibility of EPHS in older migrants.

Investigation of Leptin G19A polymorphism with bladder cancer risk: A case-control study.

BACKGROUND: A host of studies show Leptin (LEP) G19A polymorphism is correlated with the risk of various cancers, but the connection of this polymorphism with bladder cancer (BC) risk has not been reported. MATERIALS AND METHODS: This association was in explored in a case-control study involving 355 BC cases and 435 controls (all Chinese Han). Polymerase chain reaction-restriction fragment length polymorphism was conducted to genotype LEP G19A polymorphism. Analyses of allele and genotype distribution were evaluated using chi-square test. Continuous data were assessed by an independent samples t test or one-way ANOVA test. Odds ratio (OR) and 95% confidence interval (CI) were determined by logistic regression. RESULTS: LEP G19A polymorphism was significantly associated with a lower risk of BC (AA vs GG: adjusted OR, 0.40, 95% CI, 0.20-0.83, P = .013; AA + GA vs GG: adjusted OR, 0.70, 95% CI, 0.52-0.93, P = .015; AA vs GA + GG: adjusted OR, 0.45, 95% CI, 0.22-0.91, P = .026). In addition, A allele was associated with decreased risk for BC (A vs G: OR, 0.70, 95% CI, 0.55-0.89, P = .003). Stratified analyses by females, non-drinkers, and non-smokers all returned considerable relations. Furthermore, LEP G19A polymorphism was correlated with tumor size, tumor node metastasis, and distant metastasis in BC patients. CONCLUSIONS: LEP G19A polymorphism is associated with a less risk of BC.

Sociodemographic characteristics associated with the utilization of maternal health services in Cambodia.

BACKGROUND: Cambodia is a Southeast Asian country and has one the highest rates of maternal and child mortality with inadequate use of maternal healthcare services in the region. The present study aimed to analyse the progress made in terms of using maternal healthcare services since 2000. METHODS: Two rounds of Demographic and Health Surveys (DHS 2000 and DHS 2014) were used in the study. Sample population consisted 11,961 women aged between 15 and 49 years. The outcome measures were: Timing of first antenatal care (ANC) attendance, adequacy of ANC attendance, place of delivery and postnatal checkup. WHO guidelines were used to set the cut-off/define these measures. Data were analyzed in Stata version 14 using descriptive and multivariate regression analyses. RESULTS: Findings indicated that the overall prevalence of making the first ANC visit in the first trimester was 64.19% [95%CI = 62.22,66.11], and that of having at least four ANC visits was 43.80% [95%CI = 41.89,45.73]. Prevalence of health facility delivery was 48.76% [46.62,50.90] and that of postnatal checkup was 71.14% [95%CI = 69.21,73.01]. Between 2000 and 2014, the percentage of timely and adequate use of ANC increased by respectively 61.8 and 65.3%, while that of health facility delivery and postnatal care increased by respectively 74.5 and 43.9%. Important demographic, socioeconomic and geographic disparities were observed in the utilization of ANC, health facility delivery and postnatal care services. Urban residency, having better educational status, white collar job, access to electronic media showed positive association, whereas higher parity (having > 2 children) and unwanted pregnancy showed negative association with the use of maternal healthcare services. Having at least four ANC visits was associated with significantly increased higher odds of using health facility delivery and postnatal care. CONCLUSION: There has a been a remarkable increase in the prevalence of women who are using the maternal healthcare services since 2000. The current findings provide important insights regarding the sociodemographic factors associated with the utilization of maternal health services in Cambodia that could contribute to evidence-based health policy making and designing intervention programs.