Using surrogate information to improve confirmatory platform trial with sample size re-estimation.

Platform design which allows exploring multiple arms with a common control simultaneously is becoming essential for efficient drug development. However, one of the critical challenges for confirmatory platform trials is immature data for interim decisions, particularly for the treatment arm selection and sample size determination with limited data available. We use a modified conditional power (CP) for both treatment arm selection and sample size determination at interim analysis for the proposed platform trial. The modified CP uses the available data from both primary and surrogate endpoints. We also demonstrated the application in a case study of a lung cancer trial.

An economic and disease transmission model of human papillomavirus and oropharyngeal cancer in Texas.

In 2017, 46,157 and 3,127 new oropharyngeal cancer (OPC) cases were reported in the U.S. and Texas, respectively. About 70% of OPC were attributed to human papillomavirus (HPV). However, only 51% of U.S. and 43.5% of Texas adolescents have completed the HPV vaccine series. Therefore, modeling the demographic dynamics and transmission of HPV and OPC progression is needed for accurate estimation of the economic and epidemiological impacts of HPV vaccine in a geographic area. An age-structured population dynamic model was developed for the U.S. state of Texas. With Texas-specific model parameters calibrated, this model described the dynamics of HPV-associated OPC in Texas. Parameters for the Year 2010 were used as the initial values, and the prediction for Year 2012 was compared with the real age-specific incidence rates in 23 age groups for model validation. The validated model was applied to predict 100-year age-adjusted incidence rates. The public health benefits of HPV vaccine uptake were evaluated by computer simulation. Compared with current vaccination program, increasing vaccine uptake rates by 50% would decrease the cumulative cases by 4403, within 100 years. The incremental cost-effectiveness ratio of this strategy was $94,518 per quality-adjusted life year (QALY) gained. Increasing the vaccine uptake rate by 50% can: (i) reduce the incidence rates of OPC among both males and females; (ii) improve the quality-adjusted life years for both males and females; (iii) be cost-effective and has the potential to provide tremendous public health benefits in Texas.

Efficacy of combining home-based transcranial direct current stimulation with mindfulness-based meditation for pain in older adults with knee osteoarthritis: A randomized controlled pilot study.

Transcranial direct current stimulation (tDCS) has been shown to be effective for reducing pain, and a growing body of literature shows the potential analgesic effects of mindfulness-based meditation (MBM). However, few studies have investigated the potential benefits associated with combining tDCS and MBM in older adults with knee osteoarthritis (OA). Therefore, the aim of this study was to examine the feasibility and preliminary efficacy of home-based tDCS paired with MBM in older adults with knee OA. Thirty participants 50-85 years old with symptomatic knee OA were randomly assigned to receive 10 daily sessions of home-based 2 mA tDCS paired with active MBM for 20 min (n = 15) or sham tDCS paired with sham MBM (n = 15). We measured clinical pain and OA symptoms via a Numeric Rating Scale and the Western Ontario and McMaster Universities Osteoarthritis Index. Pressure pain sensitivity and conditioned pain modulation were measured using quantitative sensory testing. Participant satisfaction and side effects were assessed via a questionnaire. Active tDCS paired with active MBM significantly reduced scores on the Numeric Rating Scale and Western Ontario and McMaster Universities Osteoarthritis Index and increased pressure pain thresholds and conditioned pain modulation. Participants tolerated tDCS paired with MBM well without serious adverse effects and were satisfied with the treatment. Our findings demonstrate promising clinical efficacy of home-based tDCS paired with MBM for older adults with knee OA.

Home-based self-administered transcranial direct current stimulation in older adults with knee osteoarthritis pain: An open-label study.

Clinic-based transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been shown to improve pain. However, no published studies have reported using home-based self-administered tDCS in older adults with knee osteoarthritis (OA). The present study aimed to evaluate the preliminary efficacy and feasibility of home-based self-administered tDCS with real-time remote supervision on clinical pain, anxiety, depression, and sleep disturbances in older adults with knee OA. Twenty 50- to 85-year-old community-dwelling participants with knee OA received 10 daily home-based sessions of 2 mA tDCS for 20 min with real-time remote supervision. We measured clinical pain severity via the Visual Analog Scale, Western Ontario and McMaster Universities Osteoarthritis Index, and Short-Form McGill Pain Questionnaire. We assessed anxiety, depression, and sleep disturbances using the Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety-short form, depression-short form, and sleep disturbance-short form, respectively. All 20 participants completed all 10 home-based tDCS sessions without serious adverse effects. Both clinical pain severity and sleep disturbances were improved after completion of the 10 tDCS sessions. Anxiety and depression scores were not significantly improved. We demonstrated that home-based self-administered tDCS with real-time remote supervision was feasible and beneficial in alleviating clinical pain in older adults with knee OA. These findings support future studies with larger samples and longer-term follow-up evaluations.

The Relationship Between ß-Endorphin and Experimental Pain Sensitivity in Older Adults With Knee Osteoarthritis.

Osteoarthritis (OA) is the most common cause of pain in people aged >45 years, and the knee is the most commonly affected joint. There is a growing interest in understanding the biological factors that influence pain among older adults, but few studies have examined the relationship between ß-endorphin and experimental pain sensitivity in older adults with knee OA pain. The purpose of this study was to investigate the relationship between resting plasma levels of ß-endorphin and experimental pain sensitivity. This study was a secondary analysis of data for 40 adults with knee OA pain in whom quantitative sensory testing was used to measure experimental sensitivity to heat- and mechanically induced pain. The mean age of the sample was 60 years (SD = 9 years), and approximately half were female (53%). Regression analyses indicated that ß-endorphin level was negatively related to pressure pain threshold (ß = -17.18, p = .02) and positively related to punctate mechanical pain (ß = 17.13, p = .04), after controlling for age, gender, and OA severity. We did not find a significant relationship between ß-endorphin and heat pain tolerance. The results suggest that higher circulating levels of ß-endorphin at rest are associated with increased sensitivity to mechanical pain in older adults with knee OA. These findings add to the literature regarding biological factors associated with pain sensitivity in older adults with chronic pain. Additional studies are needed to identify mediators of the relationship between ß-endorphin and pain sensitivity in OA and other musculoskeletal pain conditions.

Age-Structured Population Modeling of HPV-related Cervical Cancer in Texas and US.

Human papillomavirus (HPV)-related cervical cancer is a major public health threat to women, with >10,000 new cases diagnosed annually in the United States between 2008 and 2012. Since HPV vaccines can protect against ~80% of HPV-associated cervical cancers, the economic and epidemiological impacts of HPV vaccination have been extensively investigated, particularly at the national level. However, vaccination policies are state-specific, and state-level models are required for state-specific policy decisions. This study adapted an age-structured population model to describe the dynamics of HPV-related cervical cancer in Texas, with model parameters calibrated for Texas. The Year 2000 parameter set was the start point, and the model's predictions from 2001-2010 were well matched with the real incidence numbers in 23 age groups, suggesting the validity of the model. Application of the model to the Year 2010 parameter set predicted that, over the next 10 decades, incidence would decrease rapidly within the first decade and more slowly thereafter. Sensitivity analysis determined the impact of selected parameters (e.g., vaccine coverage rate) on future disease incidence. When compared with the US parameter sets, the Texas population was more sensitive to changes in HPV transmission and vaccination (e.g., ~8% difference in the predicted disease decline).

The Relationship between Acculturation and Experimental Pain Sensitivity in Asian Americans with Knee Osteoarthritis.

Multiple studies in healthy populations and clinical samples have shown that ethnic minorities have greater pain sensitivity than their majority counterparts. Acculturation is speculated to be one of the sociocultural factors contributing to pain sensitivity since cultural beliefs and practices can influence the way patients perceive and respond to pain. However, the relationship of acculturation to pain sensitivity in minority populations remains poorly understood. Therefore, in this cross-sectional study, we examined the relationship between acculturation and experimental pain sensitivity in 50 Asian Americans residing in North Central Florida with knee osteoarthritis pain. The Suinn-Lew Asian Self Identity Acculturation Scale was used to assess acculturation, and multimodal quantitative sensory testing was performed to measure experimental sensitivity, including heat pain tolerance, pressure pain threshold, and punctate mechanical pain. Descriptive and regression analyses were performed. Participants' mean age was 55.7 years, and about half of this sample were Korean American (56%). The participants had lived in the United States for 21 years on average. Regression analyses indicated that lower acculturation to American culture may contribute to greater experimental pain sensitivity. Asian Americans who were more acculturated to the American culture had higher heat pain tolerance (beta = 0.61, P=0.01), higher pressure pain threshold (beta = 0.59, P=0.02), and lower ratings of punctate mechanical pain (beta = -0.70, P < 0.01). These findings add to the literature regarding sociocultural factors associated with pain in Asian Americans; additional research with a larger and more diverse sample of Asian Americans is warranted for cross-validation.

Maternal exposure to di-(2-ethylhexyl) phthalate disrupts placental growth and development in pregnant mice.

Di-(2-ethylhexyl) phthalate (DEHP) is used as a plasticizer and widely dispersed in the environment. DEHP exposure reduces embryo implantations, increases embryonic loss, and decreases fetal body weights. However, no detailed information is available about the effect of DEHP on the placentation during pregnancy. Thus, our aim was to explore the effect of DEHP on the growth and development of placenta in vivo. Mice were administered DEHP by gavages at 125, 250, 500 mg/kg/day from gestational days (GD) 1 until sacrifice. Results showed that DEHP treatment significantly reduced the weight of placenta at GD 13. Histopathologically, in DEHP-treated group, the ectoplacental cones significantly became smaller at GD9, and total area of placenta and area of spongiotrophoblast were significantly reduced at GD 13. Expression levels of Ascl2, Esx1 and Fosl1 mRNA dramatically decreased in DEHP-treated placenta at GD 13. DEHP administration disrupted labyrinth vascularization of placentas, and inhibited proliferation and induced apoptosis of placenta by the activation of caspase-3 and -8, up-regulation of Bax and down-regulation of Bcl-2 mRNA and protein at GD 13. In conclusion, these results suggest that adverse pregnancy outcomes including low birth-weight and pregnancy loss exposed to DEHP are possibly mediated, at least in part, via the suppression of placental growth and development.

Expression and function of kisspeptin during mouse decidualization.

BACKGROUND: Plasma kisspeptin levels dramatically increased during the first trimester of human pregnancy, which is similar to pregnancy specific glycoprotein-human chorionic gonadotropin. However, its particular role in the implantation and decidualization has not been fully unraveled. Here, the study was conducted to investigate the expression and function of kisspeptin in mouse uterus during early pregnancy and decidualization. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative PCR results demonstrated that Kiss1 and GPR54 mRNA levels showed dynamic increase in the mouse uterus during early pregnancy and artificially induced decidualization in vivo. KISS-1 and GPR54 proteins were spatiotemporally expressed in decidualizing stromal cells in intact pregnant females, as well as in pseudopregnant mice undergoing artificially induced decidualization. In the ovariectomized mouse uterus, the expression of Kiss1 mRNA was upregulated after progesterone or/and estradiol treatment. Moreover, in a stromal cell culture model, the expression of Kiss1 and GPR54 mRNA gradually rise with the progression of stromal cell decidualization, whereas the attenuated expression of Kiss1 using small interfering RNA approaches significantly blocked the progression of stromal cell decidualization. CONCLUSION: our results demonstrated that Kiss1/GPR54 system was involved in promoting uterine decidualization during early pregnancy in mice.