Frequency of cardiac rhabdomyomas stratified by age and gender.

<p>The rates indicate the percentages of female patients with cardiac rhabdomyomas (red) and male patients with cardiac rhabdomyomas (blue). The bars indicate the CI.</p

Association of refractory epilepsy and autism/ASD with intellectual disabilities.

<p>Frequency (%) of patients with refractory epilepsy (red column) and autism/ASD (blue column) at each intellectual level are shown. The statistical analyses of refractory epilepsy and autism/ASD in relation to intellectual disability were examined using the chi-square test, and the generalized logistic models showed significance at <i>p</i><0.001. The bars indicate the CI.</p

Frequency of each manifestation compared with historical data.

<p>SEN : subependymal nodule.</p><p>SEGA : subependymal giant cell astrocytoma.</p><p>LAM : lymphangioleiomyomatosis.</p><p>MMPH : multifocal micronodular pneumocyte hyperplasia.</p><p>CI : confidence interval.</p><p>H : significantly higher.</p><p>L : significantly lower.</p><p>ND : no significant difference.</p

Trends in the age-specific frequency of each skin manifestation.

<p>The frequency indicates the proportion of patients in each age group with A) FA (facial angiofibromas: blue), B) severe and mild FA (light blue), C) hypomelanotic macules (yellow), D) shagreen patches (purple) and E) ungual fibromas (red). The angiofibromas were divided into three classes, slight, mild and severe, as described in the text. AF includes angiofibromas of all classes. The bars indicate the CI.</p

Frequency of uterine leiomyomas and ovarian cysts in each age group.

<p>Fifty-one and 39 female patients over 20 years of age were examined for uterine leiomyomas and ovarian cysts, respectively. The rates indicate the proportions of patients in each age group with uterine leiomyomas (red) and ovarian cysts (blue). The bars indicate the CI.</p

Frequency of each pulmonary manifestation stratified by age and gender.

<p>LAM and MMPH stand for lymphangioleiomyomatosis and multifocal micronodular pneumocyte hyperplasia, respectively. A) The frequency of patients with LAM with/without MMPH, B) with both LAM and MMPH and C) with MMPH with/without LAM by age and gender are shown. The blue column indicates males, and the red column indicates females. The frequency (%) of patients with each manifestation in each examined age group. The bars indicate the CI.</p

Sample size determination for a specific region in multiregional clinical trials with multiple co-primary endpoints

<div><p>Recently, multi-regional clinical trials (MRCTs), which incorporate subjects from many countries/regions around the world under the same protocol, have been widely conducted by many global pharmaceutical companies. The objective of such trials is to accelerate the development process for a drug and shorten the drug’s approval time in key markets. Several statistical methods have been purposed for the design and evaluation of MRCTs, as well as for assessing the consistency of treatment effects across all regions with one primary endpoint. However, in some therapeutic areas (e.g., Alzheimer’s disease), the clinical efficacy of a new treatment may be characterized by a set of possibly correlated endpoints, known as multiple co-primary endpoints. In this paper, we focus on a specific region and establish three statistical criteria for evaluating consistency between the specific region and overall results in MRCTs with multiple co-primary endpoints. More specifically, two of those criteria are used to assess whether the treatment effect in the region of interest is as large as that of the other regions or of the regions overall, while the other criterion is used to assess the consistency of the treatment effect of the specific region achieving a pre-specified threshold. The sample size required for the region of interest can also be evaluated based on these three criteria.</p></div

Sample size and assurance probabilities for observing criteria (i), (ii), and (iii) given <i>α</i> = 0.025, <i>β</i> = 0.1, (Δ₁, Δ₂) = (3,0.45), (<i>σ</i>₁, <i>σ</i>₂) = (6,1), (<i>γ</i>₁, <i>γ</i>₂) = (0.5, 0.5), and <i>ρ</i>₁₂ = 0.5.

<p>Sample size and assurance probabilities for observing criteria (i), (ii), and (iii) given <i>α</i> = 0.025, <i>β</i> = 0.1, (Δ₁, Δ₂) = (3,0.45), (<i>σ</i>₁, <i>σ</i>₂) = (6,1), (<i>γ</i>₁, <i>γ</i>₂) = (0.5, 0.5), and <i>ρ</i>₁₂ = 0.5.</p

Influence of the Lactotripeptides Isoleucine–Proline–Proline and Valine–Proline–Proline on Systolic Blood Pressure in Japanese Subjects: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

<div><p>Background</p><p>The lactotripeptides isoleucine–proline–proline (IPP) and valine–proline–proline (VPP) have been shown to decrease systolic blood pressure (SBP) in several populations, but the size of the effect varies among studies. We performed a meta-analysis including all published studies to evaluate the SBP-lowering effect of IPP/VPP in Japanese subjects more comprehensively.</p><p>Methods and Findings</p><p>Eligible randomized controlled trials were searched for within four bibliographic databases, including two Japanese ones. Eighteen studies (including a total of 1194 subjects) were included in the meta-analysis. A random effect model using the restricted maximum likelihood (REML) estimator was used for the analysis. The analysis showed that consumption of IPP/VPP induced a significant reduction in SBP as compared with placebo in Japanese subjects, with an estimated effect of -5.63 mm Hg (95% CI, -6.87 to -4.39, P<0.0001) and no evidence of publication bias. A significant heterogeneity between series was evident, which could be explained by a significant influence of the baseline blood pressure status of the subjects, the effect of IPP/VPP on SBP being stronger in hypertensive subjects (-8.35 mm Hg, P<0.0001) than in non-hypertensive subjects (-3.42mm Hg, P<0.0001). Furthermore, the effect of IPP/VPP on SBP remained significant when limiting the analysis to series that tested the usual doses of IPP/VPP consumed daily (below 5 mg/d), with estimated effects of -6.01 mm Hg in the overall population and -3.32 mm Hg in non-hypertensive subjects.</p><p>Conclusions</p><p>Results from this meta-analysis show that IPP/VPP lactotripeptides can significantly reduce office SBP in Japanese subjects with or without overt hypertension, and for doses that can potentially be consumed as an everyday supplement. This suggests that these peptides could play a role in controlling blood pressure in Japanese subjects. The systematic review protocol was published on the PROSPERO register (CRD42014014322).</p></div

Characteristics of the 18 studies included in the meta-analysis of randomized controlled trials of the effect of isoleucine–proline–proline and valine–proline–proline on systolic blood pressure in Japanese subjects.

<p>BP: blood pressure. D: double-blinded. IPP: isoleucine–proline–proline. HT: hypertensive. NT: normotensive. n: number of subjects. PHT: pre-hypertensive. S: single-blinded. VPP: valine–proline–proline. y: years.</p><p>Characteristics of the 18 studies included in the meta-analysis of randomized controlled trials of the effect of isoleucine–proline–proline and valine–proline–proline on systolic blood pressure in Japanese subjects.</p