[Application of target trail emulation in real world: a case study of effect of statins on mortality in diabetes patients].

Target trail emulation is an observational research method, which can use real-world data (such as observational data and historical data) to carry out research design according to the design principles of randomized controlled trials (RCT) when RCT cannot be carried out. The intervention group and the control group were classified by simulating random grouping. Finally a high-reliable conclusion similar to RCT can be obtained. This paper summarizes the basic concepts and application process of target trail emulation based on the effect of statins on the prognosis of myocardial infarction in diabetic patients to provide reference for the application of this method in real world.

[Application of LASSO and its extended method in variable selection of regression analysis].

Multicollinearity is an important issue affecting the results of regression analysis. LASSO developed in recent years has great advantages in selecting explanatory variables, processing high-dimensional data, and solving multicollinearity problems. This method adds a penalty term to the model estimation, which can compress the regression coefficients of some unnecessary variables to zero and then remove them from the model to achieve the purpose of variable screening. This paper focuses on the LASSO method and compares it with optimal subsets, ridge regression, adaptive LASSO, and elastic net results. It is found that both LASSO and adaptive LASSO have good performance in solving independent variable multicollinearity problems and enhancing model interpretation and prediction accuracy.

Body mass index increases the recurrence risk of breast cancer: a dose-response meta-analysis from 21 prospective cohort studies.

OBJECTIVE: The purpose of this study was to investigate the effect of body mass index (BMI) on the recurrence risk of breast cancer. STUDY DESIGN: Dose-response meta-analysis. METHODS: Cohort studies that included BMI and the recurrence of breast cancer were selected through various databases including PubMed, Web of Science, the China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals (VIP), and Wanfang Data Knowledge Service Platform (WanFang) until November 30, 2021. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of literature. A two-stage random-effects meta-analysis was performed to assess the dose-response relationship between BMI and breast cancer recurrence risk. Heterogeneity between studies is assessed using I2. RESULTS: The relative risk (RR) of BMI <25 kg/m2 vs BMI ≥25 kg/m2, BMI <30 kg/m2 vs BMI ≥30 kg/m2 were 1.09 (95% CI: 1.00-1.19) and 1.15 (95% CI: 1.04-1.27), suggesting that BMI had a significant effect on the recurrence risk of breast cancer, and there might be a dose-response relationship between them. A total of 21 studies were included in dose-response meta-analysis, which showed that there was a positive linear correlation between BMI and the risk of recurrence (RR = 1.02, 95% CI: 1.01-1.03). For every 1 kg/m2 increment of BMI, the risk of recurrence increased by approximately 2%. In subgroup analyses, positive linear dose-response relationships between BMI and recurrence risk were observed among Asian and study period >10 years groups. For every 1 kg/m2 increment of BMI, the risk of recurrence increased by 3.41% and 1.87%, respectively. CONCLUSIONS: The recurrence risk of breast cancer increases with BMI, which is most obvious among Asian women.

[Application of regression discontinuity design in epidemiological research].

Regression discontinuity design (RDD) is a rigorous quasi-experimental method. Based on the randomness of the distribution of samples around the critical value, the data on both sides are used for regression respectively, so as to avoid the interference of potential confounding factors and provide strong evidence for the inference of causal correlation. This study introduces the RDD and its research progress, and expounds its application in detail combined with cases, in order to provide reference for the application of RDD in epidemiological research.

Spatiotemporal changes of CT manifestations in 110 patients with COVID-19 pneumonia.

OBJECTIVE: The aim of the study was to analyze spatiotemporal changes of CT manifestations in patients with COVID-19 pneumonia. PATIENTS AND METHODS: In this retrospective review, 110 patients with confirmed COVID-19 by RT-PCR form February 16, 2020, to March 28, 2020 were included. A total of 449 CT scans were reviewed. We analyze the type and distribution of lung abnormalities, and CT general assessment and lesion area statistics were performed. Patients were divided into mild, moderate, and severe disease based on Chinese guidelines: mild (patients with minimal symptoms, CT scans showed no pneumonia or a small area of pneumonia infection), moderate (different extent of clinical manifestations and CT scans showed multiple pneumonia infections in both lungs), severe disease (respiratory distress, CT scans lesion area exceeds 50%, and the lesion contains consolidation). The proportion of patients with mild, moderate and severe diseases was counted. RESULTS: The CT score and the area involved reached a peak (median 10) on illness days 7-12, and then, continued to be at a high level. The main abnormal pattern after symptoms appeared GGO (36/94 [36%] to 40/65 [62%] in different periods). The proportion of mixed reached its peak on illness days 13-18 (36/93 [39%]). Pure GGO was the most common subtype of GGO (24 of 60 CT scans [40%] to 23 of 33 CT scans [70%]) after symptoms onset. The ratio of GGO with irregular lines and interfaces peaked on illness days 7-12 (6/34 [18%]). The lesions are mainly distributed on both sides and under the pleura. 76/84 (90%) of discharged patients had residual lesions on the final CT scans. 4 confirmed patients' CT scans did not show lesions (on illness days 1-24 days). There were 47 mild cases (42.7%), 46 moderate cases (41.8%), and 7 severe cases (6.3%). CONCLUSIONS: The degree of lung abnormality on the CT of the patients reached the peak on the 7th to 12th days of the disease. CT performance changes with time have a certain regularity, which may indicate the progress and recovery of the disease. 90% of patients still observed residual lung abnormalities in CT images at the time of discharge. There were 4 confirmed cases where the CT images did not show the lesion; hence, CT cannot be used as a basis for judging COVID-19 as a single tool.

[Visualization of transcriptome data].

As an important method to study the phenotype and function of organisms, transcriptome has become one of hot topics in current research. The transcriptomics research usually accompanies with massive data. With the increase of the amount of data, the rules and features hidden in it are not easy to be found. Transforming big data into visual graphics is the most undoubtedly intuitive way to display the hidden information of big data. Several graphs commonly used in transcriptome study were introduced in this paper, such as Venn diagram, heat map, principal component analysis scatter plot, enrichment analysis plot, and time series analysis plot, in order to help readers to choose suitable graphics in future studies.

[Visualization of frequency distribution].

Statistical graph, as a useful tool of data visualization, plays a crucial role in the statistical description. This paper mainly introduces several common statistical charts, their characteristics, practical examples and so on for frequency distribution, including qualitative variable and quantitative variable, in order to provide application reference for readers.

Body mass index cut-off points for predicting chronic non-communicable disease should differ by gender and age group.

OBJECTIVES: The objective of this study to determine whether body mass index (BMI) in different genders and age groups need different thresholds when predicting chronic non-communicable diseases (CNCDs). STUDY DESIGN: This is a cross-sectional study. METHODS: Data were obtained from the China Health and Nutrition Survey conducted in 2009. Sequential sample cluster analysis was used to group age according to BMI. Propensity score matching was used to eliminate the influence of age. Receiver operating characteristic curve based on gender and age group was used to evaluate the cut-off values and efficiency of BMI in each group. RESULTS: A total of 8469 individuals were enrolled in this study. Results of sequential sample cluster analyses showed age was divided into three groups: 18-39, 40-59 and 60-99 years. There were significant differences in the distribution of BMI among the three groups for both males and females (P < 0.001). Statistical differences were observed in the distribution of BMI between genders in the 18-39- and 60-99-year-old age groups (P < 0.001). For men, the cut-off values of BMI were ≥25 kg/m2, ≥24 kg/m2 and ≥23 kg/m2 in the 18-39, 40-59 and 60-99 years old groups, respectively; for women, the corresponding cut-off points were ≥25 kg/m2, ≥23 kg/m2 and ≥25 kg/m2 in groups. CONCLUSIONS: The thresholds for BMI might be different between gender and age group. In addition, it might not be suitable to determine cut-off values of BMI to predict CNCDs for people aged ≥60 years.

[Using the sequenced sample cluster analysis to study the body mass index distribution characteristics of adults in different age groups and genders].

Objective: To explore the characteristics of distribution on Chinese adult body mass index (BMI) in different age groups and genders and to provide reference related to obesity and related chronic diseases. Methods: Data from the China Health and Nutrition Survey in 2009 were used. Sequential sample cluster method was used to analyze the characteristics of BMI distribution in different age groups and genders by SAS. Results: Our results showed that the adult BMI in China should be divided into 3 groups according to their age, as 20 to 40 years old, 40 to 65 years old, and> 65 years old, in females or in total when grouped by difference of 5 years. For groupings in male, the three groups should be as 20 to 40, 40 to 60 years old and>60 years old. There were differences on distribution between the male and female groups. When grouped by difference of 10 years, all of the clusters for male, female and total groups as 20-40, 40-60 and>60 years old, became similar for the three classes, respectively, with no differences of distribution between gender, suggesting that the 5-years grouping was more accurate than the 10-years one, and BMI showing gender differences. Conclusions: BMI of the Chinese adults should be divided into 3 categories according to the characteristics of their age. Our results showed that BMI was increasing with age in youths and adolescents, remained unchanged in the middle-aged but decreasing in the elderly.

Radial forearm flaps with venous compromise: correlations between salvage techniques and their rates of success.

We retrospectively analysed the reliability of anastomosis of the deep venous system as a salvage technique for a free radial forearm flap that has developed venous compromise. The primary predictors were the salvage techniques, which comprised anastomosis of the deep venous system and a repeat of the original anastomosis, and the primary outcome measure was the rate of success. The potential confounders included original venous outflow, the original causes of the venous compromise, and the number of venous anastomoses. The chi squared test, Fisher's exact test, and the Cochran-Mantel-Haenszel test were used for statistical analysis as appropriate. The final sample comprised 42 patients who required re-exploration for venous compromise. The salvage rates were 15/18 when anastomosis of the deep venous system was chosen as a salvage technique and 9/24 and when the original anastomosis was done again (p=0.003, OR 2.222, 95% CI 1.274 to 3.876). The salvage rate of venous compromise was higher in patients who had anastomoses of the deep venous system than in those in whom the original anastomosis was repeated.

Trends of Activities of Daily Living Disability Situation and Association with Chronic Conditions among Elderly Aged 80 Years and Over in China.

OBJECTIVES: In China, few studies reported the disability situation and the association between disabilities with chronic conditions in aged people. This study investigates the cross-sectional trends of prevalence and severity of activities of daily living disability (ADL) in Chinese oldest-old people from 1998 to 2008, and identified the potential risk factors of disability. DESIGN: A combination of population-based longitudinal prospective study and probabilistically sampling cross-sectional studies. SETTING: The Chinese Longitudinal Healthy Longevity Survey (CLHLS) was based on a random sampling of aged people from twenty-two provinces in China. PARTICIPANTS: A total of 52,667 participants aged from 80 years old to 105 years old sampled in the year of 1998 (n=8,768), 2000 (n=10,940), 2002 (n=10,905), 2005 (n=10,396) and 2008 (n=11,658) were analyzed respectively. RESULTS: The prevalence of ADL disability decreased from the year of 1998 (18%) to 2008 (12%). The disability prevalence significantly increased in 2002 and decreased in 2008 (P<0.001) in total participants than the year of 1998. The prevalence trends of low ADL disability level were almost identical with that of the total ADL disability. Stroke/cerebrovascular disease (CVD) and cognitive impairment were the strongest risk factors of disability. Vision impairment became less associated with ADL disability (P=0.045), while the association between multimorbidity and ADL disability became stronger (P=0.033). CONCLUSIONS: The prevalence of ADL disability declined among the oldest-old population in China from the year of 1998 to 2008 without obeying a linear pattern. Temporal trends of ADL disability mainly attributed to the change of low disability level prevalence. Stroke/CVD and cognitive impairment were the most common risk factors of disability. Vision impairment caused disability has become less common, while risks of multimorbidity related disability increased.

Corrigendum: Hemorrhagic Fever with Renal Syndrome: Pathogenesis and Clinical Picture.

[This corrects the article on p. 1 in vol. 6, PMID: 26870699.].

Hemorrhagic Fever with Renal Syndrome: Pathogenesis and Clinical Picture.

Hantaan virus (HTNV) causes hemorrhagic fever with renal syndrome (HFRS), which is a zoonosis endemic in eastern Asia, especially in China. The reservoir host of HTNV is field mouse (Apodemus agraricus). The main manifestation of HFRS, including acute kidney injury, increases vascular permeability, and coagulation abnormalities. In this paper, we review the current knowledge of the pathogenesis of HFRS including virus factor, immunity factor and host genetic factors. Furthermore, the treatment and prevention will be discussed.

A Phase I, Single Ascending Dose Study of Cimaglermin Alfa (Neuregulin 1ß3) in Patients With Systolic Dysfunction and Heart Failure.

A first-in-human, phase 1, double blind, placebo-controlled, single ascending dose study examined the safety, tolerability, and exploratory efficacy of intravenous infusion of a recombinant growth factor, cimaglermin alfa, in patients with heart failure and left ventricular systolic dysfunction (LVSD). In these patients on optimal guideline-directed medical therapy, cimaglermin treatment was generally tolerated except for transient nausea and headache and a dose-limiting toxicity was noted at the highest planned dose. There was a dose-dependent improvement in left ventricular ejection fraction lasting 90 days following infusion. Thus, cimaglermin is a potential therapy to enhance cardiac function in LVSD and warrants further investigation.

Nucleosome mapping across the CFTR locus identifies novel regulatory factors.

Nucleosome positioning on the chromatin strand plays a critical role in regulating accessibility of DNA to transcription factors and chromatin modifying enzymes. Hence, detailed information on nucleosome depletion or movement at cis-acting regulatory elements has the potential to identify predicted binding sites for trans-acting factors. Using a novel method based on enrichment of mononucleosomal DNA by bacterial artificial chromosome hybridization, we mapped nucleosome positions by deep sequencing across 250 kb, encompassing the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR shows tight tissue-specific regulation of expression, which is largely determined by cis-regulatory elements that lie outside the gene promoter. Although multiple elements are known, the repertoire of transcription factors that interact with these sites to activate or repress CFTR expression remains incomplete. Here, we show that specific nucleosome depletion corresponds to well-characterized binding sites for known trans-acting factors, including hepatocyte nuclear factor 1, Forkhead box A1 and CCCTC-binding factor. Moreover, the cell-type selective nucleosome positioning is effective in predicting binding sites for novel interacting factors, such as BAF155. Finally, we identify transcription factor binding sites that are overrepresented in regions where nucleosomes are depleted in a cell-specific manner. This approach recognizes the glucocorticoid receptor as a novel trans-acting factor that regulates CFTR expression in vivo.

Relationship between apoptosis and proliferation in granulosa and theca cells of cystic follicles in sows.

To investigate the causes of the occurrence and persistence of porcine cystic follicles, we evaluated the apoptosis and proliferation of follicular cells in these cysts. Apoptotic frequencies were examined by TUNEL assay and the expression of apoptosis regulators (XIAP, bax, bc1-2 and caspase-3) by immunohistochemistry, Western blotting and real-time quantitative PCR; cell proliferation activity was evaluated by PCNA immunohistochemistry and proliferation of in vitro cultured granulosa and theca cells. The low apoptotic frequency and weak proliferative activity were found in cystic follicles. Low frequency of apoptosis might be associated with decreased amounts of apoptotic-related factors (bax and caspase-3) and increased amounts of anti-apoptotic factors (XIAP and bcl-2) in cystic follicles. Significantly lower proliferation activity was detected in granulosa and theca cells from cystic follicles, and lesser PCNA-positive cells were found in cystic follicles. Our results indicate that the programmed cell death and cell proliferation system were altered in cystic follicles. The disorder between apoptosis and proliferation was responsible for maintaining a static condition without degeneration, which leads to the long-term persistence of follicles. These findings provide important novel insights into the pathogenesis of follicular cysts in sows.

Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance.

To investigate the role of Aire in thymic selection, we examined the cellular requirements for generation of ovalbumin (OVA)-specific CD4 and CD8 T cells in mice expressing OVA under the control of the rat insulin promoter. Aire deficiency reduced the number of mature single-positive OVA-specific CD4(+) or CD8(+) T cells in the thymus, independent of OVA expression. Importantly, it also contributed in 2 ways to OVA-dependent negative selection depending on the T-cell type. Aire-dependent negative selection of OVA-specific CD8 T cells correlated with Aire-regulated expression of OVA. By contrast, for OVA-specific CD4 T cells, Aire affected tolerance induction by a mechanism that operated independent of the level of OVA expression, controlling access of antigen presenting cells to medullary thymic epithelial cell (mTEC)-expressed OVA. This study supports the view that one mechanism by which Aire controls thymic negative selection is by regulating the indirect presentation of mTEC-derived antigens by thymic dendritic cells. It also indicates that mTECs can mediate tolerance by direct presentation of Aire-regulated antigens to both CD4 and CD8 T cells.

Comparative proteomic analysis of follicular fluids from normal and cystic follicles in sows.

Follicular fluid (FF) includes various biologically active proteins which can affect follicular growth and maturation. Certain proteins could reflect the physiological and pathological status of follicles. The aim of the present study was to explore the key proteins associated with pathogenesis of follicular cysts, some of which may be candidate biomarkers for the condition. We analysed the proteomes of FF from small, medium, large and cystic follicles by two-dimensional electrophoresis (2-DE) combined with mass spectrometry (MS). The protein components in FF were found to be significantly different among groups; about 300 proteins spots in each group were examined, and 32 differentially expressed proteins were identified from different groups. To further reveal the source of identified proteins, transcripts encoding two of these, transferrin and RBP-4, were detected in granulosa cells (GCs) by RT-PCR, as well as the proteins were detected in 24 h culture media of GCs by ELISA. High levels of RBP-4 were examined in FF of cystic follicles by 2-DE analysis, which were significantly different to those in large follicles (p < 0.05). In conclusion, the study enriches our understanding of the proteins of FF; RBP-4 and transferrin originate from passive transfer and follicular synthesized secretion, and RBP-4 might be a candidate biomarker for porcine follicular cysts. Combined with histological studies, these results further suggest that changes of the type and quantity of proteins in FF might be attributed to an abnormal metabolism of follicular cells and structure of follicular wall in cystic follicles. Our findings will contribute to further insight into the pathogenesis of follicular cysts.

Molecular networks involved in mouse cerebral corticogenesis and spatio-temporal regulation of Sox4 and Sox11 novel antisense transcripts revealed by transcriptome profiling.

BACKGROUND: Development of the cerebral cortex requires highly specific spatio-temporal regulation of gene expression. It is proposed that transcriptome profiling of the cerebral cortex at various developmental time points or regions will reveal candidate genes and associated molecular pathways involved in cerebral corticogenesis. RESULTS: Serial analysis of gene expression (SAGE) libraries were constructed from C57BL/6 mouse cerebral cortices of age embryonic day (E) 15.5, E17.5, postnatal day (P) 1.5 and 4 to 6 months. Hierarchical clustering analysis of 561 differentially expressed transcripts showed regionalized, stage-specific and co-regulated expression profiles. SAGE expression profiles of 70 differentially expressed transcripts were validated using quantitative RT-PCR assays. Ingenuity pathway analyses of validated differentially expressed transcripts demonstrated that these transcripts possess distinctive functional properties related to various stages of cerebral corticogenesis and human neurological disorders. Genomic clustering analysis of the differentially expressed transcripts identified two highly transcribed genomic loci, Sox4 and Sox11, during embryonic cerebral corticogenesis. These loci feature unusual overlapping sense and antisense transcripts with alternative polyadenylation sites and differential expression. The Sox4 and Sox11 antisense transcripts were highly expressed in the brain compared to other mouse organs and are differentially expressed in both the proliferating and differentiating neural stem/progenitor cells and P19 (embryonal carcinoma) cells. CONCLUSIONS: We report validated gene expression profiles that have implications for understanding the associations between differentially expressed transcripts, novel targets and related disorders pertaining to cerebral corticogenesis. The study reports, for the first time, spatio-temporally regulated Sox4 and Sox11 antisense transcripts in the brain, neural stem/progenitor cells and P19 cells, suggesting they have an important role in cerebral corticogenesis and neuronal/glial cell differentiation.