High Expression of Lewis y Antigen and CD44 Is Correlated with Resistance to Chemotherapy in Epithelial Ovarian Cancers

Objectives

To measure Lewis y antigen and CD44 antigen expression in epithelial ovarian carcinoma and to correlate the levels of these antigens with clinical response to chemotherapy.

Methods

The study cases included 34 cases of ovarian carcinoma with resistance to chemotherapeutic drugs, 6 partially drug-sensitive cases, and 52 drug-sensitive cases (92 total).

Results

The rates of expression of Lewis y antigen and CD44 antigen were significantly greater in the drug-resistant group than that in the partially-sensitive or sensitive groups. Surgical stage, residual tumor size and expression of CD44 and Lewis y antigen in ovarian carcinoma tissues were independent risk factors for chemotherapeutic drug resistance.

Conclusions

Over-expression of Lewis y and CD44 antigen are strong risk factors for chemotherapeutic drug resistance in ovarian carcinoma patients.     

Scalable Steady State Analysis of Boolean Biological Regulatory Networks

Background

Computing the long term behavior of regulatory and signaling networks is critical in understanding how biological functions take place in organisms. Steady states of these networks determine the activity levels of individual entities in the long run. Identifying all the steady states of these networks is difficult due to the state space explosion problem.

Methodology

In this paper, we propose a method for identifying all the steady states of Boolean regulatory and signaling networks accurately and efficiently. We build a mathematical model that allows pruning a large portion of the state space quickly without causing any false dismissals. For the remaining state space, which is typically very small compared to the whole state space, we develop a randomized traversal method that extracts the steady states. We estimate the number of steady states, and the expected behavior of individual genes and gene pairs in steady states in an online fashion. Also, we formulate a stopping criterion that terminates the traversal as soon as user supplied percentage of the results are returned with high confidence.

Conclusions

This method identifies the observed steady states of boolean biological networks computationally. Our algorithm successfully reported the G1 phases of both budding and fission yeast cell cycles. Besides, the experiments suggest that this method is useful in identifying co-expressed genes as well. By analyzing the steady state profile of Hedgehog network, we were able to find the highly co-expressed gene pair GL1-SMO together with other such pairs.

Availability

Source code of this work is available at http://bioinformatics.cise.ufl.edu/palSteady.html twocolumnfalse]     

Evaluation of the Highly Variable Agomelatine Pharmacokinetics in Chinese Healthy Subjects to Support Bioequivalence Study

Objectives

We aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy.

Methods

A single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples.

Results

The intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for C_max and AUC_0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%).

Conclusions

Agomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies.

Trial Registration

ChiCTR.org ChiCTR-TTRCC-13003835      

Molecular Pathways Involved in Prostate Carcinogenesis: Insights from Public Microarray Datasets

Background

Prostate cancer is currently the most frequently diagnosed malignancy in men and the second leading cause of cancer-related deaths in industrialized countries. Worldwide, an increase in prostate cancer incidence is expected due to an increased life-expectancy, aging of the population and improved diagnosis. Although the specific underlying mechanisms of prostate carcinogenesis remain unknown, prostate cancer is thought to result from a combination of genetic and environmental factors altering key cellular processes. To elucidate these complex interactions and to contribute to the understanding of prostate cancer progression and metastasis, analysis of large scale gene expression studies using bioinformatics approaches is used to decipher regulation of core processes.

Methodology/Principal Findings

In this study, a standardized quality control procedure and statistical analysis (http://www.arrayanalysis.org/) were applied to multiple prostate cancer datasets retrieved from the ArrayExpress data repository and pathway analysis using PathVisio (http://www.pathvisio.org/) was performed. The results led to the identification of three core biological processes that are strongly affected during prostate carcinogenesis: cholesterol biosynthesis, the process of epithelial-to-mesenchymal transition and an increased metabolic activity.

Conclusions

This study illustrates how a standardized bioinformatics evaluation of existing microarray data and subsequent pathway analysis can quickly and cost-effectively provide essential information about important molecular pathways and cellular processes involved in prostate cancer development and disease progression. The presented results may assist in biomarker profiling and the development of novel treatment approaches.     

Improving Adherence and Clinical Outcomes in Self-Guided Internet Treatment for Anxiety and Depression: Randomised Controlled Trial

Background

Depression and anxiety are common, disabling and chronic. Self-guided internet-delivered treatments are popular, but few people complete them. New strategies are required to realise their potential.

Aims

To evaluate the effect of automated emails on the effectiveness, safety, and acceptability of a new automated transdiagnostic self-guided internet-delivered treatment, the Wellbeing Course, for people with depression and anxiety.

Method

A randomised controlled trial was conducted through the website: www.ecentreclinic.org. Two hundred and fifty seven people with elevated symptoms were randomly allocated to the 8 week course either with or without automated emails, or to a waitlist control group. Primary outcome measures were the Patient Health Questionnaire 9-Item (PHQ-9) and the Generalized Anxiety Disorder 7-Item (GAD-7).

Results

Participants in the treatment groups had lower PHQ-9 and GAD-7 scores at post-treatment than controls. Automated emails increased rates of course completion (58% vs. 35%), and improved outcomes in a subsample with elevated symptoms.

Conclusions

The new self-guided course was beneficial, and automated emails facilitated outcomes. Further attention to strategies that facilitate adherence, learning, and safety will help realise the potential of self-guided interventions.

Trial Registration

Australian and New Zealand Clinical Trials Registry ACTRN12610001058066     

The Effectiveness of an Online Support Group for Members of the Community with Depression: A Randomised Controlled Trial

Background

Internet support groups (ISGs) are popular, particularly among people with depression, but there is little high quality evidence concerning their effectiveness.

Aim

The study aimed to evaluate the efficacy of an ISG for reducing depressive symptoms among community members when used alone and in combination with an automated Internet-based psychotherapy training program.

Method

Volunteers with elevated psychological distress were identified using a community-based screening postal survey. Participants were randomised to one of four 12-week conditions: depression Internet Support Group (ISG), automated depression Internet Training Program (ITP), combination of the two (ITP+ISG), or a control website with delayed access to e-couch at 6 months. Assessments were conducted at baseline, post-intervention, 6 and 12 months.

Results

There was no change in depressive symptoms relative to control after 3 months of exposure to the ISG. However, both the ISG alone and the combined ISG+ITP group showed significantly greater reduction in depressive symptoms at 6 and 12 months follow-up than the control group. The ITP program was effective relative to control at post-intervention but not at 6 months.

Conclusions

ISGs for depression are promising and warrant further empirical investigation.

Trial Registration

Controlled-Trials.com ISRCTN65657330     

Soluble Biomarkers of Cartilage and Bone Metabolism in Early Proof of Concept Trials in Psoriatic Arthritis: Effects of Adalimumab Versus Placebo

Background

There is growing interest in soluble biomarkers that could be used on the group level for screening purposes in small proof of principle studies during early drug development. We investigated early changes in serum levels of several candidate biomarkers involved in cartilage and bone metabolism following the initiation of adalimumab as a prototypic active treatment in psoriatic arthritis (PsA) compared to placebo.

Materials and Methods

Twenty-four PsA patients were randomized to receive either adalimumab 40 mg s.c. every other week or placebo for 4 weeks, followed by an open label extension phase. Serum samples were obtained at baseline and after 4 and 12 weeks of treatment and analyzed for levels of CPII and PINP (synthesis of type II and type I procollagen), melanoma inhibitory activity (MIA) (chondrocyte anabolism), matrix metalloproteinase (MMP)-3, C2C and cartilage oligomeric matrix protein (COMP) (type II collagen degradation), osteocalcin (OC) (bone formation), NTX-I and ICTP (both type I collagen degradation).

Results

After 4 weeks, there was a significant decrease in serum MMP-3 levels in adalimumab-treated patients (P<0.005), while no change was observed in the placebo group. A significant increase in serum MIA was noted after adalimumab therapy (P<0.005) but not after placebo treatment. After 12 weeks, there was a marked reduction in serum MMP-3 in both groups (P<0.005), whereas other markers did not show significant changes compared to baseline.

Conclusion

MMP-3 and MIA could serve as soluble biomarkers associated with inflammation as well as joint remodelling and destruction and may, together with clinical evaluation and in combination with other biomarkers, assist in distinguishing between effective and ineffective therapy in small, proof-of-principle studies of short duration in PsA.

Trial Registration

Current Controlled Trials ISRCTN23328456     

Oral Doxycycline Reduces Pterygium Lesions; Results from a Double Blind,Randomized, Placebo Controlled Clinical Trial

Purpose

To determine whether oral doxycycline treatment reduces pterygium lesions.

Design

Double blind, randomized, placebo controlled clinical trial.

Participants

98 adult patients with primary pterygium.

Methods

Patients were randomly assigned to receive 100 mg oral doxycycline twice a day (49 subjects), or placebo (49 subjects), for 30 days. Photographs of the lesion were taken at the time of recruitment and at the end of the treatment. Follow-up sessions were performed 6 and 12 months post-treatment. Statistical analyses for both continuous and categorical variables were applied. p values of less than 0.05 were considered to indicate statistical significance.

Main Outcome Measures

The primary endpoint was the change in lesion size after 30 days of treatment.

Results

The primary endpoint was not met for the whole population but subgroup analysis showed that doxycycline was effective in patients of Caucasian origin while other ethnicities, mostly Hispanic, did not respond to the treatment. Moreover, there was a correlation between age and better response (p = 0.003). Adverse events were uncommon, mild, and in agreement with previous reports on short doxycycline treatments.

Conclusions

Oral doxycycline was superior to placebo for the treatment of primary pterygia in older Caucasian patients. These findings support the use of doxycycline for pterygium treatment in particular populations.

Trial Registration

European Union Clinical Trials Register EudraCT 2008-007178-39     

Modafinil Alters Intrinsic Functional Connectivity of the Right Posterior Insula: A Pharmacological Resting State fMRI Study

Background

Modafinil is employed for the treatment of narcolepsy and has also been, off-label, used to treat cognitive dysfunction in neuropsychiatric disorders. In a previous study, we have reported that single dose administration of modafinil in healthy young subjects enhances fluid reasoning and affects resting state activity in the Fronto Parietal Control (FPC) and Dorsal Attention (DAN) networks. No changes were found in the Salience Network (SN), a surprising result as the network is involved in the modulation of emotional and fluid reasoning. The insula is crucial hub of the SN and functionally divided in anterior and posterior subregions.

Methodology

Using a seed-based approach, we have now analyzed effects of modafinil on the functional connectivity (FC) of insular subregions.

Principal Findings

Analysis of FC with resting state fMRI (rs-FMRI) revealed increased FC between the right posterior insula and the putamen, the superior frontal gyrus and the anterior cingulate cortex in the modafinil-treated group.

Conclusions

Modafinil is considered a putative cognitive enhancer. The rs-fMRI modifications that we have found are consistent with the drug cognitive enhancing properties and indicate subregional targets of action.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01684306","term_id":"NCT01684306"}}NCT01684306     

Effects of Aprepitant on the Pharmacokinetics of Controlled-Release Oral Oxycodone in Cancer Patients

Purpose

Oxycodone is a µ-opioid receptor agonist widely used in the treatment of cancer pain. The predominant metabolic pathway of oxycodone is CYP3A4-mediated N-demethylation to noroxycodone, while a minor proportion undergoes 3-O-demethylation to oxymorphone by CYP2D6. The aim of this study was to investigate the effects of the mild CYP3A4 inhibitor aprepitant on the pharmacokinetics of orally administered controlled-release (CR) oxycodone.

Method

This study design was an open-label, single-sequence with two phases in cancer patients with pain who continued to be administered orally with multiple doses of CR oxycodone every 8 or 12 hours. Plasma concentration of oxycodone and its metabolites were measured up to 8 hours after administration as follows: on day 1, CR oxycodone was administered alone; on day 2, CR oxycodone was administered with aprepitant (125 mg, at the same time of oxycodone dosing in the morning). The steady-state trough concentrations (Css) were measured from day 1 to day 3.

Results

Aprepitant increased the area under the plasma concentration-time curve (AUC_0–8) of oxycodone by 25% (p<0.001) and of oxymorphone by 34% (p<0.001), as well as decreased the AUC_0–8 of noroxycodone by 14% (p<0.001). Moreover, aprepitant increased Css of oxycodone by 57% (p = 0.001) and of oxymorphone by 36% (p<0.001) and decreased Css of noroxycodone by 24% (p = 0.02) at day 3 compared to day 1.

Conclusions

The clinical use of aprepitant in patients receiving multiple doses of CR oxycodone for cancer pain significantly altered plasma concentration levels, but would not appear to need modification of the CR oxycodone dose.

Trial Registration

UMIN.ac.jp UMIN000003580.     

The Effect of Souvenaid on Functional Brain Network Organisation in Patients with Mild Alzheimer’s Disease: A Randomised Controlled Study

Background

Synaptic loss is a major hallmark of Alzheimer’s disease (AD). Disturbed organisation of large-scale functional brain networks in AD might reflect synaptic loss and disrupted neuronal communication. The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to enhance synapse formation and function and has been shown to improve memory performance in patients with mild AD in two randomised controlled trials.

Objective

To explore the effect of Souvenaid compared to control product on brain activity-based networks, as a derivative of underlying synaptic function, in patients with mild AD.

Design

A 24-week randomised, controlled, double-blind, parallel-group, multi-country study.

Participants

179 drug-naïve mild AD patients who participated in the Souvenir II study.

Intervention

Patients were randomised 1∶1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks.

Outcome

In a secondary analysis of the Souvenir II study, electroencephalography (EEG) brain networks were constructed and graph theory was used to quantify complex brain structure. Local brain network connectivity (normalised clustering coefficient gamma) and global network integration (normalised characteristic path length lambda) were compared between study groups, and related to memory performance.

Results

The network measures in the beta band were significantly different between groups: they decreased in the control group, but remained relatively unchanged in the active group. No consistent relationship was found between these network measures and memory performance.

Conclusions

The current results suggest that Souvenaid preserves the organisation of brain networks in patients with mild AD within 24 weeks, hypothetically counteracting the progressive network disruption over time in AD. The results strengthen the hypothesis that Souvenaid affects synaptic integrity and function. Secondly, we conclude that advanced EEG analysis, using the mathematical framework of graph theory, is useful and feasible for assessing the effects of interventions.

Trial registration

Dutch Trial Register NTR1975.     

solGS: a web-based tool for genomic selection

Background

Genomic selection (GS) promises to improve accuracy in estimating breeding values and genetic gain for quantitative traits compared to traditional breeding methods. Its reliance on high-throughput genome-wide markers and statistical complexity, however, is a serious challenge in data management, analysis, and sharing. A bioinformatics infrastructure for data storage and access, and user-friendly web-based tool for analysis and sharing output is needed to make GS more practical for breeders.

Results

We have developed a web-based tool, called solGS, for predicting genomic estimated breeding values (GEBVs) of individuals, using a Ridge-Regression Best Linear Unbiased Predictor (RR-BLUP) model. It has an intuitive web-interface for selecting a training population for modeling and estimating genomic estimated breeding values of selection candidates. It estimates phenotypic correlation and heritability of traits and selection indices of individuals. Raw data is stored in a generic database schema, Chado Natural Diversity, co-developed by multiple database groups. Analysis output is graphically visualized and can be interactively explored online or downloaded in text format. An instance of its implementation can be accessed at the NEXTGEN Cassava breeding database, http://cassavabase.org/solgs.

Conclusions

solGS enables breeders to store raw data and estimate GEBVs of individuals online, in an intuitive and interactive workflow. It can be adapted to any breeding program.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-014-0398-7) contains supplementary material, which is available to authorized users.     

Phase 1 Study of the E-Selectin Inhibitor GMI 1070 in Patients with Sickle Cell Anemia

Background

Sickle cell anemia is an inherited disorder of hemoglobin that leads to a variety of acute and chronic complications. Abnormal cellular adhesion, mediated in part by selectins, has been implicated in the pathophysiology of the vaso-occlusion seen in sickle cell anemia, and selectin inhibition was able to restore blood flow in a mouse model of sickle cell disease.

Methods

We performed a Phase 1 study of the selectin inhibitor GMI 1070 in patients with sickle cell anemia. Fifteen patients who were clinically stable received GMI 1070 in two infusions.

Results

The drug was well tolerated without significant adverse events. There was a modest increase in total peripheral white blood cell count without clinical symptoms. Plasma concentrations were well-described by a two-compartment model with an elimination T_1/2 of 7.7 hours and CLr of 19.6 mL/hour/kg. Computer-assisted intravital microscopy showed transient increases in red blood cell velocity in 3 of the 4 patients studied.

Conclusions

GMI 1070 was safe in stable patients with sickle cell anemia, and there was suggestion of increased blood flow in a subset of patients. At some time points between 4 and 48 hours after treatment with GMI 1070, there were significant decreases in biomarkers of endothelial activation (sE-selectin, sP-selectin, sICAM), leukocyte activation (MAC-1, LFA-1, PM aggregates) and the coagulation cascade (tissue factor, thrombin-antithrombin complexes). Development of GMI 1070 for the treatment of acute vaso-occlusive crisis is ongoing.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00911495","term_id":"NCT00911495"}}NCT00911495     

Predictive Factors for Sustained Virological Response after Treatment with Pegylated Interferon α-2a and Ribavirin in Patients Infected with HCV Genotypes 2 and 3

Background

Previous trials have often defined genotype 2 and 3 patients as an “easy to treat” group and guidelines recommend similar management.

Aims

The present study looks for differences between the two genotypes and analyzes predictive factors for SVR.

Methods

Prospective, community-based cohort study involving 421 physicians throughout Germany. The analysis includes 2,347 patients with untreated chronic HCV genotype 2 (n = 391) and 3 (n = 1,956) infection treated with PEG-IFN α-2a plus ribavirin between August 2007 and July 2012.

Results

When compared with genotype 2 patients, those with genotype 3 were younger, had a shorter duration of infection, lower values of total cholesterol, LDL cholesterol and BMI, a higher frequency of drug use as infection mode and male gender (p<0.0001, respectively), and a higher APRI score (p<0.005). SVR was higher in genotype 2 when compared with genotype 3 (64.7% vs. 56.9%, p = 0.004). By multivariate analysis of genotype 2 patients, low baseline γ -GT and RVR predicted SVR. In genotype 3 age ≤45 years, cholesterol>130 mg/dl, a low APRI score, and a γ-GT ≥3-times ULN, RVR, and RBV starting dose were associated with SVR by multivariate analysis.

Conclusions

The present study corroborates that liver fibrosis is more pronounced in genotype 3 vs. 2. SVR is higher in genotype 2 versus genotype 3 partly because of follow-up problems in genotype 3 patients, in particular in those infected by drug use. Thus, subgroups of genotype 3 patients have adherence problems and need special attention also because they often have significant liver fibrosis.

Trial Registration

Verband Forschender Arzneimittelhersteller e.V., Berlin, Germany ML21645 ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02106156","term_id":"NCT02106156"}}NCT02106156     

SNPchiMp v.3: integrating and standardizing single nucleotide polymorphism data for livestock species

Background

In recent years, the use of genomic information in livestock species for genetic improvement, association studies and many other fields has become routine. In order to accommodate different market requirements in terms of genotyping cost, manufacturers of single nucleotide polymorphism (SNP) arrays, private companies and international consortia have developed a large number of arrays with different content and different SNP density. The number of currently available SNP arrays differs among species: ranging from one for goats to more than ten for cattle, and the number of arrays available is increasing rapidly. However, there is limited or no effort to standardize and integrate array- specific (e.g. SNP IDs, allele coding) and species-specific (i.e. past and current assemblies) SNP information.

Results

Here we present SNPchiMp v.3, a solution to these issues for the six major livestock species (cow, pig, horse, sheep, goat and chicken). Original data was collected directly from SNP array producers and specific international genome consortia, and stored in a MySQL database. The database was then linked to an open-access web tool and to public databases. SNPchiMp v.3 ensures fast access to the database (retrieving within/across SNP array data) and the possibility of annotating SNP array data in a user-friendly fashion.

Conclusions

This platform allows easy integration and standardization, and it is aimed at both industry and research. It also enables users to easily link the information available from the array producer with data in public databases, without the need of additional bioinformatics tools or pipelines. In recognition of the open-access use of Ensembl resources, SNPchiMp v.3 was officially credited as an Ensembl E!mpowered tool. Availability at http://bioinformatics.tecnoparco.org/SNPchimp.     

Effectiveness of a Randomized School-Based Intervention Involving Families and Teachers to Prevent Excessive Weight Gain among Adolescents in Brazil

Objective

To evaluate the effectiveness of a school-based intervention involving the families and teachers that aimed to promote healthy eating habits in adolescents; the ultimate aim of the intervention was to reduce the increase in body mass index (BMI) of the students.

Design

Paired cluster randomized school-based trial conducted with a sample of fifth graders.

Setting

Twenty classes were randomly assigned into either an intervention group or a control group.

Participants

From a total of 574 eligible students, 559 students participated in the study (intervention: 10 classes with 277 participants; control: 10 classes with 282 participants). The mean age of students was 11 years.

Intervention

Students attended 9 nutritional education sessions during the 2010 academic year. Parents/guardians and teachers received information on the same subjects.

Main Outcome Measurement

Changes in BMI and percentage of body fat.

Results

Intention-to-treat analysis showed that changes in BMI were not significantly different between the 2 groups (β = 0.003; p = 0.75). There was a major reduction in the consumption of sugar-sweetened beverages and cookies in the intervention group; students in this group also consumed more fruits.

Conclusion

Encouraging the adoption of healthy eating habits promoted important changes in the adolescent diet, but this did not lead to a reduction in BMI gain. Strategies based exclusively on the quality of diet may not reduce weight gain among adolescents.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01046474","term_id":"NCT01046474"}}NCT01046474.     

Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults

Introduction

Chagas disease, caused by the parasite Trypanosoma cruzi, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce.

Patients and Methods

Prospective population pharmacokinetic (PK) cohort study in children 2–12 years old with Chagas disease treated with oral benznidazole 5–8 mg/kg/day BID for 60 days. (clinicaltrials.gov #{"type":"clinical-trial","attrs":{"text":"NCT00699387","term_id":"NCT00699387"}}NCT00699387).

Results

Forty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F) showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs).

Discussion

Observed benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses), possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted.

Trial Registration

ClinicalTrails.gov {"type":"clinical-trial","attrs":{"text":"NCT00699387","term_id":"NCT00699387"}}NCT00699387     

Gameplay as a Source of Intrinsic Motivation in a Randomized Controlled Trial of Auditory Training for Tinnitus

Background

Previous studies of frequency discrimination training (FDT) for tinnitus used repetitive task-based training programmes relying on extrinsic factors to motivate participation. Studies reported limited improvement in tinnitus symptoms.

Purpose

To evaluate FDT exploiting intrinsic motivations by integrating training with computer-gameplay.

Methods

Sixty participants were randomly assigned to train on either a conventional task-based training, or one of two interactive game-based training platforms over six weeks. Outcomes included assessment of motivation, tinnitus handicap, and performance on tests of attention.

Results

Participants reported greater intrinsic motivation to train on the interactive game-based platforms, yet compliance of all three groups was similar (∼70%) and changes in self-reported tinnitus severity were not significant. There was no difference between groups in terms of change in tinnitus severity or performance on measures of attention.

Conclusion

FDT can be integrated within an intrinsically motivating game. Whilst this may improve participant experience, in this instance it did not translate to additional compliance or therapeutic benefit.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02095262","term_id":"NCT02095262"}}NCT02095262