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Background Hepatic macrophages play a vital role in the defense mechanisms and maintaining the internal environment stability of body, and are also major cellular components involved in liver injury and repair. Macrophages derived from hematopoietic stem cells exhibit distinct gene regulation patterns compared to resident macrophages in the liver. More than 90% of primary liver cancer occurs on the basis of cirrhosis, and the dynamic changes of macrophages in the progression of cirrhosis to hepatocellular carcinoma are worth exploring. Objective To analyze the transcriptomic differences of hepatic macrophages originating from diverse sources, analyze the dynamic pattern of macrophage changes in liver cirrhosis and liver cancer progression, and explore potential strategies for preventing the progression of liver cancer. Methods In this study, single-cell transcriptomics data of healthy, cirrhotic and hepatocellular carcinoma (HCC) tissues were obtained from the Gene Expression Omnibus (GEO) database. The healthy and liver fibrosis data were obtained from the GSE136103 dataset of the GEO database, which included samples from five healthy liver tissues and five liver cirrhosis tissues. The HCC data were obtained from the GSE149614 dataset of the GEO database, which consisted of 21 samples from ten HCC patients. Utilizing the Seurat package, a clustering analysis was conducted on the transcriptomic data derived from liver fibrosis and HCC samples to identify distinct cell types. Notably, three distinctive clusters of macrophage subtypes were identified within the fibrosis samples, from which the top 200 marker genes were extracted. Metascape online analysis software was applied to functionally analyze each subcluster-specific expressed gene. Subgroup-specific expressed genes in liver fibrosis were extracted, and the function of macrophages in cirrhosis was explored by KEGG functional analysis. The CellChat software package was utilized to analyze intercellular interactions within liver fibrosis and HCC single-cell transcriptome data, differences in macrophage communication between cirrhosis and HCC samples were compared. Additionally, normal, fibrotic and cancerous macrophages were extracted, and batch effect correction was performed using the Harmony package. Subsequently, the Monocle package was employed for pseudo-time analysis to construct the developmental trajectory of macrophages spanning from a healthy state to fibrosis and eventually to the HCC microenvironment. The limma package was utilized to find genes that are continuously up-regulated and down-regulated during the evolution of macrophages from healthy state to cirrhotic state and finally to HCC, and functional enrichment analysis was performed. Results Unsupervised clustering was performed, and a total of three macrophage subclusters (designated as Mac1, Mac2, Mac3) were identified based on the expression patterns of marker genes. Mac1 originates from tissue-resident macrophages (Kupffer cells). Mac2 and Mac3 derived from blood monocytes and their numbers were significantly increased in cirrhotic tissue. Mac1 in cirrhotic tissue showed up-regulation of adaptive immune system-related functions. Mac2 and Mac3 subgroups show down-regulation of phagosome-related functions and antigen presentation functions. There were significant differences in communication between macrophages and other cell types in cirrhotic tissue and HCC tissue. Certain intercellular communication occurs only in cirrhotic macrophages, including cell communication of signaling pathways such as IFN-Ⅱ and CD40. After batch effect correction, pseudo-time series analysis was performed on macrophages from healthy liver, liver cirrhosis and HCC, the results suggest that there is a specific temporal relationship between the three groups of macrophages. This study identified 81 genes that were continuously down-regulated during the process, however, no genes were identified that were continuously up-regulated during the evolution of healthy-cirrhotic-HCC macrophage. Functional analysis suggested that the continuously down-regulated genes are functionally enriched for immune responses to bacteria. Conclusion Cirrhotic macrophages can be divided into three subgroups, of which Mac1 derived from liver-resident Kupffer cells and Mac2 and Mac3 derive from blood monocytes. Many immune-related cell communications in liver cirrhosis, such as IFN-Ⅱ and CD40 pathways, disappear in HCC. There is a continuous down-regulation of immune responses to bacteria in the evolution of healthy -cirrhotic-HCC macrophages, which may exacerbate the destructive effect of portal hypertension-induced gut microbiota displacement. For patients with liver cirrhosis, early treatment of portal hypertension-induced intestinal leakage (leaky gut) may be an important treatment strategy.

Abstract Background Pregnant women are significantly underrepresented in clinical trials, yet most of them take medication during pregnancy despite the limited safety data. The objective of this study was to characterize medication use during pregnancy and apply propensity score matching method at scale on patient records to accelerate and prioritize the drug effect signal detection associated with the risk of preterm birth and other adverse pregnancy outcomes. Methods This was a retrospective study on continuously enrolled women who delivered live births between 2013/01/01 and 2022/12/31 (n = 365,075) at Providence St. Joseph Health. Our exposures of interest were all outpatient medications prescribed during pregnancy. We limited our analyses to medication that met the minimal sample size (n = 600). The primary outcome of interest was preterm birth. Secondary outcomes of interest were small for gestational age and low birth weight. We used propensity score matching at scale to evaluate the risk of these adverse pregnancy outcomes associated with drug exposure after adjusting for demographics, pregnancy characteristics, and comorbidities. Results The total medication prescription rate increased from 58.5 to 75.3% (P

Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed the effects of covariate stratification and interaction on body mass index (BMI) PGS (PGSBMI) across four cohorts of European (N = 491,111) and African (N = 21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R2 differences among strata. Covariates with the largest differences included age, sex, blood lipids, physical activity, and alcohol consumption, with R2 being nearly double between best- and worst-performing quintiles for certain covariates. Twenty-eight covariates had significant PGSBMI–covariate interaction effects, modifying PGSBMI effects by nearly 20% per standard deviation change. We observed overlap between covariates that had significant R2 differences among strata and interaction effects – across all covariates, their main effects on BMI were correlated with their maximum R2 differences and interaction effects (0.56 and 0.58, respectively), suggesting high-PGSBMI individuals have highest R2 and increase in PGS effect. Using quantile regression, we show the effect of PGSBMI increases as BMI itself increases, and that these differences in effects are directly related to differences in R2 when stratifying by different covariates. Given significant and replicable evidence for context-specific PGSBMI performance and effects, we investigated ways to increase model performance taking into account nonlinear effects. Machine learning models (neural networks) increased relative model R2 (mean 23%) across datasets. Finally, creating PGSBMI directly from GxAge genome-wide association studies effects increased relative R2 by 7.8%. These results demonstrate that certain covariates, especially those most associated with BMI, significantly affect both PGSBMI performance and effects across diverse cohorts and ancestries, and we provide avenues to improve model performance that consider these effects.

Abstract To explore the molecular pathogenesis of pulmonary arterial hypertension (PAH) and identify potential therapeutic targets, we performed transcriptome sequencing of lung tissue from mice with hypoxia-induced pulmonary hypertension. Our Gene Ontology analysis revealed that “extracellular matrix organization” ranked high in the biological process category, and matrix metallopeptidases (MMPs) and other proteases also played important roles in it. Moreover, compared with those in the normoxia group, we confirmed that MMP s expression was upregulated in the hypoxia group, while the hub gene Timp1 was downregulated. Crocin, a natural MMP inhibitor, was found to reduce inflammation, decrease MMPs levels, increase Timp1 expression levels, and attenuate hypoxia-induced pulmonary hypertension in mice. In addition, analysis of the cell distribution of MMPs and Timp1 in the human lung cell atlas using single-cell RNAseq datasets revealed that MMPs and Timp1 are mainly expressed in a population of fibroblasts. Moreover, in vitro experiments revealed that crocin significantly inhibited myofibroblast proliferation, migration, and extracellular matrix deposition. Furthermore, we demonstrated that crocin inhibited TGF-β1-induced fibroblast activation and regulated the pulmonary arterial fibroblast MMP2/TIMP1 balance by inhibiting the TGF-β1/Smad3 signaling pathway. In summary, our results indicate that crocin attenuates hypoxia-induced pulmonary hypertension in mice by inhibiting TGF-β1-induced myofibroblast activation.

Background The human upper extremity is characterized by inherent motor abundance, allowing a diverse array of tasks with agility and adaptability. Upper extremity functional limitations are a common sequela to Stroke, resulting in pronounced motor and sensory impairments in the contralesional arm. While many therapeutic interventions focus on rehabilitating the weaker arm, it is increasingly evident that it is necessary to consider bimanual coordination and motor control. Methods Participants were recruited to two groups differing in age (Group 1 (n = 10): 23.4 ± 2.9 years, Group 2 (n = 10): 55.9 ± 10.6 years) for an exploratory study on the use of accelerometry to quantify bilateral coordination. Three tasks featuring coordinated reaching were selected to investigate the acceleration of the upper arm, forearm, and hand during activities of daily living (ADLs). Subjects were equipped with acceleration and inclination sensors on each upper arm, each forearm, and each hand. Data was segmented in MATLAB to assess inter-limb and intra-limb coordination. Inter-limb coordination was indicated through dissimilarity indices and temporal locations of congruous movement between upper arm, forearm, or hand segments of the right and left limbs. Intra-limb coordination was likewise assessed between upper arm-forearm, upper arm-hand, and forearm-hand segment pairs of the dominant limb. Findings Acceleration data revealed task-specific movement features during the three distinct tasks. Groups demonstrated diminished similarity as task complexity increased. Groups differed significantly in the hand segments during the buttoning task, with Group 1 showing no coordination in the hand segments during buttoning, and strong coordination in reaching each button with the upper arm and forearm guiding extension. Group 2’s dissimilarity scores and percentages of similarity indicated longer periods of inter-limb coordination, particularly towards movement completion. Group 1’s dissimilarity scores and percentages of similarity indicated longer periods of intra-limb coordination, particularly in the coordination of the upper arm and forearm segments. Interpretation The Expanding Procrustes methodology can be applied to compute objective coordination scores using accessible and highly accurate wearable acceleration sensors. The findings of task duration, angular velocity, and peak roll angle are supported by previous studies finding older individuals to present with slower movements, reduced movement stability, and a reduction of laterality between the limbs. The theory of a shift towards ambidexterity with age is supported by the finding of greater inter-limb coordination in the group of subjects above the age of thirty-five. The group below the age of thirty was found to demonstrate longer periods of intra-limb coordination, with upper arm and forearm coordination emerging as a possible explanation for the demonstrated greater stability.

Abstract Tumor mutational burden (TMB) and T‐cell receptor (TCR) might predict the response to immunotherapy in patients with non–small cell lung cancer (NSCLC). However, the predictive value of the combination of TMB and TCR was not clear. Targeted DNA and TCR sequencing were performed on tumor biopsy specimens. We combined TMB and TCR diversity into a TMB‐and‐TCR (TMR) score using logistic regression. In total, 38 patients with advanced NSCLC were divided into a discovery set (n = 17) and validation set (n = 21). A higher TMR score was associated with better response and longer progression‐free survival to immunotherapy in both the discovery set and validation set. The performance of TMR score was confirmed in the two external validation cohorts of 225 NSCLC patients and 306 NSCLC patients. Tumors with higher TMR scores were more likely to combine with LRP1B gene mutation (p = 0.027) and top 1% CDR3 sequences (p = 0.001). Furthermore, LRP1B allele frequency was negatively correlated with the top 1% CDR3 sequences (r = –0.55, p = 0.033) and positively correlated with tumor shrinkage (r = 0.68, p = 0.007). The TMR score could serve as a potential predictive biomarker for the response to immunotherapy in advanced NSCLC.

Osteoarthritis (OA) is a chronic degenerative joint disease whose main characteristic is the destruction of articular cartilage, causing pain and disability in patients and seriously affecting their quality of life. OA can be induced by a variety of causes, and pathological changes in articular cartilage are considered to be one of the key driving factors for the occurrence of OA. High mobility group box-1 protein (HMGB1), as a non-histone protein in eukaryotic cells, can participate in regulating the inflammation and apoptosis process of OA chondrocytes, thus leading to the occurrence of OA. This article reviews the research on the mechanism of HMGB1 in OA chondrocytes, with a view to providing new ideas for the clinical prevention and treatment of OA.

Objective: Baicalin, which is a key bioactive constituent obtained from Scutellaria baicalensis, has been utilized in traditional Chinese medicine for many centuries. Although it has been reported that Baicalin (BA) can inhibit the replication of the Hepatitis B virus (HBV), the exact mechanism behind this process remains unclear. Interferon-stimulated genes (ISGs) are crucial in the process of antiviral defense. We aim to investigate whether BA can regulate the expression of ISGs, and thereby potentially modulate the replication of HBV. Methods: The study involved the use of CRISPR/Cas9 technology to perform knockout experiments on TRIM25 and IFIT3 genes. The expression of these genes was confirmed through techniques such as immunoblotting or Q-PCR. The levels of HBsAg and HBeAg were measured using ELISA, and the expression of interferon-stimulated genes was detected using a luciferase assay. Results: It is interesting to note that several ISGs belonging to the TRIM family, including TRIM5, TRIM25, and TRIM14, were induced after BA treatment. On the other hand, members of the IFIT family were reduced by BA stimulation. Additionally, BA-mediated HBV inhibition was found to be significantly restored in HepG2 cells where TRIM25 was knocked out. Additional research into the mechanism of action of BA found that prolonged treatment with BA activated the JAK/STAT signaling pathway while simultaneously inhibiting the NF-kB pathway. Conclusion: The findings of our study indicate that TRIM25 has a significant impact on the regulation of HBV replication following BA treatment, providing additional insight into the mechanisms by which BA exerts its antiviral effects.

Abstract Background There is little prospective evidence exists about whether adherence to a diabetes risk reduction diet (DRRD) is related to a significant reduction in renal cancer risk. We sought to clarify whether adherence to DRRD was associated with a reduced risk of renal cancer in a US population. Methods A population-based cohort of 101,755 American adults was identified from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. A DRRD score was calculated to assess adherence to this dietary pattern, where increased scores indicated greater adherence. The relationship between DRRD score and risk of renal cancer was assessed based on the hazard ratios (HRs) and 95% confidence intervals (CIs), which were both calculated using Cox regression. Non-linear association was determined through restricted cubic spline regression. Potential effect modifiers were identified through subgroup analyses. Results Over a mean follow-up of 8.8 years, 446 renal cancers were detected. In this analysis, the fully adjusted model depicted a notable 29% reduction in the risk of renal cancer among individuals in the highest quartile of DRRD score in comparison with the lowest quartile individuals (HRQ4 vs. Q1: 0.71; 95% CI = 0.54, 0.94; P trend = 0.008). This association remained consistent across a series of sensitivity analyses. A non-linear inverse dose–response association between renal cancer risk with DRRD score was observed (P nonlinearity = 0.026). Subgroup analyses showed that this favorable link was more prominent in participants with low Healthy Eating Index-2015 (P interaction = 0.015). Regarding the individual components of DRRD, a decrease in the risk of renal cancer was linked to increased intake of cereal fiber and whole fruit, and lower sugar-sweetened beverage consumption (all P trend

Abstract Pancreatic enzyme replacement therapy (PERT) has been recommended as the preferred method for pancreatic exocrine insufficiency caused by chronic pancreatitis (CP). However, at present, the patient-related factors for the poor PERT management are not clear, and there are no studies on the adherence to PERT in patients with CP in East China. This was a mixed-method study following the principle of sequential explanatory design and included two parts: a quantitative and qualitative study. A cross-sectional survey of medication adherence (MA) was first carried out, followed by a semi-structured interview to further explore and explain the influencing factors of adherence to PERT. Of the 148 patients included in this study, 48.0% had poor MA and only 12.8% had good MA. Multivariate logistic regression showed that lower levels of education and income were contributing factors for non-adherence to PERT. Semi-structured interviews with 24 patients revealed that the reasons for non-adherence also included lack of knowledge, self-adjustment of PERT, lifetime of medication, side effects of PERT, forgetfulness, financial burdens, and accessibility issues. The adherence to PERT was poor among patients with CP in East China. Healthcare providers should personalize medication strategies to improve patients’ MA.

Resistance to care (RTC) is a common abnormal behavioral manifestation of behavioral and psychological symptoms of dementia. Although RTC is strongly associated with agitation or aggressive behavior, it is a specific behavioral response of dementia patients to caregivers, and may result in a negative feedback mechanism as it often directly, negatively impacts caregivers. Currently, there are rare studies on RTC in dementia patients or measuring RTC in these patients using relevant tools in China, which may be because domestic researchers easily confuse RTC with other behavioral concepts. While the concept of RTC was introduced earlier in foreign studies, and has been systematically explored and studied. In this paper, we reviewed available relevant studies, and gave a detailed description of the concept, impact, assessment tools, and interventions regarding RTC, with a view to providing ideas and strategies for the study of RTC in patients with dementia in China.

BackgroundThe disease and mortality rates of patients with laryngeal squamous cell carcinoma (LSCC) stabilize after peaking at the age of 60 years. This study aimed to identify risk factors associated with early death (death within 6 months) in elderly (≥60 years) patients with LSCC and to establish predictive nomograms to aid clinicians in developing individualized treatment plans.MethodsData pertaining to elderly patients with LSCC between 2004 and 2015 was obtained from the Surveillance, Epidemiology, and End Results database (version 8.4.0). Multiple logistic models were used to identify the independent risk factors associated with early mortality. The overall risk of early death was predicted using a web-based probability calculator and predictive nomogram. The cohort underwent decision curve analysis (DCA), calibration, and receiver operating characteristic curves to evaluate the clinical applicability and predictability of the models during the training and validation stages.ResultsThis study included 10,031 patients, of which 1,711 (17.0%) experienced all-cause early death, and 1,129 died from cancer-specific causes. Patients with LSCC who had overlapping laryngeal lesions, advanced age, unmarried status, high tumour and node stages, presence of distant metastases, and lack of treatment were at risk for early death. According to the nomograms, the risk of all-cause death and cancer-specific early death had an area under the curve of 0.796 and 0.790, respectively. Internal validation and DCA revealed that the prediction model was accurate and could be applied clinically.ConclusionThe study provides an overview of the characteristics of early death in patients with LSCC. Among the prognostic factors, T stage and radiotherapy demonstrated the strongest predictive value for early mortality, while marital status and tumor grade had the worst prognostic value. Two nomogram plots were constructed to facilitate accurate prediction of all-cause and cancer-specific early mortality within 6 months in elderly patients with LSCC, thereby helping clinicians in providing more personalised treatment plans.

BackgroundThe Pneumonia Score Index (PSI) was developed to estimate the risk of dying within 30 days of presentation for community-acquired pneumonia patients and is a strong predictor of 30-day mortality after COVID-19. However, three of its required 20 variables (skilled nursing home, altered mental status and pleural effusion) are not discreetly available in the electronic medical record (EMR), resulting in manual chart review for these 3 factors. The goal of this study is to compare a simplified 17-factor version (PSI-17) to the original (denoted PSI-20) in terms of prediction of 30-day mortality in COVID-19.MethodsIn this retrospective cohort study, the hospitalized patients with confirmed SARS-CoV-2 infection between 2/28/20-5/28/20 were identified to compare the predictive performance between PSI-17 and PSI-20. Correlation was assessed between PSI-17 and PSI-20, and logistic regressions were performed for 30-day mortality. The predictive abilities were compared by discrimination, calibration, and overall performance.ResultsBased on 1,138 COVID-19 patients, the correlation between PSI-17 and PSI-20 was 0.95. Univariate logistic regression showed that PSI-17 had performance similar to PSI-20, based on AUC, ICI and Brier Score. After adjusting for confounding variables by multivariable logistic regression, PSI-17 and PSI-20 had AUCs (95% CI) of 0.85 (0.83-0.88) and 0.86 (0.84-0.89), respectively, indicating no significant difference in AUC at significance level of 0.05.ConclusionPSI-17 and PSI-20 are equally effective predictors of 30-day mortality in terms of several performance metrics. PSI-17 can be obtained without the manual chart review, which allows for automated risk calculations within an EMR. PSI-17 can be easily obtained and may be a comparable alternative to PSI-20.

Abstract. Background:. The hepatitis B virus (HBV) vaccine has been efficiently used for decades. However, hepatocellular carcinoma caused by HBV is still prevalent globally. We previously reported that interferon (IFN)-induced tripartite motif-containing 25 (TRIM25) inhibited HBV replication by increasing the IFN expression, and this study aimed to further clarify the anti-HBV mechanism of TRIM25. Methods:. The TRIM25-mediated degradation of hepatitis B virus X (HBx) protein was determined by detecting the expression of HBx in TRIM25-overexpressed or knocked-out HepG2 or HepG2-NTCP cells via Western blotting. Co-immunoprecipitation was performed to confirm the interaction between TRIM25 and HBx, and colocalization of TRIM25 and HBx was identified via immunofluorescence; HBV e-antigen and HBV surface antigen were qualified by using an enzyme-linked immunosorbent assay (ELISA) kit from Kehua Biotech. TRIM25 mRNA, pregenomic RNA (pgRNA), and HBV DNA were detected by quantitative real-time polymerase chain reaction. The retinoic acid-inducible gene I (RIG-I) and pgRNA interaction was verified by RNA-binding protein immunoprecipitation assay. Results:. We found that TRIM25 promoted HBx degradation, and confirmed that TRIM25 could enhance the K90-site ubiquitination of HBx as well as promote HBx degradation by the proteasome pathway. Interestingly, apart from the Really Interesting New Gene (RING) domain, the SPRY domain of TRIM25 was also indispensable for HBx degradation. In addition, we found that the expression of TRIM25 increased the recognition of HBV pgRNA by interacting with RIG-I, which further increased the IFN production, and SPRY, but not the RING domain is critical in this process. Conclusions:. The study found that TRIM25 interacted with HBx and promoted HBx-K90-site ubiquitination, which led to HBx degradation. On the other hand, TRIM25 may function as an adaptor, which enhanced the recognition of pgRNA by RIG-I, thereby further promoting IFN production. Our study can contribute to a better understanding of host-virus interaction.

With the advent of artificial intelligence (AI), machines are increasingly being used to complete complicated tasks, yielding remarkable results. Machine learning (ML) is the most relevant subset of AI in medicine, which will soon become an integral part of our everyday practice. Therefore, physicians should acquaint themselves with ML and AI, and their role as an enabler rather than a competitor. Herein, we introduce basic concepts and terms used in AI and ML, and aim to demystify commonly used AI/ML algorithms such as learning methods including neural networks/deep learning, decision tree and application domain in computer vision and natural language processing through specific examples. We discuss how machines are already being used to augment the physician’s decision-making process, and postulate the potential impact of ML on medical practice and medical research based on its current capabilities and known limitations. Moreover, we discuss the feasibility of full machine autonomy in medicine.

Objective To construct the eukaryotic expression recombinant plasmids of activator protein 2(AP-2) family genes and to identify the effect of AP-2α, AP-2β and AP-2γ on proliferation and migration of HepG2 cell line. Methods Ap-2α,AP-2β and AP-2γ gene were amplified with human mammary cDNA library as template and ligated with pCDNA3.0-FLAG vector, respectively. The eukaryotic expression vector pCDNA3.0-FLAG-AP-2α/β/γ was constructed and transfected into HepG2 cells. CCK8 assay and clone formation assay were used to detect the effect of AP-2 family genes on HepG2 cell proliferation. Scratch assay was used to detect the effect of AP-2 family genes on HepG2 cell migration. Results The pCDNA3.0-FLAG-AP-2α/β/γ were successfully constructed and expressed in HepG2 cells.AP-2 family genes significantly inhibited the proliferation and migration of HepG2 cells(P＜0.05). Conclusions Ap-2α, AP-2β and AP-2γ may inhibit the proliferation and migration of HepG2 cells.

Background: Two risk variants in the apolipoprotein L1 gene (APOL1) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease. Methods: A retrospective cohort study of 2242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality, and organ failure related to sepsis. Results: Of 2242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00–1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR = 1.14 [95% CI, 0.88–1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR = 0.99 [95% CI, 0.70–1.39; p=0.95]). APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR = 1.64 [95% CI, 1.21–2.22; p=0.001]), but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR = 1.36 [95% CI, 1.00–1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR = 1.16 [95% CI, 0.74–1.81; p=0.52]). Conclusions: APOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease. Funding: This study was supported by R01GM120523 (QF), R01HL163854 (QF), R35GM131770 (CMS), HL133786 (WQW), and Vanderbilt Faculty Research Scholar Fund (QF). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Abstract Background Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for equitable deployment of PRS to clinical practice that benefits global populations. Methods We integrated T2D GWAS in European, African, and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and assessed the prediction accuracy of the PRS in the multi-ethnic Electronic Medical Records and Genomics (eMERGE) study (11,945 cases; 57,694 controls), four Black cohorts (5137 cases; 9657 controls), and the Taiwan Biobank (4570 cases; 84,996 controls). We additionally evaluated a post hoc ancestry adjustment method that can express the polygenic risk on the same scale across ancestrally diverse individuals and facilitate the clinical implementation of the PRS in prospective cohorts. Results The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined. The top 2% of the PRS distribution can identify individuals with an approximately 2.5–4.5-fold of increase in T2D risk, which corresponds to the increased risk of T2D for first-degree relatives. The post hoc ancestry adjustment method eliminated major distributional differences in the PRS across ancestries without compromising its predictive performance. Conclusions By integrating T2D GWAS from multiple populations, we developed and validated a trans-ancestry PRS, and demonstrated its potential as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.

Abstract The Active Pulley Hypothesis (APH) is based on modern functional anatomical descriptions of the oculomotor plant, and postulates behaviors of the orbital pulleys proposed to be positioned by the extraocular muscles (EOMs). A computational model is needed to understand this schema quantitatively. We developed and evaluated a novel biomechanical model of active horizontal rectus pulleys. The orbital (OL) and global (GL) layers of the horizontal rectus EOMs were implemented as separate musculoskeletal strands. Pulley sleeves were modeled as tube-like structures receiving the OL insertion and suspended by elastic strands. Stiffnesses and orientations of pulley suspensions were determined empirically to limit horizontal rectus EOM side-slip while allowing anteroposterior pulley travel. Independent neural drives of the OL greater than GL were assumed. The model was iteratively refined in secondary gazes to implement realistic behavior using the simplest mechanical configuration and neural control strategy. Simulated horizontal rectus EOM paths and pulley positions during secondary gazes were consistent with published MRI measurements. Estimated EOM tensions were consistent with the range of experimentally measured tensions. This model is consistent with postulated bilaminar activity of the EOMs, and the separate roles of the GL in ocular rotation, and OL in pulley positioning.

Abstract The intra-image identification of DNA structures is essential to rapid prototyping and quality control of self-assembled DNA origami scaffold systems. We postulate that the YOLO modern object detection platform commonly used for facial recognition can be applied to rapidly scour atomic force microscope (AFM) images for identifying correctly formed DNA nanostructures with high fidelity. To make this approach widely available, we use open-source software and provide a straightforward procedure for designing a tailored, intelligent identification platform which can easily be repurposed to fit arbitrary structural geometries beyond AFM images of DNA structures. Here, we describe methods to acquire and generate the necessary components to create this robust system. Beginning with DNA structure design, we detail AFM imaging, data point annotation, data augmentation, model training, and inference. To demonstrate the adaptability of this system, we assembled two distinct DNA origami architectures (triangles and breadboards) for detection in raw AFM images. Using the images acquired of each structure, we trained two separate single class object identification models unique to each architecture. By applying these models in sequence, we correctly identified 3470 structures from a total population of 3617 using images that sometimes included a third DNA origami structure as well as other impurities. Analysis was completed in under 20 s with results yielding an F1 score of 0.96 using our approach.

Abstract Background Hepatocellular carcinoma (HCC) is one of the most fatal cancers. Due to limited strategies for effective treatments, patients with advanced HCC have a very poor prognosis. This study aims to identify new insights in HCC to develop novel strategies for HCC management. Methods The role of WIP1 (wild type p53 induced protein phosphatase1) in HCC was analyzed in HCC cells, xenograft model, DEN (Diethylnitrosamine) induced mice liver cancer model with WIP1 knockout mice, and TCGA database. DNA damage was evaluated by Gene Set Enrichment Analysis, western blotting, comet assay, and Immunofluorescence. Results High expression of WIP1 is associated with the poor prognosis of patients with HCC. Genetically and chemically suppression of WIP1 drastically reduced HCC cell proliferation. Besides, WIP1 knockout retarded DEN induced mice hepato-carcinogenesis. Mechanically, WIP1 inhibition induced DNA damage by increasing H2AX phosphorylation (γH2AX). Therefore, suppression of WIP1 and PARP induced synthetic lethality in HCC in vitro and in vivo by augmenting DNA damage. Conclusion WIP1 plays an oncogenic effect in HCC development, and targeting WIP1-dependent DNA damage repair alone or in combination with PARP inhibition might be a reasonable strategy for HCC management. Video abstract

Objectives Muscle health is essential for children’s physical development and future health. PPARGC1A gene encode the peroxisome proliferator-activated receptor coactivator 1α which coactivates transcription factors that control mediating skeletal muscle fiber type conversion and skeletal muscle fiber formation. The PPARGC1A rs8192678 Gly/Ser (Gly482Ser) polymorphism was associated with the regulation of skeletal muscle fibre type. This paper aims to explore the association between the PPARGC1A rs8192678 (Gly482Ser) polymorphism and muscle fitness in Chinese schoolchildren. Methods We detected the distribution of the PPARGC1A rs8192678 (Gly482Ser) polymorphism by DNA typing of saliva samples from untrained Southern Chinese Han children aged 7–12 years. Considering that muscle studies in children cannot use invasive sampling, we analyzed the association between alleles and genotypes with high validity tests of muscle fitness assesment in children(handgrip strength, standing long jump, sit-ups and push-ups). Results The results showed no significant differences in height, weight or body mass index between the sexes. The grip strength indicators were correlated with age in boys and height and weight in girls. Sit-ups were significantly higher in girls with the PPARGC1A Gly/Gly genotype than in boys, and handgrip strength and standing long jump were significantly lower in girls with the PPARGC1A rs8192678 (Gly482Ser) genotype than in boys. Genetic model analysis showed that the Gly482 allele had a dominant genetic effect on the Gly482 allele is hypothesized to influence the expression of type I fibers in skeletal muscle in girls, while the Ser482 allele affects on type II fibers in girls. The two alleles had little genetic effect on boys. Conclusions The results suggested the possible association of the PPARGC1A rs8192678 (Gly482Ser) polymorphism on myofibril type-related phenotypes in Han Chinese children in southern China, with a particular impact on girls.

Metabolic-associated fatty liver disease (MAFLD) has been proposed to replace the term non-alcoholic fatty liver disease (NAFLD) in 2020. The association between micronutrients and MAFLD has not been reported. Therefore, this study aims to explore the association between micronutrients intake and MAFLD. This was a cross-section study based on the National Health and Nutrition Examination Survey (NHANES). The dietary intake of copper, zinc, iron, and selenium was evaluated using the 24-h dietary recall interview. Logistic regression analysis was used to explore the association between micronutrients and MAFLD, and the results were shown as odds ratio (OR) with 95 % confidence intervals (CIs). A total of 5976 participants were finally included for analysis, with 3437 participants in the MAFLD group. After adjusting potential confounders, copper intake at quartile Q3 (OR = 0⋅68, 95 % CI 0⋅50, 0⋅93) and Q4 (OR = 0⋅60, 95 % CI 0⋅45, 0⋅80) was found to be associated with lower odds of MAFLD. Iron intake at Q2 (OR = 0⋅64, 95 % CI 0⋅45, 0⋅92) and Q3 (OR = 0⋅61, 95 % CI 0⋅41, 0⋅91) was associated with the lower odds of MAFLD. Our findings found that high intake of copper and adequate intake of iron were associated with MAFLD, which may provide guidance for the management of MAFLD.

Abstract. Surgical resection (SR) is recommended as a radical procedure in the treatment of hepatocellular carcinoma (HCC). However, postoperative recurrence negatively affects the long-term efficacy of SR, and preoperative adjuvant therapy has therefore become a research hotspot. Some clinicians adopt transcatheter arterial chemoembolization (TACE) as a preoperative adjuvant therapy in patients undergoing SR to increase the resection rate, reduce tumor recurrence, and improve the prognosis. However, the findings of the most relevant studies remain controversial. Some studies have confirmed that preoperative TACE cannot improve the long-term survival rate of patients with HCC and might even negatively affect the resection rate. Which factors influence the efficacy of preoperative TACE combined with SR is a topic worthy of investigation. In this review, existing clinical studies were analyzed with a particular focus on several topics: screening of the subgroups of patients most likely to benefit from preoperative TACE, exploration of the optimal treatment regimen of preoperative TACE, and determination of the extent of tumor necrosis as the deciding prognostic factor.

Abstract The MEDication-Indication (MEDI) knowledgebase has been utilized in research with electronic health records (EHRs) since its publication in 2013. To account for new drugs and terminology updates, we rebuilt MEDI to overhaul the knowledgebase for modern EHRs. Indications for prescribable medications were extracted using natural language processing and ontology relationships from six publicly available resources: RxNorm, Side Effect Resource 4.1, Mayo Clinic, WebMD, MedlinePlus, and Wikipedia. We compared the estimated precision and recall between the previous MEDI (MEDI-1) and the updated version (MEDI-2) with manual review. MEDI-2 contains 3031 medications and 186,064 indications. The MEDI-2 high precision subset (HPS) includes indications found within RxNorm or at least three other resources. MEDI-2 and MEDI-2 HPS contain 13% more medications and over triple the indications compared to MEDI-1 and MEDI-1 HPS, respectively. Manual review showed MEDI-2 achieves the same precision (0.60) with better recall (0.89 vs. 0.79) compared to MEDI-1. Likewise, MEDI-2 HPS had the same precision (0.92) and improved recall (0.65 vs. 0.55) than MEDI-1 HPS. The combination of MEDI-1 and MEDI-2 achieved a recall of 0.95. In updating MEDI, we present a more comprehensive medication-indication knowledgebase that can continue to facilitate applications and research with EHRs.

OBJECTIVES/GOALS: Prior work has established subtypes of OSA and linked them to risks of future adverse events but rarely with the longitudinality and richness of data available in the EMR. Our goal is to leverage EMR data identify clinically meaningful sub-phenotypes of OSA and better study how they affect risks of adverse outcomes. METHODS/STUDY POPULATION: Vanderbilt’s EMR database has over 61,000 adult patients with a literature-validated EMR definition of OSA with a median EMR follow-up period of 4 years after OSA diagnosis. Of these patients, 12,516 have fully recorded sleep study data in addition to EMR variables such as age at study and most recent BMI. We applied several clustering methods including to identify natural sub-phenotypes of OSA and assessed cluster quality. We also applied techniques which allow a single patient to belong to multiple clusters in various degrees. After selecting final clusters, we plan to analyze the associations between OSA sub-phenotypes and risks using statistical tools like logistic regression and Cox proportional hazards regression, with and without adjusting for factors such as age, gender, and certain medications. RESULTS/ANTICIPATED RESULTS: Preliminary clustering with primarily sleep study data has shown overlap with literature-described patient clusters, including a severe, high non-REM stage 1 sleep, high BMI cluster and a high nocturnal limb movement cluster. As we incorporate more EMR variables, we will select a final set of OSA sub-types. We anticipate patients in different clusters to have different risks of various adverse OSA-associated outcomes that are tracked in our EMR data. Notable outcomes with sufficient incidence rates (>3%) after OSA diagnosis include essential hypertension (43.4%), hyperlipidemia (28.8%), type 2 diabetes (21.9%), anxiety disorder (19.2%), coronary atherosclerosis (14.9%), cerebrovascular disease (7.7%), and pulmonary heart disease (5.9%). DISCUSSION/SIGNIFICANCE: If our results match anticipations, we will show how EMR data can be used to define OSA sub-phenotypes and predict patient risks of various OSA-associated outcomes. This analysis enables work in personalized risk and treatment predictions for OSA patients. By better understanding these risks, providers can better tailor treatments to patients.

Abstract. Background. Helicobacter pylori (HP) has been considered to be one of the primary causes of gastric mucosa-associated lymphoid tissue (MALT) lymphoma since 1993. Low-grade gastric MALT lymphoma with HP is widely treated with HP eradication therapy, according to each specific clinical situation. However, several studies and guidelines indicate that the modified HP eradication therapy is also valid for HP-negative gastric MALT lymphoma. The aim of this study was to perform a meta-analysis of the clinical efficacy of the modified HP eradication therapy for gastric MALT lymphoma without HP. Methods. We searched studies that reported the response rate of the modified HP eradication therapy regimen for gastric MALT lymphoma without HP by using PubMed, Medline, and Ebsco from January 1971 until February 2019. All statistical analyses were carried out using R 3.5.3 (Mathsoft Company, Cambridge, MA, USA). The pooled response rate was expressed as a decimal. The heterogeneity test was performed using the I-squared (I2) statistic. Results. A total of 14 studies were selected with a total of 148 patients with HP-negative gastric MALT lymphoma. The overall pooled response rate was 0.38 (95% confidence interval [CI]: 0.29–0.47). The combined estimate is I2 = 57% (P

Varicose veins of lower extremities (VVs) are a highly prevalent condition, the pathogenesis of which is still not fully elucidated. Mendelian randomization (MR) can provide useful preliminary information on the traits that are potentially causally related to the disease. The aim of the present study is to replicate the effects of the plasma levels of MHC class I polypeptide-related sequence B (MICB) and cluster of differentiation 209 (CD209) proteins reported in a previous hypothesis-free MR study. We conducted MR analysis using a fixed effects inverse-variance weighted meta-analysis of Wald ratios method. For MICB and CD209, we used data from a large-scale genome-wide association study (GWAS) for plasma protein levels (N = 3,301). For VVs, we used GWAS data obtained in the FinnGen project (N = 128,698), the eMERGE network (phase 3, N = 48,429), and the UK Biobank data available in the Gene ATLAS (N = 452,264). The data used in the study were obtained in individuals of European descent. The results for MICB did not pass criteria for statistical significance and replication. The results for CD209 passed all statistical significance thresholds, indicating that the genetically predicted increase in CD209 level is associated with increased risk of VVs (βMR (SE) = 0.07 (0.01), OR (95% CI) = 1.08 (1.05-1.10), P-value = 5.9 ×10-11 in the meta-analysis of three cohorts). Our findings provide further support that CD209 can potentially be involved in VVs. In future studies, independent validation of our results using data from more powerful GWASs for CD209 measured by different methods would be beneficial.

Asthma is a common disease with profoundly variable natural history and patient morbidity. Heterogeneity has long been appreciated, and much work has focused on identifying subgroups of patients with similar pathobiological underpinnings. Previous studies of the Severe Asthma Research Program (SARP) cohort linked gene expression changes to specific clinical and physiologic characteristics. While invaluable for hypothesis generation, these data include extensive candidate gene lists that complicate target identification and validation. In this analysis, we performed unsupervised clustering of the SARP cohort using bronchial epithelial cell gene expression data, identifying a transcriptional signature for participants suffering exacerbation-prone asthma with impaired lung function. Clinically, participants in this asthma cluster exhibited a mixed inflammatory process and bore transcriptional hallmarks of NF-κB and activator protein 1 (AP-1) activation, despite high corticosteroid exposure. Using supervised machine learning, we found a set of 31 genes that classified patients with high accuracy and could reconstitute clinical and transcriptional hallmarks of our patient clustering in an external cohort. Of these genes, IL18R1 (IL-18 Receptor 1) negatively associated with lung function and was highly expressed in the most severe patient cluster. We validated IL18R1 protein expression in lung tissue and identified downstream NF-κB and AP-1 activity, supporting IL-18 signaling in severe asthma pathogenesis and highlighting this approach for gene and pathway discovery.

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition. Methods First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI). Results Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10− 20). This effect was consistent in both pediatric (p = 9.92 × 10− 6) and adult (p = 9.73 × 10− 15) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10− 8, beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10− 4). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10− 8), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10− 11). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses. Conclusions In summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings.

Abstract Photosynthetic light response (PLR) curves of leaves are usually fitted by non-rectangular hyperbola (NRH) equation, and those fitted NRH parameters may change with leaf aging. The objectives of this study were 1) to reveal the response of NRH parameters of rice leaves, light-saturated net photosynthetic rate (P nmax), quantum yield of assimilation (φ), dark respiration rate (R d) and convexity of the curve (k), to leaf age; and 2) to improve the performance of NRH equation in simulating the PLR curves for leaves at various ages. The PLR for rice leaves at ages of 3–53 days were measured, and the general NRH equation was developed by incorporating the relationship between NRH parameters and leaf age into the NRH equation. The results showed that the NRH parameters of P nmax, φ and R d increased rapidly to maximum at approximately 10 days and then declined linearly toward the age of 53 days. However, the value of k was not sensitive to leaf age. The general NRH equation can be used to simulate leaf PLR continuously along with leaf aging.

Abstract A rapidly modulated stratified medium with a large mass density modulation depth (LMMD) is proposed to achieve non-diffraction propagation (NDP) of acoustic waves. It is found that the NDP in LMMD medium is independent of the incident angle and can be operated in a broad-band manner. Such an NDP is robust and is unhampered by medium losses. An effective medium theory (EMT) is developed for acoustic waves propagating in the LMMD medium based on the first-principles method. The LMMD EMT is verified by using the transfer-matrix method (TMM) for both propagating and evanescent waves. Furthermore, we discuss the influence of the geometry on NDP, and finite element simulations are conducted to verify the NDP in the LMMD medium.

BackgroundThe role of urate in cardiovascular diseases (CVDs) has been extensively investigated in observational studies; however, the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance.Methods and findingsA phenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic model (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 unrelated White British individuals (54% female) in the UK Biobank who were aged 40-69 years (mean age, 56.87; SD, 7.99) when recruited from 2006 to 2010. Mendelian randomization (MR) analyses were performed to replicate significant findings using various genome-wide association study (GWAS) consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for urate. PheWAS analysis, examining the association with 1,431 disease outcomes, identified 13 distinct phecodes representing 4 disease groups (inflammatory polyarthropathies, hypertensive disease, circulatory disease, and metabolic disorders) and 9 disease outcomes (gout, gouty arthropathy, pyogenic arthritis, essential hypertension, coronary atherosclerosis, ischemic heart disease, chronic ischemic heart disease, myocardial infarction, and hypercholesterolemia) that were associated with genetically determined serum urate levels after multiple testing correction (p < 3.35 × 10-4). TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases, and blood lipid levels but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with CVDs. The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and possible misclassification of cases for mild disease that did not require hospitalization.ConclusionIn this study, high serum urate levels were found to be associated with increased risk of different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a common mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities.

Heterogeneity of echo-texture and lack of sharply delineated tissue boundaries in diagnostic ultrasound images make three-dimensional (3D) registration challenging, especially when the volumes to be registered are considerably different due to local changes. We implemented a novel computational method that optimally registers volumetric ultrasound image data containing significant and local anatomical differences. It is A Multi-stage, Multi-resolution, and Multi-volumes-of-interest Volume Registration Method. A single region registration is optimized first for a close initial alignment to avoid convergence to a locally optimal solution. Multiple sub-volumes of interest can then be selected as target alignment regions to achieve confident consistency across the volume. Finally, a multi-resolution rigid registration is performed on these sub-volumes associated with different weights in the cost function. We applied the method on 3D endovaginal ultrasound image data acquired from patients during biopsy procedure of the pelvic floor muscle. Systematic assessment of our proposed method through cross validation demonstrated its accuracy and robustness. The algorithm can also be applied on medical imaging data of other modalities for which the traditional rigid registration methods would fail.

Genome-wide and phenome-wide association studies are commonly used to identify important relationships between genetic variants and phenotypes. Most studies have treated diseases as independent variables and suffered from the burden of multiple adjustment due to the large number of genetic variants and disease phenotypes. In this study, we used topic modeling via non-negative matrix factorization (NMF) for identifying associations between disease phenotypes and genetic variants. Topic modeling is an unsupervised machine learning approach that can be used to learn patterns from electronic health record data. We chose the single nucleotide polymorphism (SNP) rs10455872 in LPA as the predictor since it has been shown to be associated with increased risk of hyperlipidemia and cardiovascular diseases (CVD). Using data of 12,759 individuals with electronic health records (EHR) and linked DNA samples at Vanderbilt University Medical Center, we trained a topic model using NMF from 1,853 distinct phenotypes and identified six topics. We tested their associations with rs10455872 in LPA. Topics enriched for CVD and hyperlipidemia had positive correlations with rs10455872 (P < 0.001), replicating a previous finding. We also identified a negative correlation between LPA and a topic enriched for lung cancer (P < 0.001) which was not previously identified via phenome-wide scanning. We were able to replicate the top finding in a separate dataset. Our results demonstrate the applicability of topic modeling in exploring the relationship between genetic variants and clinical diseases.

BACKGROUND:Observations from statin clinical trials and from Mendelian randomization studies suggest that low low-density lipoprotein cholesterol (LDL-C) concentrations may be associated with increased risk of type 2 diabetes mellitus (T2DM). Despite the findings from statin clinical trials and genetic studies, there is little direct evidence implicating low LDL-C concentrations in increased risk of T2DM. METHODS AND FINDINGS:We used de-identified electronic health records (EHRs) at Vanderbilt University Medical Center to compare the risk of T2DM in a cross-sectional study among individuals with very low (≤60 mg/dl, N = 8,943) and normal (90-130 mg/dl, N = 71,343) LDL-C levels calculated using the Friedewald formula. LDL-C levels associated with statin use, hospitalization, or a serum albumin level < 3 g/dl were excluded. We used a 2-phase approach: in 1/3 of the sample (discovery) we used T2DM phenome-wide association study codes (phecodes) to identify cases and controls, and in the remaining 2/3 (validation) we identified T2DM cases and controls using a validated algorithm. The analysis plan for the validation phase was constructed at the time of the design of that component of the study. The prevalence of T2DM in the very low and normal LDL-C groups was compared using logistic regression with adjustment for age, race, sex, body mass index (BMI), high-density lipoprotein cholesterol, triglycerides, and duration of care. Secondary analyses included prespecified stratification by sex, race, BMI, and LDL-C level. In the discovery cohort, phecodes related to T2DM were significantly more frequent in the very low LDL-C group. In the validation cohort (N = 33,039 after applying the T2DM algorithm to identify cases and controls), the risk of T2DM was increased in the very low compared to normal LDL-C group (odds ratio [OR] 2.06, 95% CI 1.80-2.37; P < 2 × 10-16). The findings remained significant in sensitivity analyses. The association between low LDL-C levels and T2DM was significant in males (OR 2.43, 95% CI 2.00-2.95; P < 2 × 10-16) and females (OR 1.74, 95% CI 1.42-2.12; P = 6.88 × 10-8); in normal weight (OR 2.18, 95% CI 1.59-2.98; P = 1.1× 10-6), overweight (OR 2.17, 95% CI 1.65-2.83; P = 1.73× 10-8), and obese (OR 2.00, 95% CI 1.65-2.41; P = 8 × 10-13) categories; and in individuals with LDL-C < 40 mg/dl (OR 2.31, 95% CI 1.71-3.10; P = 3.01× 10-8) and LDL-C 40-60 mg/dl (OR 1.99, 95% CI 1.71-2.32; P < 2.0× 10-16). The association was significant in individuals of European ancestry (OR 2.67, 95% CI 2.25-3.17; P < 2 × 10-16) but not in those of African ancestry (OR 1.09, 95% CI 0.81-1.46; P = 0.56). A limitation was that we only compared groups with very low and normal LDL-C levels; also, since this was not an inception cohort, we cannot exclude the possibility of reverse causation. CONCLUSIONS:Very low LDL-C concentrations occurring in the absence of statin treatment were significantly associated with T2DM risk in a large EHR population; this increased risk was present in both sexes and all BMI categories, and in individuals of European ancestry but not of African ancestry. Longitudinal cohort studies to assess the relationship between very low LDL-C levels not associated with lipid-lowering therapy and risk of developing T2DM will be important.

Background: Intraoperative neuromonitoring (IONM) of the recurrent laryngeal nerve (RLN) has been widely applied during thyroid surgery. However, the safe range of stimulation intensity for IONM remains undetermined. Methods: Total thyroidectomies were performed on twenty dogs, and their RLNs were stimulated with a current of 5–20 mA (step-wise in 5 mA increments) for 1 min. The evoked electromyography (EMG) of vocal muscles before and after supramaximal stimulation were recorded and compared. Acute microstructural morphological changes in the RLNs were observed immediately postoperatively under an electron microscope. Results: The average stimulating threshold for RLNs stimulated with 15 mA and 20 mA showed no significant changes compared to the unstimulated RLNs (15 mA group: 0.320 ± 0.123 mA vs. 0.315 ± 0.097 mA, P = 0.847; 20 mA group: 0.305 ± 0.101 mA vs. 0.300 ± 0.103 mA, P = 0.758). Similar outcomes were shown in average evoked EMG amplitude (15 mA group: 1,026 ± 268 μV vs. 1,021 ± 273 μV, P = 0.834; 20 mA group: 1,162 ± 275 μV vs. 1,200 ± 258 μV, P = 0.148). However, obvious acute microstructural morphological changes were observed in the nerves that were stimulated with 20 mA. Conclusions: A stimulation intensity less than 15 mA might be safe for IONM of the RLN.

Elaeagnus angustifolia is one of the most extensively afforested tree species in environment-harsh regions of northern China. Despite its exceptional tolerance to saline soil, the intrinsic adaptive physiology has not been revealed. In this study, we investigated the growth, organ-level ionic relations and organic osmoregulation of the seedlings hydroponically treated with 0, 100 and 200 mM NaCl for 30 days. We found that the growth characteristics and the whole-plant dry weight were not obviously stunted, but instead, were even slightly stimulated by the treatment of 100 mM NaCl. In contrast, these traits were significantly inhibited by 200 mM NaCl treatment. Interestingly, as compared with the control (0 mM NaCl), both 100 and 200 mM NaCl treatments had a promotional effect on root growth as evidenced by 26.3% and 2.4% increases in root dry weight, respectively. Roots had the highest Na+ and Cl- concentrations and obviously served as the sink for the net increased Na+ and Cl-, while, stems might maintain the capacity of effective Na+ constraint, resulting in reduced Na+ transport to the leaves. K+, Ca2+ and Mg2+ concentrations in three plant organs of NaCl-treated seedlings presented a substantial decline, eventually leading to an enormously drop of K+/Na+ ratio. As the salt concentration increased, proline and soluble protein contents continuously exhibited a prominent and a relatively tardy accumulation, respectively, whereas soluble sugar firstly fell to a significant level and then regained to a level that is close to that of the control. Taken together, our results provided quantitative measures that revealed some robust adaptive physiological mechanisms underpinning E. angustifolia's moderately high salt tolerance, and those mechanisms comprise scalable capacity for root Na+ and Cl- storage, effectively constrained transportation of Na+ from stems to leaves, root compensatory growth, as well as an immediate and prominent leaf proline accumulation.

Background: Strain and strain-rate imaging (SRI) have been found clinically useful in the assessment of cardiac systolic and diastolic function as well as providing new insights in deciphering cardiac physiology and mechanics in cardiomyopathies, and identifying early subclinical changes in various pathologies. The aim of this study was to evaluate the regional and global left ventricular (LV) myocardial function in metabolic syndrome (MS) with SRI so that we can provide more myocardial small lesions in patients with MS, which is robust and reliable basis for early detection of LV function. Methods: Thirty-nine adults with MS were enrolled in the study. There was a control group of 39 healthy adults. In addition to classic echocardiographic assessment of LV global functional changes, SRI was used to evaluate regional and global LV function. Including: Peak systolic strain (S), peak systolic strain-rate (SR-s), peak diastolic strain-rate (SR-e). Results: There were no statistically significant differences between MS and controls in all traditional parameters of LV systolic function. On the other hand, significant differences were observed between MS and the control group in most of the parameters of S, SR-s, SR-e in regional LV function. Multiple stepwise regression analyses revealed that S and SR significantly were negatively correlated with blood pressure, waist circumference, fasting plasma glucose, uric acid, suggesting that risk factories were relevant to regional systolic dysfunction. Conclusion: In MS with normal LV ejection fraction, there was regional myocardial dysfunction, risk factors contributed to the impairment of systolic and diastolic function of the regional myocardium. Assessment of myocardial function using SRI could be more accurate in MS patient evaluation than conventional echocardiography alone.