Sepsis-trained macrophages promote antitumoral tissue-resident T cells.

Sepsis induces immune alterations, which last for months after the resolution of illness. The effect of this immunological reprogramming on the risk of developing cancer is unclear. Here we use a national claims database to show that sepsis survivors had a lower cumulative incidence of cancers than matched nonsevere infection survivors. We identify a chemokine network released from sepsis-trained resident macrophages that triggers tissue residency of T cells via CCR2 and CXCR6 stimulations as the immune mechanism responsible for this decreased risk of de novo tumor development after sepsis cure. While nonseptic inflammation does not provoke this network, laminarin injection could therapeutically reproduce the protective sepsis effect. This chemokine network and CXCR6 tissue-resident T cell accumulation were detected in humans with sepsis and were associated with prolonged survival in humans with cancer. These findings identify a therapeutically relevant antitumor consequence of sepsis-induced trained immunity.

Real-world treatment patterns of palbociclib and blood count monitoring in patients with advanced breast cancer in Japan.

Aim: To reveal the treatment patterns of palbociclib and complete blood count (CBC) monitoring in a Japanese real-world setting. Materials & methods: Deidentified data of patients with advanced breast cancer who received palbociclib from 2017 to 2020 were examined from a Japanese claims database. Results & conclusion: We identified 1074 patients. Palbociclib was commonly prescribed as second- or later-line treatment in 2017/2018; thereafter its first-line treatment increased. Regardless of treatment lines, fulvestrant was most commonly prescribed in combination with palbociclib (57-66% in the first-third-line), and this finding differed from that in the USA. Most patients initiated palbociclib at 125 mg/day; however, over a half of patients reduced doses within the first 8 weeks. Although CBC was regularly monitored, some patients did not undergo blood tests. Early dose reduction and CBC monitoring should be performed cautiously to minimize safety concern and prevent early treatment discontinuation.

Healthcare burden of recurrent Clostridioides difficile infection in Japan: A retrospective database study.

This retrospective database study aimed to assess the healthcare burden of hospitalization cost and duration associated with recurrent Clostridioides difficile infection (rCDI) by comparison with C. difficile infection (CDI) in Japan, using a health claims database of 270 acute care hospitals. Overall, 5423 hospitalized patients, with a record of one hospital-onset, healthcare facility-associated primary CDI episode within the 180-day period, from its onset between January 2012 and September 2016, were included. Of these, 353 had at least one rCDI and 5070 had no rCDI. Compared with those with no rCDI, the median total cost of hospitalization for patients with rCDI was JPY 1,184,371 (USD 11,691) higher (JPY 2,489,424 [interquartile range {IQR}: 1,597,424-4,008,751] compared with JPY 1,305,053 [624,033-2,549,569]). In addition, rCDI resulted in twice longer hospitalization duration in median compared with CDI (79 days [IQR: 53-117] compared with 40 days [20-74]). Based on a generalized linear regression model with a Gamma distribution and a logarithmic link function, the estimated mean of cost and duration of hospitalization for patients with rCDI were JPY 1,284,519 (95% confidence limit: -95,532-2,664,569) (USD 12,679) higher and 20.3 days (-9.5‒50.0) longer, compared with patients with no rCDI. The estimated mean difference in cost was higher in older patients and patients with diseases resulting in an immunosuppressive state. Higher costs and longer hospitalization for rCDI impose a great burden on healthcare system as well as patients, highlighting the importance of preventing recurrence of CDI.

Development of the Japanese Core Outcome Measures Index (COMI): cross-cultural adaptation and psychometric validation.

BACKGROUND: The patient-rated Core Outcome Measures Index (COMI) assesses the multidimensional impact of back problems on the sufferer. The brevity and comprehensibility of the tool make it practical for use in clinical and research settings. Although the COMI has been cross-culturally adapted in various languages worldwide, there is currently no Japanese version. The aim of this study was to develop a Japanese version of the COMI by: (1) performing a cross-cultural adaptation of the English version and (2) evaluating the psychometric properties of the Japanese version of the COMI in Japanese volunteers with chronic back problems. METHODS: The English version of the COMI was cross-culturally adapted for the Japanese language using established guidelines. The pre-final version was pilot-tested in five Japanese-speaking patients with low back pain (LBP) and a history of spine surgery. The psychometric properties of the Japanese COMI were tested in a group of 1052 individuals with chronic LBP (LBP ≥3 months), aged 20-69 years, who were recruited through a web-based survey. The psychometric properties that were evaluated included convergent and known-group validity, using the following reference questionnaires: EuroQol 5 Dimension, Roland Morris Disability Questionnaire, Short Form 8™ Health Survey, and the Keele STarT Back Screening Tool. RESULTS: The pre-final version of the cross-culturally adapted Japanese COMI was completed without any major problems of understanding or acceptability. For the evaluation of its psychometric properties, tests for convergent validity showed moderate correlations between COMI items and the respective reference questionnaires for symptom-specific well-being [- 0.33--0.48] and disability domains [0.48] and strong correlations (> 0.5) for the other domains and the COMI summary score. The analysis of known-group validity showed a linear trend for the COMI score in relation to prognostic risk (P < 0.001). CONCLUSIONS: The Japanese COMI retained conceptual equivalence to the original using comprehensible and acceptable Japanese expressions. We developed a Japanese version of the COMI that displayed qualities that support its convergent and known-group validity. The availability of a Japanese version of the COMI should allow for improved documentation of the care provided to patients with back problems.

Gut-associated lymphoid tissue attrition associates with response to anti-α4ß7 therapy in ulcerative colitis.

Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4ß7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (ß7+) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4ß7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of ß7+IgG+ plasmablasts in circulation, as well as IgG+ plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4ß7-targeted therapies, with major implications for this therapeutic paradigm in UC.

Impact of "time zero" of Follow-Up Settings in a Comparative Effectiveness Study Using Real-World Data with a Non-user Comparator: Comparison of Six Different Settings.

BACKGROUND: Time-related bias can lead to misleading conclusions. Properly setting the "time zero" of follow-up is crucial for avoiding these biases. However, the time-zero setting is challenging when comparing users and non-users of a study drug because the latter do not have a time point for starting treatment. OBJECTIVE: This methodological study aimed to illustrate the impact of different time-zero settings on effect estimates in a comparative effectiveness study using real-world data with a non-user comparator. METHODS: Data for type 2 diabetes patients were extracted from an administrative claims database, and the onset of diabetic retinopathy (study outcome) was compared between users (treatment group) and non-users (non-use group) of lipid-lowering agents. We applied six time-zero settings to the same dataset. The adjusted hazard ratio (HR) for the outcome was estimated using a Cox regression model in each time-zero setting, and the obtained results were compared among the settings. RESULTS: Of the six settings, three (study entry date [SED] vs SED [naïve approach], treatment initiation [TI] vs SED, TI vs Matched [random order]) showed that the treatment had a reduced risk of the outcome (HR [95% CI]: 0.65 [0.61-0.69], 0.92 [0.86-0.97], and 0.76 [0.71-0.82], respectively), one (TI vs Random) had an increased risk (HR [95% CI]: 1.52 [1.40-1.64]) , and two (SED vs SED [cloning method], and TI vs Matched [systematic order]) had neither increased nor decreased risk (HR [95% CI]: 0.95 [0.93-1.13], and 0.99 [0.93-1.07], respectively). CONCLUSIONS: This study demonstrates that different time-zero settings can lead to different conclusions, even if the same dataset is analyzed for the same research question, probably because improper settings can introduce bias. To minimize such biases, researchers should carefully define time zero, particularly when designing a non-user comparator study using real-world data.

Strategies to Address Current Challenges in Real-World Evidence Generation in Japan.

The generation of real-world evidence (RWE), which describes patient characteristics or treatment patterns using real-world data (RWD), is rapidly growing more popular as a tool for decision-making in Japan. The aim of this review was to summarize challenges to RWE generation in Japan related to pharmacoepidemiology, and to propose strategies to address some of these challenges. We first focused on data-related issues, including the lack of transparency of RWD sources, linkage across different care settings, definitions of clinical outcomes, and the overall assessment framework of RWD when used for research purposes. Next the study reviewed methodology-related challenges. As lack of design transparency impairs study reproducibility, transparent reporting of study design is critical for stakeholders. For this review, we considered different sources of biases and time-varying confounding, along with potential study design and methodological solutions. Additionally, the implementation of robust assessment of definition uncertainty, misclassification, and unmeasured confounders would enhance RWE credibility in light of RWD source-related limitations, and is being strongly considered by task forces in Japan. Overall, the development of guidance for best practices on data source selection, design transparency, and analytical methods to address different sources of biases and robustness in the process of RWE generation will enhance credibility for stakeholders and local decision-makers.

Myeloid cell influx into the colonic epithelium is associated with disease severity and non-response to anti-Tumor Necrosis Factor Therapy in patients with Ulcerative Colitis.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon with sharply rising global prevalence. Dysfunctional epithelial compartment (EC) dynamics are implicated in UC pathogenesis although EC-specific studies are sparse. Applying orthogonal high-dimensional EC profiling to a Primary Cohort (PC; n=222), we detail major epithelial and immune cell perturbations in active UC. Prominently, reduced frequencies of mature BEST4+OTOP2+ absorptive and BEST2+WFDC2+ secretory epithelial enterocytes were associated with the replacement of homeostatic, resident TRDC+KLRD1+HOPX+ γδ+ T cells with RORA+CCL20+S100A4+ TH17 cells and the influx of inflammatory myeloid cells. The EC transcriptome (exemplified by S100A8, HIF1A, TREM1, CXCR1) correlated with clinical, endoscopic, and histological severity of UC in an independent validation cohort (n=649). Furthermore, therapeutic relevance of the observed cellular and transcriptomic changes was investigated in 3 additional published UC cohorts (n=23, 48 and 204 respectively) to reveal that non-response to anti-Tumor Necrosis Factor (anti-TNF) therapy was associated with EC related myeloid cell perturbations. Altogether, these data provide high resolution mapping of the EC to facilitate therapeutic decision-making and personalization of therapy in patients with UC.

A novel human hepatoma cell line, FLC-4, exhibits highly enhanced liver differentiation functions through the three-dimensional cell shape.

We characterized three-dimensional human hepatoma cell lines, functional liver cell (FLC) cell lines, to establish a highly differentiated hepatoma cell line. We investigated the effect of extracellular matrix and cell morphology on liver-specific gene expression in FLC cells. The hepatocyte nuclear factor-4α (HNF-4α) and other liver-specific gene expressions were enhanced in spherical FLC-4 cells on EHS-gel, but other human hepatoma cells such as HepG2 did not show the enhancement. Importantly, the liver-specific gene expression levels in spherical FLC-4 cells cultured on EHS-gel were comparable to those of human liver and were much higher than those of other human hepatoma cell lines. The major matrix components and growth factors in EHS-gel did not affect cell shape and liver functions. To exclude any effect of the extracellular matrix, we made spherical FLC-4 cells by actin filament disruption. The actin-disrupted spherical cells also showed an enhanced liver-specific gene expression. We concluded that three-dimensional cell shape per se is one of the most important determinants of liver differentiation functions in FLC-4 cells. Cell morphology-dependent induction of liver-specific gene expression was mediated through microtubule organization. In conclusion, differentiation of FLC-4 human hepatoma cell line can be enhanced to a human liver-like level through the three-dimensional cell shape in a microtubule-dependent manner.

Bioinformatics training: selecting an appropriate learning content management system--an example from the European Bioinformatics Institute.

Today's molecular life scientists are well educated in the emerging experimental tools of their trade, but when it comes to training on the myriad of resources and tools for dealing with biological data, a less ideal situation emerges. Often bioinformatics users receive no formal training on how to make the most of the bioinformatics resources and tools available in the public domain. The European Bioinformatics Institute, which is part of the European Molecular Biology Laboratory (EMBL-EBI), holds the world's most comprehensive collection of molecular data, and training the research community to exploit this information is embedded in the EBI's mission. We have evaluated eLearning, in parallel with face-to-face courses, as a means of training users of our data resources and tools. We anticipate that eLearning will become an increasingly important vehicle for delivering training to our growing user base, so we have undertaken an extensive review of Learning Content Management Systems (LCMSs). Here, we describe the process that we used, which considered the requirements of trainees, trainers and systems administrators, as well as taking into account our organizational values and needs. This review describes the literature survey, user discussions and scripted platform testing that we performed to narrow down our choice of platform from 36 to a single platform. We hope that it will serve as guidance for others who are seeking to incorporate eLearning into their bioinformatics training programmes.

BioCatalogue: a universal catalogue of web services for the life sciences.

The use of Web Services to enable programmatic access to on-line bioinformatics is becoming increasingly important in the Life Sciences. However, their number, distribution and the variable quality of their documentation can make their discovery and subsequent use difficult. A Web Services registry with information on available services will help to bring together service providers and their users. The BioCatalogue (http://www.biocatalogue.org/) provides a common interface for registering, browsing and annotating Web Services to the Life Science community. Services in the BioCatalogue can be described and searched in multiple ways based upon their technical types, bioinformatics categories, user tags, service providers or data inputs and outputs. They are also subject to constant monitoring, allowing the identification of service problems and changes and the filtering-out of unavailable or unreliable resources. The system is accessible via a human-readable 'Web 2.0'-style interface and a programmatic Web Service interface. The BioCatalogue follows a community approach in which all services can be registered, browsed and incrementally documented with annotations by any member of the scientific community.

The Use of a Network Analysis to Identify Associations and Temporal Patterns Among Non-communicable Diseases in Japan Based on a Large Medical Claims Database.

BACKGROUND: Reducing the considerable non-communicable disease (NCD) burden in the aging Japanese population depends on better understanding of the comorbid and temporal relationships between different NCDs. OBJECTIVE: We aimed to identify associations between NCDs and temporal patterns of NCDs in Japan using data from a large medical claims database. METHODS: The study used three-digit International Classification of Diseases, Tenth Revision codes for NCDs for employees and their dependents included in the MinaCare database, which covers the period since 2010. Associations between pairs of NCDs were assessed by calculating risk ratios. The calculated risk ratios were used to create a network of closely associated NCDs (risk ratio > 15, statistically significant) and to assess temporal patterns of NCD diagnoses (risk ratio ≥ 5). The Infomap algorithm was used to identify clusters of diseases for different sex and age strata. RESULTS: The analysis included 4,200,254 individuals (age < 65 years: 98%). Many of the temporal associations and patterns of the diseases of interest identified in this study were previously known. Regarding the diseases of interest, these associations can be classified as comorbidities, early manifestations initially diagnosed as something else, diseases attributable to or that cause the disease of interest, or caused by pharmacological treatment. International Classification of Diseases, Tenth Revision chapters that were most associated with other chapters included L Diseases of the skin and subcutaneous tissue. In the age-stratified and gender-stratified networks, clusters with the highest numbers of International Classification of Diseases, Tenth Revision codes included I Diseases of the circulatory system and F Mental and behavioral disorders. CONCLUSIONS: Our findings reinforce established associations between NCDs and underline the importance of comprehensive NCD care.

Context and Considerations for Use of Two Japanese Real-World Databases in Japan: Medical Data Vision and Japanese Medical Data Center.

In Japan, an increasing interest in real-world evidence for hypothesis generation and decision-making has emerged in order to overcome limitations and restrictions of clinical trials. We sought to characterize the context and concrete considerations of when to use Medical Data Vision (MDV) and JMDC databases, the main Japanese real-world data (RWD) sources accessible by pharmaceutical companies. Use cases for these databases, and related issues and considerations, were identified and summarized based on a literature search and experience-based knowledge. Studies conducted using MDV or JMDC were mostly descriptive in nature, or explored potential risk factors by evaluating associations with a target outcome. Considerations such as variable ascertainment at different time points, including issues relating to treatment identification and missing data, were highlighted for these two databases. Although several issues were commonly shared (e.g., only month of event occurrence reported), some database-specific issues were also identified and need to be accounted for. In conclusion, MDV and JMDC present limitations that are relatively typical of RWD sources, though some of them are unique to Japan, such as the identification of event occurrence and the inability to track patients visiting different healthcare settings. Addressing study design and careful result interpretation with respect to the specificities and uniqueness of the Japanese healthcare system is of particular importance. This aspect is especially relevant with respect to the growing global interest of conducting RWD studies in Japan.

IL-22BP production is heterogeneously distributed in Crohn's disease.

Crohn's disease (CD), a form of inflammatory bowel disease (IBD), is characterized by impaired epithelial barrier functions and dysregulated mucosal immune responses. IL-22 binding protein (IL-22BP) is a soluble inhibitor regulating IL-22 bioactivity, a cytokine proposed to play protective roles during CD. We and others have shown that IL-22BP is produced in IBD inflamed tissues, hence suggesting a role in CD. In this work, we extended the characterization of IL-22BP production and distribution in CD tissues by applying enzyme-linked immunosorbent assays to supernatants obtained from the culture of endoscopic biopsies of patients, and reverse transcription-quantitative polymerase chain reaction on sorted immune cell subsets. We reveal that IL-22BP levels are higher in inflamed ileums than colons. We observe that in a cell-intrinsic fashion, populations of mononuclear phagocytes and eosinophils express IL-22BP at the highest levels in comparison to other sources of T cells. We suggest the enrichment of intestinal eosinophils could explain higher IL-22BP levels in the ileum. In inflamed colon, we reveal the presence of increased IL-22/IL22BP ratios compared to controls, and a strong correlation between IL-22BP and CCL24. We identify monocyte-derived dendritic cells (moDC) as a cellular subtype co-expressing both cytokines and validate our finding using in vitro culture systems. We also show that retinoic acid induces the secretion of both IL-22BP and CCL24 by moDC. Finally, we report on higher IL-22BP levels in active smokers. In conclusion, our work provides new information relevant to therapeutic strategies modulating IL-22 bioactivity in CD, especially in the context of disease location.

Direct and Indirect Pathways for Health-Related Quality of Life Change from Pain Improvement in Neuropathic Pain Patients with Spine Diseases: Path Analysis with Structural Equation Modeling Using Non-Interventional Study Results of Pregabalin.

BACKGROUND: Chronic low back pain or chronic cervical pain often has a neuropathic pain (NeP) component and patients with these conditions complain of sleep deprivation, loss of physical function, and reduced productivity due to pain. The objective of this study was to clarify the pathway by which pain, sleep disturbance due to pain, and physical function status influence QOL measures in chronic low back pain patients with NeP associated with lumbar spine diseases (CLBP-NeP) and in chronic cervical pain patients with NeP associated with cervical spine diseases (CCP-NeP). METHODS: A model assuming pain numeric rating scale (NRS), pain-related sleep interference scale (PRSIS), and functional indices (Roland Morris Disability Questionnaire [RMDQ], Neck Disability index [NDI]) as factors that can affect outcomes such as QOL (calculated using EuroQoL 5 Dimensions (EQ-5D)), the Patient Global Impression of Change (PGIC), and the Clinical Global Impression of Change (CGIC) was developed using structural equation modeling. RESULTS: Overall trends were frequently observed in both patients with CLBP-NeP and CCP-NeP. Pain NRS had the largest comprehensive direct impact on QOL based on EQ-5D and an overall impression of changing symptoms. The effects of pain NRS on each outcome were largely due to direct pain-related effects; however, for EQ-5D, an indirect effect via functional improvement was the primary factor. CONCLUSION: Although the results of this study suggest that the indirect functional improvement of pain relief may not be recognized as a significant component of therapeutic effects by both physicians and patients, the pain-relieving intervention contributes directly to improvement of patients' overall QOL and also indirectly via functional improvement in Japanese primary care settings. Accordingly, to achieve the therapeutic goal for patients with NeP and minimize the impact of pain burden, our findings indicate that pain relief interventions are also crucial from the perspective of the patient's HRQOL.

Changes in the Penetration Rate of Biosimilar Infliximab Within Japan Using a Japanese Claims Database.

PURPOSE: Infliximab, which was approved in 2002, had its first biosimilar launched in 2014 across Japan. However, the penetration rate of this biosimilar remains unclear given the limited data regarding its current clinical use throughout Japan. This study was conducted to describe the current clinical characteristics of patients receiving infliximab and the penetration rate of the reference infliximab and/or biosimilar infliximab using a Japanese administrative claims database. PATIENTS AND METHODS: This retrospective, descriptive study utilized the Japan Medical Data Vision database, a nationwide hospital-based database. Data on patients receiving infliximab recorded from April 2008 to March 2019 were extracted from the database. Patient characteristics of the reference and biosimilar infliximab groups and penetration rates according to fiscal year, target diseases diagnosis, and subsidy for intractable diseases were examined. RESULTS: A total of 9735 patients were extracted for analysis, among whom 92% (n=8950) and 8% (n=785) received only reference infliximab and its biosimilar, respectively. Both groups exhibited similar clinical characteristics. The biosimilar penetration rate increased from 0.8% in 2014 to 22.5% in 2018, with overall penetration rates throughout the period according to diagnosis (with or without subsidy) being 14.4% (with, 4.1%; without, 16.4%), 4.7% (with, 3.7%; without, 10.6%), 5.7% (with, 4.5%; without, 13.5%), and 7.5% (with, 4.4%; without, 8.2%) for rheumatoid arthritis, Crohn's disease, ulcerative colitis, and psoriasis, respectively. CONCLUSION: Biosimilar infliximab is prescribed for patients with similar characteristics to reference infliximab. Despite the increasing penetration rates according to target disease, they remain much lower among patients receiving subsidy for intractable disease than among those who do not.

Delayed Meal Timing, a Breakfast Skipping Model, Increased Hepatic Lipid Accumulation and Adipose Tissue Weight by Disintegrating Circadian Oscillation in Rats Fed a High-Cholesterol Diet.

Background: To investigate whether shifted timing of eating, breakfast skipping, induces alterations in the circadian clock and abnormal lipid metabolism, we have established a delayed meal timing (DMT) protocol for rats, which started eating food 4 h delay. In the present study, control and DMT rats were fed a high-cholesterol diet during zeitgeber time (ZT) 12-24 and ZT 16-4, respectively. The DMT protocol increased the hepatic lipids and epididymal adipose tissue weight without changes in food intake and body weight. The surge in body temperature was delayed by 4 h in the DMT group, suggesting that energy expenditure was decreased in response to DMT. The peaks of the diurnal rhythm of serum non-esterified fatty acids and insulin were delayed by 2 and 4 h due to DMT, respectively. The oscillation peaks of hepatic de novo fatty acid synthesis gene expression was delayed by 4 h in response to DMT, whereas the peak of hepatic clock genes were 2 h delayed or not by DMT. Although metabolic oscillation is considered to be controlled by clock genes, the disintegration rhythms between the clock genes and lipid metabolism-related genes were not observed in rats fed a high-fat diet in our previous study. These data suggest that the circadian rhythm of de novo fatty acid metabolism is regulated by timing of eating, but is not directly controlled by clock genes. The present study suggests that breakfast skipping would complicate fatty liver and body fat accumulation.

Comparison of hospital length of stay of acute ischemic stroke patients with non-valvular atrial fibrillation started on rivaroxaban or warfarin treatment during hospitalization.

OBJECTIVE: To compare the hospital length of stay (LOS) between rivaroxaban and warfarin in hospitalized acute stroke patients with non-valvular atrial fibrillation (NVAF) in Japan. METHODS: This was a retrospective, observational study using a Japanese hospital claims database. Data of NVAF patients who were started on oral anticoagulant (OAC) treatment during hospitalization were extracted and LOS-OAC (period from the initiation of index OAC therapy to the end of hospitalization or censoring date) and medical costs were compared between rivaroxaban and warfarin treatments. To compare LOS-OAC, a time-to-event analysis was performed using the Kaplan-Meier method. The analysis period was from April 2012 to December 2015. RESULTS: This study included 773 rivaroxaban users and 1077 warfarin users. After the propensity score matching, 546 patients for each treatment constituted the matched cohorts. Although the rivaroxaban users had a similar LOS-OAC to warfarin users (median, 18 vs. 19 days, p = .657) in the matched cohorts, 3 days shorter LOS-OAC was observed in the rivaroxaban users (median, 17 vs. 20 days, p = .043) after IPTW adjustment. Subgroup analysis by the severity of stroke after IPTW adjustment demonstrated that rivaroxaban users had a shorter LOS-OAC than warfarin users among patients with mild (median, 10 vs. 14 days) and moderate stroke severity (22 vs. 27 days), but not among those with severe stroke severity (26 vs. 25 days). LIMITATIONS: It is not possible to say that the only confounder was stroke severity and therefore other possible known and unknown confounders could not be ruled out. CONCLUSIONS: The rivaroxaban users had a 3-day shorter LOS-OAC after IPTW-adjustment. Using rivaroxaban was associated with 4-5 days shorter LOS-OAC than using warfarin in patients with mild or moderate stroke, though treatment selection did not have a large impact in patients with severe stroke.

Characterization of Rat ILCs Reveals ILC2 as the Dominant Intestinal Subset.

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that lack antigen-specific receptors and exhibit innate effector functions such as cytokine production that play an important role in immediate responses to pathogens especially at mucosal sites. Mouse and human ILC subsets have been extensively characterized in various tissues and in blood. In this study, we present the first characterization of ILCs and ILC subsets in rat gut and secondary lymphoid organs using flow cytometry and single cell RNA sequencing. Our results show that phenotype and function of rat ILC subsets are conserved as compared to human and mouse ILCs. However, and in contrast to human and mouse, our study unexpectedly revealed that ILC2 and not ILC3 was the dominant ILC subset in the rat intestinal lamina propria. ILC2 predominance in the gut was independent of rat strain, sex or housing facility. In contrast, ILC3 was the predominant ILC subset in mesenteric lymph nodes and Peyer patches. In conclusion, our study demonstrates that in spite of highly conserved phenotype and function between mice, rat and humans, the distribution of ILC subsets in the intestinal mucosa is dependent on the species likely in response to both genetic and environmental factors.