Group sequential multi-arm multi-stage survival trial design with treatment selection

Multi-arm trials are increasingly of interest because for many diseases; there are multiple experimental treatments available for testing efficacy. Several novel multi-arm multi-stage (MAMS) clinical trial designs have been proposed. However, a major hurdle to adopting the group sequential MAMS routinely is the computational effort of obtaining stopping boundaries. For example, the method of Jaki and Magirr for time-to-event endpoint, implemented in R package MAMS, requires complicated computational efforts to obtain stopping boundaries. In this study, we develop a group sequential MAMS survival trial design based on the sequential conditional probability ratio test. The proposed method is an improvement of the Jaki and Magirr’s method in the following three directions. First, the proposed method provides explicit solutions for both futility and efficacy boundaries to an arbitrary number of stages and arms. Thus, it avoids complicated computational efforts for the trial design. Second, the proposed method provides an accurate number of events for the fixed sample and group sequential designs. Third, the proposed method uses a new procedure for interim analysis which preserves the study power.</p

Synthesis of Heteroaryl Compounds through Cross-Coupling Reaction of Aryl Bromides or Benzyl Halides with Thienyl and Pyridyl Aluminum Reagents

An efficient method for synthesis of useful biaryl building blocks containing 2-thienyl, 3-thienyl, 2-pyridyl, and 3-pyridyl moieties was provided through cross-coupling reactions of aryl bromides or benzyl halides with heteroaryl aluminum reagents in the presence of Pd­(OAc)₂ and (<i>o</i>-tolyl)₃P. The coupling reaction also worked efficiently with heteroaryl bromides affording series of heterobiaryl compounds. The reaction of phenylbromide with in situ prepared 3-pyridyl aluminum was demonstrated to afford the product <b>8a</b> in high yield. Additionally, the catalytic system was also suited well for the coupling reaction of benzyl halides with pyridyl aluminum reagents to afford series of pyridyl-arylmethane

Table_1_Non-linear associations of cardiometabolic index with insulin resistance, impaired fasting glucose, and type 2 diabetes among US adults: a cross-sectional study.docx

BackgroundCardiometabolic index (CMI) is a novel indicator for predicting the risk of obesity-related diseases. We aimed to determine the relationships of CMI with insulin resistance (IR), impaired fasting glucose (IFG), and type 2 diabetes mellitus (T2DM) using NHANES data from 1999 to 2020.MethodsAfter CMI values were estimated, weighted univariate and multivariate logistic regression analyses were used to ascertain whether CMI was an independent risk indicator for IR, IFG, and T2DM. Furthermore, stratified analyses and interaction analyses were carried out to investigate the heterogeneity of correlations across various subgroups. Subsequently, restricted cubic splines (RCS) were used to examine nonlinear relationships.Results21,304 US adults were enrolled in our study, of whom 5,326 (22.38%) had IR, 4,706 (20.17%) had IFG, and 3,724 (13.02%) had T2DM. In the studied population, a higher CMI index value was significantly associated with an elevated likelihood of IR, IFG, and T2DM. In the RCS regression model, the relationship between CMI and IR, IFG, and T2DM was identified as nonlinear. A nonlinear inverted U-shaped relationship was found between CMI and IFG, and an inverse L-shaped association was observed between CMI and IR, CMI and T2DM. The cut-off values of CMI were 1.35, 1.48, and 1.30 for IR, IFG, and T2DM, respectively.ConclusionOur results indicate that CMI was positively correlated with an increase in IR, IFG, and T2DM in the studied population. CMI may be a simple and effective surrogate indicator of IR, IFG, and T2DM.</p

Asymmetric Addition of Pyridyl Aluminum Reagents to Aldehydes Catalyzed by a Titanium(IV) Catalytic System of (<i>R</i>)‑H₈‑BINOLate

The asymmetric addition of pyridyl aluminum reagents to aldehydes has been successfully developed by employing a titanium­(IV) catalytic system of (<i>R</i>)-H₈-BINOLate, which affords a series of valuable optically active diarylmethanols containing various pyridyl groups in high yields with excellent enantioselectivities of up to 98% ee

Transmetal-Catalyzed Enantioselective Cross-Coupling Reaction of Racemic Secondary Benzylic Bromides with Organoaluminum Reagents

The transmetal-catalyzed enantioselective cross-coupling reaction of secondary benzylic electrophiles with organoaluminum reagents has been developed. The reaction of secondary benzylic electrophiles with alkynylaluminum reagents provides a mild way for the chiral propargyl compounds bearing aromatic group in high yields with good enantioselectivities using NiBr₂·diglyme and (<i>R</i>)-<i>i</i>Pr-Pybox as the catalytic system. The reaction of secondary benzylic electrophiles with alkenylaluminum reagents affords the corresponding chiral aryl alkenes in moderate yields with excellent stereoselectivities using commercially available PdCl₂ and (<i>R</i>)-BINAP as the catalytic system

Spatiotemporal Patterns of Tumor Occurrence in Children with Intraocular Retinoblastoma - Fig 6

<p>The tumor centroid distribution rendered in the azimuthal-equidistant projection by (A) tumor area quartiles and (B) mutation type. C) Scatter plot of tumor centroid eccentricity vs. tumor area. The range of each tumor area quartile is indicated on the x-axis. The black curve shows the approximate maximum eccentricity for a tumor of a given size (see text). Plotting symbol color indicates age at diagnosis quartile (magenta, yellow, blue, green) and shape indicates mutation type and disease laterality.</p

The distribution of age at diagnosis and tumor size varied between patients with germline or somatic mutations.

<p>A) Age at diagnosis and B) tumor area (expressed as % of the mapped retinal area) as a function of mutation type. C) Parallel coordinate plot illustrating the relationship among age at diagnosis, mutation type, and tumor area for all mapped tumors. Color indicates the age quartile. Tumor area quartiles: μ = smallest, S = small, M = medium, L = large. D) The cumulative tumor burden was mapped over the retina by superimposing the mapped areas of all tumors enrolled in this study. Tumors in the left eye were inverted around the nasal-temporal axis to preserve spatial symmetry with right eye tumors. The color legend indicates the number of tumors which were mapped over a specific point.</p

Descriptive characteristics of the mapped patients and eyes in relation to those eligible and those unmapped.

<p>^<b>1</b>Values indicate number of items in a category, with the number as a percentage of the group in parentheses, except under Age as per note <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132932#t001fn004" target="_blank">⁴</a>.</p><p>² Fisher’s Exact test to compare the proportions in a category between eligible and mapped groups, except under Age as per note <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132932#t001fn004" target="_blank">⁴</a>.</p><p>³ Fisher’s Exact test to compare the proportions in a category between mapped and unmapped groups, except under Age as per note <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132932#t001fn004" target="_blank">⁴</a>.</p><p>⁴ Values indicate the median and range of age at diagnosis, and p-value is for the Kolomogorov-Smirnov test to compare the age at diagnosis distributions between the groups.</p><p>Descriptive characteristics of the mapped patients and eyes in relation to those eligible and those unmapped.</p

Distribution of approximated locations for all 50 unmapped tumors with respect to each patient age quartile.

<p>With increasing age at diagnosis, there was a significant increase in tumor frequency in the inferior quadrants while the number of tumors noted in superior quadrants decreased. No significant effect was noted in variation of tumor occurrence between nasal and temporal quadrants with respect to age.</p

Overview of eligible, mapped, and unmapped patients and eyes.

<p>A) The distribution of age at diagnosis. Heavy bar indicates the median, vertical extent of the box indicates the interquartile range, and the whiskers indicate the full range. B) The wide bars indicate the relative proportions of the eyes in each group. The diagram at right summarizes study exclusion criteria and the number of patients and eyes excluded for each one.</p