A multi-bin rarefying method for evaluating alpha diversities in TCR sequencing data.

MOTIVATION: T cell receptors (TCRs) constitute a major component of our adaptive immune system, governing the recognition and response to internal and external antigens. Studying the TCR diversity via sequencing technology is critical for a deeper understanding of immune dynamics. However, library sizes differ substantially across samples, hindering the accurate estimation/comparisons of alpha diversities. To address this, researchers frequently use an overall rarefying approach in which all samples are sub-sampled to an even depth. Despite its pervasive application, its efficacy has never been rigorously assessed. RESULTS: In this paper, we develop an innovative "multi-bin" rarefying approach that partitions samples into multiple bins according to their library sizes, conducts rarefying within each bin for alpha diversity calculations, and performs meta-analysis across bins. Extensive simulations using real-world data highlight the inadequacy of the overall rarefying approach in controlling the confounding effect of library size. Our method proves robust in addressing library size confounding, outperforming competing normalization strategies by achieving better-controlled type-I error rates and enhanced statistical power in association tests. AVAILABILITY AND IMPLEMENTATION: The code is available at https://github.com/mli171/MultibinAlpha. The datasets are freely available at https://doi.org/10.21417/B7001Z and https://doi.org/10.21417/AR2019NC.

Association of oral microbiome with oral human papillomavirus infection: a population study of the National Health and Nutrition Examination Survey, 2009-2012.

BACKGROUND: Oral human papillomavirus(HPV) infection and the oral microbiome are associated with oropharyngeal cancer. However, population-based data on the association of oral microbiome with oral HPV infection are limited. METHOD: We performed a cross-sectional analysis of 5,496 participants aged 20-59 in National Health and Nutrition Examination Surveys(NHANES):2009-2012. The association between either oral microbiome alpha diversity or beta diversity and oral HPV infection was assessed using multivariable logistic regression or principal coordinate analyses(PCoA) and multivariate analysis of variance(PERMANOVA). RESULTS: For alpha diversity, we found a lower number of observed Amplicon sequence variants(ASVs) (adjusted odds ratio[aOR] = 0.996; 95%CI = 0.992-0.999) and reduced Faith's Phylogenetic Diversity(aOR = 0.95; 95%CI = 0.90-0.99) associated with high-risk oral HPV infection in the overall population. This trend was observed in males for both high-risk and any oral HPV infection. Beta diversity showed differentiation of oral microbiome community by high-risk oral HPV infection as measured by Bray-Curtis dissimilarity (R2 = 0.054%; P = .029) and unweighted UniFrac distance (R2 = 0.046%; P = .045) among the overall population, and associations were driven by males. CONCLUSIONS: Both oral microbiome alpha diversity(within-sample richness and phylogenetic diversity) and beta diversity(heterogeneous dispersion of oral microbiome community) are associated with HPV infection. Longitudinal studies are needed to characterize the role of the microbiome in the natural history of oral HPV infection.

The sequence kernel association test for multicategorical outcomes.

Disease heterogeneity is ubiquitous in biomedical and clinical studies. In genetic studies, researchers are increasingly interested in understanding the distinct genetic underpinning of subtypes of diseases. However, existing set-based analysis methods for genome-wide association studies are either inadequate or inefficient to handle such multicategorical outcomes. In this paper, we proposed a novel set-based association analysis method, sequence kernel association test (SKAT)-MC, the sequence kernel association test for multicategorical outcomes (nominal or ordinal), which jointly evaluates the relationship between a set of variants (common and rare) and disease subtypes. Through comprehensive simulation studies, we showed that SKAT-MC effectively preserves the nominal type I error rate while substantially increases the statistical power compared to existing methods under various scenarios. We applied SKAT-MC to the Polish breast cancer study (PBCS), and identified gene FGFR2 was significantly associated with estrogen receptor (ER)+ and ER- breast cancer subtypes. We also investigated educational attainment using UK Biobank data ( N = 127 , 127 $N=127,127$ ) with SKAT-MC, and identified 21 significant genes in the genome. Consequently, SKAT-MC is a powerful and efficient analysis tool for genetic association studies with multicategorical outcomes. A freely distributed R package SKAT-MC can be accessed at https://github.com/Zhiwen-Owen-Jiang/SKATMC.

Fine particulate matter contributes to COPD-like pathophysiology: experimental evidence from rats exposed to diesel exhaust particles.

BACKGROUND: Ambient fine particulate matter (PM2.5) is considered a plausible contributor to the onset of chronic obstructive pulmonary disease (COPD). Mechanistic studies are needed to augment the causality of epidemiologic findings. In this study, we aimed to test the hypothesis that repeated exposure to diesel exhaust particles (DEP), a model PM2.5, causes COPD-like pathophysiologic alterations, consequently leading to the development of specific disease phenotypes. Sprague Dawley rats, representing healthy lungs, were randomly assigned to inhale filtered clean air or DEP at a steady-state concentration of 1.03 mg/m3 (mass concentration), 4 h per day, consecutively for 2, 4, and 8 weeks, respectively. Pulmonary inflammation, morphologies and function were examined. RESULTS: Black carbon (a component of DEP) loading in bronchoalveolar lavage macrophages demonstrated a dose-dependent increase in rats following DEP exposures of different durations, indicating that DEP deposited and accumulated in the peripheral lung. Total wall areas (WAt) of small airways, but not of large airways, were significantly increased following DEP exposures, compared to those following filtered air exposures. Consistently, the expression of α-smooth muscle actin (α-SMA) in peripheral lung was elevated following DEP exposures. Fibrosis areas surrounding the small airways and content of hydroxyproline in lung tissue increased significantly following 4-week and 8-week DEP exposure as compared to the filtered air controls. In addition, goblet cell hyperplasia and mucus hypersecretions were evident in small airways following 4-week and 8-week DEP exposures. Lung resistance and total lung capacity were significantly increased following DEP exposures. Serum levels of two oxidative stress biomarkers (MDA and 8-OHdG) were significantly increased. A dramatical recruitment of eosinophils (14.0-fold increase over the control) and macrophages (3.2-fold increase) to the submucosa area of small airways was observed following DEP exposures. CONCLUSIONS: DEP exposures over the courses of 2 to 8 weeks induced COPD-like pathophysiology in rats, with characteristic small airway remodeling, mucus hypersecretion, and eosinophilic inflammation. The results provide insights on the pathophysiologic mechanisms by which PM2.5 exposures cause COPD especially the eosinophilic phenotype.

Study on the antidepressive effects and mechanism of raw and fried Ziziphi Spinosae Semen via metabolomics and gut microbiota analysis.

Ziziphi Spinosae Semen (ZSS) and fried ZSS (FZSS) have been used for treating insomnia and depression in China. However, the potential influence of chemical variations on their efficacy remains unclear. This study demonstrated that compared with ZSS, FZSS exhibited an increase in the content of seven compounds, while the fatty oil content decreased. Both ZSS and FZSS exhibited antidepressive effects in a chronic unpredictable mild stress rat model, indicating a synergistic regulation of deficiencies in 5-hydroxytryptamine in the brain and the hyperactivation of severe peripheral inflammation. ZSS demonstrated a superior modulatory effect compared with FZSS, as indicated by integrated pharmacodynamic index, metabolic profile, and relative distance value. The potential mechanism underlying their antidepressive effects involved the modulation of gut microbiota structure to alleviate excessive inflammatory responses and imbalanced tryptophan metabolism. Correlation analysis indicated that the higher fatty oil contents should be comprehensively considered as the main reason for ZSS's superior antidepressive effects, achieved through the regulation of pyroglutamic acid levels.

Accommodating multiple potential normalizations in microbiome associations studies.

BACKGROUND: Microbial communities are known to be closely related to many diseases, such as obesity and HIV, and it is of interest to identify differentially abundant microbial species between two or more environments. Since the abundances or counts of microbial species usually have different scales and suffer from zero-inflation or over-dispersion, normalization is a critical step before conducting differential abundance analysis. Several normalization approaches have been proposed, but it is difficult to optimize the characterization of the true relationship between taxa and interesting outcomes.  RESULTS: To avoid the challenge of picking an optimal normalization and accommodate the advantages of several normalization strategies, we propose an omnibus approach. Our approach is based on a Cauchy combination test, which is flexible and powerful by aggregating individual p values. We also consider a truncated test statistic to prevent substantial power loss. We experiment with a basic linear regression model as well as recently proposed powerful association tests for microbiome data and compare the performance of the omnibus approach with individual normalization approaches. Experimental results show that, regardless of simulation settings, the new approach exhibits power that is close to the best normalization strategy, while controling the type I error well.  CONCLUSIONS: The proposed omnibus test releases researchers from choosing among various normalization methods and it is an aggregated method that provides the powerful result to the underlying optimal normalization, which requires tedious trial and error. While the power may not exceed the best normalization, it is always much better than using a poor choice of normalization.

In-Plane Chemical Ordering (Mo2/3 R1/3 )2 AlB2 (R = Tb, Dy, Ho, Er, Tm, and Lu) i-MAB Phases and their Two-Dimensional Derivatives (MBene): Synthesis, Structure, Magnetic, and Supercapacitor Performance.

A family of hexagonal in-plane chemical ordering (Mo2/3 R1/3 )2 AlB2 (R = Tb, Dy, Ho, Er, Tm, and Lu) i-MAB phases are synthesized with R-3m hexagonal structure. The i-MAB phases with R = Tb to Tm are considered to have a nonlinear ferromagnetic-like coupling magnetic ground state with gradually weakened magnetocrystalline anisotropy due to variant R-R distances and 4f electrons. Their 2D derivatives (2D-MBene) with rare-earth (R) atom vacancies are obtained by chemical etching. The delamination solvent, surface functional terminations, and chemical bond of 2D-MBene can be modified by one-step nitridation in environment-friendly nitrogen instead of ammonia. A phase conversion is caused by nitridation at 973 K from 2D-MBene to Mo2 N, leading to the optimized specific capacitance of 229 F g-1 . Besides exploring more rare-earth-containing laminated boride systems, this work also demonstrates the promising application of their 2D derivatives with R vacancies in supercapacitors.

Pre-pregnancy body mass index and gut microbiota of mothers and children 5 years postpartum.

BACKGROUND: Maternal pre-pregnancy body mass index (BMI) has been linked to altered gut microbiota in women shortly after delivery and in their offspring in the first few years of life. But little is known about how long these differences persist. METHODS: We followed 180 mothers and children from pregnancy until 5-year postpartum in the Gen3G cohort (Canada, enrolled 2010-2013). At 5 years postpartum we collected stool samples from mothers and children and estimated the gut microbiota by 16 S rRNA sequencing (V4 region) using Illumina MiSeq, and assigning amplicon sequence variants (ASV). We examined whether overall microbiota composition (as measured by microbiota ß diversity) was more similar between mother-child pairs compared to between mothers or between children. We also assessed whether mother-child pair sharing of overall microbiota composition differed by the weight status of mothers before pregnancy and of children at 5-year. Furthermore, in mothers, we examined whether pre-pregnancy BMI, BMI 5-year postpartum, and change in BMI between time points was associated with maternal gut microbiota 5-year postpartum. In children, we further examined associations of maternal pre-pregnancy BMI and child 5-year BMI z-score with child 5-year gut microbiota. RESULTS: Mother-child pairs had greater similarity in overall microbiome composition compared to between mothers and between children. In mothers, higher pre-pregnancy BMI and 5-year postpartum BMI were associated with lower microbiota observed ASV richness and Chao 1 index; in children's gut microbiota, higher maternal pre-pregnancy BMI was weakly associated with lower microbiota Shannon index, whereas child's 5-year BMI z-score was associated with higher observed ASV richness. Pre-pregnancy BMI was also linked to differential abundances of several microbial ASVs in the Ruminococcaceae and Lachnospiraceae families, but no specific ASV had overlapping associations with BMI measures in both mothers and children. CONCLUSIONS: Pre-pregnancy BMI was associated with gut microbiota diversity and composition of mothers and children 5 years after birth, however, the nature and direction of most associations differed for mothers and children. Future studies are encouraged to confirm our findings and look into potential mechanisms or factors that may drive these associations.

The mediating roles of the oral microbiome in saliva and subgingival sites between e-cigarette smoking and gingival inflammation.

BACKGROUND: Electronic cigarettes (ECs) have been widely used by young individuals in the U.S. while being considered less harmful than conventional tobacco cigarettes. However, ECs have increasingly been regarded as a health risk, producing detrimental chemicals that may cause, combined with poor oral hygiene, substantial inflammation in gingival and subgingival sites. In this paper, we first report that EC smoking significantly increases the odds of gingival inflammation. Then, through mediation analysis, we seek to identify and explain the mechanism that underlies the relationship between EC smoking and gingival inflammation via the oral microbiome. METHODS: We collected saliva and subgingival samples from 75 EC users and 75 non-users between 18 and 34 years in age and profiled their microbial compositions via 16S rRNA amplicon sequencing. We conducted raw sequence data processing, denoising and taxonomic annotations using QIIME2 based on the expanded human oral microbiome database (eHOMD). We then created functional annotations (i.e., KEGG pathways) using PICRUSt2. RESULTS: We found significant increases in α-diversity for EC users and disparities in ß-diversity between EC users and non-users. We also found significant disparities between EC users and non-users in the relative abundance of 36 microbial taxa in the saliva site and 71 microbial taxa in the subgingival site. Finally, we found that 1 microbial taxon in the saliva site and 18 microbial taxa in the subgingival site significantly mediated the effects of EC smoking on gingival inflammation. The mediators on the genus level, for example, include Actinomyces, Rothia, Neisseria, and Enterococcus in the subgingival site. In addition, we report significant disparities between EC users and non-users in the relative abundance of 71 KEGG pathways in the subgingival site. CONCLUSIONS: These findings reveal that continued EC use can further increase microbial dysbiosis that may lead to periodontal disease. Our findings also suggest that continued surveillance for the effect of ECs on the oral microbiome and its transmission to oral diseases is needed.

Preventive effect of LCZ696 on hypoxic pulmonary hypertension in rats via regulating the PI3K/AKT signaling pathway.

Hypoxic pulmonary hypertension (HPH) is a devastating disease worldwide; however, effective therapeutic drugs are lacking. This study investigated the effects and underlying mechanisms of LCZ696 treatment on hypoxia-induced pulmonary hypertension. Male Sprague-Dawley (SD) rats were kept in a hypobaric chamber with an oxygen concentration of 5% for 4 weeks. Rats were treated with either LCZ696 (18 mg/kg, 36 mg/kg, and 72 mg/kg) or sildenafil. The mean pulmonary artery pressure (mPAP), right ventricle hypertrophy index (RVHI), and lung system index were measured. Hematoxylin-eosin (HE) staining, Masson staining, and immunofluorescence staining were used for histological analysis. Enzyme linked immunosorbent assay (ELISA) kits were used to determine the concentrations of inflammatory and hypoxia-related factors. Western blotting was used to examine the expression of apoptotic and PI3K/AKT signaling pathway proteins in rat lung tissue. Hypoxia increased mPAP, RVHI, and lung system index and induced pulmonary vascular remodeling, pulmonary arteriomyosis, and pulmonary artery fibrosis. LCZ696 treatment reduced the increase in mPAP, RVHI, and the lung system index and ameliorated the induced pathological changes. Hypoxia upregulated expression of NF-kB, TNF-α, IL-6, HIF-1α, and Vascular endothelial growth factor (VEGF), decreased the ratio of Bax/Bcl-2, and activated the PI3K/AKT signaling pathway in lung tissue, and these effects were partially reversed by treatment with LCZ696. These results demonstrated that LCZ696 can ameliorate hypoxia-induced HPH by suppressing apoptosis, inhibiting the inflammatory response, and inhibiting the PI3K/AKT signaling pathway. It provides a reference for clinical rational drug use and lays a foundation for the study of HPH therapeutic drugs.

Association Between Online Health Information-Seeking Behaviors by Caregivers and Delays in Pediatric Cancer: Mixed Methods Study in China.

BACKGROUND: Pediatric cancer patients in China often present at an advanced stage of disease resulting in lower survival and poorer health outcomes. One factor hypothesized to contribute to delays in pediatric cancer has been the online health information-seeking (OHIS) behaviors by caregivers. OBJECTIVE: This study aims to examine the association between OHIS behaviors by caregivers and delays for Chinese pediatric cancer patients using a mixed methods approach. METHODS: This study used a mixed methods approach, specifically a sequential explanatory design. OHIS behavior by the caregiver was defined as the way caregivers access information relevant to their children's health via the Internet. Delays in pediatric cancer were defined as any one of the following 3 types of delay: patient delay, diagnosis delay, or treatment delay. The quantitative analysis methods included descriptive analyses, Student t tests, Pearson chi-square test, and binary logistic regression analysis, all performed using Stata. The qualitative analysis methods included conceptual content analysis and the Colaizzi method. RESULTS: A total of 303 pediatric cancer patient-caregiver dyads was included in the quantitative survey, and 29 caregivers completed the qualitative interview. Quantitative analysis results revealed that nearly one-half (151/303, 49.8%) of patients experienced delays in pediatric cancer, and the primary type of delay was diagnosis delay (113/303, 37.3%), followed by patient delay (50/303, 16.5%) and treatment delay (24/303, 7.9%). In this study, 232 of the 303 (76.6%) caregiver participants demonstrated OHIS behaviors. When those engaged in OHIS behaviors were compared with their counterparts, the likelihood of patient delay more than doubled (odds ratio=2.21; 95% CI 1.03-4.75). Qualitative analysis results showed that caregivers' OHIS behaviors impacted the cancer care pathway by influencing caregivers' symptom appraisal before the first medical contact and caregivers' acceptance of health care providers' diagnostic and treatment decisions. CONCLUSIONS: Our findings suggest that OHIS among Chinese pediatric caregivers may be a risk factor for increasing the likelihood of patient delay. Our government and society should make a concerted effort to regulate online health information and improve its quality. Specialized freemium consultations provided by health care providers via online health informatic platforms are needed to shorten the time for caregivers' cancer symptom appraisal before the first medical contact.

Comparison of AngioJet Thrombectomy System Versus Suction Catheter with the Adjunct of Catheter-Directed Thrombolysis for Lower Extremity Deep Venous Thrombosis.

BACKGROUND: This study aims to investigate the value of the AngioJet thrombectomy system with adjunct of catheter-directed thrombolysis (CDT) in treating lower extremity deep venous thrombosis (LEDVT). METHODS: 48 patients who were clinically confirmed LEDVT and treated by percutaneous mechanical thrombectomy (PMT) combined with CDT, were included in this retrospective study (AJ-CDT, n = 33; Suction-CDT, n = 15). Baseline characteristics, clinical outcomes and surveillance data were reviewed and analyzed. RESULTS: The overall clot reduction rate of AJ-CDT group was significantly higher than that of Suction-CDT group (77.86% vs 64.47%, P = .027). The CDT therapeutic time (5.75 ± 3.04 vs 7.67 ± 2.82 days, P = .045) and urokinase dosage (3.63 ± 2.16 vs 5.76 ± 2.12 million IU, P = .003) were lower in AJ-CDT group, respectively. There was statistical significance in the transient hemoglobinuria between 2 groups (72.73% vs 6.67%, P < .001). At postoperative 48 hours, the serum creatinine (Scr) value was higher in AJ-CDT group compared to Suction-CDT group statistically (78.56 ± 32.16 vs 60.21 ± 15.72 µmol/l, P = .049). However, the incidence of acute kidney injury (AKI) and uric acid (UA) concentration at postoperative 48 hours between these 2 groups were no statistical difference. There was no statistical significance in the Villalta score and post-thrombosis syndrome (PTS) incidence during postoperative follow-up. CONCLUSIONS: AngioJet thrombectomy system is more effective for the treatment of LEDVT by providing a higher clot reduction rate with shorter thrombolytic time and lower thrombolytic drug dosage. However, the device-related potential risk of renal function injury should be taken appropriate precautions.

Oral Human Papillomavirus Associated With Differences in Oral Microbiota Beta Diversity and Microbiota Abundance.

BACKGROUND: Although cervicovaginal microbiome has been associated with cervical human papillomavirus (HPV) infection, little is known regarding the association of oral microbiome with oral HPV, a cause of oropharyngeal cancer. METHODS: A cross-sectional analysis of 495 participants from the Men and Women Offering Understanding of Throat HPV study was conducted. 16S rRNA gene amplicon sequencing was performed on saliva samples. HPV DNA in oral rinse samples was tested. Associations of oral microbiome diversity, taxon abundance, and predicted functional pathways with oral HPV were assessed, adjusting for age, race/ethnicity, education, human immunodeficiency virus, current smoking, and sequencing batch. RESULTS: Participants with oral HPV (n = 68) compared with those without HPV had similar oral microbiome alpha-diversity yet different beta-diversity (Bray-Curtis distance for bacterial taxa, P = .009; functional pathways, P = .02). Participants with oral HPV had higher abundance of Actinomycetaceae, Prevotellaceae, Veillonellaceae, Campylobacteraceae, Bacteroidetes, and lower abundance of Gemellaceae (false discovery rate <0.10). We also found differential functional potential of oral microbiome by oral HPV status: xenobiotic biodegradation-related pathways were less abundant among participants with oral HPV, suggesting potential xenobiotic-induced toxic effects with implications for HPV susceptibility. CONCLUSIONS: Our findings suggest a shift in oral microbiome community structure, composition, and functional potential between individuals with and without oral HPV.

Angiotensin-converting enzyme 2 in peripheral lung club cells modulates the susceptibility to SARS-CoV-2 in chronic obstructive pulmonary disease.

Accumulating evidence has confirmed that chronic obstructive pulmonary disease (COPD) is a risk factor for development of severe pathological changes in the peripheral lungs of patients with COVID-19. However, the underlying molecular mechanisms remain unclear. Because bronchiolar club cells are crucial for maintaining small airway homeostasis, we sought to explore whether the altered susceptibility to SARS-CoV-2 infection of the club cells might have contributed to the severe COVID-19 pneumonia in COPD patients. Our investigation on the quantity and distribution patterns of angiotensin-converting enzyme 2 (ACE2) in airway epithelium via immunofluorescence staining revealed that the mean fluorescence intensity of the ACE2-positive epithelial cells was significantly higher in club cells than those in other epithelial cells (including ciliated cells, basal cells, goblet cells, neuroendocrine cells, and alveolar type 2 cells). Compared with nonsmokers, the median percentage of club cells in bronchiolar epithelium and ACE2-positive club cells was significantly higher in COPD patients. In vitro, SARS-CoV-2 infection (at a multiplicity of infection of 1.0) of primary small airway epithelial cells, cultured on air-liquid interface, confirmed a higher percentage of infected ACE2-positive club cells in COPD patients than in nonsmokers. Our findings have indicated the role of club cells in modulating the pathogenesis of SARS-CoV-2-related severe pneumonia and the poor clinical outcomes, which may help physicians to formulate a novel therapeutic strategy for COVID-19 patients with coexisting COPD.

A Novel Role of SLC26A3 in the Maintenance of Intestinal Epithelial Barrier Integrity.

BACKGROUND & AIMS: The down-regulated in adenoma (DRA) protein, encoded by SLC26A3, a key intestinal chloride anion exchanger, has recently been identified as a novel susceptibility gene for inflammatory bowel disease (IBD). However, the mechanisms underlying the increased susceptibility to inflammation induced by the loss of DRA remain elusive. Compromised barrier is a key event in IBD pathogenesis. The current studies were undertaken to elucidate the impact of DRA deficiency on epithelial barrier integrity and to define underlying mechanisms. METHODS: Wild-type and DRA-knockout (KO) mice and crypt-derived colonoids were used as models for intestinal epithelial response. Paracellular permeability was measured by using fluorescein isothiocyanate-dextran flux. Immunoblotting, immunofluorescence, immunohistochemistry, and ribonucleoprotein immunoprecipitation assays were performed. Gut microbiome analysis was conducted to investigate the impact of DRA deficiency on gut microbial communities. RESULTS: DRA-KO mice exhibited an increased colonic paracellular permeability with significantly decreased levels of tight junction/adherens junction proteins, including ZO-1, occludin, and E-cadherin. A similar expression pattern of occludin and E-cadherin was observed in colonoids derived from DRA-KO mice and short hairpin RNA-mediated DRA knockdown in Caco-2 cells. Microbial analysis showed gut dysbiosis in DRA-KO mice. However, cohousing studies showed that dysbiosis played only a partial role in maintaining tight junction protein expression. Furthermore, our results showed increased binding of RNA-binding protein CUGBP1 with occludin and E-cadherin genes in DRA-KO mouse colon, suggesting that posttranscriptional mechanisms play a key role in gut barrier dysfunction. CONCLUSIONS: To our knowledge, our studies demonstrate a novel role of DRA in maintaining the intestinal epithelial barrier function and potential implications of its dysregulation in IBD pathogenesis.

A mixed-model approach for powerful testing of genetic associations with cancer risk incorporating tumor characteristics.

Cancers are routinely classified into subtypes according to various features, including histopathological characteristics and molecular markers. Previous genome-wide association studies have reported heterogeneous associations between loci and cancer subtypes. However, it is not evident what is the optimal modeling strategy for handling correlated tumor features, missing data, and increased degrees-of-freedom in the underlying tests of associations. We propose to test for genetic associations using a mixed-effect two-stage polytomous model score test (MTOP). In the first stage, a standard polytomous model is used to specify all possible subtypes defined by the cross-classification of the tumor characteristics. In the second stage, the subtype-specific case-control odds ratios are specified using a more parsimonious model based on the case-control odds ratio for a baseline subtype, and the case-case parameters associated with tumor markers. Further, to reduce the degrees-of-freedom, we specify case-case parameters for additional exploratory markers using a random-effect model. We use the Expectation-Maximization algorithm to account for missing data on tumor markers. Through simulations across a range of realistic scenarios and data from the Polish Breast Cancer Study (PBCS), we show MTOP outperforms alternative methods for identifying heterogeneous associations between risk loci and tumor subtypes. The proposed methods have been implemented in a user-friendly and high-speed R statistical package called TOP (https://github.com/andrewhaoyu/TOP).

MiRKAT: kernel machine regression-based global association tests for the microbiome.

SUMMARY: Distance-based tests of microbiome beta diversity are an integral part of many microbiome analyses. MiRKAT enables distance-based association testing with a wide variety of outcome types, including continuous, binary, censored time-to-event, multivariate, correlated and high-dimensional outcomes. Omnibus tests allow simultaneous consideration of multiple distance and dissimilarity measures, providing higher power across a range of simulation scenarios. Two measures of effect size, a modified R-squared coefficient and a kernel RV coefficient, are incorporated to allow comparison of effect sizes across multiple kernels. AVAILABILITY AND IMPLEMENTATION: MiRKAT is available on CRAN as an R package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Hemodialysis Arteriovenous Fistula Dysfunction: Retrospective Comparison of Post-thrombotic Percutaneous Endovascular Interventions with Pre-emptive Angioplasty.

BACKGROUND: We aimed to compare the clinical outcomes of pre-emptive angioplasty versus post-thrombotic percutaneous endovascular restoration of dysfunctional arteriovenous fistula (AVF). METHODS: This retrospective study reviewed the data from 80 patients who underwent 114 endovascular interventions for a malfunctioning AVF from July 2016 to August 2019. Stenotic AVFs were treated with pre-emptive angioplasty. Thrombosed AVFs were treated with percutaneous pharmacomechanical fibrinolysis with urokinase used only during the operation or continuously infused. The differences in patency rates were evaluated using the Kaplan-Meier method. In addition, univariate and multivariate regression Cox models were used to determine influential factors on the postintervention primary patency. RESULTS: Post-thrombotic interventions and pre-emptive angioplasty yielded statistically similar rates in clinical success (100 vs. 100%), anatomic success (94 vs. 89%; P = 0.52), complication (4 vs. 11%; P = 0.29), as well as postintervention primary, assisted primary and secondary patency (P = 0.80; 0.57; 0.57). The use of pre-emptive angioplasty was associated with reduced total cost (¥25,108 vs. ¥30,833, P < 0.001). The patients who used urokinase only during the operation prolonged both the primary and assisted primary patency (P = 0.02; 0.002), while those with continuous infusion of urokinase had worst patency rates and high costs (¥39,275 vs. ¥25,108 vs. ¥27,140, P < 0.001). Compared with the other locations, dysfunction in the anastomotic or juxta-anastomotic segment (HR = 0.41, P = 0.001) was associated with prolonged postintervention primary patency. CONCLUSIONS: No clinical outcome differences were found between the post-thrombotic percutaneous endovascular interventions and pre-emptive angioplasty. However, pre-emptive angioplasty decreased access expenditure.

A Multi-Pass Optically Pumped Rubidium Atomic Magnetometer with Free Induction Decay.

A free-induction-decay (FID) type optically-pumped rubidium atomic magnetometer driven by a radio-frequency (RF) magnetic field is presented in this paper. Influences of parameters, such as the temperature of rubidium vapor cell, the power of pump beam, and the strength of RF magnetic field and static magnetic field on the amplitude and the full width at half maximum (FWHM) of the FID signal, have been investigated in the time domain and frequency domain. At the same time, the sensitivities of the magnetometer for the single-pass and the triple-pass probe beam cases have been compared by changing the optical path of the interaction between probe beam and atomic ensemble. Compared with the sensitivity of ∼21.2 pT/Hz1/2 in the case of the single-pass probe beam, the amplitude of FID signal in the case of the triple-pass probe beam has been significantly enhanced, and the sensitivity has been improved to ∼13.4 pT/Hz1/2. The research in this paper provids a reference for the subsequent study of influence of different buffer gas pressure on the FWHM and also a foundation for further improving the sensitivity of FID rubidium atomic magnetometer by employing a polarization-squeezed light as probe beam, to achieve a sensitivity beyond the photo-shot-noise level.

Sensitive, High-Speed, and Broadband Perovskite Photodetectors with Built-In TiO2 Metalenses.

Monolithic integration of nanostructured metalenses with broadband light transmission and good charge transport can simultaneously enhance the sensitivity, speed, and efficiency of photodetectors. The realization of built-in broadband metalenses in perovskite photodetectors, however, has been largely challenged by the limited choice of materials and the difficulty in nanofabrication. Here a new type of broadband-transmitting built-in TiO2 metalens (meta-TiO2 ) is devised, which is readily fabricated by one-step and lithograph-free glancing angle deposition. The meta-TiO2 , which comprises of sub-100 nm TiO2 nanopillars randomly spaced with a wide range of sub-wavelength distances in 5-200 nm, shows high transmittance of light in the wavelength range of 400-800 nm. The meta-TiO2 also serves as an efficient electron transporting layer to prevent the exciton recombination and facilitate the photoinduced electron extraction and transport. Replacing the conventional mesoporous TiO2 with the meta-TiO2 comprehensively leads to enhancing the detection speed by three orders of magnitude to a few hundred nanoseconds, improving the responsivity and detectivity by one order of magnitude to 0.5 A W-1 and 1013 Jones, respectively, and extending the linear dynamic range by 50% to 120 dB.