Hisashi Noma

Differentiation-defective phenotypes revealed by large-scale analyses of human pluripotent stem cells

Significance In the past few years, findings have been controversial in regard to whether human induced pluripotent stem cells (hiPSCs) are distinct from human embryonic stem cells (hESCs) in their molecular signatures and differentiation properties. In this study, hiPSCs and hESCs have overlapping variations in molecular signatures such as RNA expression and DNA methylation. However, some hiPSC clones retained a significant number of undifferentiated cells even after neural differentiation culture and formed teratoma when transplanted into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression levels of several genes, including those expressed from long terminal repeats of specific human endogenous retroviruses. They need to be identified and eliminated prior to applications in regenerative medicine. We examined the gene expression and DNA methylation of 49 human induced pluripotent stem cells (hiPSCs) and 10 human embryonic stem cells and found overlapped variations in gene expression and DNA methylation in the two types of human pluripotent stem cell lines. Comparisons of the in vitro neural differentiation of 40 hiPSCs and 10 human embryonic stem cells showed that seven hiPSC clones retained a significant number of undifferentiated cells even after neural differentiation culture and formed teratoma when transplanted into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression levels of several genes, including those expressed from long terminal repeats of specific human endogenous retroviruses. These data demonstrated a subset of hiPSC lines that have aberrant gene expression and defective potential in neural differentiation, which need to be identified and eliminated before applications in regenerative medicine.

Waiting list may be a nocebo condition in psychotherapy trials: a contribution from network meta‐analysis

Various control conditions have been employed in psychotherapy trials, but there is growing suspicion that they may lead to different effect size estimates. The present study aims to examine the differences among control conditions including waiting list (WL), no treatment (NT) and psychological placebo (PP).

Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis

BACKGROUND Lithium is the established standard in the long-term treatment of bipolar disorder, but several new drugs have been assessed for this indication. We did a network meta-analysis to investigate the comparative efficacy and tolerability of available pharmacological treatment strategies for bipolar disorder. METHODS We systematically searched Embase, Medline, PreMedline, PsycINFO, and the Cochrane Central Register of Controlled Trials for randomised controlled trials published before June 28, 2013, that compared active treatments for bipolar disorder (or placebo), either as monotherapy or as add-on treatment, for at least 12 weeks. The primary outcomes were the number of participants with recurrence of any mood episode, and the number of participants who discontinued the trial because of adverse events. We assessed efficacy and tolerability of bipolar treatments using a random-effects network meta-analysis within a Bayesian framework. FINDINGS We screened 114 potentially eligible studies and identified 33 randomised controlled trials, published between 1970 and 2012, that examined 17 treatments for bipolar disorder (or placebo) in 6846 participants. Participants assigned to all assessed treatments had a significantly lower risk of any mood relapse or recurrence compared with placebo, except for those assigned to aripiprazole (risk ratio [RR] 0·62, 95% credible interval [CrI] 0·38-1·03), carbamazepine (RR 0·68, 0·44-1·06), imipramine (RR 0·95, 0·66-1·36), and paliperidone (RR 0·84, 0·56-1·24). Lamotrigine and placebo were significantly better tolerated than carbamazepine (lamotrigine, RR 5·24, 1·07-26·32; placebo, RR 3·60, 1·04-12·94), lithium (RR 3·76, 1·13-12·66; RR 2·58, 1·33-5·39), or lithium plus valproate (RR 5·95, 1·02-33·33; RR 4·09, 1·01-16·96). INTERPRETATION Although most of the drugs analysed were more efficacious than placebo and generally well tolerated, differences in the quality of evidence and the side-effect profiles should be taken into consideration by clinicians and patients. In view of the efficacy in prevention of both manic episode and depressive episode relapse or recurrence and the better quality of the supporting evidence, lithium should remain the first-line treatment when prescribing a relapse-prevention drug in patients with bipolar disorder, notwithstanding its tolerability profile. FUNDING None.

Hand-sewn versus mechanical esophagogastric anastomosis after esophagectomy: a systematic review and meta-analysis.

OBJECTIVE To evaluate the risks and benefits of using a circular stapler (CS) compared with the hand-sewn (HS) method for the esophagogastric anastomosis after esophageal resection. BACKGROUND DATA Previous randomized controlled trials (RCTs) indicated that the use of a CS might prevent anastomotic leakage, whereas it was more likely to lead to anastomotic strictures. The relative efficacy of this intervention in comparison with the HS method has not been conclusively determined. METHODS A systematic review and meta-analysis of all RCTs that compared HS versus mechanical anastomosis using a CS was conducted regarding the leakage, strictures, operative time, and mortality. The study protocol was established a priori according to the recommendations of the Cochrane Collaboration. RESULTS Twelve RCTs were included with a total of 1407 patients. The use of a CS, compared with the HS method, (1) led to no significant difference in the incidence of anastomotic leakage [risk ratio (RR): 1.02, 95% confidence interval (CI): 0.66-1.59] or postoperative mortality (RR: 1.64, 95% CI: 0.95-2.83), (2) increased the incidence of anastomotic strictures (RR: 1.67, 95% CI: 1.16-2.42), and (3) reduced the length of the operation time (mean: -15.3 minutes, range: -28.1 to -2.39). For these results, a subgroup analysis and a meta-regression analysis yielded no significant differences for the anastomotic site, diameter of the CS, layer, or configuration. CONCLUSION The use of a CS contributed to reducing the length of the operation, but was associated with an increased risk of anastomotic strictures. Both the CS and the HS method are viable alternatives in the reconstruction after esophagectomy.

Confidence intervals for a random-effects meta-analysis based on Bartlett-type corrections

In medical meta-analysis, the DerSimonian-Laird confidence interval for the average treatment effect has been widely adopted in practice. However, it is well known that its coverage probability (the probability that the interval actually includes the true value) can be substantially below the target level. One particular reason is that the validity of the confidence interval depends on the assumption that the number of synthesized studies is sufficiently large. In typical medical meta-analyses, the number of studies is fewer than 20. In this article, we developed three confidence intervals for improving coverage properties, based on (i) the Bartlett corrected likelihood ratio statistic, (ii) the efficient score statistic, and (iii) the Bartlett-type adjusted efficient score statistic. The Bartlett and Bartlett-type corrections improve the large sample approximations for the likelihood ratio and efficient score statistics. Through numerical evaluations by simulations, these confidence intervals demonstrated better coverage properties than the existing methods. In particular, with a moderate number of synthesized studies, the Bartlett and Bartlett-type corrected confidence intervals performed well. An application to a meta-analysis of the treatment for myocardial infarction with intravenous magnesium is presented.

Asymmetry Analysis of Macular Inner Retinal Layers for Glaucoma Diagnosis

PURPOSE To determine if asymmetry in thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer, ganglion cell complex, and total retina between upper and lower macula halves can predict glaucoma. DESIGN Retrospective case-control series. METHODS One hundred twenty-two eyes of 122 patients (30 normal eyes and 30 preperimetric, 31 early, and 31 advanced glaucoma eyes) were studied. The RNFL, ganglion cell layer, ganglion cell complex, and total retina were segmented and measured on 10 vertical B-scans over a 30 × 15 degree macular area. The equation asymmetry index =|log10 (lower hemiretinal thickness/upper hemiretinal thickness)| was used to calculate asymmetry indices for 8 pairs of upper and lower 0.5-mm segments equidistant from the fovea on each scan. Areas under the receiver operating characteristic curve (AROCs) for mean thickness and mean asymmetry index of 10 B-scans were compared. RESULTS The overlap in values for normal and glaucomatous eyes was minimal for the ganglion cell layer asymmetry index. Thickness parameters decreased with the severity of glaucoma, whereas asymmetry indices did not. AROCs for thickness measurements tended to increase with increasing glaucoma severity (preperimetric, 0.746-0.808; early, 0.842-0.940; advanced, 0.943-0.995), whereas AROCs for asymmetry indices did not have distinct ranges according to glaucoma severity (advanced, 0.819-0.996; early, 0.861-0.998; preperimetric, 0.773-0.994). The AROC for the ganglion cell layer asymmetry index remained almost perfect regardless of glaucoma severity (0.994-0.998). CONCLUSIONS Macular retinal layer thickness asymmetry indices, particularly for the ganglion cell layer, show promise as early indicators of glaucomatous retinal damage.

Nationwide epidemiological survey of 169 patients with adult Still's disease in Japan.

Abstract Objectives. A nationwide survey was conducted to assess the number of patients, clinical aspects, treatment, and prognosis of adult Stills disease (ASD) in Japan. Methods. A primary questionnaire was sent to randomly selected medical institutions in order to estimate the number of patients. We sent a secondary questionnaire to the same institutions to characterize the clinical manifestations and treatment of ASD. Results. The estimated prevalence of ASD was 3.9 per 100,000. Analysis of 169 patients showed a mean age at onset of 46 years. The main clinical symptoms were fever, arthritis, and typical rash in agreement with previous surveys. Oral glucocorticoids were used to treat 96% of the patients, while methotrexate was used in 41% and biological agents were used in 16%. Lymphadenopathy and macrophage activation syndrome were significantly associated with increased risk of relapse (P < 0.05, each). Patients who achieved remission after tocilizumab therapy had significantly longer disease duration (6.2 years) than patients who did not (1.9 years) (p < 0.05). Conclusions. The 2010–2011 nationwide survey of ASD identified important changes in treatment and improvement of prognosis compared with previous surveys.

Estimating effect sizes of differentially expressed genes for power and sample-size assessments in microarray experiments.

In microarray screening for differentially expressed genes using multiple testing, assessment of power or sample size is of particular importance to ensure that few relevant genes are removed from further consideration prematurely. In this assessment, adequate estimation of the effect sizes of differentially expressed genes is crucial because of its substantial impact on power and sample-size estimates. However, conventional methods using top genes with largest observed effect sizes would be subject to overestimation due to random variation. In this article, we propose a simple estimation method based on hierarchical mixture models with a nonparametric prior distribution to accommodate random variation and possible large diversity of effect sizes across differential genes, separated from nuisance, nondifferential genes. Based on empirical Bayes estimates of effect sizes, the power and false discovery rate (FDR) can be estimated to monitor them simultaneously in gene screening. We also propose a power index that concerns selection of top genes with largest effect sizes, called partial power. This new power index could provide a practical compromise for the difficulty in achieving high levels of usual overall power as confronted in many microarray experiments. Applications to two real datasets from cancer clinical studies are provided.

Bayesian ranking and selection methods using hierarchical mixture models in microarray studies

The main purpose of microarray studies is screening to identify differentially expressed genes as candidates for further investigation. Because of limited resources in this stage, prioritizing or ranking genes is a relevant statistical task in microarray studies. In this article, we develop 3 empirical Bayes methods for gene ranking on the basis of differential expression, using hierarchical mixture models. These methods are based on (i) minimizing mean squared errors of estimation for parameters, (ii) minimizing mean squared errors of estimation for ranks of parameters, and (iii) maximizing sensitivity in selecting prespecified numbers of differential genes, with the largest effect. Our methods incorporate the mixture structures of differential and nondifferential components in empirical Bayes models to allow information borrowing across differential genes, with separation from nuisance, nondifferential genes. The accuracy of our ranking methods is compared with that of conventional methods through simulation studies. An application to a clinical study for breast cancer is provided.

The Maternal and Child Health (MCH) Handbook in Mongolia: A Cluster-Randomized, Controlled Trial

Objective To assess the effectiveness of the Maternal and Child Health (MCH) handbook in Mongolia to increase antenatal clinic attendance, and to enhance health-seeking behaviors and other health outcomes. Methods A cluster randomized trial was conducted using the translated MCH handbook in Bulgan, Mongolia to assess its effectiveness in promoting antenatal care attendance. Pregnant women were recruited from 18 randomly allocated districts using shuffled, sealed envelopes. The handbook was implemented immediately for women at their first antenatal visit in the intervention group, and nine months later in the control group. The primary outcome was the number of antenatal care visits of all women residing in the selected districts. Cluster effects were adjusted for using generalized estimation equation. Masking was not possible among care providers, pregnant women and assessors. Findings Nine districts were allocated to the intervention group and the remainder to the control group. The intervention group (253 women) attended antenatal clinics on average 6•9 times, while the control group (248 women) attended 6•2 times. Socioeconomic status affected the frequency of clinic attendance: women of higher socioeconomic status visited antenatal clinics more often. Pregnancy complications were more likely to be detected among women using the handbook. Conclusion The MCH handbook promotes continuous care and showed an increase in antenatal visits among the intervention group. The intervention will help to identify maternal morbidities during pregnancy and promote health-seeking behaviors. Trial Registration UMIN Clinical Trial Registry UMIN000001748