Purpose This study proposes phenomenological models for total normal tissue complication probability (TNTCP) and NTCP0. NTCP0 is a new acronym for reformulating the current complication-free cure (P+) and uncomplicated tumor control probability (UTCP) concepts; and TNTCP will reformulate the current NTCP involving multiple organs at risks. The current probabilistic concepts are incoherently formulated with mathematical operations of tumor control probability (TCP) and normal tissue complication probability (NTCP) that are associated to different stochastic processes and random variables. NTCP0 is equal to NTCP0 (normal tissue non-complication probability) that is calculated as ratio of number of patients of a population without late complications and total of them. As a cumulative distribution function (CDF) of late complications, TNTCP = sum(NTCPi), where NTCPi NTCP of the ith late complication. TNTCP is also a new acronym, and the probabilistic complement of NTCP0, then NTCP0 = 100%-TNTCP.Conclusions The NTCP0/TNTCP (D(d)) proposing models are based on relationship between the NTCP0/TNTCP and total dose (D = n*d; where d dose per fraction, and n number of fractions). TNTCP(D) model will be correlated with LKB model (the normal CDF) that is an increasing function; and NTCP0(D) model with a decreasing function, which additionally will define clear limits of three possible regions for NTCP0 0% and 100% deterministic, and a stochastic. These models are function D, which is widely used for characterizing radiation therapies.In clinical trials, the efficacy of treatment might be dependent on the value of a covariate variable. Therefore, it might be possible to detect the region over the covariate variable where the two treatments under investigation do not have significantly different efficacy or the region of superiority of one treatment. The non-significant region can be verified to be a confidence interval for the abscissa of the intersection point of two regression lines, and each of the complementary regions of the confidence interval corresponds to a region of superiority. In this study, we develop a method of constructing the confidence interval based on the concept of a generalized pivotal quantity, so as to perform the task of detecting the possible three regions for a clinical trial. Two real-world examples are given to illustrate the application of our proposed method, and a simulation study is conducted to evaluate its performance.Objective Validation of a prospective new therapeutic concept in a proof of concept study is costly and time-consuming. In particular, pharmacologically active tool compounds often lack suitable pharmacokinetic (PK) properties for subsequent studies. The current work describes a PLGA-based formulation platform, encapsulating different preclinical research compounds into extended release microparticles, to optimize their PK properties after subcutaneous administration.Significance Developing a PLGA-based formulation platform offers the advantage of enabling early proof of concept studies in pharmaceutical research for a variety of preclinical compounds by providing a tailor-made PK profile.Methods Different model compounds were encapsulated into PLGA microparticles, utilizing emulsification solvent evaporation or spray drying techniques. Formulations aiming different release rates were manufactured and characterized. Optimized formulations were assessed in in vivo studies to determine their PK properties, with the mean residence time (MRT) as one key PK parameter.Results Utilizing both manufacturing methods, tested tool compounds were encapsulated successfully, with a drug load between 5% and 40% w/w, and an extended release time up to 250 h. In the following PK studies, the MRT was extended by a factor of 90, resulting in prolonged coverage of the required target through level. This approach was confirmed to be equally successful for additional internal compounds, verifying a general applicability of the platform.Conclusion For different active pharmaceutical ingredients (API), an optimized, tailor-made PK profile was obtained utilizing the described formulation platform. This approach is applicable for a variety of pharmacologically active tool compounds, reducing timelines and costs in preclinical research.We investigate the association of uric acid with hypertension among Han, Uygur, and Kazakh populations in the Xinjiang Province of Western China. Our study aims to evaluate the relationships of serum uric acid (SUA) with hypertension in the Chinese population according to the menopausal status. Medical data of 1684 Han, 1895 Uygur, and 294 Kazakh people was examined. The prevalence of hypertension was calculated by the quartiles of SUA. Correlation between hypertension-related risk factors calculated and compared between men and women. SUA was higher in men than in women. The level was significantly higher in postmenopausal than premenopausal women (4.40 ± 1.75 v.s 4.06 ± 1.63 mg/dl, P less then  .01). Logistic regression analysis showed Body mass index (BMI) [OR = 1.08, P less then  .01]; and eGFR less then 60 vs.≥60 [OR = 1.22, P = .04] were independent risk factors for hypertension in women. Age and diabetes were independent risk factors for the participants with hypertension [OR = 1.04, P less then  .01] and [OR = 2.24, P less then  .01]. High quartile SUA group has increased the risk for hypertension in postmenopausal women [OR = 1.34, P = .048]. We found that postmenopausal women have high SUA compared to premenopausal women. The high SUA quartiles uric acid may be an independent risk for hypertension in postmenopausal women.Background - The common intronic deletion, MYBPC3Δ25, detected in 4-8% of South Asian populations, is reported to be associated with cardiomyopathy, with ~7-fold increased risk of disease in variant carriers. Here we examine the contribution of MYBPC3Δ25 to hypertrophic cardiomyopathy (HCM) in a large patient cohort. Methods - Sequence data from two HCM cohorts (n=5,393) was analysed to determine MYBPC3Δ25 frequency and co-occurrence of pathogenic variants in HCM genes. Case-control and haplotype analyses were performed to compare variant frequencies and assess disease association.  https://www.selleckchem.com/MEK.html  Analyses were also undertaken to investigate the pathogenicity of a candidate variant, MYBPC3 c.1224-52G>A. Results - Our data suggest that the risk of HCM, previously attributed to MYBPC3Δ25, can be explained by enrichment of a derived haplotype, MYBPC3Δ25/-52, whereby a small subset of individuals bear both MYBPC3Δ25 and a rare pathogenic variant, MYBPC3 c.1224-52G>A. The intronic MYBPC3 c.1224-52G>A variant, which is not routinely evaluated by gene panel or exome sequencing, was detected in ~1% of our HCM cohort.