Inflammatory bowel disease and the associated risk of dry eye and ocular surface injury: a nationwide matched cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with lacrimal gland dysfunction and ocular inflammation. The objective of this research was to elucidate the temporal relationships between IBD, dry eye disease (DED), and corneal surface damage. METHODS: In a matched nationwide cohort study, we evaluated the risk of DED and corneal surface damage associated with IBD. Multivariable Cox proportional hazards regression analyses were implemented to estimate the risk of ocular complications. RESULTS: A total of 54,293 matched pairs were included for analyses. The median follow-up time was 8.3 years (interquartile range: 5.5 - 10.5). The period incidence of DED was 8.18 and 5.42 per 1000 person-years in the IBD and non-IBD groups, respectively. After adjusting for confounders, statistically significant associations were found between IBD and DED [adjusted hazard ratio (aHR): 1.43, 95% confidence interval (CI): 1.35 - 1.51, p < 0.0001], Sjögren's syndrome-related (aHR: 1.67, 95% CI:1.46 - 1.90, p < 0.0001) and non-Sjögren's syndrome-related subtypes (aHR: 1.38, 95% CI: 1.30 - 1.46, p < 0.0001). Furthermore, increased risks of corneal surface damage (aHR: 1.13, 95% CI: 1.03 - 1.24, p = 0.0094) among the patients with IBD were observed when compared with the controls. Other independent factors associated with corneal surface damage were age (aHR: 1.003), sex (male vs. female, aHR: 0.85), and monthly insurance premium (501-800 vs. 0-500 U.S. dollars, aHR: 1.45; ≥ 801 vs. 0-500 U.S. dollars, aHR: 1.32). CONCLUSIONS: Our results suggested that IBD was an independent risk factor for DED and ocular surface damage. Clinical strategies are needed to prevent visual impairment or losses in these susceptible patients.

The internal ribosome entry site determines the neurotropic potential of enterovirus A71.

The mechanisms underlying tissue-specific replication of enteroviruses are currently unclear. Although enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are both common pathogens that cause hand-foot-mouth disease, they display quite different neurotropic properties. Herein, we characterized the role of the internal ribosome entry site (IRES) in determining neurovirulence using an oral inoculation model of EV-A71. The receptor transgenic (hSCARB2-Tg) mice developed neurological symptoms after being infected with a mouse-adapted EV-A71 strain (MP4) via different administrative routes. Intragastric administration of the MP4 strain caused pathological changes such as neuronal loss and neuropil vacuolation, whereas replacing EV-A71 IRES with CV-A16 abolished the neuropathological phenotypes. The attenuated neurotropic potential of IRES-swapped EV-A71 was observed even in mice that received intraperitoneal and intracerebral inoculations. Fewer chimeric MP4 viral RNAs and proteins were detected in the mouse tissues, regardless of the inoculation route. Tissue-specific replication can be reflected in cell-based characterization. While chimeric MP4 virus replicated poorly in human intestinal C2BBe1 and neuroblastoma SH-SY5Y cells, its replication in susceptible rhabdomyosarcoma cells was not affected. Overall, our results demonstrated that the IRES determined the neurotropic potential of EV-A71 and CV-A16, emphasizing the importance of the IRES in tissue tropism, along with the host receptors.

Outcome analysis in 270 radiologically guided implantations of totally implantable venous access ports via basilic vein.

BACKGROUND: Totally implantable venous access ports (TIVAPs) are widely applied in patients who require chemotherapy, parenteral nutrition, or frequent intravenous drug infusion. Although various venous access routes are possible for TIVAP insertion, the best method remains a topic of controversy. We present a single-center retrospective study of radiologically guided placement of TIVAPs through the basilic vein, with analysis of technical feasibility, patient safety, and device-related complications. METHODS: We retrospectively reviewed 270 patients who received TIVAP implantation through the basilic vein from November 2013 to July 2016, under imaging guidance by an interventional radiology team at our institution. Fluoroscopic images, chest radiographs, computed tomography scans, and medical records were reviewed after port implantation. Catheter maintenance days were calculated and catheter-related complications were recorded. RESULTS: The procedural success rate was 99.3%. In total, 270 TIVAPs were implanted in 270 patients, of which 150 remained functional at the end of the study period. The total catheter maintenance days was 77 543 days, and the mean catheter indwelling duration was 287 ± 207 days. In 20 (7.4%) patients, TIVAP-related complications occurred during the follow-up period, resulting in a postprocedural complication rate of 0.26 incidences per 1000 catheter days. No significant relationship was observed between complications and gender (p = 0.188), age (p = 0.528), body mass index (p = 0.547), the type of primary malignancy (p = 0.914), or between the left and right basilic veins (p = 0.319). CONCLUSION: Real-time ultrasound and fluoroscopic guidance provides a safe method for TIVAP implantation through the basilic vein, with a high technical success rate and few device-related complications.

CASAnova: a multiclass support vector machine model for the classification of human sperm motility patterns.

The ability to accurately monitor alterations in sperm motility is paramount to understanding multiple genetic and biochemical perturbations impacting normal fertilization. Computer-aided sperm analysis (CASA) of human sperm typically reports motile percentage and kinematic parameters at the population level, and uses kinematic gating methods to identify subpopulations such as progressive or hyperactivated sperm. The goal of this study was to develop an automated method that classifies all patterns of human sperm motility during in vitro capacitation following the removal of seminal plasma. We visually classified CASA tracks of 2817 sperm from 18 individuals and used a support vector machine-based decision tree to compute four hyperplanes that separate five classes based on their kinematic parameters. We then developed a web-based program, CASAnova, which applies these equations sequentially to assign a single classification to each motile sperm. Vigorous sperm are classified as progressive, intermediate, or hyperactivated, and nonvigorous sperm as slow or weakly motile. This program correctly classifies sperm motility into one of five classes with an overall accuracy of 89.9%. Application of CASAnova to capacitating sperm populations showed a shift from predominantly linear patterns of motility at initial time points to more vigorous patterns, including hyperactivated motility, as capacitation proceeds. Both intermediate and hyperactivated motility patterns were largely eliminated when sperm were incubated in noncapacitating medium, demonstrating the sensitivity of this method. The five CASAnova classifications are distinctive and reflect kinetic parameters of washed human sperm, providing an accurate, quantitative, and high-throughput method for monitoring alterations in motility.

Male Infertility Is Responsible for Nearly Half of the Extinction Observed in the Mouse Collaborative Cross.

The goal of the Collaborative Cross (CC) project was to generate and distribute over 1000 independent mouse recombinant inbred strains derived from eight inbred founders. With inbreeding nearly complete, we estimated the extinction rate among CC lines at a remarkable 95%, which is substantially higher than in the derivation of other mouse recombinant inbred populations. Here, we report genome-wide allele frequencies in 347 extinct CC lines. Contrary to expectations, autosomes had equal allelic contributions from the eight founders, but chromosome X had significantly lower allelic contributions from the two inbred founders with underrepresented subspecific origins (PWK/PhJ and CAST/EiJ). By comparing extinct CC lines to living CC strains, we conclude that a complex genetic architecture is driving extinction, and selection pressures are different on the autosomes and chromosome X Male infertility played a large role in extinction as 47% of extinct lines had males that were infertile. Males from extinct lines had high variability in reproductive organ size, low sperm counts, low sperm motility, and a high rate of vacuolization of seminiferous tubules. We performed QTL mapping and identified nine genomic regions associated with male fertility and reproductive phenotypes. Many of the allelic effects in the QTL were driven by the two founders with underrepresented subspecific origins, including a QTL on chromosome X for infertility that was driven by the PWK/PhJ haplotype. We also performed the first example of cross validation using complementary CC resources to verify the effect of sperm curvilinear velocity from the PWK/PhJ haplotype on chromosome 2 in an independent population across multiple generations. While selection typically constrains the examination of reproductive traits toward the more fertile alleles, the CC extinct lines provided a unique opportunity to study the genetic architecture of fertility in a widely genetically variable population. We hypothesize that incompatibilities between alleles with different subspecific origins is a key driver of infertility. These results help clarify the factors that drove strain extinction in the CC, reveal the genetic regions associated with poor fertility in the CC, and serve as a resource to further study mammalian infertility.

The Mouse Universal Genotyping Array: From Substrains to Subspecies.

Genotyping microarrays are an important resource for genetic mapping, population genetics, and monitoring of the genetic integrity of laboratory stocks. We have developed the third generation of the Mouse Universal Genotyping Array (MUGA) series, GigaMUGA, a 143,259-probe Illumina Infinium II array for the house mouse (Mus musculus). The bulk of the content of GigaMUGA is optimized for genetic mapping in the Collaborative Cross and Diversity Outbred populations, and for substrain-level identification of laboratory mice. In addition to 141,090 single nucleotide polymorphism probes, GigaMUGA contains 2006 probes for copy number concentrated in structurally polymorphic regions of the mouse genome. The performance of the array is characterized in a set of 500 high-quality reference samples spanning laboratory inbred strains, recombinant inbred lines, outbred stocks, and wild-caught mice. GigaMUGA is highly informative across a wide range of genetically diverse samples, from laboratory substrains to other Mus species. In addition to describing the content and performance of the array, we provide detailed probe-level annotation and recommendations for quality control.

The Founder Strains of the Collaborative Cross Express a Complex Combination of Advantageous and Deleterious Traits for Male Reproduction.

Surveys of inbred strains of mice are standard approaches to determine the heritability and range of phenotypic variation for biomedical traits. In addition, they may lead to the identification of novel phenotypes and models of human disease. Surprisingly, male reproductive phenotypes are among the least-represented traits in the Mouse Phenome Database. Here we report the results of a broad survey of the eight founder inbred strains of both the Collaborative Cross (CC) and the Diversity Outbred populations, two new mouse resources that are being used as platforms for systems genetics and sources of mouse models of human diseases. Our survey includes representatives of the three main subspecies of the house mice and a mix of classical and wild-derived inbred strains. In addition to standard staples of male reproductive phenotyping such as reproductive organ weights, sperm counts, and sperm morphology, our survey includes sperm motility and the first detailed survey of testis histology. As expected for such a broad survey, heritability varies widely among traits. We conclude that although all eight inbred strains are fertile, most display a mix of advantageous and deleterious male reproductive traits. The CAST/EiJ strain is an outlier, with an unusual combination of deleterious male reproductive traits including low sperm counts, high levels of morphologically abnormal sperm, and poor motility. In contrast, sperm from the PWK/PhJ and WSB/EiJ strains had the greatest percentages of normal morphology and vigorous motility. Finally, we report an abnormal testis phenotype that is highly heritable and restricted to the WSB/EiJ strain. This phenotype is characterized by the presence of a large, but variable, number of vacuoles in at least 10% of the seminiferous tubules. The onset of the phenotype between 2 and 3 wk of age is temporally correlated with the formation of the blood-testis barrier. We speculate that this phenotype may play a role in high rates of extinction in the CC project and in the phenotypes associated with speciation in genetic crosses that use the WSB/EiJ strain as representative of the Mus muculus domesticus subspecies.

A novel multi-alignment pipeline for high-throughput sequencing data.

Mapping reads to a reference sequence is a common step when analyzing allele effects in high-throughput sequencing data. The choice of reference is critical because its effect on quantitative sequence analysis is non-negligible. Recent studies suggest aligning to a single standard reference sequence, as is common practice, can lead to an underlying bias depending on the genetic distances of the target sequences from the reference. To avoid this bias, researchers have resorted to using modified reference sequences. Even with this improvement, various limitations and problems remain unsolved, which include reduced mapping ratios, shifts in read mappings and the selection of which variants to include to remove biases. To address these issues, we propose a novel and generic multi-alignment pipeline. Our pipeline integrates the genomic variations from known or suspected founders into separate reference sequences and performs alignments to each one. By mapping reads to multiple reference sequences and merging them afterward, we are able to rescue more reads and diminish the bias caused by using a single common reference. Moreover, the genomic origin of each read is determined and annotated during the merging process, providing a better source of information to assess differential expression than simple allele queries at known variant positions. Using RNA-seq of a diallel cross, we compare our pipeline with the single-reference pipeline and demonstrate our advantages of more aligned reads and a higher percentage of reads with assigned origins. Database URL: http://csbio.unc.edu/CCstatus/index.py?run=Pseudo.

ZnO nanorod arrays for various low-bandgap polymers in inverted organic solar cells.

Due to the limited diffusion length of carriers in polymer solar cells (PSCs), the path of carriers is a crucial factor that determines the device performance. Zinc oxide nanorods (NRs) as the electron transport channel can reduce electron-hole recombination and transport the electron to the electrode efficiently for poly(3-hexylthiophene) (P3HT), but have been seldom demonstrated for low-bandgap polymers. Here we successfully applied ZnO NRs, which were grown via the hydrothermal method, as a platform to enhance PSC efficiency for various low-bandgap polymers. In order to assure that the nanorod morphology functioned properly for PSCs, the growth time, the concentration, and the resulting morphology were systematically investigated in depths. Such ZnO NRs were applied to different organic systems, resulting in the increase of the PCE for PBDTTT-C/PC71BM from 4.76% to 6.07% and PBDTTT-C-T/PC71BM from 5.40% to 7.34%. Through those experiments, we established a potentially universal and efficient ZnO NRs platform for various low-bandgap polymers to achieve high efficiency of inverted PSCs.