Using gamification to enhance clinical trial start-up activities.

Background: The Trial Innovation Network (TIN) is a collaborative initiative within the National Center for Advancing Translational Science (NCATS) Clinical and Translational Science Awards (CTSA) Program. To improve and innovate the conduct of clinical trials, it is exploring the uses of gamification to better engage the trial workforce and improve the efficiencies of trial activities. The gamification structures described in this article are part of a TIN website gamification toolkit, available online to the clinical trial scientific community. Methods: The game designers used existing electronic trial platforms to gamify the tasks required to meet trial start-up timelines to create friendly competitions. Key indicators and familiar metrics were mapped to scoreboards. Webinars were organized to share and applaud trial and game performance. Results: Game scores were significantly associated with an increase in achieving start-up milestones in activation, institutional review board (IRB) submission, and IRB approval times, indicating the probability of completing site activation faster by using games. Overall game enjoyment and feelings that the game did not apply too much pressure appeared to be an important moderator of performance in one trial but had little effect on performance in a second. Conclusion: This retrospective examination of available data from gaming experiences may be a first-of-kind use in clinical trials. There are signals that gaming may accelerate performance and increase enjoyment during the start-up phase of a trial. Isolating the effect of gamification on trial outcomes will depend on a larger sampling from future trials, using well-defined, hypothesis-driven statistical analysis plans.

Bayesian deep learning outperforms clinical trial estimators of intracerebral and intraventricular hemorrhage volume.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) clinical trials rely on manual linear and semi-quantitative (LSQ) estimators like the ABC/2, modified Graeb and IVH scores for timely volumetric estimation from CT. Deep learning (DL) volumetrics of ICH have recently approached the accuracy of gold-standard planimetry. However, DL and LSQ strategies have been limited by unquantified uncertainty, in particular when ICH and IVH estimates intersect. Bayesian deep learning methods can be used to approximate uncertainty, presenting an opportunity to improve quality assurance in clinical trials. METHODS: A DL model was trained to simultaneously segment ICH and IVH using diagnostic CT data from the Minimally Invasive Surgery Plus Alteplase for ICH Evacuation (MISTIE) III and Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR) III clinical trials. Bayesian uncertainty approximation was performed using Monte-Carlo dropout. We compared the performance of our model with estimators used in the CLEAR IVH and MISTIE II trials. The reliability of planimetry, DL, and LSQ volumetrics in the setting of high ICH and IVH intersection is quantified using consensus estimates. RESULTS: Our DL model produced volume correlations and median Dice scores of .994 and .946 for ICH in MISTIE II, and .980 and .863 for IVH in CLEAR IVH, respectively, outperforming LSQ estimates from the clinical trials. We found significant linear relationships between ICH uncertainty, Dice scores (r = -.849), and relative volume difference (r = .735). CONCLUSION: In our validation clinical trial dataset, DL models with Bayesian uncertainty approximation provided superior volumetric estimates to LSQ methods with real-time estimates of model uncertainty.

GGCX mutations in a patient with overlapping pseudoxanthoma elasticum/cutis laxa-like phenotype.

Pseudoxanthoma elasticum (PXE) is a multisystem disorder characterized by ectopic mineralization of connective tissues with primary manifestations in the skin, eyes and the cardiovascular system. The classic forms of PXE are caused by mutations in the ABCC6 gene encoding the ABCC6 protein, expressed primarily in the liver. Cutis laxa (CL) manifests with loose and sagging skin with loss of recoil. In 2009 we investigated a 19-year-old patient with overlapping cutaneous features of PXE and CL, together with alpha thalassaemia. Genetic analysis failed to identify pathogenic mutations in ABCC6. More recently we developed a gene-targeted panel of next-generation sequencing technology. This panel has 29 genes, 22 of which, including ABCC6 and GGCX, are associated with ectopic mineralization phenotypes. Mutation analysis in the patient identified two heterozygous GGCX mutations: c.200_201delTT in exon 2 and c.763G>A, p.V255M in exon 7. The GGCX gene encodes a γ-glutamyl carboxylase necessary for activation of blood coagulation factors in the liver. The p.V255M mutation was previously reported to result in reduced γ-glutamyl carboxylase activity in vitro, while the c.200_201delTT mutation is novel. Previous studies reported that mutations in GGCX cause overlapping PXE/CL skin phenotypes in association with or without multiple vitamin K-dependent coagulation factor deficiency. Our patient had loose redundant skin, moderate-to-severe angioid streaks and characteristic calcification of elastic structures in the mid dermis, consistent with PXE/CL overlap, but no coagulation abnormalities. Our studies expand the GGCX mutation landscape in patients with PXE-like phenotypes.

Antioxidant, antibacterial, and anti-adhesive activities of biosurfactants isolated from Bacillus strains.

Biosurfactants are surface-active compounds that display a range of physiological functions. The present study investigated the antioxidant, antimicrobial, and anti-adhesive or anti-biofilm potential of biosurfactants isolated from Bacillus subtilis VSG4 and Bacillus licheniformis VS16. The antioxidant activity of the biosurfactants was studied in vitro using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radicals. At 5 mg/mL of the biosurfactant concentration, the scavenging of DPPH and hydroxyl radicals was found to be between 69.1-73.5% and 63.3-69.8%, respectively. The biosurfactants also displayed significant antibacterial activities against both Gram-positive and Gram-negative bacteria. The anti-adhesive activities of the biosurfactants were evaluated against Staphylococcus aureus ATCC 29523, Salmonella typhimurium ATCC 19430, and Bacillus cereus ATCC 11778. The biosurfactants exhibited anti-adhesive activity, even at concentrations of 3-5 mg/mL. Moreover, both biosurfactants displayed notable anti-biofilm activities with a biofilm eradication percentage ranging from 63.9 to 80.03% for VSG4 biosurfactant, and from 61.1-68.4% for VS16 biosurfactant. Furthermore, VSG4 biosurfactant exhibited emulsification and surface tension stability over a wide range of pH (4-10) and temperature up to 100 °C. These results show that VSG4 and VS16 biosurfactants can be potentially used as natural antioxidants, antimicrobials, and/or anti-adhesive agents for food and biomedical applications.

Usefulness of asthma predictive index in ascertaining asthma status of children using medical records: An explorative study.

BACKGROUND: Frequent wheezing in original asthma predictive index (API) was defined by parental report of recurrent wheezing within 1 year during the first 3 years of life. The nature of frequent wheezing in children, particularly aged over 3 years, has not been studied. We aimed to assess the frequency and interval of wheezing to define frequent wheezing in ascertaining asthma for children using medical records. METHODS: Among children who participated in a previous study (n = 427), all wheezing episodes documented in medical records were collected for children who had ≥2 wheezing episodes PLUS met one major criterion or two minor criteria of API. We compared the distribution of known risk factors for asthma between subjects having two consecutive wheezing episodes with shorter interval (≤1 year) compared to those with longer interval (1 to 3 years). RESULTS: A total of 62 children met API at median age of 2.3 years. During follow-up period (median age: 11.3 years), a total of 198 wheezing episodes were observed. 81% of wheezing intervals were within 3 years from the earlier wheezing episode, including 60% within 1 year. Children who met API based on 1-year interval (n = 40) vs 1- to 3-year interval (n = 13) appeared to be similar in regard to the known risk factors for asthma. CONCLUSIONS: Our exploratory study finding suggests that children who had frequent wheezing episodes with longer interval (<3 years) need to be considered to be determined as asthma cases when API is applied to retrospective medical records. Prospective studies with a larger sample size need to replicate this finding.

Predicting hypertension among Korean cancer survivors: A nationwide population-based study.

Hypertension is the most common comorbidity among cancer survivors, although there is no model for predicting hypertension in this population. Therefore, we developed a model for predicting hypertension using data from 6,480 Korean cancer survivors who were ≥20 years old. The odds ratios (ORs) for hypertension were calculated using stepwise logistic regression analyses, and a nomogram was generated to predict hypertension. Hypertension was independently associated with an age of ≥65 years (OR: 3.058), male gender (OR: 1.195), obesity (OR: 1.998), prehypertension (OR: 2.06), dyslipidaemia (OR: 2.011) and diabetes mellitus (OR: 2.297). Each variable in the nomogram was assigned a specific number of points, and the total score (range: 0-400) was used to obtain a value for predicting hypertension. The estimated prevalence of hypertension increased when the total nomogram score exceeded the sixth decile (total points: 128; p for trend <.001). Therefore, among Korean cancer survivors, hypertension was significantly associated with an age of >65 years, male gender, obesity, and having various comorbidities (e.g., prehypertension, dyslipidaemia and diabetes mellitus). Furthermore, our nomogram could predict the incidence of hypertension, and the sixth decile of the total nomogram score predicted an increased risk of hypertension.

Effects of symptom clusters and depression on the quality of life in patients with advanced lung cancer.

People with advanced lung cancer experience later symptoms after treatment that is related to poorer psychosocial and quality of life (QOL) outcomes. The purpose of this study was to identify the effect of symptom clusters and depression on the QOL of patients with advanced lung cancer. A sample of 178 patients with advanced lung cancer at the National Cancer Center in Korea completed a demographic questionnaire, the M.D. Anderson Symptom Inventory-Lung Cancer, the Center for Epidemiological Studies Depression Scale, and the Functional Assessment of Cancer Therapy-General scale. The most frequently experienced symptom was fatigue, anguish was the most severe symptom-associated distress, and 28.9% of participants were clinically depressed. Factor analysis was used to identify symptom clusters based on the severity of patients' symptom experiences. Three symptom clusters were identified: treatment-associated, lung cancer and psychological symptom clusters. The regression model found a significant negative impact on QOL for depression and lung cancer symptom cluster. Age as the control variable was found to be significant impact on QOL. Therefore, psychological screening and appropriate intervention is an essential part of advanced cancer care. Both pharmacological and non-pharmacological approaches for alleviating depression may help to improve the QOL of lung cancer patients.

Does high relatedness promote cheater-free multicellularity in synthetic lifecycles?

The evolution of multicellularity is one of the key transitions in evolution and requires extreme levels of cooperation between cells. However, even when cells are genetically identical, noncooperative cheating mutants can arise that cause a breakdown in cooperation. How then, do multicellular organisms maintain cooperation between cells? A number of mechanisms that increase relatedness amongst cooperative cells have been implicated in the maintenance of cooperative multicellularity including single-cell bottlenecks and kin recognition. In this study, we explore how relatively simple biological processes such as growth and dispersal can act to increase relatedness and promote multicellular cooperation. Using experimental populations of pseudo-organisms, we found that manipulating growth and dispersal of clones of a social amoeba to create high levels of relatedness was sufficient to prevent the spread of cheating mutants. By contrast, cheaters were able to spread under low-relatedness conditions. Most surprisingly, we saw the largest increase in cheating mutants under an experimental treatment that should create intermediate levels of relatedness. This is because one of the factors raising relatedness, structured growth, also causes high vulnerability to growth rate cheaters.

Leveraging electronic health records to study pleiotropic effects on bipolar disorder and medical comorbidities.

Patients with bipolar disorder (BD) have a high prevalence of comorbid medical illness. However, the mechanisms underlying these comorbidities with BD are not well known. Certain genetic variants may have pleiotropic effects, increasing the risk of BD and other medical illnesses simultaneously. In this study, we evaluated the association of BD-susceptibility genetic variants with various medical conditions that tend to co-exist with BD, using electronic health records (EHR) data linked to genome-wide single-nucleotide polymorphism (SNP) data. Data from 7316 Caucasian subjects were used to test the association of 19 EHR-derived phenotypes with 34 SNPs that were previously reported to be associated with BD. After Bonferroni multiple testing correction, P<7.7 × 10(-5) was considered statistically significant. The top association findings suggested that the BD risk alleles at SNP rs4765913 in CACNA1C gene and rs7042161 in SVEP1 may be associated with increased risk of 'cardiac dysrhythmias' (odds ratio (OR)=1.1, P=3.4 × 10(-3)) and 'essential hypertension' (OR=1.1, P=3.5 × 10(-3)), respectively. Although these associations are not statistically significant after multiple testing correction, both genes have been previously implicated with cardiovascular phenotypes. Moreover, we present additional evidence supporting these associations, particularly the association of the SVEP1 SNP with hypertension. This study shows the potential for EHR-based analyses of large cohorts to discover pleiotropic effects contributing to complex psychiatric traits and commonly co-occurring medical conditions.

Biobanks and personalized medicine.

We provide a mini-review of how biobanks can support clinical genetics in the era of personalized medicine. We discuss types of biobanks, including disease specific and general biobanks not focused on one disease. We present considerations in setting up a biobank, including consenting and governance, biospecimens, risk factor and related data, informatics, and linkage to electronic health records for phenotyping. We also discuss the uses of biobanks and ongoing considerations, including genotype-driven recruitment, investigations of gene-environment associations, and the re-use of data generated from studies. Finally, we present a brief discussion of some of the unresolved issues, such as return of research results and sustaining biobanks over time. In summary, carefully designed biobanks can provide critical research and infrastructure support for clinical genetics in the era of personalized medicine.

Variations in the memory capability of nonvolatile memory devices fabricated using hybrid composites of InP nanoparticles and a polystyrene layer due to the scale-down.

InP nanoparticles were formed using a solution method, and the InP nanoparticles that were embedded in a polystyrene (PS) layer were formed using the spin-coating method. The transmission electron microscopy images showed that the InP nanoparticles were randomly distributed in the PS layer. The measured capacitance-voltage (C-V) of the Al/InP nanoparticles embedded in the PS layer/PS/p-Si(100) device at 300 K showed a clockwise hysteresis of the C-V curve. Based on the C-V results, the origin of variations in the memory storage of nonvolatile memory devices that were fabricated using InP nanoparticles embedded in a PS layer due to the scale-down was described.

Upregulation of Fas and downregulation of CD94/NKG2A inhibitory receptors on circulating natural killer cells in patients with new-onset psoriasis.

BACKGROUND: Psoriasis has been considered as a T-helper 1 cell-mediated autoimmune disease driven by collaboration with multiple components of innate and acquired immune cells. Natural killer (NK) cells have been shown to bridge innate and acquired immunity, and thus could potentially contribute to the pathophysiology of psoriasis. OBJECTIVES: To investigate the phenotypic changes of circulating NK cells in patients with new-onset psoriasis. METHODS: Fifteen patients with plaque psoriasis (eight women and seven men) who visited our clinic after their first episode of psoriasis and did not have a history of previous systemic therapy or phototherapy participated in this study. Peripheral blood mononuclear cells were isolated and stained with a panel of antibodies against cell surface receptors expressed on T and/or NK cells and analysed by flow cytometry. RESULTS: As compared with normal healthy volunteers, patients with new-onset psoriasis showed no significant changes in numbers of peripheral NK, NK-T or T cells. NK activating receptors 2B4, CD48, NKG2D, CD16 and CD56 were found to be unchanged in new-onset psoriasis. However, the expression of Fas (activation-induced death receptor) was upregulated, whereas the expression of the NK inhibitory receptors CD94 and NKG2A was dramatically reduced on NK cells of new-onset psoriasis. These changes occurred at the level of mean fluorescent intensity, but minimally affected percentages of cells expressing Fas, CD94 and NKG2A. CONCLUSIONS: Our findings demonstrate that changes in the expression of Fas and CD94/NKG2A receptors on NK cells may occur during new-onset psoriasis, and are likely to contribute to the pathogenesis of psoriasis.

In vivo evaluation of lumbrokinase, a fibrinolytic enzyme extracted from Lumbricus rubellus, in a prosthetic vascular graft.

BACKGROUND: Lumbrokinase (LK) is a fibrinolytic enzyme purified from the earthworm Lumbricus rubellus. To investigate the fibrinolytic and antithrombotic effects of lumbrokinase, a series of animal experiments were performed. METHODS: The Dacron graft (3 mm in diameter, 3 cm in length) were treated with LK via two different methods, simple dipping and covalent bonding METHODS: Covalent bonding was performed by UV reaction to polyacrylic acid. The grafts were interposed into the inferior vena cava of the rabbits and harvested for 5 hours, 1, 2 and 4 weeks after the implantation. RESULTS: The LK non-treated graft (n=4) were totally occluded with thrombus 5 hours after the implantation. Both types of LK treated graft (n=8) were patent 1 week after the implantation. The grafts treated with the simple dipping method (n=4) were occluded with thrombus 2 weeks after the implantation. The grafts treated with covalent bonding (n=4) were patent 4 weeks after the implantation. Ultrastructural analysis of the luminal surface of the patent grafts by scanning electron microscopy revealed the thin plasma protein layer to be about 5 micro in thickness with platelet adhesions. CONCLUSIONS: Lumbrokinase has potential antithrombotic effects in a small diameter vascular prosthesis. The covalent bonding method proved to be more effective than the simple dipping method.

Synthesis and antibacterial activities of novel C(3)-aminopyrimidinyl substituted cephalosporins including against respiratory tract pathogens.

The variety of cephalosporins 1 and 2 which possessed C(3)-aminopyrimidinyl substituents were prepared and evaluated for their antibacterial activities. They exhibited excellent in vitro activities especially against respiratory tract pathogens such as penicillin resistant Streptococcus pneumonia. Moraxella catarrhalis and Haemophilus influenza.

Characterization of antithrombotic activity of lumbrokinase-immobilized polyurethane valves in the total artificial heart.

Thirty ng/mm2 lumbrokinase, a potent fibrinolytic enzyme, was immobilized in a Korean type total artificial heart (KORTAH) valve by photoreaction; polyallylamine was used as a photoreactive linker. Lumbrokinase-immobilized polyurethane valves were then fitted to the total artificial hearts of 3 healthy 50 kg lambs. In the control lamb, the valves were untreated; in one other, only valves on the right were treated; and in the remaining animal, only those on the left. Implants were in place for up to 3 days, and cardiac output was 5 L/min. To facilitate thrombus formation, low doses of heparin were administered. In the control lamb, thrombi was observed only in the inlet parts of the valves. In the other 2 experiments, thrombi formed in untreated control valves but not in lumbrokinase treated valves. The grade of thrombus formation in untreated valves was 1.06+/-1.37 versus 0+/-0 in the treated part by one-sided Student's t-test (p < 0.1). After implantation, fibrinolytic activity was only observed in treated valves by fibrin plate methods. The proteolytic activity of the treated valves was 3 times higher than that of untreated valves using the azocasein method. These data show that lumbrokinase treated polyurethane valves lead to decreased thrombus formation in vivo and that their biocompatibility is therefore greater than that of untreated valves.

Chromosome aberrations in workers of nuclear-power plants.

The frequencies of chromosome aberrations in 135 workers from nuclear- power plants were compared with those in 135 age-matched controls. A total of 135,000 cells was scored. The frequencies of dicentric chromosome were 1.67 x 10(-3) in the exposed group and 0.49 x 10(-3) in the control group and those of chromosome-type deletion were 3.33 x 10(-3) and 1.10 x 10(-3), respectively. The frequencies of all types of chromosome aberrations in the exposed subjects were higher than those in the control group, but no significant trend of dose-dependent increase was observed when only the exposed group were considered. Poisson regression analysis, with both exposed and control included, showed that there was a significant association of chromosome aberration with radiation dose and the duration of work, but not with age, smoking habit and alcohol intake. It was also found that recent exposure to radiation, within the last 5 years, had contributed more to the observed chromosome aberration than earlier exposure.

Synthesis of 2-isoxazoline and alpha-hydroxy ketomethylene dipeptide isosteres.

We have developed a simple and stereoselective method for synthesizing novel dipeptide isosteres using nitrile oxide cycloaddition as a key reaction. Employing this method, we have prepared efficiently various peptidomimetics containing 2-isoxazolines and alpha-hydroxy ketomethylene dipeptide isosteres.

Protective effect of nicotinamide and 3-aminobenzamide on islet cell damage induced by gamma-interferon and tumor necrosis factor.

Mouse islet cell monolayers were damaged when cultured for five days in a medium containing 200 U/ml of recombinant murine interferon-gamma (IFN-gamma) and 300 U/ml of recombinant tumor necrosis factor (TNF). The cells formed granular clusters and ultimately floated in the medium; the floating cells proved to be dead by the trypan-blue dye-exclusion method. When 20 mM of nicotinamide or 5 mM of 3-aminobenzamide was supplemented to the medium, islet cell monolayers remained in the presence of the cytokines. 51Cr release studies showed that specific 51Cr release during five-day incubation with 200 U/ml of IFN-gamma and 300 U/ml of TNF was 30 +/- 4% (mean +/- SE). In a medium containing 20 mM of nicotinamide, together with IFN-gamma and TNF, specific 51Cr release was significantly reduced (12 +/- 3%, p less than 0.01). 3-aminobenzamide was effective at the level of 5 mM; specific 51Cr release was 2 +/- 5% (p less than 0.01). These results suggest that the mechanism by which IFN-gamma and TNF damage islet cells may be similar to that of streptozotocin and/or alloxan.