Health-related quality of life in patients with advanced melanoma treated with ipilimumab: prognostic implications and changes during treatment.

BACKGROUND: We have previously reported that the safety and efficacy of ipilimumab in real-world patients with metastatic melanoma were comparable to clinical trials. Few studies have explored health-related quality of life (HRQL) in real-world populations receiving checkpoint inhibitors. This study reports HRQL in real-world patients receiving ipilimumab and assesses the prognostic value of patient-reported outcome measures. PATIENTS AND METHODS: Ipi4 (NCT02068196) was a prospective, multicentre, interventional phase IV trial. Real-world patients (N = 151) with metastatic melanoma were treated with ipilimumab 3 mg/kg intravenously as labelled. HRQL was assessed by the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire at baseline and after 10-12 weeks. RESULTS: The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire was completed by 93% (141/151 patients) at baseline, and by 82% at 10-12 weeks. Poor performance status and elevated C-reactive protein (CRP) were associated with worse baseline HRQL. Clinically relevant and statistically significant deteriorations in HRQL from baseline to weeks 10-12 were reported (P <0.05). Baseline physical functioning [hazard ratio (HR) 1.96, P = 0.016], role functioning (HR 2.15, P <0.001), fatigue (HR 1.60, P = 0.030), and appetite loss (HR 1.76, P = 0.012) were associated with poorer overall survival independent of performance status, lactate dehydrogenase (LDH), and CRP. We further developed a prognostic model, combining HRQL outcomes with performance status, LDH, and CRP. This model identified three groups with large and statistically significant differences in survival. CONCLUSIONS: Systemic inflammation is associated with impaired HRQL. During treatment with ipilimumab, HRQL deteriorated significantly. Combining HRQL outcomes with objective risk factors provided additional prognostic information that may aid clinical decision making.

Simultaneous Measurement of Proton and Lepton Kinematics in Quasielasticlike ν_{µ}-Hydrocarbon Interactions from 2 to 20 GeV.

Neutrino charged-current quasielastic-like scattering, a reaction category extensively used in neutrino oscillation measurements, probes nuclear effects that govern neutrino-nucleus interactions. This Letter reports the first measurement of the triple-differential cross section for ν_{µ} quasielastic-like reactions using the hydrocarbon medium of the MINERvA detector exposed to a wideband beam spanning 2≤E_{ν}≤20 GeV. The measurement maps the correlations among transverse and longitudinal muon momenta and summed proton kinetic energies, and compares them to predictions from a state-of-art simulation. Discrepancies are observed that likely reflect shortfalls with modeling of pion and nucleon intranuclear scattering and/or spectator nucleon ejection from struck nuclei. The separate determination of leptonic and hadronic variables can inform experimental approaches to neutrino-energy estimation.

Towards equitable conservation: Social capital, fear and livestock loss shape perceived benefit from a protected area.

Providing sufficient benefits to local people can be an important component of effective and equitable conservation, especially where local communities face substantial opportunity costs or disbenefits from conservation. However, the distribution of benefits to local people is often inadequate or inequitable. In this study we investigated the heterogeneity in the extent to which people living near Hwange National Park (HNP), Zimbabwe, perceive benefit from the presence of the park. Specifically, we examined the relationships between a diverse set of candidate predictor variables and perceived benefit from HNP. Our candidate predictor variables broadly relate to personal assets, social capital, value orientation, fear of lions, and belief and participation in human-wildlife conflict mitigation schemes. One third of respondents reported that their household experienced at least some benefits from HNP. Of all respondents, 6% perceived their household to benefit strongly from HNP and 2% very strongly. Livestock loss to wildlife was the most important factor for predicting perceived benefit, with those suffering more loss less likely to perceive benefit. Multiple demographic factors predicted perceived benefit with, for instance, older people and those with less education perceiving less benefit. Employment in conservation-related work positively affected perceived benefit, whereas fear of lions had a negative impact. Social capital appeared to have a positive influence on perceived benefit from HNP. The relationship between social capital and perceived benefit was positive and plateauing, which suggests that social capital is especially impactful on the benefit perceived by individuals reporting the least social capital. We also found a positive association between belief in compensation schemes and perceived benefit from HNP. We posit hypotheses for this association but are unable to determine the underlying drivers of this relationship. Finally, participation in the community guardians programme, a human-lion conflict mitigation programme, was positively related to perceived benefit from HNP. Thus, our findings emphasise the value of considering a diverse array of factors when investigating park-people relationships and yield insights for improving the equitability of conservation in and around HNP and similar systems.

Pre-clinical evaluation of the effect of co-medication with antibiotics and oral steroids in Göttingen Minipigs on the biological activity of the probiotic medicinal product TSO (Trichuris suis ova).

The probiotic medicinal product TSO (Trichuris suis ova) is administered to patients with active ulcerative colitis in an ongoing clinical phase IIb trial where the typical co-medications are steroids (prednisolone or budesonide) and antibiotics (e.g., phenoxymethylpenicillin). The present pre-clinical study evaluates the effects of these co-medications on the biological activity of TSO in Göttingen Minipigs. This translationally relevant pre-clinical model allows administration of TSO with and without oral steroids or antibiotics in a manner similar to the administration to patients, followed by quantification of the biological activity of TSO. The biological activity of TSO was not affected by oral steroids but was reduced by oral antibiotics. Fecal calprotectin, the common marker of intestinal inflammation in patients with UC, did not differ between groups.

Immobilization of peroxidase on textile carrier materials and their application in the bleaching of colored whey.

Textiles represent promising support materials for enzymes. The goal of the present work was to investigate the immobilization of commercial peroxidase on a polyester needle felt and the repeated use in the gentle degradation of norbixin in whey from dairy cheese as a practical application. High enzyme loads were obtained by a 2-step immobilization procedure. First, the number of functional groups on the textile surface was increased by a modification with amino-functional polyvinylamine. Second, the enzyme was immobilized by using 2 types of crosslinking agents. Due to the iron content of peroxidase, inductively coupled plasma-optical emission spectrometry was used for the quantitative determination of the enzyme load on the textile. The enzyme activity was evaluated using common 2,2'-azino-di-(3-ethylbenzthiazoline-6-sulfonic acid) assay for peroxidases. By the variation of enzyme input and crosslinker concentration, a maximal enzyme load of 80 mg/g of textile was achieved, and a maximum specific activity of 57 U/g of textile. For the visualization of the enzyme on the fiber surface, fluorescence microscopy as well as scanning probe microscopy were used. The immobilized peroxidase showed significant activity, even after 50 reuse cycles. In addition, the potential of the new support and enzyme combination in commercial whey bleaching was demonstrated successfully on a 10-L scale.

Enzymatic epoxidation of cyclohexene by peroxidase immobilization on a textile and an adapted reactor design.

A textile-based reaction system for new peroxidase reactions in non-native media was implemented. The epoxidation of cyclohexene by the commercial peroxidase MaxiBright® was realized with the textile-immobilized enzyme in an adapted liquid-liquid two-phase reactor. A commercially available polyester felt was used as low-price carrier and functionalized with polyvinyl amine. The covalent immobilization with glutardialdehyde lead to an enzyme loading of 0.10 genzyme/gtextile. The textile-based peroxidase shows a high activity retention in the presence of organic media. This catalyst is shown to enable the epoxidation of cyclohexene in various solvents as well as under neat conditions. A model reactor was produced by 3D printing which places the textile catalyst at the interphase between the liquid reaction phase and the product extracting solvent.

Prognostic biomarkers for immunotherapy with ipilimumab in metastatic melanoma.

New therapies, including the anti-cytotoxic T lymphocyte antigen (CTLA)-4 antibody, ipilimumab, is approved for metastatic melanoma. Prognostic biomarkers need to be identified, because the treatment has serious side effects. Serum samples were obtained before and during treatment from 56 patients with metastatic or unresectable malignant melanoma, receiving treatment with ipilimumab in a national Phase IV study (NCT0268196). Expression of a panel of 17 inflammatory-related markers reflecting different pathways including extracellular matrix remodeling and fibrosis, vascular inflammation and monocyte/macrophage activation were measured at baseline and the second and/or third course of treatment with ipilimumab. Six candidate proteins [endostatin, osteoprotegerin (OPG), C-reactive protein (CRP), pulmonary and activation-regulated chemokine (PARC), growth differentiation factor 15 (GDF15) and galectin-3 binding-protein (Gal3BP)] were persistently higher in non-survivors. In particular, high Gal3BP and endostatin levels were also independently associated with poor 2-year survival after adjusting for lactate dehydrogenase, M-stage and number of organs affected. A 1 standard deviation increase in endostatin gave 1·74 times [95% confidence interval (CI) = 1·10-2·78, P = 0·019] and for Gal3BP 1·52 times (95% CI = 1·01-2·29, P = 0·047) higher risk of death in the adjusted model. Endostatin and Gal3BP may represent prognostic biomarkers for patients on ipilimumab treatment in metastatic melanoma and should be further evaluated. Owing to the non-placebo design, we could only relate our findings to prognosis during ipilimumab treatment.

Grid-Based Projector Augmented Wave (GPAW) Implementation of Quantum Mechanics/Molecular Mechanics (QM/MM) Electrostatic Embedding and Application to a Solvated Diplatinum Complex.

A multiscale density functional theory-quantum mechanics/molecular mechanics (DFT-QM/MM) scheme is presented, based on an efficient electrostatic coupling between the electronic density obtained from a grid-based projector augmented wave (GPAW) implementation of density functional theory and a classical potential energy function. The scheme is implemented in a general fashion and can be used with various choices for the descriptions of the QM or MM regions. Tests on H2O clusters, ranging from dimer to decamer show that no systematic energy errors are introduced by the coupling that exceeds the differences in the QM and MM descriptions. Over 1 ns of liquid water, Born-Oppenheimer QM/MM molecular dynamics (MD) are sampled combining 10 parallel simulations, showing consistent liquid water structure over the QM/MM border. The method is applied in extensive parallel MD simulations of an aqueous solution of the diplatinum [Pt2(P2O5H2)4]4- complex (PtPOP), spanning a total time period of roughly half a nanosecond. An average Pt-Pt distance deviating only 0.01 Å from experimental results, and a ground-state Pt-Pt oscillation frequency deviating by <2% from experimental results were obtained. The simulations highlight a remarkable harmonicity of the Pt-Pt oscillation, while also showing clear signs of Pt-H hydrogen bonding and directional coordination of water molecules along the Pt-Pt axis of the complex.

Exome chip analyses in adult attention deficit hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.

Oral Hygiene and Handwashing Practices among Middle School Students in 15 Latin American and Caribbean Countries.

OBJECTIVE: To examine the relationship between infrequent toothbrushing and infrequent handwashing among middle school students from 15 Latin American and Caribbean countries (Antigua and Barbuda, Argentina, British Virgin Islands, Cayman Islands, Costa Rica, Grenada, Guatemala, Guyana, Peru, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and Grenadines, Suriname, Trinidad and Tobago, and Uruguay). METHODS: A secondary analysis was done of nationally-representative data from 33 174 middle school students who participated in the Global School-based Student Health Survey (GSHS) between 2006 and 2011. RESULTS: In all 15 countries, the association between rarely brushing or cleaning teeth and rarely handwashing after using the toilet was significant for both boys and girls. The pooled odds ratio for this association was 6.7 (5.8, 7.7). CONCLUSION: Healthcare providers who notice signs of poor dental hygiene or infrequent bathing in adolescents should consider providing comprehensive hygiene education to their patients, since infrequent oral and body hygiene behaviours tend to co-exist and both are threats to health.

The role of TMEM16A (ANO1) and TMEM16F (ANO6) in cell migration.

Members of the TMEM16 family have recently been described as Ca(2+)-activated Cl(-) channels. They have been implicated in cancer and appear to be associated with poor patient prognosis. Here, we investigate the role of TMEM16 channels in cell migration, which is largely unknown. We focused on TMEM16A and TMEM16F channels that have the highest expression of TMEM16 channels in Ehrlich Lettre ascites (ELA) cells. Due to the lack of specific pharmacological modulators, we employed a miRNA approach and stably knocked down the expression of TMEM16A and TMEM16F channels, respectively. Migration analysis shows that TMEM16A KD clones are affected in their directional migration, whereas TMEM16F KD clones show a 40 % reduced rate of cell migration. Moreover, TMEM16A KD clones have a smaller projected cell area, and they are rounder than TMEM16F KD clones. The morphological changes are linearly correlated with the directionality of cells. TMEM16A and TMEM16F, thus, have an important function in cell migration-TMEM16A in directional migration, TMEM16F in determination of the speed of migration. We conclude that TMEM16A and TMEM16F channels have a distinct impact on the steering and motor mechanisms of migrating ELA cells.

Parental involvement and bullying among middle-school students in North Africa.

Bullying, especially in developing countries, has not been much examined, especially the influence of parents on the risk of being bullied. The aim of this study was to determine whether active parenting is associated with reduced peer victimization among middle-school students in North Africa. A secondary analysis of data from more than 13,000 middle-school students who participated in the Global School-based Student Health Survey (GSHS) in Egypt, Libya, Morocco and Tunisia between 2006 and 2008, was conducted using multiple logistic regression models. About 60% of students in Egypt and one-third of students in Libya, Morocco and Tunisia reported having been bullied in the past month. In all 4 countries, boys reported more peer victimization than girls. In Egypt, Morocco and Tunisia, students who reported that their parents checked their homework, were understanding, and knew how the student spent free time had a reduced likelihood of peer victimization but this association was not significant in Libya. Interventions for reducing bullying should consider the positive impact of involved parents.

Correlations between serum levels of beta amyloid, cerebrospinal levels of tau and phospho tau, and delayed response tasks in young and aged cynomolgus monkeys (Macaca fascicularis).

BACKGROUND: In an attempt to explore cynomolgus monkeys as an animal model for Alzheimer's disease, the present study focused on the Alzheimer's biomarkers beta amyloid 1-42 (Aß42 ) in serum, and total tau (t-tau) and phosphorylated tau (p-tau) levels in cerebrospinal fluid. METHODS: We measured biomarker levels in Young and Aged cynomolgus monkeys and correlated these with performance on three delayed response tasks. RESULTS: The Aß42 concentration of the Aged monkeys was significantly lower than in the Young subjects, while the t-tau and p-tau did not significantly differ between the groups. The Young subjects performed significantly better than the Aged individuals on the memory tests. Only Aß42 levels were significantly correlated with performance in the three delayed response tasks. CONCLUSIONS: Circulating Aß42 levels were lower in Aged monkeys and were correlated with inferior performance on delayed response tasks in Aged animals; therefore, both measures may be useful in establishing cynomolgus monkeys as models for studies of AD.

Bullying, mental health, and parental involvement among adolescents in the Caribbean.

OBJECTIVE: To examine the relationships between peer victimization, mental health, and parental involvement among middle school students in the Caribbean. METHODS: Data from the Global School-based Student Health Survey (GSHS) conducted in the Cayman Islands, St Lucia, St Vincent and the Grenadines, and Trinidad and Tobago in 2007 were analysed using age- and gender-adjusted logistic regression models. RESULTS: About one-quarter of the 6780 participants reported having been bullied in the past month. Rates of bullying were similar for boys and girls, and younger children reported higher rates of peer victimization. Nearly 25% of students reported sadness and hopelessness, more than 10% reported loneliness and anxiety and more than 15% reported having seriously considered suicide in the past year. Bullied students were much more likely than non-bullied students to report mental health issues (p < 0.01). Students who felt that their parents were understanding and monitored their free time activities reported fewer mental health issues and were somewhat less likely to report being a victim of a bully. CONCLUSION: The strong association between bullying and poor mental health in the Caribbean emphasizes the need to develop and implement strategies for reducing bullying among children and adolescents.

Ab initio calculations of the electronic properties of polypyridine transition metal complexes and their adsorption on metal surfaces in the presence of solvent and counterions.

Os(II)/(III) and Co(II)/(III) polypyridine complexes in aqueous solution are robust molecular entities both in freely solute state and adsorbed on Au(111)- and Pt(111)-electrode surfaces. This class of robust coordination chemical compounds have recently been characterized by electrochemical scanning tunneling microscopy (in situ STM). The Os-complexes were found to display strong tunneling spectroscopic (STS) features at the level of resolution of the single molecule while STS features of the Co complexes, although clear, were much weaker. The data was framed by concise but phenomenological theory of interfacial electrochemical electron transfer extended to the electrochemical in situ STM configuration. With a view on first-principle insight into the in situ STM behavior of robust redox (as opposed to nonredox) molecules, we present in this report a density functional theory (DFT) study of the complexes in both free and adsorbate state, in either state exposed to both stoichiometric counterions and a large assembly of solvent water molecules. The oxidation states of the complexes were controlled, first by introducing chlorine counter atoms followed by spontaneous attraction of electrons from the complexes, also at first in electrostatically neutral form. Second, the solvent is found to provide strong dielectric screening of this charge transfer process and to be crucial for achieving the full chemically meaningful charge separated ionic oxidation states. The molecular charge and structure of the complexes in the presence of the solvent, are conserved upon adsorption, whereas the structural features of the different oxidation states are completely lost upon adsorption under vacuum conditions. Detailed microscopic insight such as offered by the present study will be important in molecular-based approaches to "smart" redox molecules enclosed in in situ STM or other nanoscale and single-molecules scale configurations in condensed matter environments.

A genome-wide association study of bipolar disorder and comorbid migraine.

Both migraine and bipolar affective disorder (BPAD) are complex phenotypes with significant genetic and nongenetic components. Epidemiological and clinical studies have showed a high degree of comorbidity between migraine and BPAD, and overlapping regions of linkage have been shown in numerous genome-wide linkage studies. To identify susceptibility factors for the BPAD/migraine phenotype, we conducted a genome-wide association study (GWAS) in 1001 cases with bipolar disorder collected through the NIMH Genetics Initiative for Bipolar Disorder and genotyped at 1 m single-nucleotide polymorphisms (SNPs) as part of the Genetic Association Information Network (GAIN). We compared BPAD patients without any headache (n = 699) with BPAD patients with doctor diagnosed migraine (n = 56). The strongest evidence for association was found for several SNPs in a 317-kb region encompassing the uncharacterized geneKIAA0564 {e.g. rs9566845 [OR = 4.98 (95% CI: 2.6-9.48), P = 7.7 × 10(-8)] and rs9566867 (P = 8.2 × 10(-8))}. Although the level of significance was significantly reduced when using the Fisher's exact test (as a result of the low count of cases with migraine), rs9566845 P = 1.4 × 10(-5) and rs9566867 P = 1.5 × 10(-5), this region remained the most prominent finding. Furthermore, marker rs9566845 was genotyped and found associated with migraine in an independent Norwegian sample of adult attention deficit hyperactivity disorder (ADHD) patients with and without comorbid migraine (n = 131 and n = 324, respectively), OR = 2.42 (1.18-4.97), P = 0.013. This is the first GWAS examining patients with bipolar disorder and comorbid migraine. These data suggest that genetic variants in the KIAA0564 gene region may predispose to migraine headaches in subgroups of patients with both BPAD and ADHD.

An international multicenter association study of the serotonin transporter gene in persistent ADHD.

Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting children and adults. It has been suggested that gene variants related to serotonin neurotransmission are associated with ADHD. We tested the functional promoter polymorphism 5-HTTLPR and seven single nucleotide polymorphisms in SLC6A4 for association with ADHD in 448 adult ADHD patients and 580 controls from Norway. Replication attempts were performed in a sample of 1454 Caucasian adult ADHD patients and 1302 controls from Germany, Spain, the Netherlands and USA, and a meta-analysis was performed also including a previously published adult ADHD study. We found an association between ADHD and rs140700 [odds ratio (OR ) = 0.67; P = 0.01] and the short (S) allele of the 5-HTTLPR (OR = 1.19; P = 0.06) in the Norwegian sample. Analysis of a possible gender effect suggested that the association might be restricted to females (rs140700: OR = 0.45; P = 0.00084). However, the meta-analysis of 1894 cases and 1878 controls could not confirm the association for rs140700 [OR = 0.85, 95% confidence interval (CI) = 0.67-1.09; P = 0.20]. For 5-HTTLPR, five of six samples showed a slight overrepresentation of the S allele in patients, but meta-analysis refuted a strong effect (OR = 1.10, 95% CI = 1.00-1.21; P = 0.06). Neither marker showed any evidence of differential effects for ADHD subtype, gender or symptoms of depression/anxiety. In conclusion, our results do not support a major role for SLC6A4 common variants in persistent ADHD, although a modest effect of the 5-HTTLPR and a role for rare variants cannot be excluded.

Communications: Elementary oxygen electrode reactions in the aprotic Li-air battery.

We discuss the electrochemical reactions at the oxygen electrode of an aprotic Li-air battery. Using density functional theory to estimate the free energy of intermediates during the discharge and charge of the battery, we introduce a reaction free energy diagram and identify possible origins of the overpotential for both processes. We also address the question of electron conductivity through the Li(2)O(2) electrode and show that in the presence of Li vacancies Li(2)O(2) becomes a conductor.

Electronic structure calculations with GPAW: a real-space implementation of the projector augmented-wave method.

Electronic structure calculations have become an indispensable tool in many areas of materials science and quantum chemistry. Even though the Kohn-Sham formulation of the density-functional theory (DFT) simplifies the many-body problem significantly, one is still confronted with several numerical challenges. In this article we present the projector augmented-wave (PAW) method as implemented in the GPAW program package (https://wiki.fysik.dtu.dk/gpaw) using a uniform real-space grid representation of the electronic wavefunctions. Compared to more traditional plane wave or localized basis set approaches, real-space grids offer several advantages, most notably good computational scalability and systematic convergence properties. However, as a unique feature GPAW also facilitates a localized atomic-orbital basis set in addition to the grid. The efficient atomic basis set is complementary to the more accurate grid, and the possibility to seamlessly switch between the two representations provides great flexibility. While DFT allows one to study ground state properties, time-dependent density-functional theory (TDDFT) provides access to the excited states. We have implemented the two common formulations of TDDFT, namely the linear-response and the time propagation schemes. Electron transport calculations under finite-bias conditions can be performed with GPAW using non-equilibrium Green functions and the localized basis set. In addition to the basic features of the real-space PAW method, we also describe the implementation of selected exchange-correlation functionals, parallelization schemes, ΔSCF-method, x-ray absorption spectra, and maximally localized Wannier orbitals.