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Insulin-resistance (IR) is one of the most important precursors of type 2 diabetes (T2D). Recent evidence suggests an association of depression with the onset of T2D. Accumulating evidence shows that depression and T2D share common biological origins, and DNA methylation examination might reveal the link between lifestyle, disease risk, and potential therapeutic targets for T2D. Here we hypothesize that integrative mining of IR and depression cohort data will facilitate predictive biomarkers identification for T2D. We utilized a newly proposed method to extract gene-level information from probe level data on genome-wide DNA methylation array. We identified a set of genes associated with IR and depression in clinical cohorts. By overlapping the IR-related nutraceutical-gene network with depression networks, we identified a common subnetwork centered with Vitamin D Receptor (VDR) gene. Preliminary clinical validation of gene methylation set in a small cohort of T2D patients and controls was established using the Sequenome matrix-assisted laser desorption ionization-time flight mass spectrometry. A set of sites in the promoter regions of VDR showed a significant difference between T2D patients and controls. Using a logistic regression model, the optimal prediction performance of these sites was AUC = 0.902，and an odds ratio = 19.76. Thus, monitoring the methylation status of specific VDR promoter region might help stratify the high-risk individuals who could potentially benefit from vitamin D dietary supplementation. Our results highlight the link between IR and depression, and the DNA methylation analysis might facilitate the search for their shared mechanisms in the etiology of T2D.

Background Urothelial carcinoma (UC) is the most common subtype of bladder cancer. The randomized phase 3 KEYNOTE-045 trial showed that pembrolizumab, used as second-line therapy significantly prolonged overall survival with fewer treatment-related adverse events than chemotherapy for advanced UC. Pembrolizumab has been approved by the European Medicines Agency for the treatment of locally advanced or metastatic UC in adults who have received platinum-containing chemotherapy. Many European countries use cost-effectiveness analysis to inform reimbursement decisions. Objective To assess the cost-effectiveness of pembrolizumab as second-line therapy for the treatment of advanced UC from a Swedish health care perspective. Design, setting, and participants We developed a partitioned-survival model to assess the costs and effectiveness of pembrolizumab compared with vinflunine (base case), paclitaxel, or docetaxel monotherapy in patients with advanced UC over a 15-yr time horizon. We obtained Kaplan-Meier estimates for survival endpoints, adverse events, and utility data from KEYNOTE-045. Outcome measurements and statistical analysis We performed parametric extrapolations to estimate overall and progression-free survival beyond the clinical trial period. Swedish costs and utility weights were used to estimate total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). We performed deterministic and probabilistic sensitivity analyses to assess the robustness of the model results. Results and limitations In the base-case analysis, pembrolizumab resulted in a mean survival gain of 1.66 years (1.38 QALYs) at an incremental cost of €69 852 and an ICER of €50 529/QALY gained versus vinflunine monotherapy. ICERs for other chemotherapies were €81 356/QALY for pembrolizumab versus paclitaxel or docetaxel monotherapy, and €71 924/QALY for pembrolizumab versus paclitaxel, docetaxel, or vinflunine monotherapy. Long-term follow-up from KEYNOTE-045 and real-world data are needed to validate the extrapolations. Conclusions The results indicate that pembrolizumab improves survival, increases QALYs, and is cost-effective as second-line therapy at a willingness-to-pay threshold of €100 000/QALY for the treatment of advanced UC. Patient summary To date, pembrolizumab is the only treatment associated with a significant overall survival benefit compared with chemotherapy in a randomized controlled trial as second-line therapy for advanced urothelial carcinoma. Our trial-based cost-effectiveness analysis suggests that pembrolizumab is a cost-effective option over chemotherapy in patients with advanced urothelial carcinoma after platinum-based therapy in Sweden.

A current popular feature extraction method of classifying cognitive states and task engagements from electroencephalographs (EEG) is common spatial patterns (CSP). However, the classical CSP only focuses on the correlation between the signals and ignores all characteristics of the signals in the time domain and the frequency domain. In this paper we propose Common cross-spectral patterns (CCSP) a novel EEG feature extraction method for combining spectral and spatial patterns based on cross-spectral density (CSD) to overcome the disadvantages of classical CSP. In CCSP method. the cross-power matrices (CPMs) are extracted to measure the spatial correlation of each task in the band of interest. Then, an orthogonal linear transformation is constructed by simultaneously diagonalizing the CPMs of two tasks. Finally, each band's logarithmic power of the transformed signals is extracted for the support vector machine (SVM) classifier. The experiment results on multiple datasets showed that the CCSP algorithm is fully applicable to multi-channel EEG for reliable multi-cognitive-task identification.

Purpose DSF has been proven safe and shows the promising anti-tumor effect in preclinical studies. However, the precise mechanism of DSF on tumor is rarely reported. This study aims to fully understand the mechanism of action of DSF with a systems perspective in anti-cancer effects. Experimental design SILAC-based quantitative proteomics strategy was used to systematically identify DEPs after DSF treatment in HeLa cells. Bioinformatical analysis (PANTHER, DAVID and STRING) were performed to characterize biological functions of DEPs. Functional studies was performed to explore underlying mechanisms of DSF in cancer cells. Results In total, 201 proteins were dys-regulated significantly after DSF exposure. Functional studies of HK2, which catalyzed the first irreversible enzymatic step in glucose metabolism, revealed that various phenotypic effects observed after DSF treatment in cancer cells, at least partly, through the regulation of HK2 expression. Conclusions and clinical relevance By correlating the proteomics data with these functional studies, the current results provided novel insights into the mechanism underlying DSF function in cancer cells. Meanwhile, these provided theoretical basis for the new use of old drugs in clinical therapy. This article is protected by copyright. All rights reserved.

Thiamine metabolism dysfunction syndrome 2 (THMD2) is a rare metabolic disorder caused by SLC19A3 mutations, inherited in autosomal recessive pattern. As a treatable disease, early diagnosis and therapy with vitamin supplementation is important to improve the prognosis. So far, the reported cases were mainly from Saudi Arab regions, and presented with relatively simple clinical course because of the hot spot mutation (T422A). Rare Chinese cases were described until now. In this study, we investigated 18 Chinese THMD2 patients with variable phenotypes, and identified 23 novel SLC19A3 mutations, which expanded the genetic and clinical spectrum of the disorder. Meanwhile, we reviewed all 146 reported patients from different countries. Approximately 2/3 of patients presented with classical BTBGD, while 1/3 of patients manifested as much earlier onset and poor prognosis, including infantile Leigh-like syndrome, infantile spasms, neonatal lactic acidosis and infantile BTBGD. Literature review showed that elevated lactate in blood and CSF, as well as abnormal OXPHOS activities of muscle or skin usually correlated with infantile phenotypes, which indicated poor outcome. Brainstem involvement on MRI was more common in deceased cases. Thiamine supplementation is indispensable in the treatment of THMD2, whereas combination of biotin and thiamine is not superior to thiamine alone. But biotin supplementation does work in some patients. Genotypic-phenotypic correlation remains unclear which needs further investigation, and biallelic truncated mutations usually led to more severe phenotype.

There is a body of evidence that the aging immune system is linked to cancer. In this study, with aging- and immune-related DNA methylation data, we investigated the DNA methylation regulation changes in promoters with other regions of genes during aging and their association with the immune-cell proportion in the circulating whole blood of individuals. The analyses for aging- and CD4+ T cell proportion-derived differential genes showed that ubiquitination plays an important role in the aging immune system and tumorigenesis. Therefore, starting from a set of pre-annotated ubiquitination genes, we found that among the differentially ubiquitinated genes, DZIP3, an E3 ubiquitin ligase with no reports on its function in immune cells and tumorigenesis, was significantly associated with both aging (P-value = 3.86e-06) and CD4+ T cell proportion (P-value = 1.97e-05) in circulating blood. By collecting a cohort of 100 colon cancer patients and 50 healthy individuals, we validated that the 1st exon DNA methylation of DZIP3 could predict the onset of early stage (AUC = 0.833, OR = 8.82) and all pTNM stages of colorectal cancer (AUC = 0.782, OR = 5.70). Thus, the epigenetically regulated ubiquitination machine plays an important role in immune aging and tumorigenesis.

Introduction Birth defects are a leading cause of infant death. Pregnant women spend a large amount of time indoors, and little research from population-based studies has investigated the association between indoor air pollution and birth defects. We aimed to examine whether using coal, biomass, or electromagnetic stoves for cooking is associated with risk of birth defects compared to using gas stoves. Methods A birth cohort study was conducted from 2010 to 2012 in Lanzhou, China. Cases (n = 264) were singleton births with birth defects, which were defined as abnormalities of structure or function, including metabolism, presented at birth based on the International Classification of Diseases (ICD)-10 codes. Controls (n = 9926) were defined as singleton live births without birth defects. Unconditional logistic regression models were employed to estimate the association adjusting for confounding variables. Results Compared to gas stoves for cooking, biomass (OR = 2.66, 95%CI: 1.38–5.13), and electromagnetic stove (OR = 1.90, 95%CI: 1.26–2.88) for cooking were associated with an increased risk of birth defects. The significant associations remained among non-congenital heart disease (CHD) defects but not CHDs. Conclusions Using biomass or electromagnetic stoves for cooking during pregnancy was associated with an increased risk of birth defects. Additional studies are warranted to confirm these novel findings. Studies with larger sample size or greater statistical power are also warranted to better estimate the associations for individual birth defects.

ObjectiveThere is a body of evidence that the aging immune system is linked to cancer. Here, we hypothesized that ubiquitination might play a key gatekeeper role in immune system aging and tumorigenesis in CRC. Therefore, we will systematically study the DNA methylation of ubiquitination genes and screen candidate CRC marker that are correlated with both aging and immune cell compositions.DesignThrough aging- and immune-related DNA methylation data, we investigated the DNA methylation regulation changes in promoters with other regions of genes during aging and their association with the immune cell proportion in the circulating whole blood of healthy individuals. Then, by collecting a cohort of 100 colon cancer patients and 50 healthy individuals, we used nucleic acid mass spectrometry to test whether ubiquitination genes can be used as candidate markers for the early screening of CRC.ResultsThe biological analyses for aging- and CD4 T cell proportion-derived differential genes showed that they are associated with ubiquitination. Among them, DZIP3 was significantly associated with both aging (P-value = 3.86E-06) and CD4 T cell proportion (P-value = 1.97E-05) in circulating blood. Then, we validated that the 1st exon DNA methylation of DZIP3 could predict the onset of early stage CRC (AUC = 0.833, OR = 8.82) and all pTNM stages of CRC (AUC = 0.782, OR = 5.70).ConclusionsThe epigenetically regulated ubiquitination plays an important role in immune aging and tumorigenesis. DNA methylation characteristic of DZIP3 can be used as a promising marker of CRC early screening.Summary boxWhat is already known about this subject?The aging immune system is associated with cancer.Ubiquitination plays potent roles in regulating a variety of signals in both innate and adaptive immune cells.The abnormalities of ubiquitination are closely related to the occurrence of various tumors.Blood cell DNA methylome analysis provides a promising tool to probe the key components of immune cell dysregulation in aging and tumorigenesis.What are the new findings?The aging- and immune cell proportion-derived differential genes are associated with ubiquitination.The epigenetically regulated ubiquitination plays an important role in immune aging and tumorigenesis.DNA methylation characteristic of DZIP3, an E3 ubiquitin ligase with no reports on its function in immune cells and tumorigenesis, can be used as a promising markers of CRC early screening.How might it impact on clinical practice in the foreseeable future?The in-depth study for DNA methylome of ubiquitination will open up a new path for the study of CRC pathogenesis, diagnosis and treatment.In addition, DZIP3-focused screening technique only needs to extract the whole blood of individuals for MassARRAY analysis; the samples are easy to obtain, and the results are objective. Therefore, this method may have important applications in clinical CRC screening.

Electroencephalographic (EEG) based emotion recognition has attracted increasing attention in the field of human-computer interaction (HCI). But, how to use the cognitive principles to enhance the emotion recognition model is still a challenge. The purpose of this research paper is to investigate the emotion cognitive process and its application. Firstly, to evoke the response emotions, a three-stage experimental paradigm of long-time music stimuli was designed. The EEG signals were recorded in 15 healthy adults during the listening of 16 music clips respectively. Then, the time course analysis method of music-evoked emotions was proposed to examine the differences of brain activities. There was great increase of the spectral power in alpha band and a slight decrease in high-frequency beta and gamma bands during music listening. Through time analysis, the characteristics of the inspiring–keeping–fading were also found in different emotional states. After that, the most relevant EEG features were selected based on the time correlation analysis between EEG and music features. Finally, based on the cognitive principles inspired EEG features, an emotional prediction system was built. From the results, the accuracies of binary classification were 66.8% for valence and 59.5% for arousal. The accuracies of 3-classes classification performed as 45.9% for valence and 45.1% for arousal. These results suggest that with the help of cognitive principles, a better emotional recognition system could be built. Understanding the cognitive process could promote the development of artificial intelligence.

Background/Objectives Incidence of herpes zoster (HZ) increases with age. The vaccine to prevent HZ is available for those who are 50 and older. This study aims to investigate the cost-effectiveness of HZ vaccine on population older than 50 years old from a societal perspective in Singapore. Methods The established decision analytic (Markov) model was utilized to simulate the results of vaccination for adults who were older than 50 years of age, compared to those without vaccination. The total number of HZ cases, postherpetic neuralgia (PHN) cases, total direct cost of treatment and indirect cost due to productivity loss were estimated based on the characteristics of population, and treatment costs were collected from a local institute in Singapore. The public health consensus for the ICER benchmark in Singapore was S$65,000. Results One million individuals were simulated in this health economics analysis. Vaccination would reduce 48% of HZ cases and 33% of PHN cases over their life time. When a vaccination strategy for adults who are 50 years old and older was compared to a strategy with no vaccination, incremental cost-effectiveness ratio (ICER) was S$49,023 per quality adjusted life years (QALY) gained from the societal perspective. Conclusion The herpes zoster vaccination is likely to be cost-effective in societal perspective for adult over 50 years of age in Singapore.

To determine optimal gestational weight gain (GWG) for the Chinese population.Live singleton deliveries at the largest maternal & childcare hospital in northwest China from 2010 to 2012 were analyzed retrospectively. Multivariable logistic regression analysis was conducted to determine the lowest aggregated risk of interested perinatal outcomes based on Chinese adult body mass index (BMI) categories.Eight thousand eight hundred seventy enrolled parturients were divided into 4 groups according to their prepregnancy BMI: underweight (21.31%, BMI

Objectives Our objectives were to evaluate the cost effectiveness of pembrolizumab compared with standard-of-care (SoC) platinum-based chemotherapy as first-line treatment in patients with metastatic non-small-cell lung cancer (NSCLC) that expresses high levels of programmed death ligand-1 (PD-L1) [tumour proportion score (TPS) ≥50%], from a US third-party public healthcare payer perspective. Methods We conducted a partitioned-survival model with a cycle length of 1 week and a base-case time horizon of 20 years. Parametric models were fitted to Kaplan–Meier estimates of time on treatment, progression-free survival and overall survival from the KEYNOTE-024 randomized clinical trial (patients aged ≥18 years with stage IV NSCLC, TPS ≥50%, without epidermal growth factor receptor (EGFR)-activating mutations or anaplastic lymphoma kinase (ALK) translocations who received no prior systemic chemotherapy) and validated with long-term registry data. Quality-adjusted life-years (QALYs) were calculated based on EuroQoL-5 Dimensions (EQ-5D) utility data collected in the trial. Costs ($US, year 2016 values) for drug acquisition/administration, adverse events and clinical management were included. Costs and outcomes were discounted at 3% per year. A series of deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results. Results In the base-case scenario, pembrolizumab resulted in an expected gain of 1.31 life-years (LYs) and 1.05 QALYs and an incremental cost of $US102,439 compared with SoC. The incremental cost per QALY gain was $US97,621/QALY and the incremental cost per LY gain was $US78,344/LY. Conclusions Pembrolizumab is projected to be a cost-effective option compared with SoC platinum-based chemotherapy as first-line treatment in adults with metastatic NSCLC expressing high levels of PD-L1. Electronic supplementary material The online version of this article (doi:10.1007/s40273-017-0527-z) contains supplementary material, which is available to authorized users.

Recent clinical trials have shown that pembrolizumab significantly prolonged progression-free survival and overall survival compared with ipilimumab in ipilimumab-naïve patients with unresectable or metastatic melanoma. However, there has been no published evidence on the cost-effectiveness of pembrolizumab for this indication.To assess the long-term cost-effectiveness of pembrolizumab versus ipilimumab in ipilimumab-naïve patients with unresectable or meta-static melanoma from a U.S. integrated health system perspective.A partitioned-survival model was developed, which divided overall survival time into progression-free survival and postprogression survival. The model used Kaplan-Meier estimates of progression-free survival and overall survival from a recent randomized phase 3 study (KEYNOTE-006) that compared pembrolizumab and ipilimumab. Extrapolation of progression-free survival and overall survival beyond the clinical trial was based on parametric functions and literature data. The base-case time horizon was 20 years, and costs and health outcomes were discounted at a rate of 3% per year. Clinical data-including progression-free survival and overall survival data spanning a median follow-up time of 15 months, as well as quality of life and adverse event data from the ongoing KEYNOTE-006 trial-and cost data from public sources were used to populate the model. Costs included those of drug acquisition, treatment administration, adverse event management, and disease management of advanced melanoma. The incremental cost-effectiveness ratio (ICER) expressed as cost difference per quality-adjusted life-year (QALY) gained was the main outcome, and a series of sensitivity analyses were performed to test the robustness of the results.In the base case, pembrolizumab was projected to increase the life expectancy of U.S. patients with advanced melanoma by 1.14 years, corresponding to a gain of 0.79 discounted QALYs over ipilimumab. The model also projected an average increase of $63,680 in discounted perpatient costs of treatment with pembrolizumab versus ipilimumab. The corresponding ICER was $81,091 per QALY ($68,712 per life-year) over a 20-year time horizon. With $100,000 per QALY as the threshold, when input parameters were varied in deterministic one-way sensitivity analyses, the use of pembrolizumab was cost-effective relative to ipilimumab in most ranges. Further, in a comprehensive probabilistic sensitivity analysis, the ICER was cost-effective in 83% of the simulations.Compared with ipilimumab, pembrolizumab had higher expected QALYs and was cost-effective for the treatment of patients with unresectable or metastatic melanoma from a U.S. integrated health system perspective.This study was supported by funding from MerckCo., which reviewed and approved the manuscript before journal submission. Wang, Pellissier, Xu, Stevinson, and Liu are employees of, and own stock in, MerckCo. Chmielowski has served as a paid consultant for MerckCo. and received a consultant fee for clinical input in connection with this study. Chmielowski also reports receiving advisory board and speaker bureau fees from multiple major pharmaceutical companies. Wang led the modeling and writing of the manuscript. Chmielowski, Xu, Stevinson, and Pellissier contributed substantially to the modeling design and methodology. Liu led the data collection work and contributed substantially to writing the manuscript. In conducting the analysis and writing the manuscript, the authors followed Merck publication polices and the "cost-effectiveness analysis alongside clinical trials-good research practices and the CHEERS reporting format as recommended by the International Society for Pharmacoeconomics and Outcomes Research.

Background There is an unmet need for effective therapies for patients with advanced or metastatic urothelial cancer who cannot tolerate cisplatin-based chemotherapy. Cisplatin-ineligible patients experience a high frequency of adverse events from the most commonly used standard of care treatment, carboplatin plus gemcitabine, or alternative treatment with gemcitabine monotherapy. Pembrolizumab is a potent, highly selective humanised monoclonal antibody that releases checkpoint inhibition of the immune response system, and provides a new alternative for these patients. Objective To assess the cost-effectiveness of pembrolizumab for first-line treatment of urothelial carcinoma ineligible for cisplatin-based therapy in patients with strongly PD-L1–positive tumours in Sweden. Design, setting, and participants Parametric survival curves were fitted to overall survival, progression-free survival, and time on treatment data from KEYNOTE-052 to extrapolate clinical outcomes. A simulated treatment comparison and a network meta-analysis were conducted to estimate the comparative efficacy of pembrolizumab versus carboplatin plus gemcitabine and gemcitabine monotherapy. EQ-5D data from KEYNOTE-052 were used to estimate utility, while resource use and cost inputs were estimated using Swedish regional pricing lists and clinician opinion. Outcome measurements and statistical analysis The model reported costs, life years, and quality-adjusted life years (QALYs), and results were tested using deterministic and probabilistic sensitivity analysis. Results and limitations We estimated that pembrolizumab would improve survival by 2.11 and 2.16 years and increase QALYs by 1.71 and 1.75 compared to carboplatin plus gemcitabine and gemcitabine monotherapy, respectively. Pembrolizumab was associated with a cost increase of €90 520 versus carboplatin plus gemcitabine and €95 055 versus gemcitabine, with corresponding incremental cost-effectiveness ratios of €53 055/QALY and €54 415/QALY. Conclusions At a willingness-to-pay threshold of €100 000/QALY, pembrolizumab is a cost-effective treatment versus carboplatin plus gemcitabine and versus gemcitabine. Patient summary This is the first analysis to show that pembrolizumab is a cost-effective option for first-line treatment of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma in Sweden.

Background Patients with recurrent Clostridium difficile infection (rCDI) are more likely to have a hospital readmission and spend increased time in inpatient settings compared with patients with primary CDI. MODIFY I and II demonstrated that bezlotoxumab significantly reduced rCDI vs placebo. A post hoc within-trial analysis assessed whether bezlotoxumab was associated with a reduction in cumulative inpatient-days. Methods Data were pooled from the MODIFY trials to estimate the cumulative hospitalized days summed over the 84-day follow-up period. We adjusted inpatient use data from pooled MODIFY I and II for survival and censoring to estimate 84-day cumulative inpatient-days, overall and for subgroups. Treatment effects were obtained using recycled predictions based on trial protocol and rCDI risk, and 95% confidence intervals were obtained using 1000 bootstrap replicates. Results Mean cumulative inpatient-days were greater in the placebo arm (14.1 days) vs the bezlotoxumab arm (12.1 days) in the overall population. The mean difference between treatment groups was 2.1 days (95% confidence interval, –0.4 to –3.7). This was consistent in participants with risk factors for rCDI: age ≥65 years, compromised immunity, severe CDI, prior CDI, and ribotype 027/078/244 infection. As the number of risk factors increased, bezlotoxumab resulted in greater reductions in the number of inpatient-days compared with placebo (difference: –1.2 days, –2.3 days, –2.5 days, and –3.0 days for 0, 1, 2, and ≥3 risk factors, respectively). Conclusions Bezlotoxumab was associated with a reduction in cumulative inpatient-days, suggesting that treatment with bezlotoxumab may substantially reduce rCDI-associated health care resource use. Trial registrations. MODIFY I (MK-3415A-001, NCT01241552) and II (MK-3415A-002, NCT01513239)

A herpes zoster vaccine has been approved by the FDA for use in prevention of herpes zoster in individuals who are aged 50 years or older. The Advisory Committee on Immunization Practices (ACIP) recommends vaccination only in individuals who are aged 60 years and older.To (a) estimate the overall budget and health impact of either the introduction of a new vaccination strategy (individuals over the age of 50 years vs. individuals over the age of 60 years) within a hypothetical health plan or simply an increase in coverage within the population aged 60 years and over and (b) discern what effect copayments and changes to copayments have on the health plan's budget.A decision-analytic economic model was developed to inform managed care decision makers of the potential effect on costs and outcomes associated with the use of the herpes zoster vaccine for prevention of herpes zoster (i.e., simple zoster or shingles). The model took a U.S. payer perspective. The number of eligible patients entering the model was estimated by considering the age distribution of the plan population and the percentage of patients contraindicated for vaccination (i.e., those who were immunocompromised or who had a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine). Eligible patients were vaccinated based on the projected uptake rates among the unvaccinated population in 2 possible vaccination scenarios: (1) a vaccination strategy in which only individuals over age 60 years can be vaccinated and (2) a vaccination strategy in which individuals over age 50 years can be vaccinated. Vaccination was assumed to reverse the age-related decline in immunity against zoster. The population vaccinated each year was estimated based on the uptake rates (percentage of the eligible unvaccinated that are vaccinated) required to reach a target annual coverage (percentage ever vaccinated). Patients could experience costs and outcomes related to vaccination or related to herpes zoster. Specifically, vaccination could cause adverse events that would require the use of health care resources. Patients who developed zoster could experience postherpetic neuralgia or develop nonpain complications that would require the use of health care resources. Vaccine costs, zoster cases (with and without postherpetic neuralgia or nonpain complication), and vaccine-related adverse events for the 2 vaccination scenarios were estimated for each budget year.For a managed care organization population of 5 million members, the model estimated that a vaccination program that included patients over age 50 years instead of a program limiting vaccination to those over age 60 years was associated with a decrease in the number of patients developing zoster (2,372-3,392 cases avoided over 5 years). Annual incremental per-member-per-month (PMPM) costs associated with this vaccination program change were estimated to range from $0.08 to $0.14. When the vaccination program was kept at age 60 years and over and coverage was increased, the model estimated that the annual incremental PMPM costs ranged from $0.04 to $0.06. Differences in costs were driven primarily by vaccination costs. The results of the scenario analyses showed that lower vaccination costs because of the application of copayments for a managed care organization reduced the magnitude of the total cost increase associated with the increase in uptake.Vaccinating individuals aged 50 to 59 years with the herpes zoster vaccine would likely have an impact on a health plan's budget because of the expected increase in the total number of individuals being vaccinated in the population, with limited cost savings because of fewer cases of herpes zoster. Higher coverage of vaccinations resulted in a greater increase in total costs each year. However, increasing coverage would also result in a decrease in the number of individuals developing zoster and associated postherpetic neuralgia and nonpain complications over the next 5 years.MerckCo. funded this study/research and was involved in all stages of study conduct, including analysis of the data. MerckCo. also undertook all costs associated with the development and publication of this manuscript. Graham and Mauskopf (and/or their institutions) received research funding from MerckCo. to develop the budget-impact estimates and for other research studies. Johnson, Xu, and Acosta are employees of MerckCo. Kawai was employed by MerckCo. during part of the time of this study. Graham and Mauskopf were primarily responsible for the design and programming of the economic model, identification and final selection of the input parameter values, interpretation of the study results, and preparation of the study report. Johnson, Kawai, Xu, and Acosta contributed to model design, input parameter estimation, interpretation of the results, and review of and revisions to the study report. All authors had access to the data, participated in the development of this manuscript, and gave final approval before submission. All authors have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Emotion recognition based on electroencephalogram (EEG) signal is attracting more and more attention. Many feature engineering based models have been investigated. However, these models require a lot of effort for manually designing feature set. And these features can be hardly transformed among different problems. To reduce the manual effort on features used in EEG-based recognition and improve the performance, we propose an end-to-end model which is based on Convolutional Neural Networks (CNNs). In order to represent the EEG signals better, the original channels of EEG are firstly rearranged by Pearson Correlation Coefficient and the rearranged EEGs are fed into CNN. experiments were carried on DEAP dataset. The experimental results on the DEAP dataset show that the proposed method achieves 77.98% accuracy on the Valence recognition and 72.98% on the Arousal recognition.

Emotion recognition based on electroencephalogram (EEG) signals provides a direct access to inner state of a user, which is considered an important factor in Human-Machine-Interaction (HMI). Traditional feature extraction methods for EEG signals always suffer from high dimension and unsatisfactory interpretability. In this paper, we propose a novel symbolic representation approach of EEG signals for emotion recognition. By applying the Symbolic Aggregate approXimation(SAX) algorithm, the continuous EEG signals are represented as discrete symbol strings. The bag of words model and Latent Semantic Indexing algorithm are then performed to extract and select the word features from the symbolic strings as the discriminative features in a Support Vector Machine based classifier for emotion classification. The evaluations on DEAP dataset show that our proposed approach outperforms the three typical methods stably. Meanwhile, the symbolic representation is shown helpful to improve the interpretability of similar EEG signals. The more important issue is that this approach brings a new way to represent the EEG signal. It is helpful to introduce the natural language processing techniques to EEG signal analysis and classification research.

Importance: Exposure to ambient particulate matter during pregnancy has been suggested as a risk factor for preterm birth. However results from limited epidemiologic studies have been inconclusive. Very few studies have been conducted in areas with high air pollution levels. Objective: We investigated the hypothesis that high level exposure to particulate matter with aerodynamic diameter no larger than 10 μm (PM10) during pregnancy increases the risk of preterm birth. Methods: A birth cohort study was carried out between 2010 and 2012 in Lanzhou, China, including 8969 singleton live births with available information on daily PM10 levels from four monitoring stations, individual exposures during pregnancy were calculated using inverse-distance weighting based on both home and work addresses. Unconditional logistic regression modeling was used to examine the associations between PM10 exposure and risk of preterm birth and its clinical subtypes. Results: Increased risk of very preterm birth was associated with exposure to PM10 during the last two months of pregnancy (OR, 1.07; 95%CI, 1.02–1.13 per 10 μg/m3 increase for last four weeks before delivery; 1.09; 1.02–1.15 for last six weeks before delivery; 1.10; 1.03–1.17 for last eight weeks before delivery). Compared to the U.S. National Ambient Air Quality Standard (150 μg/m3), higher exposure level (≥150 μg/m3) of PM10 during entire pregnancy was associated with an increased risk of preterm birth (1.48; 1.22–1.81) and the association was higher for medically indicated preterm birth (1.80, 1.24–2.62) during entire pregnancy and for very preterm during last 6 weeks before delivery (2.03, 1.11–3.72). Conclusions and relevance: Our study supports the hypothesis that exposure to high levels of ambient PM10 increases the risk of preterm birth. Our study also suggests that the risk may vary by clinical subtypes of preterm birth and exposure time windows. Our findings are relevant for health policy makers from China and other regions with high levels of air pollution to facilitate the efforts of reducing air pollution level in order to protect public health. Keywords: China, Epidemiology, PM10, Preterm birth, Birth cohort, Air pollution

Since 2006, the vaccine, ZOSTAVAX(®), has been licensed to prevent herpes zoster. Only limited clinical follow-up data are available to evaluate duration of protection, an important consideration when developing HZ vaccination policy recommendations. Four Poisson regression models were developed based on an integrated analysis of data from the Shingles Prevention Study and its Short Term Persistence extension to estimate the effects of years-since-vaccination and chronological-age on vaccine efficacy among people ≥60 years old. The models included number of HZ cases parsed into categories by chronological-age and time-since-vaccination as the dependent variable with different explanatory variables in each model. In all models, the interaction between vaccine-group and chronological-age was statistically significant indicating that vaccine efficacy decreases with the expected effects of advancing age but the interaction between vaccine-group and time-since-vaccination was not statistically significant indicating that much of the reduction in vaccine efficacy over time-since-vaccination can be explained by increasing age.

The purpose of this research was to establish an analytical method for analysing the 1-[6-chloro-3-methyl-pyridyl-8-nitro-7-methyl-1 2 3 5 6 7-hexahydro imidazo-(1,2a)]-pyridine (IPP) residue levels and to evaluate the difference in plant growth and its physical condition. A high performance liquid chromatography connected to a diode array detector (HPLC-DAD) was also employed. The results showed that the content of protein and water soluble carbohydrate (WSC) treated by IPP were initially higher with a significant delayed decrease. The biomarker response showed, even at a lower dose rate, exposure to the IPP caused stress effects and modified the activity of superoxide dismutase (SOD), guaiacol peroxidase (POD), catalase (CAT) and polyphenol oxidase (PPO). Different patterns of biomarker responses were observed by an increase in SOD and malondialdehyde (MDA), and differential effects for antioxidant enzymes with a decrease in CAT, POD and PPO. The conclusions show that this profile of biomarker variation could represent a useful method to characterise exposure to IPP in a wheat plant.

DNA-binding proteins are crucial for various cellular processes, such as recognition of specific nucleotide, regulation of transcription, and regulation of gene expression. Developing an effective model for identifying DNA-binding proteins is an urgent research problem. Up to now, many methods have been proposed, but most of them focus on only one classifier and cannot make full use of the large number of negative samples to improve predicting performance. This study proposed a predictor called enDNA-Prot for DNA-binding protein identification by employing the ensemble learning technique. Experiential results showed that enDNA-Prot was comparable with DNA-Prot and outperformed DNAbinder and iDNA-Prot with performance improvement in the range of 3.97–9.52% in ACC and 0.08–0.19 in MCC. Furthermore, when the benchmark dataset was expanded with negative samples, the performance of enDNA-Prot outperformed the three existing methods by 2.83–16.63% in terms of ACC and 0.02–0.16 in terms of MCC. It indicated that enDNA-Prot is an effective method for DNA-binding protein identification and expanding training dataset with negative samples can improve its performance. For the convenience of the vast majority of experimental scientists, we developed a user-friendly web-server for enDNA-Prot which is freely accessible to the public.

Background The aim of this study was to assess the cost-effectiveness of pembrolizumab in treating patients with ipilimumab-naive advanced melanoma in Portugal. Methods A cost-effectiveness model was developed to analyze the costs and consequences of treatment with pembrolizumab compared to treatment with ipilimumab in patients with advanced melanoma not previously treated with ipilimumab. The model was parameterized by using data from a head-to-head phase III randomized clinical trial, KEYNOTE-006. Extrapolation of long-term outcomes was based on approaches previously applied, combining ipilimumab data and melanoma patients' registry data. The analysis was conducted from the perspective of the Portuguese National Health Service, and a lifetime horizon (40 years) was used. Portugal-specific disease management costs were estimated by convening a panel of six clinical experts to derive health state resource use and multiplying the results by national unit costs. To test for the robustness of the conclusions, we conducted deterministic and probabilistic sensitivity analyses. Results Pembrolizumab increases life expectancy in 1.57 undiscounted life-years (LYs) and is associated with an increase in costs versus that of ipilimumab. The estimated incremental cost-effectiveness ratio is €47,221 per quality-adjusted life-year (QALY) and €42,956 per LY. Deterministic sensitivity analysis showed that the results were robust to the change of most input values or assumptions and were sensitive to time on treatment scenarios. According to the probabilistic sensitivity analysis performed, pembrolizumab is associated with a cost per QALY gained inferior to €50,000 in 75% of the cases. Conclusions Considering the usually accepted thresholds in oncology, pembrolizumab is a cost-effective alternative for treating patients with advanced melanoma in Portugal.

This analysis aimed to evaluate the cost-effectiveness of pembrolizumab compared with docetaxel in patients with previously treated advanced non-squamous cell lung cancer (NSCLC) with PD-L1 positive tumors (total proportion score [TPS] ≥ 50%). The analysis was conducted from a US third-party payer perspective.A partitioned-survival model was developed using data from patients from the KEYNOTE 010 clinical trial. The model used Kaplan-Meier (KM) estimates of progression-free survival (PFS) and overall survival (OS) from the trial for patients treated with either pembrolizumab 2 mg/kg or docetaxel 75 mg/mBase case results project for PD-L1 positive (TPS ≥50%) patients treated with pembrolizumab a mean survival of 2.25 years. For docetaxel, a mean survival time of 1.07 years was estimated. Expected QALYs were 1.71 and 0.76 for pembrolizumab and docetaxel, respectively. The incremental cost per QALY gained with pembrolizumab vs docetaxel is $168,619/QALY, which is cost-effective in the US using a threshold of 3-times GDP per capita. Sensitivity analyses showed the results to be robust over plausible values of the majority of inputs. Results were most sensitive to extrapolation of overall survival.Pembrolizumab improves survival, increases QALYs, and can be considered as a cost-effective option compared to docetaxel in PD-L1 positive (TPS ≥50%) pre-treated advanced NSCLC patients in the US.

To elucidate the influence of recreational physical activity, body mass index (BMI), and waist circumference on the risk of specific types of urinary incontinence.We conducted a population-based cross-sectional survey in Gansu, China among 2603 women aged 20 years or older.The study found that BMI was positively associated with urinary incontinence (P for trend=0.008) and the association was mainly observed for stress urinary incontinence (OR=1.4, 95% CI: 1.1, 1.9 for BMI=24.0-27.9 kg/m²; OR=2.3, 95% CI: 1.5, 3.6 for BMI ≥ 28.0 kg/m²; P for trend=0.0005). A positive association between stress incontinence (OR=1.7, 95% CI: 1.2, 2.5) and waist circumference was observed for women who had waist circumference between 70 cm and 75 cm compared to waist circumference less than 70 cm. Recreational physical activity was inversely associated with overall and mixed urinary incontinence (P for trend0.0001 for both). A significant interaction between physical activity and waist circumference was found for overall (P=0.0007) and stress incontinence (P=0.001).The findings that physical activity inversely associated with urinary incontinence and its interaction with waist circumference warrant further investigation, particularly in prospective studies.

Introduction: Some studies have suggested an association of residence near major roads with adverse birth outcomes. However, little is known about this relationship in large Chinese cities, where i...

The emotion recognition using the electroencephalogram (EEG) receives a lot of attentions in recent years. Various features extracted from different angles are proposed. In this paper, we propose an EEG-based emotion recognition framework based on the weighted fusion of outputs from base classifiers. Threebase classifiers based on the SVM with RBF kernel using Power Spectral, Higuchi Fractal Dimension and Lempel-Ziv Complexity features are developed, respectively. The outputs of base classifiers are integrated by the weighted fusion strategy which is based on the confidence estimation on each class by each base classifier. The evaluation on the DEAP dataset shows that our proposed decision fusion based method outperforms individual base classifiers and the feature fusion based classifier integration for EEG-based emotion recognition.

Folic acid supplementation has been suggested to reduce the risk of preterm birth. However, results from previous epidemiologic studies have been inconclusive. We investigated the hypothesis that folic acid supplementation and dietary folate intake during pre- and post-conception reduces the risk of preterm birth. We analyzed data from a birth cohort study conducted between 2010 and 2012 in Lanzhou, China, including 10,179 pregnant women with live singleton births. Compared to non-users, folic acid supplement users with >12-week duration had a reduced risk of preterm birth (OR 0.67, 95 % CI 0.55–0.83) with a significant dose–response relationship (P for trend = 0.01). A similar pattern was observed for spontaneous preterm birth. Stronger associations were seen for ever use of folic acid supplement and very preterm birth (OR 0.50, 95 % CI 0.36–0.69) and spontaneous very preterm birth (OR 0.42, 95 % CI 0.29–0.63). Dietary folate intake during preconception and pregnancy were also associated with reduced risk of preterm birth (OR 0.68, 95 % CI 0.56–0.83, OR 0.57, 95 % CI 0.47–0.70 for the highest quartiles, respectively), particularly for spontaneous very preterm (OR 0.41, 95 % CI 0.24–0.72, OR 0.26, 95 % CI 0.15–0.47 for the highest quartiles, respectively). There were also decreased risks of preterm birth observed per 10-µg increase in dietary folate intake, and similar associations were found after stratification by folic acid supplementation status. Our results suggest that folic acid supplementation and higher dietary folate intake during preconception and pregnancy reduces the risk of preterm birth, and the protective effect varies by preterm subtypes.

Backgroud: Exposure to high levels of ambient air pollutant PM10 during pregnancy has been suggested as a risk factor for preterm birth. However results from limited epidemiological studies have be...

Studies investigating the relationship between maternal passive smoking and the risk of preterm birth have reached inconsistent conclusions. A birth cohort study that included 10,095 nonsmoking women who delivered a singleton live birth was carried out in Lanzhou, China, between 2010 and 2012. Exposure to passive smoking during pregnancy was associated with an increased risk of very preterm birth (

Background To estimate utility values for different levels of migraine pain severity from a United Kingdom (UK) sample of migraineurs. Methods One hundred and six migraineurs completed the EQ-5D to evaluate their health status for mild, moderate and severe levels of migraine pain severity for a recent migraine attack, and for current health defined as health status within seven days post-migraine attack. Statistical tests were used to evaluate differences in mean utility scores by migraine severity. Results Utility scores for each health state were significantly different from 1.0 (no problems on any EQ-5D dimension) (p Conclusions Results indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Results can be used in cost-utility models examining the relative economic value of therapeutic strategies for migraine in the UK.

Monodispersed carboxymethyl cellulose (CMC)-stabilized Fe-Cu bimetal nanoparticles with an average diameter of less than 20nm were successfully synthesized by a modified water-based approach. The as-resulting particles exhibit a core-shell structure and are quite uniform in size and shape. Batch experiments demonstrated that these nanoparticles could effectively dechlorinate 1,2,4-trichlorobenzene (1,2,4-TCB). Near 90% of reduction efficiency was achieved by CMC-stabilized Fe-Cu for 24h treatment. By monitoring the reaction products with time by GC-MS, it was found that 1,2,4-TCB transformation mainly followed the sequential hydrogenolysis to 1,2-dichlorobenzene (12DCB), then chlorobenzene (CB) and eventually benzene. The pseudo first order 1,2,4-TCB degradation rate were 0.09h(-1) and 0.06h(-1) as CMC-to-Fe molar ratios were 0.00248 and 0.00124, respectively. Dechlorination mechanism was also proposed in this study.

Previous studies have reported health utilities for migraine patients as generally measured between migraine attacks, but health utility data for within a migraine attack are unavailable. We evaluated within-attack health utilities among acute migraine patients experiencing different grades of headache severity. We examined data for 330 20–65-year-old adults, in good physical health, who had 1–6 moderate/severe migraine attacks per month in the 2 months prior to the screening visit. Data were collected from a multicenter, double-blind study of a treatment for acute migraine in the United States. The EQ-5D system was used to measure generic health status at baseline and 24 h post-treatment within an acute migraine attack, and patients were also asked to rate their pain level at these time points (no, mild, moderate, or severe pain). The D1 time-trade-off scoring algorithm for the U.S. population was applied. Confidence intervals were estimated by bootstrap methods. The study population was 88% women and 78% white ethnicity, with 60% of subjects over age 40. The disutility of mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Within-attack disutilities estimated for migraine in this study are much greater than those reported for migraine when evaluated as a chronic health condition (e.g., valuations collected at random time points). These data can be of value in adapting results from clinical trials of migraine interventions to cost-utility policy analyses.

Background: The relationship between air borne particulate matter ≤10 μm (PM10) exposure and pregnancy-induced hypertension (PIH) is inconclusive. Few studies have been conducted, and fewer were conducted in areas with high levels of PM10. Methods: To examine the association between PM10 and PIH by different exposure time windows during pregnancy, we analyzed data from a birth cohort study conducted in Lanzhou, China including 8 745 pregnant women with available information on air pollution during pregnancy. A total of 333 PIH cases (127 gestational hypertension (GH) and 206 preeclampsia (PE)) were identified. PM10 daily average concentrations of each subject were calculated according to the distance between home/work addresses and monitor stations using an inverse-distance weighting approach. Results: Average PM10 concentration over the duration of entire pregnancy was significantly associated with PIH (OR = 1.12, 95%CI: 1.02, 1.23 per 10 μg m−3 increase), PE (OR = 1.16, 95%CI: 1.03, 1.30 per 10 μg m−3 increase), late onset PE (OR = 1.17, 95% CI: 1.03, 1.32 per10 μg m−3 increase), and severe PE (OR = 1.25, 95% CI: 1.06, 1.48 per 10 μg m−3 increase). Average PM10 during the first 12 gestational weeks was associated with the risk of GH (OR = 1.10, 95% CI: 1.00, 1.21 per 10 μg m−3 increase), and PM10 exposure before 20 gestational weeks was associated with the risk of severe PE (OR = 1.14, 95% CI: 1.01, 1.30 per 10 μg m−3 increase). Conclusions: We found that high level exposure to ambient PM10 during pregnancy was associated with an increased risk of PIH, GH and PE and that the strength of the association varied by timing of exposure during pregnancy.

Background Studies investigating the relationship between maternal tea drinking and risk of preterm birth have reached inconsistent results. Methods The present study analyzed data from a birth cohort study including 10,179 women who delivered a singleton live birth were conducted in Lanzhou, China between 2010 and 2012. Results Drinking tea (OR = 1.36, 95 % CI: 1.09–1.69), and specifically green (OR = 1.42, 95 % CI: 1.08–1.85) or scented tea (OR = 1.61, 95 % CI: 1.04–2.50), was associated with an increased risk of preterm birth. Drinking tea was associated with both moderate preterm (OR = 1.41, 95 % CI: 1.12–1.79) and spontaneous preterm birth (OR = 1.41, 95 % CI: 1.09–1.83). Risk of preterm birth increased with decreasing age of starting tea drinking (

Background Early studies have suggested that biomass cooking fuels were associated with increased risk of low birth weight (LBW). However it is unclear if this reduced birth weight was due to prematurity or intrauterine growth restriction (IUGR). Methods In order to understand the relationship between various cooking fuels and risk of LBW and small for gestational age (SGA), we analyzed data from a birth cohort study conducted in Lanzhou, China which included 9,895 singleton live births. Results Compared to mothers using gas as cooking fuel, significant reductions in birth weight were observed for mothers using coal (weight difference = 73.31 g, 95 % CI: 26.86, 119.77) and biomass (weight difference = 87.84 g, 95 % CI: 10.76, 164.46). Using biomass as cooking fuel was associated with more than two-fold increased risk of LBW (OR = 2.51, 95 % CI: 1.26, 5.01), and the risk was mainly seen among preterm births (OR = 3.43, 95 % CI: 1.21, 9.74). No significant associations with LBW were observed among mothers using coal or electromagnetic stoves for cooking. Conclusions These findings suggest that exposure to biomass during pregnancy is associated with risk of LBW, and the effect of biomass on LBW may be primarily due to prematurity rather than IUGR.