Effects of blastocyst elongation and implantation chamber formation on the alignment of the embryonic axis and uterine axis in mice.

Embryo implantation involves a series of events that bring the embryo and maternal tissues into contact to support post-implantation development in mammals. During implantation, alignment of the embryonic-abembryonic (E-Ab) axis of the blastocyst with the mesometrial-antimesometrial (M-AM) axis of the uterus precedes post-implantation embryonic development and placentation. In the present study, we observed the morphological changes in blastocysts and the endometrial luminal epithelium (LE) that occur during the alignment of the embryonic and the uterine axes. We found that at the time that the blastocysts attached to the LE at the mural trophectoderm, the embryonic axis was not aligned with the uterine axis. Alignment of the embryonic E-Ab axis with the uterine M-AM axis occurred after E4.0, and the embryo was significantly elongated during the process. The depth of the implantation chamber (IC) correlated with the degree of alignment, suggesting that elongated embryos are oriented along the M-AM axis during IC formation. Transplantation of the Concanavalin A (Con A)-coated beads induced IC formation, and the alignment of two Con A-coated beads present in the same IC in the M-AM direction suggested that elongated materials can align along the M-AM axis. These data suggest that an elongated shape of the embryo and IC formation coordinate the alignment of the embryonic and uterine axes.

Unincreased mortality of patients with early rheumatoid arthritis compared to the general population in the past 17 years: Analyses from the IORRA cohort.

OBJECTIVES: The aim of this article is to investigate the mortality rate of patients with early rheumatoid arthritis (RA) over the past 17 years. METHODS: Japanese patients with early RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis cohort from 2001 to 2012 were classified into Groups A (2001-06) and B (2007-12). The standardized mortality ratio (SMR) and 5-year survival rate were calculated. RESULTS: Groups A and B had 1609 and 1608 patients, of which 167 and 178 patients were lost during follow-up and 47 and 45 deaths were confirmed, respectively. The SMR (95% confidence intervals) for Groups A and B were 0.81 (0.59-1.08) and 0.78 (0.57-1.04), respectively, with the condition that all untraceable patients were alive. Assuming that the mortality rate of untraceable patients was twice as high as that of the general population, the SMR was 0.90 (0.68-1.19) for Group A and 0.92 (0.68-1.23) for Group B. The 5-year survival rates were 96.9% and 97.0% for Groups A and B, respectively. CONCLUSIONS: The 5-year mortality of patients with early RA has been comparable to that of the general Japanese population. The 5-year survival rate has been stable over the past 17 years.

Evaluation of RABBIT risk score in Japanese patients with rheumatoid arthritis starting first bDMARDs: a validation study using the IORRA cohort data.

OBJECTIVE: To examine the ability of the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) risk score to predict the occurrence of serious infections in Japanese patients with rheumatoid arthritis (RA), after initiating their first biologic disease-modifying antirheumatic drug (bDMARD). METHODS: We used data from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort from 2008 to 2020. Patients with RA who were started on their first bDMARDs were included. Those with missing data required to calculate the score were excluded. A receiver operating characteristic (ROC) curve was used to evaluate the discriminatory ability of the RABBIT score. RESULTS: A total of 1,081 patients were enrolled. During the one-year observational period, 23 (1.7%) patients had serious infections; the most frequent one was bacterial pneumonia (n=11, 44%). The median RABBIT score in the serious infection group was significantly higher than that in the non-serious infection group (2.3 [1.5-5.4] vs 1.6 [1.2-2.5], p<0.001). The area under the ROC curve for the occurrence of serious infections was 0.67 (95% confidence interval 0.52-0.79), suggesting that the score had low accuracy. CONCLUSION: Our present study revealed that the RABBIT risk score did not have sufficient discriminatory ability for predicting the development of severe infections in Japanese patients with rheumatoid arthritis after initiating their first bDMARD.

Trends in risks of malignancies in Japanese patients with rheumatoid arthritis: Analyses from a 14-year observation of the IORRA cohort.

OBJECTIVES: The aim is to investigate the trends in risks of overall and site-specific malignancies in patients with rheumatoid arthritis (RA). METHODS: Among Japanese patients with RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis cohort, all malignancies that occurred from 2000 to 2013 were extracted. The standardized incidence ratios and 95% confidence intervals for overall and site-specific malignancies were calculated during three periods: pre-biologics, 2000-04; early biologics, 2005-09; and recent biologics, 2010-13. Risk factors for overall and specific malignancies were analysed using time-dependent Cox regression models. RESULTS: Among 11,299 patients with RA (68,483 person-years), 507 malignancies were confirmed. Similar risks were observed versus the general Japanese population for overall malignancies throughout the three periods, with standardized incidence ratios (95% confidence intervals) of 0.96 (0.80-1.14) in the pre-biologics period, 0.95 (0.82-1.09) in the early biologics period, and 0.87 (0.75-1.01) in the recent biologics period. A significantly increased risk for malignant lymphoma was observed throughout the observation period (standardized incidence ratio 4.61, 95% confidence interval 3.58-5.85). The disease activity was a significant risk factor for overall malignancies and lung cancer. CONCLUSIONS: Despite the expanding use of methotrexate and biologics, there were no increases in malignancy risk in Japanese patients with RA.

Impact of concomitant chronic kidney disease on hospitalised infections and remission in patients with rheumatoid arthritis: results from the IORRA cohort.

OBJECTIVES: To investigate the impact of concomitant chronic kidney disease (CKD) on unfavourable clinical events and remission in Japanese patients with rheumatoid arthritis (RA). METHODS: We included 5103 patients with RA and CKD from the Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort in 2012. CKD stages were classified into four groups: CKD with normal eGFR ≥60 ml/min/1.73 m2 and proteinuria; mild CKD, eGFR ≥45 to < 60; moderate CKD, eGFR ≥30 to < 45; and severe CKD, eGFR <30. We assessed the association between concomitant CKD and the occurrence of unfavourable clinical events or achieving remission during a 5-year observational period. RESULTS: Of the 5103 patients with RA, 686 (86.6%) had CKD. Concomitant CKD was associated with hospitalised infections [adjusted hazard ratio (aHR) 1.52, 95% confidence interval (CI) 1.07-2.13, p = .02], especially in the moderate to severe CKD group (aHR 1.93, 95% CI 1.12-3.13, p = .02). Of all subjects, 2407 (47.2%) had active RA at baseline and 401 (16.7%) had CKD. Concomitant CKD was also associated with the failure of achieving remission (aHR 0.82, 95% CI 0.68-0.99, p = .04). CONCLUSIONS: Concomitant CKD was a risk factor for hospitalised infections in Japanese patients with RA and failure of achieving remission in patients with active RA.

Differences in patients' population and efficacy/effectiveness of biologic disease-modifying antirheumatic drugs between randomized controlled trials and real-world settings in patients with rheumatoid arthritis - using the IORRA cohort.

OBJECTIVES: To evaluate the differences in patients' population and efficacy/effectiveness of biological disease-modifying antirheumatic drugs (bDMARDs) between randomized controlled trials (RCTs) and clinical practice in patients with rheumatoid arthritis. METHODS: We reviewed inclusion criteria in Phase II or III RCTs of bDMARDs conducted in Japan. The Institute of Rheumatology, Rheumatoid Arthritis study participants during the period when each RCT was conducted (Cohort A) and new bDMARD users at our institute in 2016 (Cohort B) were assessed for the fulfilment of the inclusion criteria. The effectiveness of bDMARDs in our cohort and their efficacy in RCTs were compared using the inverse-variance method. RESULTS: Nineteen RCTs were selected. The mean proportions of patients fulfilling all inclusion criteria of each RCT in Cohorts A and B were 2.3% and 7.6%, respectively. The pooled proportion ratios (95% confidence interval) for achieving the American College of Rheumatology 20 (ACR20), ACR50, ACR70, and disease activity score 28 remission in non-eligible cases for eight RCTs versus all corresponding RCTs were 0.38 (0.30-0.51), 0.41 (0.30-0.57), 0.54 (0.35-0.82), and 1.28 (1.10-1.56), respectively. CONCLUSIONS: Few rheumatoid arthritis patients fulfilled the inclusion criteria of the RCTs in clinical settings. There was a difference in the efficacy/effectiveness of bDMARDs between RCTs and clinical practice.

Risk of herpes zoster in patients with rheumatoid arthritis in the biologics era from 2011 to 2015 and its association with methotrexate, biologics, and corticosteroids.

OBJECTIVES: To elucidate the incidence and risk factors of herpes zoster (HZ) in patients with rheumatoid arthritis (RA) in the biologics era. METHODS: We determined the rate of HZ occurrence among the RA patients that participated in the Institute of Rheumatology, Rheumatoid Arthritis surveys from 2011 to 2015, by assessing medical records. The standardised incidence rate per 1000 patient-years with a 95% confidence interval (CI) was calculated, and risk factors for HZ were analysed using a time-dependent Cox regression analysis. RESULTS: Among 7815 patients (female, 84.7%) contributing to 25,863 patient-years of observation, 340 HZ events in 309 patients were confirmed. The standardised incidence rate (95% CI) per 1000 patient-years was 8.5 (6.9-10.5) in total, 6.0 (3.7-9.2) in men, and 11.0 (8.7-13.7) in women. Risk factors for HZ were age per 10 years (hazard ratio 1.14, 95% CI 1.03-1.26, p < .05), Japanese version of the Health Assessment Questionnaire (J-HAQ) score of 0.5-1.5 (versus J-HAQ = 0; 1.51, 1.09-2.10, p < .05), methotrexate use (1.58, 1.06-2.36, p < .05), and biologic use (1.88, 1.44-2.47, p < .01). CONCLUSIONS: In the era when biologics were frequently used and corticosteroid use and doses were decreasing, methotrexate and biologics increased the risk for HZ.

Successful discontinuation of biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis in real-world settings.

OBJECTIVES: To analyze the proportion of successful biological disease-modifying antirheumatic drugs (bDMARDs) discontinuation and related factors in patients with rheumatoid arthritis (RA) in clinical settings. METHODS: Among 1775 RA patients who started bDMARDs between 2003 and 2012, 43 patients with DAS28-ESR <3.2 at the time of bDMARD discontinuation were extracted. Patients were divided into two groups (bio-free success: BS and bio-free failure: BF groups) based on bDMARD usage and disease activity 1 year after discontinuation. We evaluated the proportion of bio-free success and assessed factors related to bio-free success. RESULTS: Twenty-five patients (58.1%: BS group) maintained discontinuation of bDMARDs and DAS28-ESR <3.2 at 1 year after discontinuation. The median DAS28-ESR at bDMARD initiation was lower in the BS group than in the BF group (3.95 vs 5.04; p = .04). The BS group experienced a larger decrease in average glucocorticoid (GC) dose during bDMARD use than the BF group (-3.0 mg/day vs 0 mg/day; p = .01). CONCLUSION: bDMARDs were discontinued without flare up of RA in 58.1% of patients with RA in clinical settings. A lower DAS28-ESR at initiation and reduction of GC dose before discontinuation of bDMARD were important factors associated with bio-free success.

Intercellular and intracellular cilia orientation is coordinated by CELSR1 and CAMSAP3 in oviduct multi-ciliated cells.

The molecular mechanisms by which cilia orientation is coordinated within and between multi-ciliated cells (MCCs) are not fully understood. In the mouse oviduct, MCCs exhibit a characteristic basal body (BB) orientation and microtubule gradient along the tissue axis. The intracellular polarities were moderately maintained in cells lacking CELSR1 (cadherin EGF LAG seven-pass G-type receptor 1), a planar cell polarity (PCP) factor involved in tissue polarity regulation, although the intercellular coordination of the polarities was disrupted. However, CAMSAP3 (calmodulin-regulated spectrin-associated protein 3), a microtubule minus-end regulator, was found to be critical for determining the intracellular BB orientation. CAMSAP3 localized to the base of cilia in a polarized manner, and its mutation led to the disruption of intracellular coordination of BB orientation, as well as the assembly of microtubules interconnecting BBs, without affecting PCP factor localization. Thus, both CELSR1 and CAMSAP3 are responsible for BB orientation but in distinct ways; their cooperation should therefore be critical for generating functional multi-ciliated tissues.

Artificial Optic Flow Guides Visual Attention in a Driving Scene.

OBJECTIVE: The objective of this study was to investigate whether an artificial optic flow created by dot motion guides attention in a driving scene. BACKGROUND: To achieve safe driving, it is essential to understand the characteristics of human visual information processing as well as to provide appropriate support for drivers. Past research has demonstrated that expanding optic flow guides visual attention to the focus of expansion. Optic flow is an attractive candidate for use as a cue to direct drivers' attention toward the significant information. The question addressed concerns whether an artificial optic flow can successfully guide attention even in a traffic situation involving the optic flow that naturally occurs while driving. METHOD: We developed a visual search paradigm embedded in a video of a driving scene. Participants first observed an optic flow motion pattern superimposed on the video for brief period; next, when the optic flow and video ceased, they searched a static display for a target among multiple distractors. RESULTS: The target detection was faster when a target's locus coincided with the implied focus of expansion from the preceding optic flow (vs. other loci). CONCLUSION: The artificial optic flow guides attention and facilitates searching objects at the focus of expansion even when the optic flow was superimposed on a driving scene. APPLICATION: Optic flow can be an effective cue for guiding drivers' attention in a traffic situation. This finding contributes to the understanding of visual attention in moving space and helps develop technology for traffic safety.

Spatial variability induces generalization in contextual cueing.

We can incidentally learn regularities in a visual scene, and this kind of learning facilitates subsequent processing of similar scenes. One example of incidental learning is referred to as contextual cueing, a phenomenon in which repetitive exposure to a particular spatial configuration facilitates visual search performance in the configuration. Previous studies have demonstrated that effects of contextual cueing generalize to similar, but not entirely identical configurations. Although humans may be capable of extracting regularity from variable instances and applying it to a new instance, the mechanisms underlying generalization in contextual cueing are not fully understood. We hypothesized that contextual cueing results from extraction of variance in item locations, and the variance is used to calculate the similarity between the learned and new configuration. Based on this hypothesis, we predicted that contextual cueing would generalize more widely when the variability of item locations during learning is large compared with when it is small. The results supported our hypothesis, indicating that spatial variability induced generalization in contextual cueing. This finding suggests that, in incidental learning, the similarity between a learned and new representation is computed based on the variance of inputs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Task-irrelevant optic flow guides attention in visual search.

Motion is an important factor in visual information processing. Studies have shown that global optic flow guides attention, but it remains unclear whether this attentional guidance occurs regardless of top-down attentional control settings for another endogenous cue. To address this issue, we developed a visual search paradigm in which a task-irrelevant optic flow starts and stops prior to a visual search task itself. Participants first observed an initial optic flow motion pattern for a brief period; next, they searched a static display for a target amongst multiple distractors. Results showed faster target detection when a target's locus coincided with the implied focus of expansion (FOE) from the preceding optic flow (vs. other loci). Eye-movement analyses revealed that initial saccades were drawn to the FOE during optic flow exposures and that relatively few saccades were needed to find targets contingent to the preceding FOE. The advantage of FOE for finding target occurred even when a salient feature singleton captured attention or when a task-relevant feature singleton was prioritized. Results of six experiments suggest that attentional control settings for a feature singleton do not over-ride a sustained influence of optic flow on attentional guidance.

Task-relevant information is prioritized in spatiotemporal contextual cueing.

Implicit learning of visual contexts facilitates search performance-a phenomenon known as contextual cueing; however, little is known about contextual cueing under situations in which multidimensional regularities exist simultaneously. In everyday vision, different information, such as object identity and location, appears simultaneously and interacts with each other. We tested the hypothesis that, in contextual cueing, when multiple regularities are present, the regularities that are most relevant to our behavioral goals would be prioritized. Previous studies of contextual cueing have commonly used the visual search paradigm. However, this paradigm is not suitable for directing participants' attention to a particular regularity. Therefore, we developed a new paradigm, the "spatiotemporal contextual cueing paradigm," and manipulated task-relevant and task-irrelevant regularities. In four experiments, we demonstrated that task-relevant regularities were more responsible for search facilitation than task-irrelevant regularities. This finding suggests our visual behavior is focused on regularities that are relevant to our current goal.

Difference in mitochondrial gene expression in granulosa cells between recombinant FSH and hMG cycles under in vitro fertilization and transfer.

PURPOSE: Examination of the mitochondrial mRNA expression in granulosa cells from an unspecified population of infertile patients to evaluate whether recombinant follicle stimulating hormone (recFSH) is more effective in producing higher quality embryo rates compared with human menopausal gonadotropin (hMG). METHOD: Thirty-nine patients who underwent the in vitro fertilization and embryo transfer program were retrospectively examined. Patients were administered recFSH (n = 18) or hMG (n = 20) in a long protocol where GnRH agonist was used. Granulosa cells were obtained during oocyte retrieval and examined for mitochondria mRNA expression ratio against GAPDH. Expressions of mitochondria mRNA were evaluated by real-time PCR analysis. RESULTS: The high-quality embryo rate in the hMG cycle was higher than in the recFSH cycle, and the total dose of hMG showed a positive correlation with the expression level of mitochondrial genes in granulosa cells. Moreover, mitochondria mRNA expression was higher in the hMG cycle than in the recFSH cycle. CONCLUSIONS: Compared with recFSH, hMG induces a higher mitochondrial gene expression ratio in granulosa cells at the time of oocyte retrieval and, therefore, may lead to higher quality embryo rates.