Adaptive two-stage seamless sequential design for clinical trials

We propose an adaptive sequential testing procedure for the selection and testing of multiple treatment options, such as dose/regimen, different drugs, sub-populations, endpoints, or a mixture of them in a seamlessly combined phase II/III trial. The selection is to be made at the end of phase 2 stage. Unlike in many of the published literature, the selection rule is not required to be to “select the best”, and does not need to be pre-specified, which provides flexibility and allows the trial investigators to use any efficacy and safety information/criteria, or surrogate or intermediate endpoint to make the selection. Sample size and power calculations are provided. The calculations have been confirmed to be accurate by simulations. Interim analysis can be performed after the selection, sample size can be modified if the observed efficacy deviates from the assumed. Inference after the trial, including p-value, median unbiased point estimate and confidence intervals, are provided. By applying a dominance theorem, the procedure can be applied to normal, binary, Poisson, negative binomial distributed endpoints and time-to-event endpoints, and a mixture of these distributions (in trials involving endpoint selection).</p

Tortoise-shell glue ameliorates male infertility through the hypothalamic-pituitary-gonadal axis in obese rats

Male infertility is a worldwide population health concern, but its etiology remains poorly understood. Tortoise-shell glue (TSG) is widely utilized as a pharmaceutical or dietary supplement for various health ailments. This study aimed to evaluate the effects of TSG on male infertility in obese rats. A male infertility with obesity rat model was established after a high-fat diet (HFD) and cyclophosphamide (CTX) treatment. The body weight, testis weight, and weight of adipose tissues around the epididymis were detected. We then evaluated spermatozoon motility and concentration and testis pathological changes. Next, we assessed the hypothalamic-pituitary-gonadal (HPG) axis. Moreover, serum metabolomics was used to identify differential metabolites. The Spearman correlation analysis was employed to assess the correlation between differential metabolites and sex hormone levels. Here, we demonstrated that TSG alleviated obesity and male infertility. Meanwhile, TSG restored the function of the HPG axis in obese infertility rats, including mRNA levels of GnRH, GnRHR, RFRP-3, and kisspeptin in the hypothalamus and pituitary and sex hormone levels in the serum. In addition, 16 potentially significant metabolites, such as Quinapril and Malabaricone C, were identified as significant in the therapeutic effects of TSG on male infertility. The majority of these differential metabolites exhibited recovery following TSG treatment. The further Spearman analysis demonstrated the close correlation between differential metabolites and sex hormones, especially Kamahine C. TSG attenuated obesity and male infertility in rats through the HPG axis by regulating serum metabolites. It shows potential as a viable treatment option for male infertility.</p

Effects of Dietary Protein from Different Sources on Biotransformation, Antioxidation, and Inflammation in the Rat Liver

In this work, the effects of different sources of meat protein on liver metabolic enzymes were investigated. Rats were fed for 90 days with semisynthetic diets in which casein was fully replaced by isolated soybean, fish, chicken, pork, or beef proteins. Then, liver proteomics was performed using iTRAQ and LC–ESI–MS/MS. The results indicated that intake of meat protein diets significantly reduced the protein levels of CYP450s, GSTs, UGTs, and SULTs compared to those of the casein and soybean protein diet groups. The total antioxidant capacity and lipid peroxidation values did not differ between four meat protein diet groups and the casein diet group. However, GSH activity in the fish, chicken, and beef protein groups was significantly higher than those of the casein and soybean protein groups. The beef protein diet significantly upregulated the expression of immune-related proteins. The Keap1-Nrf2-ARE signaling pathway was suggested to involve the diet-mediated regulation of biotransformation, inflammation, and redox status

Effect of the type of dietary protein on growth performance and food intake of rats.

<p>Effect of the type of dietary protein on growth performance and food intake of rats.</p

Relative abundance of <i>Bacteroides</i> and <i>Lactobacillus</i> in different diet groups.

<p>The mean and median relative abundances are indicated with solid and dashed lines respectively. Each column represents one biological sample and there are 49 biological samples in total, including 11 from the casein group, 11 from the soy protein group, 8 from the beef protein group, 9 from the pork protein group and 10 from the fish protein group. The samples were classified into "non-meat" (casein and soy protein) and "meat" (beef, pork and fish proteins).</p

Relative abundance of gut bacteria at the phylum level.

<p>Pie charts show the composition of gut bacteria at the phylum level. Bray-Curtis similarity cluster analysis shows that the composition of gut bacteria in feces from the beef, pork and fish protein-fed groups could be separated from those of the casein and soy protein-fed groups.</p

Relative abundance of gut bacteria in rat feces at the family and genus levels.

<p>a) At the family level. b) At the genus level.</p

Effect of the type of dietary protein on SCFA levels (μmol/g, means ± standard deviations).

<p>Effect of the type of dietary protein on SCFA levels (μmol/g, means ± standard deviations).</p

Differences in bacterial communities at the OTU level.

<p>The figure includes three parts: 1) The right panel shows the relative abundance (log 10 transformation) of OTUs. Each column represents one biological sample and each row represents one OTU; 2) the middle panel shows the fold-changes of OTUs that changed significantly (p < 0.05) compared to the casein group. Red denotes an increase, blue denotes a decrease. S, soy protein group; B, beef protein group; P, pork protein group; F, fish protein group; 3) the left panel lists significantly changed OTUs and the corresponding phyla, families and genera.</p

The composition of five formulated diets.

<p>The composition of five formulated diets.</p