過活動膀胱発症予測モデルの構築と検証：ながはまスタディ

京都大学新制・課程博士博士(医学)甲第24191号医博第4885号京都大学大学院医学研究科医学専攻(主査)教授 中山 健夫, 教授 松村 由美, 教授 万代 昌紀学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Estimating Patient-Specific Relative Benefit of Adding Biologics to Conventional Rheumatoid Arthritis Treatment: An Individual Participant Data Meta-Analysis.

IMPORTANCE Current evidence remains ambiguous regarding whether biologics should be added to conventional treatment of rheumatoid arthritis for specific patients, which may cause potential overuse or treatment delay. OBJECTIVES To estimate the benefit of adding biologics to conventional antirheumatic drugs for the treatment of rheumatoid arthritis given baseline characteristics. DATA SOURCES Cochrane CENTRAL, Scopus, MEDLINE, and the World Health Organization International Clinical Trials Registry Platform were searched for articles published from database inception to March 2, 2022. STUDY SELECTION Randomized clinical trials comparing certolizumab plus conventional antirheumatic drugs with placebo plus conventional drugs were selected. DATA EXTRACTION AND SYNTHESIS Individual participant data of the prespecified outcomes and covariates were acquired from the Vivli database. A 2-stage model was fitted to estimate patient-specific relative outcomes of adding certolizumab vs conventional drugs only. Stage 1 was a penalized logistic regression model to estimate the baseline expected probability of the outcome regardless of treatment using baseline characteristics. Stage 2 was a bayesian individual participant data meta-regression model to estimate the relative outcomes for a particular baseline expected probability. Patient-specific results were displayed interactively on an application based on a 2-stage model. MAIN OUTCOMES AND MEASURES The primary outcome was low disease activity or remission at 3 months, defined by 3 disease activity indexes (ie, Disease Activity Score based on the evaluation of 28 joints, Clinical Disease Activity Index, or Simplified Disease Activity Index). RESULTS Individual participant data were obtained from 3790 patients (2996 female [79.1%] and 794 male [20.9%]; mean [SD] age, 52.7 [12.3] years) from 5 large randomized clinical trials for moderate to high activity rheumatoid arthritis with usable data for 22 prespecified baseline covariates. Overall, adding certolizumab was associated with a higher probability of reaching low disease activity. The odds ratio for patients with an average baseline expected probability of the outcome was 6.31 (95% credible interval, 2.22-15.25). However, the benefits differed in patients with different baseline characteristics. For example, the estimated risk difference was smaller than 10% for patients with either low or high baseline expected probability. CONCLUSIONS AND RELEVANCE In this individual participant data meta-analysis, adding certolizumab was associated with more effectiveness for rheumatoid arthritis in general. However, the benefit was uncertain for patients with low or high baseline expected probability, for whom other evaluations were necessary. The interactive application displaying individual estimates may help with treatment selection

Predicting the treatment response of certolizumab for individual adult patients with rheumatoid arthritis: protocol for an individual participant data meta-analysis.

BACKGROUND A model that can predict treatment response for a patient with specific baseline characteristics would help decision-making in personalized medicine. The aim of the study is to develop such a model in the treatment of rheumatoid arthritis (RA) patients who receive certolizumab (CTZ) plus methotrexate (MTX) therapy, using individual participant data meta-analysis (IPD-MA). METHODS We will search Cochrane CENTRAL, PubMed, and Scopus as well as clinical trial registries, drug regulatory agency reports, and the pharmaceutical company websites from their inception onwards to obtain randomized controlled trials (RCTs) investigating CTZ plus MTX compared with MTX alone in treating RA. We will request the individual-level data of these trials from an independent platform (http://vivli.org). The primary outcome is efficacy defined as achieving either remission (based on ACR-EULAR Boolean or index-based remission definition) or low disease activity (based on either of the validated composite disease activity measures). The secondary outcomes include ACR50 (50% improvement based on ACR core set variables) and adverse events. We will use a two-stage approach to develop the prediction model. First, we will construct a risk model for the outcomes via logistic regression to estimate the baseline risk scores. We will include baseline demographic, clinical, and biochemical features as covariates for this model. Next, we will develop a meta-regression model for treatment effects, in which the stage 1 risk score will be used both as a prognostic factor and as an effect modifier. We will calculate the probability of having the outcome for a new patient based on the model, which will allow estimation of the absolute and relative treatment effect. We will use R for our analyses, except for the second stage which will be performed in a Bayesian setting using R2Jags. DISCUSSION This is a study protocol for developing a model to predict treatment response for RA patients receiving CTZ plus MTX in comparison with MTX alone, using a two-stage approach based on IPD-MA. The study will use a new modeling approach, which aims at retaining the statistical power. The model may help clinicians individualize treatment for particular patients. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number pending (ID#157595)

Optimal duration of antibiotic treatment for community-acquired pneumonia in adults: a systematic review and duration-effect meta-analysis.

OBJECTIVES To find the optimal treatment duration with antibiotics for community-acquired pneumonia (CAP) in adults. DESIGN Systematic review and duration-effect meta-analysis. DATA SOURCES MEDLINE, Embase and CENTRAL through 25 August 2021. ELIGIBILITY CRITERIA All randomised controlled trials comparing the same antibiotics used at the same daily dosage but for different durations for CAP in adults. Both outpatients and inpatients were included but not those admitted to intensive care units. We imposed no date, language or publication status restriction. DATA EXTRACTION AND SYNTHESIS Data extraction by two independent reviewers. We conducted a random-effects, one-stage duration-effect meta-analysis with restricted cubic splines. We tested the non-inferiority with the prespecified non-inferiority margin of 10% examined against 10 days . The primary outcome was clinical improvement on day 15 (range 7-45 days). SECONDARY OUTCOMES all-cause mortality, serious adverse events and clinical improvement on day 30 (15-60 days). RESULTS We included nine trials (2399 patients with a mean (SD) age of 61.2 (22.1); 39% women). The duration-effect curve was monotonic with longer duration leading to a lower probability of improvement, and shorter treatment duration (3-9 days) was likely to be non-inferior to 10-day treatment. Harmful outcome curves indicated no association. The weighted average percentage of the primary outcome in the 10-day treatment arms was 68%. Using that average, the absolute clinical improvement rates of the following durations were: 3-day treatment 75% (95% CI: 68% to 81%), 5-day treatment 72% (95% CI: 66% to 78%) and 7-day treatment 69% (95% CI: 61% to 76%). CONCLUSIONS Shorter treatment duration (3-5 days) probably offers the optimal balance between efficacy and treatment burden for treating CAP in adults if they achieved clinical stability. However, the small number of included studies and the overall moderate-to-high risk of bias may compromise the certainty of the results. Further research on the shorter duration range is required. PROSPERO REGISTRATION NUMBER CRD 42021273357

microRNA-875-5p plays critical role for mesenchymal condensation in epithelial-mesenchymal interaction during tooth development

Epithelial-mesenchymal interaction has critical roles for organ development including teeth, during which epithelial thickening and mesenchymal condensation are initiated by precise regulation of the signaling pathway. In teeth, neural crest-derived mesenchymal cells expressed PDGF receptors migrate and become condensed toward invaginated epithelium. To identify the molecular mechanism of this interaction, we explored the specific transcriptional start sites (TSSs) of tooth organs using cap analysis of gene expression (CAGE). We identified a tooth specific TSS detected in the chromosome 15qD1 region, which codes microRNA-875 (mir875). MiR875-5p is specifically expressed in dental mesenchyme during the early stage of tooth development. Furthermore, PRRX1/2 binds to the mir875 promoter region and enhances the expression of mir875. To assess the role of miR875-5p in dental mesenchyme, we transfected mimic miR875-5p into mouse dental pulp (mDP) cells, which showed that cell migration toward dental epithelial cells was significantly induced by miR875-5p via the PDGF signaling pathway. Those results also demonstrated that miR875-5p induces cell migration by inhibiting PTEN and STAT1, which are regulated by miR875-5p as part of post-transcriptional regulation. Together, our findings indicate that tooth specific miR875-5p has important roles in cell condensation of mesenchymal cells around invaginated dental epithelium and induction of epithelial-mesenchymal interaction

Cognitive behavioral therapy for overactive bladder in women: study protocol for a randomized controlled trial

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Development and validation of prediction model for incident overactive bladder: The Nagahama study.

OBJECTIVES We aimed to develop models to predict new-onset overactive bladder in 5 years using a large prospective cohort of the general population. METHODS This is a secondary analysis of a longitudinal cohort study in Japan. The baseline characteristics were measured between 2008 and 2010, with follow-ups every 5 years. We included subjects without overactive bladder at baseline and with follow-up data 5 years later. Overactive bladder was assessed using the overactive bladder symptom score. Baseline characteristics (demographics, health behaviors, comorbidities, and overactive bladder symptom scores) and blood test data were included as predictors. We developed two competing prediction models for each sex based on logistic regression with penalized likelihood (LASSO). We chose the best model separately for men and women after evaluating models' performance in terms of discrimination and calibration using an internal validation via 200 bootstrap resamples and a temporal validation. RESULTS We analyzed 7218 participants (male: 2238, female: 4980). The median age was 60 and 55 years, and the number of new-onset overactive bladder was 223 (10.0%) and 288 (5.8%) per 5 years in males and females, respectively. The in-sample estimates for C-statistic, calibration intercept, and slope for the best performing models were 0.77 (95% confidence interval 0.74-0.80), 0.28 and 1.15 for males, and 0.77 (95% confidence interval 0.74-0.80), 0.20 and 1.08 for females. Internal and temporal validation gave broadly similar estimates of performance, indicating low optimism. CONCLUSION We developed risk prediction models for new-onset overactive bladder among men and women with good predictive ability

Movie- and mobile-therapy without therapist involvment for patients with obsessive–compulsive disorder: Protocol for a randomized controlled trial

Background: Self-help programs without therapist involvement for obsessive–compulsive disorder (OCD) are promising, but the high dropout rate is a significant issue. Our software, which incorporates entertainment elements, showed a completion rate of over 80% in a pre–post comparison study, with superior effectiveness. This is the protocol for a study that aims to evaluate the efficacy and tolerability of a video-based mobile application for OCD treatment through a randomized controlled trial. Methods: This study is designed as a randomized controlled trial with two parallel group comparison, with assessors blinded to group allocation. The study will include outpatients aged 18 years or older diagnosed with OCD. The intervention group will receive a mobile-device-based intervention using an application grounded in cognitive behavioral therapy. The treatment period will be 8 weeks, during which 21 sessions will be conducted. Participants not allocated to the intervention group will be assigned to a waitlist control group for 8 weeks. The primary outcome for effectiveness will be the comparison of the Yale–Brown Obsessive Compulsive Scale. As the primary outcome for tolerability, participants in the intervention group who complete 80% or more of the sessions by the 8-week point will be defined as treatment completers, and the proportion of completers will be calculated. Assuming a 10% attrition rate, a total of 88 participants will be needed. Results: Results will be presented according to the protocol. Conclusions: If this study demonstrates that OCD can be improved through mobile-based self-help treatment without therapist involvement, it will become an important treatment option for patients

Nephronectin plays critical roles in Sox2 expression and proliferation in dental epithelial stem cells via EGF-like repeat domains

Tooth development is initiated by epithelial-mesenchymal interactions via basement membrane (BM) and growth factors. In the present study, we found that nephronectin (Npnt), a component of the BM, is highly expressed in the developing tooth. Npnt localizes in the BM on the buccal side of the tooth germ and shows an expression pattern opposite that of the dental epithelial stem cell marker Sox2. To identify the roles of Npnt during tooth development, we performed knockdown and overexpression experiments using ex vivo organ and dental epithelial cell cultures. Our findings showed that loss of Npnt induced ectopic Sox2-positive cells and reduced tooth germ size. Over expression of Npnt showed increased proliferation, whereas the number of Sox2-positive cells was decreased in dental epithelial cells. Npnt contains 5 EGF-like repeat domains, as well as an RGD sequence and MAM domain. We found that the EGF-like repeats are critical for Sox2 expression and cell proliferation. Furthermore, Npnt activated the EGF receptor (EGFR) via the EGF-like repeat domains and induced the PI3K-Akt signaling pathway. Our results indicate that Npnt plays a critical scaffold role in dental epithelial stem cell differentiation and proliferation, and regulates Sox2 expression during tooth development

A Study on the Timing of Introduction of Knot Education : Report on the Youth Science Festival 2023 in Osaka

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