Dose-finding Designs for Phase II Clinical Trials

Most existing dose-finding designs have been proposed for Phase I oncology trials where the main outcome is toxicity, and dose escalation is guided by ethical considerations. Most of these designs have been developed assuming that dose-response curve is strictly increasing and the outcome is binary. The main outcome in Phase II non-oncology trials is efficacy, which is often continuous. A bivariate outcome combining efficacy and safety is also constantly considered in Phase II non-oncology trials. The goal of this work is to investigate the suitability of Phase I oncology designs for Phase II non-oncology trials and to develop dose-finding designs that better address the needs of Phase II non-oncology trials. Specifically, the first paper investigates which of the several known dose-finding methods is most suitable when dose response curve plateaus. Some of the designs tend to spread the allocation among the doses on the plateau, others, like the continual reassessment method and the t-statistic design, concentrate allocation at one of the doses with the t-statistic design selecting the lowest dose on the plateau more frequently. The second paper examines the optimal allocation for estimating the minimum effective and peak doses in a dose-ranging trial when the set of dose level is fixed and isotonic regression is used as a method of estimation. We propose fully sequential strategy for subject assignment. The proposed strategy includes adaptive randomization procedure to balance the allocation to placebo and active doses. We also consider estimation in presence of covariates, where randomization procedure also balances the allocation with respect to a set of known covariates. Simulations show that the new adaptive strategy is superior to equal allocation. The third paper investigates a Bayesian adaptive two-stage design to efficiently estimate the minimum effective dose or the maximum dose in a dose-finding trial where some monotonicity assumptions regarding dose-response relationship can be made. The new design allocates subjects in stage 2 according to the posterior distribution of the location of the target dose. Simulations show that the proposed two-stage design is superior to equal allocation and to two-stage strategy where only one dose is left in stage 2

μ-Benzene-1,2,4,5-tetra­carboxyl­ato-κ4 O 1,O 2:O 4,O 5-bis­[diaqua(phen­an­thro­line-κ2 N,N′)nickel(II)] 0.67-hydrate

The asymmetric unit of the title compound, [Ni2(C10H2O8)(C12H8N2)2(H2O)4]·0.67H2O, contains one complete binuclear complex and one half-mol­ecule, the latter being completed by crystallographic inversion symmetry, and 0.67 of a solvent water molecule. Each Ni2+ cation is coordinated by a 1,10-phenanthroline ligand, a bidentate benzene-1,2,4,5-tetra­carboxyl­ate (btec) tetra-anion and two water mol­ecules to generate a distorted cis-NiN2O4 octa­hedral coordination geometry. The btec species bridges the metal ions. In the crystal, the clusters and uncoordinated water mol­ecules are linked by O—H⋯O hydrogen bonds and π–π inter­actions [shortest centroid–centroid separation = 3.596 (2) Å] to form a three-dimensional network

Dose finding when the target dose is on a plateau of a dose-response curve: comparison of fully sequential designs

Consider the problem of estimating a dose with a certain response rate. Many multistage dose-finding designs for this problem were originally developed for oncology studies where the mean dose-response is strictly increasing in dose. In non-oncology Phase II dose-finding studies the dose-response curve often plateaus in the range of interest and there are several doses with the mean response equal to the target. In this case it is usually of interest to find the lowest of these doses since higher doses might have higher adverse event rates. It is often desirable to compare the response rate at the estimated target dose with a placebo and/or active control. We investigate which of the several known dose-finding methods developed for oncology Phase I trials is the most suitable when the dose response curve plateaus. Some of the designs tend to spread the allocation among the doses on the plateau. Others, like the continual reassessment method and the t-statistic design, concentrate allocation at one of the doses with the t-statistic design selecting the lowest dose on the plateau more frequently

Adaptive isotonic estimation of the minimum effective and peak doses in the presence of covariates

We consider a problem of estimating the minimum effective and peak doses in the presence of covariates. We propose a sequential strategy for subject assignment that includes an adaptive randomization component to balance the allocation to placebo and active doses with respect to covariates. We conclude that either adjusting for covariates in the model or balancing allocation with respect to covariates is required to avoid bias in the target dose estimation. We also compute optimal allocation to estimate the minimum effective and peak doses in discrete dose space using isotonic regression

Two-stage designs for Phase 2 dose-finding trials

We propose a Bayesian adaptive two-stage design for the efficient estimation of the maximum dose or the minimum effective dose in a dose-finding trial. The new design allocates subjects in stage two according to the posterior distribution of the target dose location. Simulations show that the proposed two-stage design is superior to equal allocation and to a two-stage strategy where only one dose is left in the second stage

Living grass mulching improves soil enzyme activities through enhanced available nutrients in citrus orchards in subtropical China

Living grass mulching (LGM) is an important orchard floor management that has been applied worldwide. Although LGM can effectively enhance soil nutrient availability and fertility, its effects on microbial-mediated soil nutrient cycling and main drivers are unclear. Meanwhile, the variation of enzyme activities and soil nutrient availability with LGM duration have been rarely studied. This study aims to explore the effects of mulching age and soil layer on enzyme activities and soil nutrients in citrus orchards. In this study, three LGM (Vicia villosa) treatments were applied, i.e., mulching for eight years, mulching for four years, and no mulching (clean tillage). Their effects on the enzyme activities and soil nutrients were analyzed in different soil layers of citrus orchards in subtropical China, i.e., 0-10, 10-20, and 20-40 cm. Compared to clean tillage, mulching for four years had fewer effects on enzyme activities and soil nutrients. In contrast, mulching for eight years significantly increased available nitrogen (N), phosphorus (P) nutrients, β-glucosidase, and cellobiohydrolase activities in the soil layer of 0-20 cm. In the soil layer of 0-40 cm, microbial biomass carbon (C), N, P, N-acetylglucosaminidase, leucine aminopeptidase, and acid phosphatase activities also increased (P < 0.05). Mulching for eight years significantly promoted C, N, and P-cycling enzyme activities and total enzyme activities by 2.45-6.07, 9.29-54.42, 4.42-7.11, and 5.32-14.91 times, respectively. Redundancy analysis shows that mulching treatments for eight and four years had soil layer-dependent positive effects on soil enzyme activities. Microbial C and P showed the most significant positive correlation with enzyme activities, followed by moisture content, organic C, and available N (P < 0.05). Available nutrients contributed almost 70% to affect enzyme activities significantly and were the main drivers of the enzyme activity variation. In summary, LGM could improve soil enzyme activities by increasing available nutrients. The promotion effect was more significant under mulching for eight years. Therefore, extending mulching age and improving nutrient availability are effective development strategies for sustainable soil management in orchard systems. Our study can provide valuable guidelines for the design and implementation of more sustainable management practices in citrus orchards

Effects of thinning and understory removal on soil phosphorus fractions in subtropical pine plantations

Forest management changes the physical environments and nutrient dynamics and then regulates the forest productivity. Soil phosphorus (P) availability is critical for productivity in tropical and subtropical forests. However, it was still poorly understood how soil P content and fraction respond to various forest management practices in these regions. Here, we measured the soil total P, available P, and Hedley’s P fractions, including inorganic and organic P (Pi and Po), in subtropical pine plantations treated with understory removal (UR), non-dominant species thinning (NDST) and dominant species thinning (DST) after nine years. Compared to plantations without management (CK), treatments such as UR, NDST, and DST decreased soil total P at 0–10 cm and soil available P at 0–10 cm and 10–20 cm. Increases in resin-Pi, NaOH-Pi, and C.HCl-Pi resulted in a higher total Pi in 0–10 cm (p < 0.05) in treated plots (UR, NDST, and DST) than in CK plots. UR, NDST, and DST treatments increased NaHCO3-Po and NaOH-Po (p < 0.05) but decreased C.HCl-Po at a depth of 0–10 cm. Regardless of management treatments, soil total P, available P, and P fractions in 0–10 cm showed higher contents than those in 10–20 cm. There were positive relationships between total P and total Po (p < 0.01) and between available P and total Pi. There were also positive relationships between total P, available P, NaHCO3-Pi, and NaOH-Pi (p < 0.05). In conclusion, forest management such as UR, NDST, and DST decreased soil total P and available P, and transforming soil P fractions to available P will meet the P demand following management in the pine plantations of subtropical China

Use of Complementary and Alternative Medicine Among Patients With Arthritis

Introduction: Previous studies suggest that people with arthritis have high rates of using complementary and alternative medicine (CAM) approaches for managing their arthritis, in addition to conventional treatments such as prescription medications. However, little is known about the use of CAM by diagnosis, or which forms of CAM are most frequently used by people with arthritis. This study was designed to provide detailed information about use of CAM for symptoms associated with arthritis in patients followed in primary care and specialty clinics in North Carolina. Methods: Using a cross-sectional design, we drew our sample from primary care (n = 1,077) and specialist (n = 1,063) physician offices. Summary statistics were used to calculate differences within and between diagnostic groups, practice settings, and other characteristics. Logistic regression models clustered at the site level were used to determine the effect of patient characteristics on ever and current use of 9 CAM categories and an overall category of "any use." Results: Most of the participants followed by specialists (90.5%) and a slightly smaller percentage of those in the primary care sample (82.8%) had tried at least 1 complementary therapy for arthritis symptoms. Participants with fibromyalgia used complementary therapies more often than those with rheumatoid arthritis, osteoarthritis, or chronic joint symptoms. More than 50% of patients in both samples used over-the-counter topical pain relievers, more than 25% used meditation or drew on religious or spiritual beliefs, and more than 19% used a chiropractor. Women and participants with higher levels of education were more likely to report current use of alternative therapies. Conclusion: Most arthritis patients in both primary care and specialty settings have used CAM for their arthritis symptoms. Health care providers (especially musculoskeletal specialists) should discuss these therapies with all arthritis patients

Supplementation of hyaluronic acid injections with vitamin D improve knee function by attenuating synovial fluid oxidative stress in osteoarthritis patients with vitamin D insufficiency

ObjectivesThere is still controversy about the effect of vitamin D supplementation on osteoarthritis (OA). The purpose of this study was to investigate the effects of vitamin D supplementation with Hyaluronic acid (HA) injection on OA.MethodsWe investigated serum vitamin D levels and oxidative stress (OS) in synovial fluid from patients with OA who underwent total knee arthroplasty (grade IV, n = 24) and HA injection (grade II and III, n = 40). The effects of HA injection with or without oral vitamin D supplementation on synovial fluid OS and knee pain and function were then further investigated. Finally, patients underwent HA injection were divided into two groups according to vitamin D levels (vitamin D < or > 30 ng/ml), and the efficacy of the two groups were compared.ResultsThe results showed that the levels of glutathione peroxidase (GSH-PX) (P < 0.05) in the synovial fluid were lower in patients with stage IV OA than that in patients with stage II-III OA, while the levels of malondialdehyde (MDA) (P < 0.05) and lactate dehydrogenase (LDH) (P < 0.01) were significantly higher. Moreover, we found that age, BMI and vitamin D levels were significantly associated with the levels of oxidants and/or antioxidants in synovial fluid, and that vitamin D was significantly negatively correlated with BMI (R = −0.3527, p = 0.0043). Supplementation of HA injections with vitamin D significantly reduced the OS status in synovial fluid, attenuated knee pain and improved knee function in OA patients with vitamin D insufficiency.ConclusionWe conclude that maintenance of vitamin D sufficiency may be beneficial for the treatment of OA by improving OS in synovial fluid

Trends of overweight and obesity prevalence in school-aged children among Henan Province from 2000 to 2019

ObjectivesOverweight and obesity are harmful to human health. However, the latest trends of Chinese childhood overweight and obesity prevalence are not available. The aim of this study was to examine the trends from 2000 to 2019 among students in China.MethodsWe analyzed data of 66,072 students in the Chinese National Survey on Students' Constitution and Health from 2000 to 2019. Overweight and obesity were defined based on the standard formulated by the International Obesity Task Force (IOTF standard), the World Health Organization (WHO standard), and the Working Group on Obesity in China (WGOC standard), respectively. The χ2-test was used to test the trends of overweight and obesity prevalence and logistic regression was conducted to evaluate the prevalence odds ratios of boys vs. girls and urban vs. rural areas.ResultsThe prevalence of obesity/overweight and obesity combined was 6.03/23.58% (IOTF standard), 10.56/25.88% (WGOC standard) and 10.75/29.69% (WHO standard) in 2019. From 2000 to 2019, according to the WGOC standard, the prevalence increased from 2.51 to 10.56% for obesity and increased from 9.81 to 25.88% for overweight and obesity combined (P for trend < 0.001). Obesity/overweight and obesity were greater problems in boys than girls and urban than rural areas, but urban-rural differences decreased over time.ConclusionOverweight and obesity prevalence increased significantly in children and adolescents in China from 2000 to 2019. The prevalence of overweight and obesity in rural areas may contribute to a large percentage of children with overweight and obesity