Sweet promises: Candy advertising to children and implications for industry self-regulation.
Candy advertising illustrates limitations of the Children's Food and Beverage Advertising Initiative (CFBAI) self-regulatory program to improve food marketing to children. Participating companies pledge to not advertise candy in child-directed media. Yet independent analyses show that children viewed 65% more candy ads on U.S. television in 2011 than in 2007, before CFBAI implementation. The present research corroborates these findings, characterizes the increase, and examines how CFBAI-participating and non-participating companies use child-targeted techniques and media placement to advertise candy on U.S. television. Content analysis identified child-targeted messages and techniques in 2011 television candy ads, and Nielsen data (2008-2011) quantified candy advertising viewed on children's and other types of television programming. Differences between brands according to CFBAI status and use of child-targeted techniques in ads are evaluated. Data were obtained and analyzed in 2013. CFBAI-company non-approved brands represented 65% of candy ads viewed by children in 2011, up from 45% in 2008, and 77% of these ads contained child-targeted techniques. Although CFBAI companies only placed ads for approved brands on children's networks, 31% of ads viewed by children for CFBAI non-approved brands appeared on networks with higher-than-average youth audiences. CFBAI non-participating companies placed child-targeted candy ads primarily on children's networks. Despite CFBAI pledges, companies continue to advertise candy during programming with large youth audiences utilizing techniques that appeal to children. Both increased CFBAI participation and a more effective definition of "child-directed advertising" are required to reduce children's exposure to targeted advertising for foods that can harm their health.


Sex-dependent expression and activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP/ABCG2) in liver.
The breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette drug efflux transporter present in the liver and other tissues that affects the pharmacological behavior of many compounds. To assess the possible role of BCRP in sex-dependent pharmacokinetics, we studied the in vivo disposition of several murine Bcrp1 substrates in male and female wild-type and Bcrp1 knockout mice. After oral administration of the antibiotic nitrofurantoin, the area under the plasma concentration-time curve in wild-type female mice was approximately 2-fold higher than in wild-type male mice. Moreover, after i.v. administration of nitrofurantoin, the antiulcerative cimetidine, the anticancer drug topotecan, and the carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the plasma levels in wild-type female mice were all significantly higher than those in wild-type male mice. Analysis of the expression of murine Bcrp1 in several pharmacokinetically important tissues showed that only the hepatic Bcrp1 expression was higher in male mice compared with female mice. In line with this difference, the hepatobiliary excretion for nitrofurantoin and PhIP was, respectively, 9-fold higher and approximately 2-fold higher in male compared with female wild-type mice. No significant sex differences were observed in plasma levels or hepatobiliary excretion for any of the tested compounds in Bcrp1-/- mice, indicating that Bcrp1 was the main cause of the sex difference in wild-type mice. Analysis of hepatic expression of human BCRP also indicated a higher expression in men compared with women. In conclusion, sex-dependent expression of BCRP/Bcrp1 in the liver may be a cause of sex-specific variability in the pharmacokinetics of BCRP substrates, with potential impact on the clinical-therapeutic applications and toxicity risks of drugs.


Protein degradation fragments as diagnostic and prognostic biomarkers of connective tissue diseases: understanding the extracellular matrix message and implication for current and future serological biomarkers.
The aim of this review is to discuss the potential usefulness of novel biochemical markers of connective tissues: neo-epitopes of extracellular matrix proteins generated by post-translational modifications by tissue proteinases. As each modification results from a specific local physiological or pathobiological process, the identification of specific proteinase-mediated cleavage products of tissue-specific proteins may produce a unique disease-specific biochemical marker. The authors present a novel interpretation of the process of tissue degradation described by neo-epitope fragments of the interstitial and basement membrane matrix in fibrotic disease, and the diagnostic and prognostic potential of such markers. Moreover, the authors highlight the importance of matrix protein fragments not only as markers of tissue remodeling, but also as players in tissue remodeling, due to their signaling properties.


MDs must help eliminate 911 calls after "expected" home deaths, medical examiner advises.
More and more Canadians are choosing to die at home. Unfortunately, family members may not know how to respond when death does occur. Some call 911 seeking advice, and soon find police, ambulance and fire services arriving at their door. If calls are made before terminal patients die, they may even be rushed to hospital for emergency care. The wasted energy wastes money and creates additional stress. Dr. John Butt, Nova Scotia's chief medical examiner, says physicians must help educate the public and emergency services about how to respond after an expected death occurs at home.


Lung transplantation: opportunities for research and clinical advancement.
Lung transplantation is the only definitive therapy for many forms of end-stage lung diseases. However, the success of lung transplantation is limited by many factors: (1) Too few lungs available for transplantation due to limited donors or injury to the donor lung; (2) current methods of preservation of excised lungs do not allow extended periods of time between procurement and implantation; (3) acute graft failure is more common with lungs than other solid organs, thus contributing to poorer short-term survival after lung transplant compared with that for recipients of other organs; (4) lung transplant recipients are particularly vulnerable to pulmonary infections; and (5) chronic allograft dysfunction, manifest by bronchiolitis obliterans syndrome, is frequent and limits long-term survival. Scientific advances may provide significant improvements in the outcome of lung transplantation. The National Heart, Lung, and Blood Institute convened a working group of investigators on June 14-15, 2004, in Bethesda, Maryland, to identify opportunities for scientific advancement in lung transplantation, including basic and clinical research. This workshop provides a framework to identify critical issues related to clinical lung transplantation, and to delineate important areas for productive scientific investigation.


Odintifier--A computational method for identifying insertions of organellar origin from modern and ancient high-throughput sequencing data based on haplotype phasing.
Cellular organelles with genomes of their own (e.g. plastids and mitochondria) can pass genetic sequences to other organellar genomes within the cell in many species across the eukaryote phylogeny. The extent of the occurrence of these organellar-derived inserted sequences (odins) is still unknown, but if not accounted for in genomic and phylogenetic studies, they can be a source of error. However, if correctly identified, these inserted sequences can be used for evolutionary and comparative genomic studies. Although such insertions can be detected using various laboratory and bioinformatic strategies, there is currently no straightforward way to apply them as a standard organellar genome assembly on next-generation sequencing data. Furthermore, most current methods for identification of such insertions are unsuitable for use on non-model organisms or ancient DNA datasets. We present a bioinformatic method that uses phasing algorithms to reconstruct both source and inserted organelle sequences. The method was tested in different shotgun and organellar-enriched DNA high-throughput sequencing (HTS) datasets from ancient and modern samples. Specifically, we used datasets from lions (Panthera leo ssp. and Panthera leo leo) to characterize insertions from mitochondrial origin, and from common grapevine (Vitis vinifera) and bugle (Ajuga reptans) to characterize insertions derived from plastid genomes. Comparison of the results against other available organelle genome assembly methods demonstrated that our new method provides an improvement in the sequence assembly. Using datasets from a wide range of species and different levels of complexity we showed that our novel bioinformatic method based on phasing algorithms can be used to achieve the next two goals: i) reference-guided assembly of chloroplast/mitochondrial genomes from HTS data and ii) identification and simultaneous assembly of odins. This method represents the first application of haplotype phasing for automatic detection of odins and reference-based organellar genome assembly.


Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings.
Despite the advent and increasingly wide availability of antiretroviral therapy, cryptococcal meningitis (CM) remains a significant cause of mortality and morbidity amongst individuals with HIV infection in resource-limited settings. The ideal management of CM remains unclear. The aim of this review is to assess the evidence for deciding on which antifungal regimen to use as well as other modalities of management to utilise especially resource poor settings in order to achieve the best possible outcome and enable an individual with CM to survive their acute illness and benefit from antiretroviral therapy. To determine the most effective initial and consolidation treatment strategy for CM in HIV infected adults. The Cochrane HIV/AIDS group search strategy was used. Key words in the search included, meningitis, cryptococcus neoformans, treatment, trial, human immunodeficiency virus, acquired immunodeficiency syndrome, antifungal agents, amphotericin, flucytosine, fluconazole, azole, lumbar puncture, cerebrospinal fluid (CSF) pressure and acetazolamide. Randomised of HIV-infected adults with a first episode of CM diagnosed on CSF examination, by India ink staining, CSF culture or cryptococcal antigen testing. Data were extracted using standardised forms and analysed using Rev Man 4.2.7 software. Six studies are included in the review. Five of the studies compared antifungal treatments and one study addressed lowering intracranial pressure. This study was stopped early due to excess adverse effects. The results of the other five studies as summarised as follows.Mayanja-Kizza 1998 compared fluconazole to fluconazole with 5 flucytosine. The dose of fluconazole used 200mg initially is lower than the recommended initial dose of 400mg. No survival advantage was found with the use of 5 flucytosine in addition to fluconazole.Two studies Brouwer 2004 and van der Horst 1997 compared Amphotericin (AmB) to AmB with 5 flucytosine. Both drugs were given at currently recommended doses for 2 weeks. No survival difference was found at 14 days or at 10 weeks (only recorded in Brouwer 2004). There were significantly more patients with sterile CSF cultures at 14 days in the group that received AmB with flucytosine.Brouwer 2004 compared AmB given alone to AmB given with flucytosine and fluconazole alone or in combination. This was a small study and no differences in mortality were noted between the groups.Bicanic 2008 compared high to standard dose AmB both with flucytosine. There was no difference in mortality between the two groups or adverse events.Leenders 1997 compared standard AmB to liposomal AmB. There was no difference in death rates between the two groups. But there were significantly fewer side effects in the group treated with liposomal AmB. The main aim of this review was to determine the best treatment for cryptococcal meningitis in resource-limited settings. In these settings usually only AmB and fluconazole are available. No studies suitable for inclusion in the review were found that compared these two drugs. Therefore we are unable to recommend either treatment as superior to the other. The recommended treatment for CM is a combination of AmB and flucytosine. The optimal dosing of AmB remains unclear. Liposomal AmB is associated with less adverse events than AmB and may be useful in selected patients where resources allow.Future research into the management of cryptococcal meningitis in resource-limited settings should focus on the most effective use of medications that are available in these settings.Flucytosine in combination with AmB leads to faster and increased sterilisation of CSF compared to using AmB alone. As Flucytosine is often not available in developing countries, policy makers and national departments of heath should consider procuring this drug for HIV treatment programmes.


Enhanced photovoltaic performance and stability with a new type of hollow 3D perovskite {en}FASnI3.
Perovskite solar cells have revolutionized the fabrication of solution-processable solar cells. The presence of lead in the devices makes this technology less attractive, and alternative metals in perovskites are being researched as suitable alternatives. We demonstrate a new type of tin-based perovskite absorber that incorporates both ethylenediammonium (en) and formamidinium (FA), forming new materials of the type {en}FASnI3. The three-dimensional ASnI3 structure is stable only with methylammonium, FA, and Cs cations, and the bandgap can be tuned with solid solutions, such as ASnI3-x Br x . We show that en can serve as a new A cation capable of achieving marked increases in the bandgap without the need for solid solutions. The en introduces a new bandgap tuning mechanism that arises from massive Schottky style defects. In addition, incorporation of the en cation in the structure markedly increases the air stability and improves the photoelectric properties of the tin-based perovskite absorbers. Our best-performing {en}FASnI3 solar cell has the highest efficiency of 7.14%, which is achieved for a lead-free perovskite cell, and retains 96% of its initial efficiency after aging over 1000 hours with encapsulation. Our results introduce a new approach for improving the performance and stability of tin-based, lead-free perovskite solar cells.


The transcription factor Sox10 is a key regulator of peripheral glial development.
The molecular mechanisms that determine glial cell fate in the vertebrate nervous system have not been elucidated. Peripheral glial cells differentiate from pluripotent neural crest cells. We show here that the transcription factor Sox10 is a key regulator in differentiation of peripheral glial cells. In mice that carry a spontaneous or a targeted mutation of Sox10, neuronal cells form in dorsal root ganglia, but Schwann cells or satellite cells are not generated. At later developmental stages, this lack of peripheral glial cells results in a severe degeneration of sensory and motor neurons. Moreover, we show that Sox10 controls expression of ErbB3 in neural crest cells. ErbB3 encodes a Neuregulin receptor, and down-regulation of ErbB3 accounts for many changes in development of neural crest cells observed in Sox10 mutant mice. Sox10 also has functions not mediated by ErbB3, for instance in the melanocyte lineage. Phenotypes observed in heterozygous mice that carry a targeted Sox10 null allele reproduce those observed in heterozygous Sox10(Dom) mice. Haploinsufficiency of Sox10 can thus cause pigmentation and megacolon defects, which are also observed in Sox10(Dom)/+ mice and in patients with Waardenburg-Hirschsprung disease caused by heterozygous SOX10 mutations.


Time-generalized multivariate analysis of EEG responses reveals a cascading architecture of semantic mismatch processing.
Event-related brain potentials have a strong impact on neurocognitive models, as they inform about the temporal sequence of cognitive processes. Nevertheless, their value for deciding among alternative cognitive architectures is partly limited by component overlap and the possibility of ambiguity regarding component identity. Here, we apply temporally-generalized multivariate pattern analysis - a recently-proposed machine learning method capable of tracking the evolution of neurocognitive processes over time - to constrain possible alternative architectures underlying the processing of semantic incongruency in sentences. In a spoken sentence paradigm, we replicate established N400/P600 correlates of semantic mismatch. Time-generalized decoding indicates that early vs. late mismatch-sensitive processes are (i) distinct in their neural substrate, arguing against recurrent or latency-shifted single process architectures, and (ii) partially overlapping in time, inconsistent with predictions of strictly serial models. These results are in accordance with an incremental-cascading neurocognitive organization of semantic mismatch processing. We propose time-generalized multivariate decoding as a valuable tool for neurocognitive language studies.


A histone arginine methylation localizes to nucleosomes in satellite II and III DNA sequences in the human genome.
Applying supervised learning/classification techniques to epigenomic data may reveal properties that differentiate histone modifications. Previous analyses sought to classify nucleosomes containing histone H2A/H4 arginine 3 symmetric dimethylation (H2A/H4R3me2s) or H2A.Z using human CD4+ T-cell chromatin immunoprecipitation sequencing (ChIP-Seq) data. However, these efforts only achieved modest accuracy with limited biological interpretation. Here, we investigate the impact of using appropriate data pre-processing -deduplication, normalization, and position- (peak-) finding to identify stable nucleosome positions - in conjunction with advanced classification algorithms, notably discriminatory motif feature selection and random forests. Performance assessments are based on accuracy and interpretative yield. We achieved dramatically improved accuracy using histone modification features (99.0%; previous attempts, 68.3%) and DNA sequence features (94.1%; previous attempts, <60%). Furthermore, the algorithms elicited interpretable features that withstand permutation testing, including: the histone modifications H4K20me3 and H3K9me3, which are components of heterochromatin; and the motif TCCATT, which is part of the consensus sequence of satellite II and III DNA. Downstream analysis demonstrates that satellite II and III DNA in the human genome is occupied by stable nucleosomes containing H2A/H4R3me2s, H4K20me3, and/or H3K9me3, but not 18 other histone methylations. These results are consistent with the recent biochemical finding that H4R3me2s provides a binding site for the DNA methyltransferase (Dnmt3a) that methylates satellite II and III DNA. Classification algorithms applied to appropriately pre-processed ChIP-Seq data can accurately discriminate between histone modifications. Algorithms that facilitate interpretation, such as discriminatory motif feature selection, have the added potential to impart information about underlying biological mechanism.


Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX.
Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors. We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively). We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (-1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska.


A common genetic variant in zinc transporter ZnT2 (Thr288Ser) is present in women with low milk volume and alters lysosome function and cell energetics.
Suboptimal lactation is a common, yet underappreciated cause for early cessation of breastfeeding. Molecular regulation of mammary gland function is critical to the process lactation; however, physiological factors underlying insufficient milk production are poorly understood. The zinc (Zn) transporter ZnT2 is critical for regulation of mammary gland development and maturation during puberty, lactation, and postlactation gland remodeling. Numerous genetic variants in the gene encoding ZnT2 (SLC30A2) are associated with low milk Zn concentration and result in severe Zn deficiency in exclusively breastfed infants. However, the functional impacts of genetic variation in ZnT2 on key mammary epithelial cell functions have not yet been systematically explored at the cellular level. Here we determined a common mutation in SLC30A2/ZnT2 substituting serine for threonine at amino acid 288 (Thr288Ser) was found in 20% of women producing low milk volume (n = 2/10) but was not identified in women producing normal volume. Exploration of cellular consequences in vitro using phosphomimetics showed the serine substitution promoted preferential phosphorylation of ZnT2, driving localization to the lysosome and increasing lysosome biogenesis and acidification. While the substitution did not initiate lysosome-mediated cell death, cellular ATP levels were significantly reduced. Our findings demonstrate the Thr288Ser mutation in SLC30A2/ZnT2 impairs critical functions of mammary epithelial cells and suggest a role for genetic variation in the regulation of milk production and lactation performance.


A heat-sensitive TRP channel expressed in keratinocytes.
Mechanical and thermal cues stimulate a specialized group of sensory neurons that terminate in the skin. Three members of the transient receptor potential (TRP) family of channels are expressed in subsets of these neurons and are activated at distinct physiological temperatures. Here, we describe the cloning and characterization of a novel thermosensitive TRP channel. TRPV3 has a unique threshold: It is activated at innocuous (warm) temperatures and shows an increased response at noxious temperatures. TRPV3 is specifically expressed in keratinocytes; hence, skin cells are capable of detecting heat via molecules similar to those in heat-sensing neurons.


Computational Kinetics of Hydroperoxybutylperoxy Isomerizations and Decompositions: A Study of the Effect of Hydrogen Bonding.
Hydroperoxyalkylperoxy (OOQOOH) radicals are important intermediates in combustion chemistry. The conventional isomerization of OOQOOH radicals to form ketohydroperoxides has been long believed to be the most important chain branching reaction under the low-temperature combustion conditions. In this work, the kinetics of competing pathways (alternative isomerization, concerted elimination, and H-exchange pathways) to the conventional isomerization of different β-, γ- and Δ-OOQOOH butane isomers are investigated. Six- and seven-membered ring conventional isomerizations are found to be the dominant pathways, whereas alternative isomerizations are more important than conventional isomerization, when the latter proceeded via a more strained transition state ring. The oxygen atoms in OOQOOH radicals introduce intramolecular hydrogen bonding (HB) that significantly affects the energies of reacting species and transition states, ultimately influencing chemical kinetics. Conceptually, HB has a dual effect on the stability of chemical species, the first being the stabilizing effect of the actual intramolecular HB force, and the second being the destabilizing effect of ring strain imposed by the HB conformer. The overall effect can be quantified by determining the difference between the minimum energy conformers of a chemical species or transition state that have HB and that do not have HB (non-hydrogen bonding (NHB)). The stabilization effect of HB on the species and transition sates is assessed, and its effect on the calculated rate constants is also considered. Our results show that, for most species and transition states, HB stabilizes their energies by as much as 2.5 kcal/mol. However, NHB conformers are found to be more stable by up to 2.7 kcal/mol for a few of the considered species. To study the effect of HB on rate constants, reactions are categorized into two groups ( groups one and two) based on the structural similarity of the minimum energy conformers of the reactant and transition state, for a particular reaction. For cases where the reactant and transition state conformers are similar (i.e., both HB or NHB structures), group one, the effect of HB on reaction kinetics is major only if the magnitudes of the stabilization energy of the reactant and transition state are quite different. Meanwhile, for group two, where the reactant and transition state prefer different conformers (one HB and the other NHB), HB affects the kinetics when the stabilization energy of the reactant or transition state is significant or the entropy effect is important. This information is useful in determining corrections accounting for HB effects when assigning rate parameters for chemical reactions using estimation and/or analogy, where analogies usually result in inaccuracies when modeling atmospheric and combustion processes.


Preventive effect of probiotics and α-tocopherol on ethanol-induced gastric mucosal injury in rats.
The protective effect of a probiotic mixture of 13 different bacteria and α-tocopherol on 98% ethanol-induced gastric mucosal injury was evaluated. Levels of gastric mucosal pro- and anti-inflammatory cytokines, malondialdehyde, and secretory immunglobulin A were measured. Rats were allocated into four groups: control, ethanol, probiotic, and α-tocopherol. The control and ethanol groups received skim milk for 14 days. Probiotic and α-tocopherol groups were administered probiotic mixture suspended in skim milk and 100 mg/kg α-tocopherol, respectively, by daily gavage for 14 days. On Day 15, gastric lesions were induced by administration of ethanol 98% (1 mL) to all rats except those in the control group. Probiotic, but not α-tocopherol, seemed to inhibit ethanol-induced gastric mucosal tumor necrosis factor-α, interferon-γ, and interleukin-2 production (P > .05). Ethanol caused the elevation of mucosal interleukin-4 level (compared to the control, P < .05). Probiotic pretreatment significantly suppressed the ethanol-induced increase of gastric mucosal interleukin-4 levels. Pretreatment with either probiotic or α-tocopherol inhibited the ethanol-induced increase of mucosal malondialdehyde concentration (P < .01 and P < .05, respectively). Probiotic pretreatment enhanced the gastric mucosal secretory immunoglobulin A concentration (P < .001). In conclusion, probiotic mixture and α-tocopherol reduced ethanol-induced gastric mucosal lipid peroxidation, suggesting that they may be beneficial for gastric lesions induced by lower ethanol concentration.


Shifting Spatial Neglect With Repeated Line Bisections: Possible Role of Lateralized Attentional Fatigue.
Many patients who have signs of neglect immediately after a right hemisphere stroke remain disabled even when they improve on tests of neglect. Few patients are tested for attentional persistence and fatigue despite their importance in many instrumental activities. To investigate whether stimulus repetition might alter the allocation of attention, we repeatedly tested a patient 16 weeks after she developed hemispatial neglect from a right hemisphere stroke. During each of three testing sessions given in 1 day, we asked the patient to bisect 90 lines of two lengths, presented in 30-trial blocks in three locations: left, center, and right of her midsagittal plane, partially counterbalanced across sessions. We adjusted multiple regression analyses and analysis of variance as well as post hoc regression and t tests for persistence in the repeated measures using variance-sample size analysis to estimate self-similarity, a measure related to the fractal correlation dimension. In each session, the patient's line bisections revealed transient leftward bias in her left peripersonal space, and constant rightward bias in her right peripersonal space. Her leftward bias shifted to a rightward bias over repeated trials in her left space. The patient's left-to-right shift with repeated trials suggests either fatigue from an attempted compensation for leftward inattention or habituation of a contralesional spatial attentional attraction, revealing contralesional left-sided neglect in both the left and right spaces. Future studies are needed to learn if other patients show similar or different deficits with repetition, and how best to treat them.


Qualitative analysis of an intensive care unit family satisfaction survey.
To describe the qualitative findings from a family satisfaction survey to identify and describe the themes that characterize family members' intensive care unit experiences. As part of a larger mixed-methods study to determine the relationship between organizational culture and family satisfaction in critical care, family members of eligible patients in intensive care units completed a Family Satisfaction Survey (FS-ICU 24), which included three open-ended questions about strengths and weaknesses of the intensive care unit based on the family members' experiences and perspectives. Responses to these questions were coded and analyzed to identify key themes. Surveys were administered in 23 intensive care units from across Canada. Surveys were completed by family members of patients who were in the intensive care unit for >48 hrs and who had been visited by the family member at least once during their intensive care unit stay. None. A total of 1381 surveys were distributed and 880 responses were received. Intensive care unit experiences were found to be variable within and among intensive care units. Six themes emerged as central to respondents' satisfaction: quality of staff, overall quality of medical care, compassion and respect shown to the patient and family, communication with doctors, waiting room, and patient room. Within three themes, positive comments were more common than negative comments: quality of the staff (66% vs. 23%), overall quality of medical care provided (33% vs. 2%), and compassion and respect shown to the patient and family (29% vs. 12%). Within the other three themes, positive comments were less common than negative comments: communication with doctors (18% vs. 20%), waiting room (1% vs. 8%), and patient rooms (0.4% vs. 5%). The study provided improved understanding of why family members are satisfied or dissatisfied with particular elements of the intensive care unit and this knowledge can be used to modify intensive care units to better meet the physical and emotional needs of the families of intensive care unit patients.


Oxygen-regulated and transactivating domains in endothelial PAS protein 1: comparison with hypoxia-inducible factor-1alpha.
Endothelial PAS protein 1 (EPAS1) is a basic helix-loop-helix Per-AHR-ARNT-Sim transcription factor related to hypoxia-inducible factor-1alpha (HIF-1alpha). To analyze EPAS1 domains responsible for transactivation and oxygen-regulated function, we constructed chimeric fusions of EPAS1 with a GAL4 DNA binding domain, plus or minus the VP16 activation domain. Two transactivation domains were defined in EPAS1; a C-terminal domain (amino acids 828-870), and a larger internal domain (amino acids 517-682). These activation domains were interspersed by functionally repressive sequences, several of which independently conveyed oxygen-regulated activity. Two types of activity were defined. Sequences lying N-terminal to and overlapping the internal transactivation domain conferred regulated repression on the VP16 transactivator. Sequences lying C-terminal to this internal domain conveyed repression and oxygen-regulated activity on the native EPAS1 C-terminal activation domain, but not the Gal/VP16 fusion. Fusions containing internal but not C-terminal regulatory domains manifested regulation of fusion protein level. Comparison of EPAS1 with HIF-1alpha demonstrated a similar organization for both proteins, and for the C terminus defined a conserved RLL motif critical for inducibility. Overall, EPAS1 sequences were less inducible than those of HIF-1alpha, and inducibility was strikingly reduced as their expression level was increased. Despite these quantitative differences, EPAS1 regulation appeared similar to HIF-1alpha, conforming to a model involving the modulation of both protein level and activity, through distinct internal and C-terminal domains.


Narrative Based Medicine as a tool for needs assessment of patients undergoing hematopoietic stem cell transplantation.
In the last years we have seen an ever increasing number of patients with haematologic disorders who need hematopoietic stem cell transplantation (HSCT). The whole sector of HSCT results, infact to be in a continous scientific and technological clinical progress, offering a very advanced care. Despite this, some aspects are underconsidered, some of which could be fundamental to determine the success of the care pathway, such as the experience of the illness by the patient. Using a Narrative Based Medicine approach we wanted to investigate clinical, psychosocial and organizational aspects of the patient's journey whilst undergoing HSCT. Various narrative interviews were conducted using non-structured approach. Results were analysed by thematic contents. Psycological dimension is the most compromised: above all emerged sentiments of oppression linked to the isolation period in the Low Bacterial Load (LBL) room. To note are also the different dynamics with which the patients perceive the organisation and hospital structures, and how much these factors can influence their care experience. Results suggest the need in clinical practice of an integration between qualitative and clinical approach, so as to permit the psychosocial and relational necessities to emerge, often unexpressed by patients undergoing HSCT.


Trunk elongation and ontogenetic changes in the axial skeleton of Triturus newts.
Body elongation in vertebrates can be achieved by lengthening of the vertebrae or by an increase in their number. In salamanders, longer bodies are mostly associated with greater numbers of vertebrae in the trunk or tail region. However, studies on the relative contribution of the length of single vertebra to body elongation are lacking. In this study, we focus on evolutionary and ontogenetic changes in differentiation of the trunk vertebrae and the relative contribution of individual vertebrae to trunk lengthening in Triturus newts, a monophyletic group of salamanders that shows remarkable disparity in body shape. We compared juveniles and adults of the most elongated T. dobrogicus, which has 17 trunk vertebrae, with juveniles and adults of two closely related species (T. ivanbureschi and T. anatolicus belonging to the T. karelinii species complex) representing a stout and robust morphotype with thirteen trunk vertebrae. We show that trunk vertebrae are uniform in size at the juvenile stage of both analyzed morphotypes. In adults, the trunk vertebrae of the elongated T. dobrogicus are largely uniform, while in those of T. anatolicus, the first two vertebrae differ from the remaining trunk vertebrae. There was no difference in the relative contribution of individual vertebrae to body lengthening between species or stages. We conclude that body elongation in Triturus newts is achieved by increasing the number of vertebrae but not their length.


Balancing the risk of mortality and major bleeding in the treatment of NSTEMI patients - a report from the National Cardiovascular Data Registry.
We sought to describe real-world patterns of care in NSTEMI patients across different risk profiles for bleeding and mortality. The NCDR ACTION Registry-GWTG in-hospital mortality and major bleeding risk scores were developed to assess patient risk and optimize treatment decisions. However, little is known about the alignment of contemporary clinical management patterns with these risk estimates. We studied 61,366 NSTEMI patients in the NCDR ACTION-Registry-GWTG from January 2007 to March 2009, stratifying them into four groups based on estimated risk of mortality and major bleeding. There were 24,709 (40.3%) patients in each of the concordant risk groups (low:low; high:high) and 5974 (9.7%) in each of the discordant risk groups (low:high; high:low). Subjects at high estimated risk for both mortality and major bleeding were least likely to receive guideline-based adjunctive pharmacotherapy or to undergo angiography within 48 hours but most likely to receive an excess dose of an antithrombotic agent. Patients at low estimated risk for mortality and bleeding received the most intensive adjunctive therapy and were most likely to undergo invasive angiography. There are significant differences in contemporary patterns of care across varying risk profiles of mortality and major bleeding. Despite practice patterns which seem to emphasize avoiding harm with reduced use of antithrombotic therapy, patients at high risk for major bleeding continue to receive excess doses of antithrombotic therapy. Additional performance improvement efforts are needed to optimize outcomes in NSTEMI patients with high risk for both bleeding and mortality.


STED-FLCS: An Advanced Tool to Reveal Spatiotemporal Heterogeneity of Molecular Membrane Dynamics.
Heterogeneous diffusion dynamics of molecules play an important role in many cellular signaling events, such as of lipids in plasma membrane bioactivity. However, these dynamics can often only be visualized by single-molecule and super-resolution optical microscopy techniques. Using fluorescence lifetime correlation spectroscopy (FLCS, an extension of fluorescence correlation spectroscopy, FCS) on a super-resolution stimulated emission depletion (STED) microscope, we here extend previous observations of nanoscale lipid dynamics in the plasma membrane of living mammalian cells. STED-FLCS allows an improved determination of spatiotemporal heterogeneity in molecular diffusion and interaction dynamics via a novel gated detection scheme, as demonstrated by a comparison between STED-FLCS and previous conventional STED-FCS recordings on fluorescent phosphoglycerolipid and sphingolipid analogues in the plasma membrane of live mammalian cells. The STED-FLCS data indicate that biophysical and biochemical parameters such as the affinity for molecular complexes strongly change over space and time within a few seconds. Drug treatment for cholesterol depletion or actin cytoskeleton depolymerization not only results in the already previously observed decreased affinity for molecular interactions but also in a slight reduction of the spatiotemporal heterogeneity. STED-FLCS specifically demonstrates a significant improvement over previous gated STED-FCS experiments and with its improved spatial and temporal resolution is a novel tool for investigating how heterogeneities of the cellular plasma membrane may regulate biofunctionality.


P-wave dispersion and heart rate variability in children with mitral valve prolapse.
Previous studies have reported that patients with mitral valve prolapse (MVP) may display autonomic dysfunction. Measurement of heart rate variability (HRV) and P-wave dispersion (PWD) may provide insights into the functional state of the autonomic nervous system. Heart rate variability (HRV) has been used as a noninvasive marker of autonomic activity. However, to the authors' knowledge, PWD has not been studied in the context of MVP. This study aimed to examine HRV and PWD in patients with MVP and to determine whether differences exist between symptomatic and asymptomatic patients. The study population consisted of 54 healthy children (17 boys and 37 girls) ages 6-18 years and 76 patients with MVP (20 boys and 56 girls) ages 6-18 years. The duration and dispersion of the P-wave were measured by surface 12-lead electrocardiograms (ECGs). Heart rate variability was quantified using both time-domain and frequency-domain analyses of Holter ECGs. The minimum duration of the P-wave was significantly lower in the MVP patients (42.4 ± 10.0 ms) than in the control subjects (54.4 ± 12.8 ms) (p < 0.01), and the PWD was significantly increased in the MVP group (42.7 ± 10.8 ms) compared with the control subjects (31.8 ± 10.9 ms) (p < 0.01). However, no significant differences were found between the symptomatic and asymptomatic patients. In addition, the HRV parameters were not statistically different between the two groups. In conclusion, although HRV parameters were not significantly different between the MVP and control groups, the findings show that PWD was increased for the children with MVP. However, no relationship could be established between PWD and clinical symptoms.


High-resolution loss of heterozygosity screening implicates PTPRJ as a potential tumor suppressor gene that affects susceptibility to Non-Hodgkin's lymphoma.
We employed a Hidden-Markov-Model (HMM) algorithm in loss of heterozygosity (LOH) analysis of high-density single nucleotide polymorphism (SNP) array data from Non-Hodgkin's lymphoma (NHL) entities, follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). This revealed a high frequency of LOH over the chromosomal region 11p11.2, containing the gene encoding the protein tyrosine phosphatase receptor type J (PTPRJ). Although PTPRJ regulates components of key survival pathways in B-cells (i.e., BCR, MAPK, and PI3K signaling), its role in B-cell development is poorly understood. LOH of PTPRJ has been described in several types of cancer but not in any hematological malignancy. Interestingly, FL cases with LOH exhibited down-regulation of PTPRJ, in contrast no significant variation of expression was shown in DLBCLs. In addition, sequence screening in Exons 5 and 13 of PTPRJ identified the G973A (rs2270993), T1054C (rs2270992), A1182C (rs1566734), and G2971C (rs4752904) coding SNPs (cSNPs). The A1182 allele was significantly more frequent in FLs and in NHLs with LOH. Significant over-representation of the C1054 (rs2270992) and the C2971 (rs4752904) alleles were also observed in LOH cases. A haplotype analysis also revealed a significant lower frequency of haplotype GTCG in NHL cases, but it was only detected in cases with retention. Conversely, haplotype GCAC was over-representated in cases with LOH. Altogether, these results indicate that the inactivation of PTPRJ may be a common lymphomagenic mechanism in these NHL subtypes and that haplotypes in PTPRJ gene may play a role in susceptibility to NHL, by affecting activation of PTPRJ in these B-cell lymphomas.


Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity.
Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. How metabolism is implicated in specific phenotypes and whether lineage-restricted mechanisms control key metabolic vulnerabilities remain poorly understood. In melanoma, downregulation of the lineage addiction oncogene microphthalmia-associated transcription factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, although how MITF promotes proliferation and suppresses invasion is poorly defined. Here, we show that MITF is a lineage-restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signaling, and an ATF4-mediated feedback loop that maintains de-differentiation. Our results reveal that MITF is a lineage-specific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype switching, and highlight that cell phenotype dictates the response to drugs targeting lipid metabolism.


Biogenic iron oxides for phosphate removal.
Biogenic iron oxides (BioFeO) formed by Leptothrix sp. and Gallionella sp. were compared with chemically formed iron oxides (ChFeO) for their suitability to remove and recover phosphate from solutions. The ChFeO used for comparison included a commercial iron-based adsorbent (GEH) and chemically oxidized iron precipitates from groundwater. Despite contrary observations in earlier studies, the batch experiments showed that BioFeO do not have superior phosphate adsorption capacities compared to ChFeO. However, it seems multiple mechanisms are involved in phosphate removal by BioFeO which make their overall phosphate removal capacity higher than that of ChFeO. The overall phosphate removal capacity of Leptothrix sp. deposits was 26.3 mg P/g d.s., which could be attributed to multiple mechanisms. This included adsorption on the solid phase (6.4 mg P/g d.s.) as well as removal via precipitation and/or adsorption onto suspended complexes released from the BioFeO of Leptothrix sp. (19.6 mg P/g d.s.). Only a very small part of phosphorus (0.3 mg P/g d.s.) was retained in the Leptothrix sp. sheats during bacterial growth. Deposits of Gallionella sp. had an overall phosphate removal capacity of 39.6 mg P/g d.s. Significant amounts of phosphate were apparently incorporated into the Gallionella sp. stalks during their growth (31.0 mg P/g d.s.) and only one-fifth of the total phosphate removal can be related to adsorption (8.6 mg P/g d.s.). Their overall ability to immobilize large quantities of phosphate from solutions indicates that BioFeO could play an important role in environmental and engineered systems for removal of contaminants.


Maternal PTSD and Children's Adjustment: Parenting Stress and Emotional Availability as Proposed Mediators.
Maternal posttraumatic stress disorder (PTSD) is a risk factor for negative child adjustment, but it is unclear whether this association is direct (e.g., a mother's PTSD symptoms are observed, learned, and internalized by children which results in behavioral and emotional problems) or indirect, through parent-child relationship difficulties or parenting stress. We hypothesized that parenting stress and maternal emotional availability would exhibit indirect effects on relationships between maternal PTSD and children's functioning. Participants were 52 trauma-exposed mothers and their children (aged 7-12 years). Mothers completed measures of PTSD and parenting stress and reported on their children's functioning. Emotional availability was assessed through observer-rated mother-child interactions. Emotional availability was not related to PTSD or child outcomes. Parenting stress had a substantial indirect effect on the relationships between maternal PTSD and child emotion regulation, internalizing, and externalizing behaviors. Results highlight the need to target parenting stress in interventions with trauma-exposed families.


Native-likeness in second language lexical categorization reflects individual language history and linguistic community norms.
SECOND LANGUAGE LEARNERS FACE A DUAL CHALLENGE IN VOCABULARY LEARNING: First, they must learn new names for the 100s of common objects that they encounter every day. Second, after some time, they discover that these names do not generalize according to the same rules used in their first language. Lexical categories frequently differ between languages (Malt et al., 1999), and successful language learning requires that bilinguals learn not just new words but new patterns for labeling objects. In the present study, Chinese learners of English with varying language histories and resident in two different language settings (Beijing, China and State College, PA, USA) named 67 photographs of common serving dishes (e.g., cups, plates, and bowls) in both Chinese and English. Participants' response patterns were quantified in terms of similarity to the responses of functionally monolingual native speakers of Chinese and English and showed the cross-language convergence previously observed in simultaneous bilinguals (Ameel et al., 2005). For English, bilinguals' names for each individual stimulus were also compared to the dominant name generated by the native speakers for the object. Using two statistical models, we disentangle the effects of several highly interactive variables from bilinguals' language histories and the naming norms of the native speaker community to predict inter-personal and inter-item variation in L2 (English) native-likeness. We find only a modest age of earliest exposure effect on L2 category native-likeness, but importantly, we find that classroom instruction in L2 negatively impacts L2 category native-likeness, even after significant immersion experience. We also identify a significant role of both L1 and L2 norms in bilinguals' L2 picture naming responses.


A genome-wide CRISPR library for high-throughput genetic screening in Drosophila cells.
The simplicity of the CRISPR/Cas9 system of genome engineering has opened up the possibility of performing genome-wide targeted mutagenesis in cell lines, enabling screening for cellular phenotypes resulting from genetic aberrations. Drosophila cells have proven to be highly effective in identifying genes involved in cellular processes through similar screens using partial knockdown by RNAi. This is in part due to the lower degree of redundancy between genes in this organism, whilst still maintaining highly conserved gene networks and orthologs of many human disease-causing genes. The ability of CRISPR to generate genetic loss of function mutations not only increases the magnitude of any effect over currently employed RNAi techniques, but allows analysis over longer periods of time which can be critical for certain phenotypes. In this study, we have designed and built a genome-wide CRISPR library covering 13,501 genes, among which 8989 genes are targeted by three or more independent single guide RNAs (sgRNAs). Moreover, we describe strategies to monitor the population of guide RNAs by high throughput sequencing (HTS). We hope that this library will provide an invaluable resource for the community to screen loss of function mutations for cellular phenotypes, and as a source of guide RNA designs for future studies.


Beta Blockade and Clinical Outcomes in Aneurysmal Subarachnoid Hemorrhage.
Aneurysmal subarachnoid hemorrhages are frequently complicated by hypertension and neurogenic myocardial stunning. Beta blockers may be used for management of these complications. We sought to investigate sympathetic nervous system modulation by beta blockers and their effect on radiographic vasospasm, delayed cerebral infarction, discharge destination and death. Retrospective chart review of 218 adults admitted to the ICU between 8/2004 and 9/2010 was performed. Groups were identified relevant to beta blockade: 77 were never beta blocked (No/No), 123 received post-admission beta blockers (No/Yes), and 18 were continued on their home beta blockers (Yes/Yes). Records were analyzed for baseline characteristics and the development of vasospasm, delayed cerebral infarction, discharge destination and death, expressed as adjusted odds ratio. Of the 218 patients 145 patients developed vasospasm, 47 consequently infarcted, and 53 died or required care in a long-term facility. When compared to No/No patients, No/Yes patients had significantly increased vasospasm (OR 2.11 (1.06-4.16)). However, these patients also had significantly fewer deaths or need for long term care (OR 0.17 (0.05-0.64)), with decreased tendency for infarcts (OR 0.70 (0.32-1.55)). When compared to No/No patients, Yes/Yes patients demonstrated a trend toward increased vasospasm (OR 1.61 (0.50-5.29)) that led to infarction (OR 1.51 (0.44-5.13)), but with decreased mortality or need for long term care in a facility (OR 0.13 (0.01-1.30)). Post-admission beta blockade in aneurysmal subarachnoid hemorrhage patients was associated with increased incidence of vasospasm. However, despite the increased occurrence of vasospasm, beta blockers were associated with improved discharge characteristics and fewer deaths.


Enhanced THz radiation emission from plasmonic complementary Sierpinski fractal emitters.
We present a new class of plasmonic photoconductive THz emitters based on a complementary Sierpinski gasket fractal geometry. Due to the presence of sub-wavelength perforations on the surface of the antenna, these antennae operate in the plasmonic regime. By utilizing the unique self-similar and space filling of the tailored fractal surface and the plasmonic surface current spatial distribution, photoconductive THz emitters exhibiting superior performance (~80% increase in the emitted THz radiation power) to conventional bow-tie and Sierpinski gasket THz emitters are demonstrated. It is shown that the self-similarity of the surface plasmon current present on the antenna surface is responsible for this emission enhancement.


Metabolic phenotyping for understanding the gut microbiome and host metabolic interplay.
There is growing interest in the role of the gut microbiome in human health and disease. This unique complex ecosystem has been implicated in many health conditions, including intestinal disorders, inflammatory skin diseases and metabolic syndrome. However, there is still much to learn regarding its capacity to affect host health. Many gut microbiome research studies focus on compositional analysis to better understand the causal relationships between microbial communities and disease phenotypes. Yet, microbial diversity and complexity is such that community structure alone does not provide full understanding of microbial function. Metabolic phenotyping is an exciting field in systems biology that provides information on metabolic outputs taking place in the system at a given moment in time. These readouts provide information relating to by-products of endogenous metabolic pathways, exogenous signals arising from diet, drugs and other lifestyle and environmental stimuli, as well as products of microbe-host co-metabolism. Thus, better understanding of the gut microbiome and host metabolic interplay can be gleaned using such analytical approaches. In this review, we describe research findings focussed on gut microbiota-host interactions, for functional insights into the impact of microbiome composition on host health. We evaluate different analytical approaches for capturing metabolic activity and discuss analytical methodological advancements that have made a contribution to the field. This information will aid in developing novel approaches to improve host health in the future, and therapeutic modulation of the microbiome may soon augment conventional clinical strategies.


Unimolecular decomposition of formamide via direct chemical dynamics simulations.
Formamide (NH2CHO), being the simplest organic molecule containing an amide functional group, serves as a prototype to study protein and peptide chemistry. Formamide has been found in Comets and interstellar media and its decomposition results in smaller molecules such as NH3, CO, HCN, HNCO, etc. These smaller molecules are considered to have been potential precursors for the formation of complex biological molecules, such as nucleic acids and nucleobases, in the early Earth. Several experimental and theoretical investigations of formamide decomposition have been reported in the literature. In the present work, unimolecular decomposition of formamide in the electronic ground state was investigated by classical direct chemical dynamics simulations. The calculations were performed at three different energies using the density functional B3LYP/aug-cc-pVDZ level of electronic structure theory. The major dissociation products observed were NH3, CO, H2, HNCO, H2O, HCN, and HNC along with products of a few minor dissociation channels. Reactivity, atomic level mechanisms, and product branching ratios were investigated as a function of total energy.


The Diabetes Mellitus-Atherosclerosis Connection: The Role of Lipid and Glucose Metabolism and Chronic Inflammation.
Diabetes mellitus comprises a group of carbohydrate metabolism disorders that share a common main feature of chronic hyperglycemia that results from defects of insulin secretion, insulin action, or both. Insulin is an important anabolic hormone, and its deficiency leads to various metabolic abnormalities in proteins, lipids, and carbohydrates. Atherosclerosis develops as a result of a multistep process ultimately leading to cardiovascular disease associated with high morbidity and mortality. Alteration of lipid metabolism is a risk factor and characteristic feature of atherosclerosis. Possible links between the two chronic disorders depending on altered metabolic pathways have been investigated in numerous studies. It was shown that both types of diabetes mellitus can actually induce atherosclerosis development or further accelerate its progression. Elevated glucose level, dyslipidemia, and other metabolic alterations that accompany the disease development are tightly involved in the pathogenesis of atherosclerosis at almost every step of the atherogenic process. Chronic inflammation is currently considered as one of the key factors in atherosclerosis development and is present starting from the earliest stages of the pathology initiation. It may also be regarded as one of the possible links between atherosclerosis and diabetes mellitus. However, the data available so far do not allow for developing effective anti-inflammatory therapeutic strategies that would stop atherosclerotic lesion progression or induce lesion reduction. In this review, we summarize the main aspects of diabetes mellitus that possibly affect the atherogenic process and its relationship with chronic inflammation. We also discuss the established pathophysiological features that link atherosclerosis and diabetes mellitus, such as oxidative stress, altered protein kinase signaling, and the role of certain miRNA and epigenetic modifications.


Central common drive to antagonistic ankle muscles in relation to short-term cocontraction training in nondancers and professional ballet dancers.
Optimization of cocontraction of antagonistic muscles around the ankle joint has been shown to involve plastic changes in spinal and cortical neural circuitries. Such changes may explain the ability of elite ballet dancers to maintain a steady balance during various ballet postures. Here we investigated whether short-term cocontraction training in ballet dancers and nondancers leads to changes in the coupling between antagonistic ankle motor units. Eleven ballet dancers and 10 nondancers were recruited for the study. Prior to training, ballet dancers and nondancers showed an equal amount of coherence in the 15- to 35-Hz frequency band and short-term synchronization between antagonistic tibialis anterior and soleus motor units. The ballet dancers tended to be better at maintaining a stable cocontraction of the antagonistic muscles, but this difference was not significant (P = 0.09). Following 27 min of cocontraction training, the nondancers improved their performance significantly, whereas no significant improvement was observed for the ballet dancers. The nondancers showed a significant increase in 15- to 35-Hz coherence following the training, whereas the ballet dancers did not show a significant change. A group of control subjects (n = 4), who performed cocontraction of the antagonistic muscles for an equal amount of time, but without any requirement to improve their performance, showed no change in coherence. We suggest that improved ability to maintain a stable cocontraction around the ankle joint is accompanied by short-term plastic changes in the neural drive to the involved muscles, but that such changes are not necessary for maintained high-level performance.


A Significant Regulatory Mutation Burden at a High-Affinity Position of the CTCF Motif in Gastrointestinal Cancers.
Somatic mutations drive cancer and there are established ways to study those in coding sequences. It has been shown that some regulatory mutations are over-represented in cancer. We develop a new strategy to find putative regulatory mutations based on experimentally established motifs for transcription factors (TFs). In total, we find 1,552 candidate regulatory mutations predicted to significantly reduce binding affinity of many TFs in hepatocellular carcinoma and affecting binding of CTCF also in esophagus, gastric, and pancreatic cancers. Near mutated motifs, there is a significant enrichment of (1) genes mutated in cancer, (2) tumor-suppressor genes, (3) genes in KEGG cancer pathways, and (4) sets of genes previously associated to cancer. Experimental and functional validations support the findings. The strategy can be applied to identify regulatory mutations in any cell type with established TF motifs and will aid identifications of genes contributing to cancer.


Robust H infinity control for networked systems with random packet losses.
In this paper, the robust H infinity control problem is considered for a class of networked systems with random communication packet losses. Because of the limited bandwidth of the channels, such random packet losses could occur, simultaneously, in the communication channels from the sensor to the controller and from the controller to the actuator. The random packet loss is assumed to obey the Bernoulli random binary distribution, and the parameter uncertainties are norm-bounded and enter into both the system and output matrices. In the presence of random packet losses, an observer-based feedback controller is designed to robustly exponentially stabilize the networked system in the sense of mean square and also achieve the prescribed H infinity disturbance-rejection-attenuation level. Both the stability-analysis and controller-synthesis problems are thoroughly investigated. It is shown that the controller-design problem under consideration is solvable if certain linear matrix inequalities (LMIs) are feasible. A simulation example is exploited to demonstrate the effectiveness of the proposed LMI approach.


Digit ratio (2D:4D) and the spatial representation of magnitude.
Digit ratio (as a putative indicator of prenatal androgen exposure) is related to a range of sexually dimorphic abilities, including spatial skills and mathematical ability. This study examined a phenomenon known as the SNARC effect (Spatial Numerical Association of Response Codes), which is taken as evidence of a mental representation of magnitude along a left-right-oriented number line, with low magnitudes associated with the left side of space, and high numbers with the right side of space. Participants made a parity judgement of numbers with responses made with a left key to odd numbers and a right key to even numbers. This was reversed for a second block of trials. Response times to numbers one to nine with both the right and left hand were calculated, and regression analyses conducted to analyse whether lower magnitudes were responded to faster with the left hand and higher magnitudes with the right hand. Participants with lower (more masculine) digit ratios on the right hand showed a stronger SNARC effect compared to participants with high digit ratios. This pattern of results was also found when the analyses were conducted separately for men and women. Results from left hand digit ratios indicated that only low digit ratio females showed a significant SNARC effect. These findings add to a growing literature on the relationship between digit ratio and cognitive abilities; in this case, simple cognitive representations that are accessed automatically rather than complex skills such as mental rotation or "mathematics" where a variety of solution strategies may be utilised.


Effects of omega-3 fatty acids on depression and quality of life in maintenance hemodialysis patients.
Depression and health-related quality of life (HRQoL) are closely interrelated among hemodialysis (HD) patients and associated with negative impacts on patients' clinical outcomes. Considering previous reports on clinical benefits of omega-3 fatty acids in major depression and HRQoL in other patient populations, this study examined effects of omega-3 fatty acids on depression and HRQoL in chronic HD patients. In this randomized placebo-controlled trial, 40 adult patients with a Beck Depression Inventory (BDI) score of ≥16 and HD vintage of at least 3 months were randomized to ingest 6 soft-gel capsules of either omega-3 fatty acids (180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid in each capsule) or corresponding placebo, daily for 4 months. At baseline and after 4 months, 2 questionnaires of BDI and the Medical Outcome Study 36-Item Short-Form Health Survey were completed by each patient. Although baseline BDI score was comparable between the 2 groups, it was significantly lower in the omega-3 group compared with the placebo group at the end of the study (P = 0.008). Except for mental health, social functioning, and general health, other domains of HRQoL showed significant improvement in the omega-3 group compared with the placebo group at month 4 of the study (P < 0.05 for all). Regression analysis revealed that ameliorated BDI score by omega-3 treatment had considerable role in the improvement of overall HRQoL score, physical and mental component dimensions, and score of physical functioning, role-physical, and bodily pain. Supplemental use of omega-3 fatty acids in HD patients with depressive symptoms seems to be efficacious in improving depressive symptoms and HRQoL.


SWITCH-China: A Systems Approach to Decarbonizing China's Power System.
We present an integrated model, SWITCH-China, of the Chinese power sector with which to analyze the economic and technological implications of a medium to long-term decarbonization scenario while accounting for very-short-term renewable variability. On the basis of the model and assumptions used, we find that the announced 2030 carbon peak can be achieved with a carbon price of ∼$40/tCO2. Current trends in renewable energy price reductions alone are insufficient to replace coal; however, an 80% carbon emission reduction by 2050 is achievable in the Intergovernmental Panel on Climate Change Target Scenario with an optimal electricity mix in 2050 including nuclear (14%), wind (23%), solar (27%), hydro (6%), gas (1%), coal (3%), and carbon capture and sequestration coal energy (26%). The co-benefits of carbon-price strategy would offset 22% to 42% of the increased electricity costs if the true cost of coal and the social cost of carbon are incorporated. In such a scenario, aggressive attention to research and both technological and financial innovation mechanisms are crucial to enabling the transition at a reasonable cost, along with strong carbon policies.


Iterative random forests to discover predictive and stable high-order interactions.
Genomics has revolutionized biology, enabling the interrogation of whole transcriptomes, genome-wide binding sites for proteins, and many other molecular processes. However, individual genomic assays measure elements that interact in vivo as components of larger molecular machines. Understanding how these high-order interactions drive gene expression presents a substantial statistical challenge. Building on random forests (RFs) and random intersection trees (RITs) and through extensive, biologically inspired simulations, we developed the iterative random forest algorithm (iRF). iRF trains a feature-weighted ensemble of decision trees to detect stable, high-order interactions with the same order of computational cost as the RF. We demonstrate the utility of iRF for high-order interaction discovery in two prediction problems: enhancer activity in the early Drosophila embryo and alternative splicing of primary transcripts in human-derived cell lines. In Drosophila, among the 20 pairwise transcription factor interactions iRF identifies as stable (returned in more than half of bootstrap replicates), 80% have been previously reported as physical interactions. Moreover, third-order interactions, e.g., between Zelda (Zld), Giant (Gt), and Twist (Twi), suggest high-order relationships that are candidates for follow-up experiments. In human-derived cells, iRF rediscovered a central role of H3K36me3 in chromatin-mediated splicing regulation and identified interesting fifth- and sixth-order interactions, indicative of multivalent nucleosomes with specific roles in splicing regulation. By decoupling the order of interactions from the computational cost of identification, iRF opens additional avenues of inquiry into the molecular mechanisms underlying genome biology.


Factors associated with low bone mineral density in female patients with systemic lupus erythematosus.
To study risk factors for low bone mineral density (BMD, g/cm) in patients with systemic lupus erythematosus (SLE). Ninety-two consecutive patients with SLE followed by rheumatology faculty between 1997 and 1999 completed a questionnaire regarding lifestyle during the clinic visit, a chart review was performed, and data were collected for the time of the first dual energy x-ray absorptiometry (DXA) examination. Univariate and multivariate statistical analyses were used to assess relationships between various risk factors and BMD. Ninety-eight percent of patients had received prednisone, 51% were postmenopausal (9 of whom received hormone replacement therapy), 68% had received hydroxychloroquine, and 15% were osteoporotic. The following factors were found to be significantly related to lower BMD by univariate analysis: Caucasian race, older age at diagnosis, higher age at the time of the first DXA, longer disease duration, higher cumulative corticosteroid dose, higher SLE Damage Index score, and postmenopausal status. In the multivariate analysis only the following factors were significant: Caucasian race, increased number of pregnancies, postmenopausal status, higher SLE Damage Index, and higher cumulative corticosteroid dose. An unexpected finding was that taking hydroxychloroquine was the only factor associated with higher BMD of the hip and spine in the univariate analysis, and it remained predictive of higher BMD of the hip and spine in the multivariate analysis. Hydroxychloroquine appears to protect against low BMD in corticosteroid treated patients with SLE.


Pediatric urinary tract infections: diagnosis and treatment.
Urinary tract infection (UTI) is the most common serious bacterial infection in childhood. Prompt diagnosis and treatment are required for the optimal clinical outcome and the prevention of long-term morbidity and sequelae. Diagnosis and treatment of UTI may seem to be easy tasks, but they remain among the most controversial issues in pediatrics. Consequently, children suspected for UTIs are investigated and treated differently in different settings. The absence of typical clinical presentation and the uncertainties in setting the index of suspicion, collecting appropriate urine samples and interpreting results, combined with different antibiotic policies in the face of increasing resistance of uropathogens, contribute to the controversy. Recently issued guidelines have attempted to settle several thorny aspects in diagnosis and treatment, but quite a few issues still remain controversial. In this review, the authors explore the current situation on diagnosis and treatment of childhood UTI in better understanding their pathogenesis and prevalence in different child populations, discuss recently evaluated diagnostic tests and the new management guidelines.


On the competition among aerosol number, size and composition in predicting CCN variability: a multi-annual field study in an urbanized desert.
A 2-year data set of measured CCN (cloud condensation nuclei) concentrations at 0.2 % supersaturation is combined with aerosol size distribution and aerosol composition data to probe the effects of aerosol number concentrations, size distribution and composition on CCN patterns. Data were collected over a period of 2 years (2012-2014) in central Tucson, Arizona: a significant urban area surrounded by a sparsely populated desert. Average CCN concentrations are typically lowest in spring (233 cm-3), highest in winter (430 cm-3) and have a secondary peak during the North American monsoon season (July to September; 372 cm-3). There is significant variability outside of seasonal patterns, with extreme concentrations (1 and 99 % levels) ranging from 56 to 1945 cm-3 as measured during the winter, the season with highest variability. Modeled CCN concentrations based on fixed chemical composition achieve better closure in winter, with size and number alone able to predict 82% of the variance in CCN concentration. Changes in aerosol chemical composition are typically aligned with changes in size and aerosol number, such that hygroscopicity can be parameterized even though it is still variable. In summer, models based on fixed chemical composition explain at best only 41% (pre-monsoon) and 36% (monsoon) of the variance. This is attributed to the effects of secondary organic aerosol (SOA) production, the competition between new particle formation and condensational growth, the complex interaction of meteorology, regional and local emissions and multi-phase chemistry during the North American monsoon. Chemical composition is found to be an important factor for improving predictability in spring and on longer timescales in winter. Parameterized models typically exhibit improved predictive skill when there are strong relationships between CCN concentrations and the prevailing meteorology and dominant aerosol physicochemical processes, suggesting that similar findings could be possible in other locations with comparable climates and geography.


Longitudinal changes in extended roles in radiography: A new perspective.
The purpose of this research was to update data on the scope of changes to radiographic practice since the principal author's last survey in 2000. The study also sought to identify any regional patterns in the adoption and diffusion of extended roles and to map the implementation of the 4-tier structure. Structured questionnaires were sent to radiology managers at acute National Health Service (NHS) trusts across the United Kingdom. Information sought included region, teaching/non-teaching status, the nature of extended role tasks undertaken and the year in which these tasks were adopted, numbers of radiographers and radiologists in post. Information was also sought on the implementation of the '4-tier structure'. Some 177 questionnaires were returned from a total of 258 dispatched giving a 68.6% response rate. In 166 trusts, radiographers administered intravenous injections; they performed barium enemas in 147 trusts and barium meals in 19 trusts, while a red dot system was in operation in 143 trusts. Each category showed an increase from that reported in 2000. Likewise reporting by radiographers had increased since 2000. Responses indicated that at 146 trusts, radiographers were reporting in ultrasound; reporting of the appendicular skeleton was undertaken at 81 trusts and axial skeletal reporting at 70 trusts. Barium enemas were reported by radiographers in 78 trusts. Reporting was also undertaken by radiographers on barium meals, mammography, nuclear medicine, paediatric and chest radiography; and all showed an increase in frequency since 2000. Regional differences were again apparent in reporting, with a greater prevalence in the English regions, with the exception of London. In respect of the 4-tier structure, 59% of the sample employed assistant practitioners, 47% advanced practitioners and 3% employed consultants. The numbers reported in each category (excluding practitioners) were 158 assistants, 623 advanced practitioners and six consultants. There were a number of trusts that had plans to introduce assistants, advanced practitioners and/or consultants over the following two-year period. The study provided data that illustrated the extent to which NHS acute trusts are utilising the skills of radiographers and recognizing the extended scope of radiographic practice. Implementation of the 4-tier structure is underway with the greatest number of staff (excluding practitioners) categorized as advanced practitioners. This does provide some evidence of trusts responding to the 2000 NHS Plan in introducing new ways of working. The number of consultants, as could be expected at the time of the survey was low.


Plio-Pleistocene diversification and biogeographic barriers in southern Australia reflected in the phylogeography of a widespread and common lizard species.
Palaeoclimatic events and biogeographical processes since the mid-Tertiary have played an important role in shaping the evolution and distribution of Australian fauna. However, their impacts on fauna in southern and arid zone regions of Australia are not well understood. Here we investigate the phylogeography of an Australian scincid lizard, Tiliqua rugosa, across southern Australia using mitochondrial DNA (mtDNA) and 11 nuclear DNA markers (nuDNA), including nine anonymous nuclear loci. Phylogenetic analyses revealed three major mtDNA lineages within T. rugosa, geographically localised north and south of the Murray River in southern Australia, and west of the Nullarbor Plain. Molecular variance and population analyses of both mtDNA and nuDNA haplotypes revealed significant variation among the three populations, although potential introgression of nuDNA markers was also detected for the Northern and Southern population. Coalescent times for major mtDNA lineages coincide with an aridification phase, which commenced after the early Pliocene and increased in intensity during the Late Pliocene-Pleistocene. Species distribution modelling and a phylogeographic diffusion model suggest that the range of T. rugosa may have contracted during the Last Glacial Maximum and the locations of optimal habitat appear to coincide with the geographic origin of several distinct mtDNA lineages. Overall, our analyses suggest that Plio-Pleistocene climatic changes and biogeographic barriers associated with the Nullarbor Plain and Murray River have played a key role in shaping the present-day distribution of genetic diversity in T. rugosa and many additional ground-dwelling animals distributed across southern Australia.


Evaluation of physical activity among adults with diabetes mellitus from Sri Lanka.
We evaluated the patterns of physical activity (PA) and the prevalence of physical inactivity among Sri Lankan adults with diabetes mellitus. Data were collected as part of a wider cross-sectional national study on diabetes in Sri Lanka. PA during the past week was assessed using the short version of the IPAQ. Overall prevalence of physical inactivity was 13.9%. Females (3091 ± 2119) had a significantly higher mean weekly total MET minutes than males (2506 ± 2084) (p < 0.01). Inactivity of those residing in urban (17.2%) areas was higher than rural (12.6%) in all adults. Participants from Moor ethnicity were more inactive compared to others. Adults who were physically active had significantly low waist and hip circumferences, BMI and systolic blood pressure.


Hip resurfacing with the Biomet Hybrid ReCap-Magnum system: 7-year results.
The purpose of this study was to report our clinical outcome of a large series of metal-on-metal hip resurfacing arthroplasty (HRA) using the hybrid Biomet ReCap-Magnum system. This is a single-designer surgeon series with an average of 5 ± 1 years. Seven hundred forty consecutive hybrid HRAs were performed in 653 patients. Kaplan-Meier survivorship with any revision as an end point was 96.4% at 7 years. Twenty-five (3.4%) cases were revised: 8 due to acetabular component loosening, 6 due to femoral neck facture, 4 due to failure of femoral component fixation, 2 due to deep infection, 2 due to adverse wear, 1 due to psoas tendonitis, 1 due to recurrent dislocation, and 1 due to unexplained pain. Biomet ReCap and Magnum HRA components with hybrid fixation methods showed excellent survivorship for a minimally selected young patient cohort at 7 years.


Bipolar and related disorders in DSM-5 and ICD-10.
Bipolar disorders are a group of psychiatric disorders with profound negative impact on affected patients. Even if their symptomatology has long been recognized, diagnostic criteria have changed over time and diagnosis often remains difficult. The Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), issued in May 2013, comprises several changes regarding the diagnosis of bipolar disorders compared to the previous edition. Diagnostic categories and criteria for bipolar disorders show some concordance with the internationally also widely used Tenth Edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). However, there are also major differences that are worth highlighting. The aim of the following text is to depict and discuss those.


Rivaroxaban in patients with a recent acute coronary syndrome.
Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).


The relationship between growth hormone polymorphism and growth hormone receptor genes with milk yield and reproductive performance in Holstein dairy cows.
The aim of this study was to investigate the potential association between growth hormone GH/AluI and growth hormone receptor GHR/AluI polymorphisms with milk yield and reproductive performances in Holstein dairy cows in Iran. Blood samples of 150 Holstein cows were collected and their genomic DNA was extracted using Gene-Fanavaran DNA extracting kit. Fragments of the 428 bp of exon 5 growth hormone (GH) gene and the 342 bp of exon 10 growth hormone receptor (GHR) gene were amplified using the polymerase chain reaction (PCR) method. PCR products were digested by the AluI restriction enzyme and electrophoresed on 3% agarose gel. Continuous and categorical data were analyzed using linear mixed models through Proc MIXED and logistic regression models through Proc GENMOD of SAS software, respectively. The results showed no relationship between the examined traits and GH/AluI or GHR/AluI genes. A significant relationship was found between GH/AluI polymorphism and dystocia, but the presence of the GH-L allele reduced the incidence of dystocia. The results suggest that the GH-LL genotype reduces dystocia probably by affecting the release of growth hormone; nevertheless, further studies will be needed to examine the relationship between dystocia and GH genotypes.


Using formative research with older adults to inform a community physical activity programme: Get Healthy, Get Active.
The purpose of this formative study was to explore current knowledge and attitudes towards physical activity, as well as perceived barriers, facilitators and opportunities for physical activity participation among older adults living in the community. The findings have subsequently informed the design, delivery and recruitment strategies of a local community physical activity intervention programme which forms part of Sport England's national Get Healthy, Get Active initiative. There is a growing public health concern regarding the amount of time spent in sedentary and physical activity behaviours within the older adult population. Between March and June 2016, 34 participants took part in one of six focus groups as part of a descriptive formative study. A homogenous purposive sample of 28 community dwelling white, British older adults (six male), aged 65-90 years (M=78, SD=7 years) participated in one of five focus group sessions. An additional convenience pragmatic sub-sample of six participants (three male), aged 65-90 years (M=75, SD=4 years), recruited from an assisted living retirement home participated in a sixth focus group. Questions for focus groups were structured around the PRECEDE stage of the PRECEDE-PROCEDE model of health programme design, implementation and evaluation. Questions addressed knowledge, attitudes and beliefs towards physical activity, as well as views on barriers and opportunities for physical activity participation. All data were transcribed verbatim. Thematic analysis was then conducted with outcomes represented as pen profiles. Consistent views regarding both the potential physical and psychosocial benefits of physical activity were noted regardless of living status. The themes of, opportunities and awareness for physical activity participation, cost, transport, location and season/weather varied between participants living in an assisted living retirement home and community dwelling older adults. Further comparative research on the physical activity requirements of older adults living in assisted living versus community settings are warranted.


Bioinformatic analyses revealed underlying biological functions correlated with oxaliplatin responsiveness.
Colorectal cancer is one of the most common cancers worldwide. Surgery is usually the primary treatment for colon cancers that have not spread to distant sites. However, chemotherapy may be considered after surgery to eliminate remaining cancer cells or in case the cancer has a high risk of recurrence. Oxaliplatin is often used in combination regimens such as FOLFOX, CapeOX, and FOLFOXIRI because of the cost-effectiveness of adjuvant treatment for patients and also the good tolerability profile. However, some patients show resistance to oxaliplatin which causes poor treatment outcomes. Most colon cancer studies focused on treatments and patient survival. Some studies focused on genetic associations of specific genes. However, pathway and network analyses of oxaliplatin resistance in colon cancer cells using gene expression patterns are still lacking. We performed a microarray analysis and found that endothelin-1 (EDN1), dishevelled segment polarity protein (DV1), toll-like receptor 5(TLR5), mitogen-activated protein kinase 3 (MAP2K3), phosphatidylinositol-4,5-bisphosphate 3-kinase, and catalytic subunit beta (PIK3CB) were closely related to responsiveness to oxaliplatin treatment. Furthermore, we found that the signal transduction, melanogenesis, and toll-like receptor signaling pathways might be involved in oxaliplatin-resistant colon cancer. These genes and pathways might be potential targets for improving oxaliplatin treatment in colon cancer patients.


Evolution of preprofessional pharmacy curricula.
To examine changes in preprofessional pharmacy curricular requirements and trends, and determine rationales for and implications of modifications. Prerequisite curricular requirements compiled between 2006 and 2011 from all doctor of pharmacy (PharmD) programs approved by the Accreditation Council of Pharmacy Education were reviewed to ascertain trends over the past 5 years. An online survey was conducted of 20 programs that required either 3 years of prerequisite courses or a bachelor's degree, and a random sample of 20 programs that required 2 years of prerequisites. Standardized telephone interviews were then conducted with representatives of 9 programs. In 2006, 4 programs required 3 years of prerequisite courses and none required a bachelor's degree; by 2011, these increased to 18 programs and 7 programs, respectively. Of 40 programs surveyed, responses were received from 28 (70%), 9 (32%) of which reported having increased the number of prerequisite courses since 2006. Reasons given for changes included desire to raise the level of academic achievement of students entering the PharmD program, desire to increase incoming student maturity, and desire to add clinical sciences and experiential coursework to the pharmacy curriculum. Some colleges and schools experienced a temporary decrease in applicants. The preprofessional curriculum continues to evolve, with many programs increasing the number of course prerequisites. The implications of increasing prerequisites were variable and included a perceived increase in maturity and quality of applicants and, for some schools, a temporary decrease in the number of applicants.


Inner-shell spectroscopy by the Gaussian and augmented plane wave method.
We present an approach for calculating near-edge X-ray absorption spectra at the density functional theory level, which is suited for condensed matter simulations. The method is based on the standard solution of the all-electron KS equations with a modified core-hole potential, which reproduces the relaxation of the orbitals induced by the promotion of the core electron to an unoccupied valence level. The all-electron description of the charge density is based on the Gaussian and augmented plane wave formalism. The reliability of the proposed method is assessed by comparing the computed spectra of some small molecules in the gas phase to the experimental spectra reported in literature. The sensitivity of the computed spectra to the local environment, i.e. the specific bonds formed by the absorbing atom or the presence of hydrogen bonds, open promising perspective for this technique as a predictive tool in the investigation of a more complex system of an unknown structure. The straightforward extension of the method to condensed matter is demonstrated by the calculation of the C K-edge in diamond.


Spatio-temporal pattern formation on spherical surfaces: numerical simulation and application to solid tumour growth.
In this paper we examine spatio-temporal pattern formation in reaction-diffusion systems on the surface of the unit sphere in 3D. We first generalise the usual linear stability analysis for a two-chemical system to this geometrical context. Noting the limitations of this approach (in terms of rigorous prediction of spatially heterogeneous steady-states) leads us to develop, as an alternative, a novel numerical method which can be applied to systems of any dimension with any reaction kinetics. This numerical method is based on the method of lines with spherical harmonics and uses fast Fourier transforms to expedite the computation of the reaction kinetics. Numerical experiments show that this method efficiently computes the evolution of spatial patterns and yields numerical results which coincide with those predicted by linear stability analysis when the latter is known. Using these tools, we then investigate the rĵle that pre-pattern (Turing) theory may play in the growth and development of solid tumours. The theoretical steady-state distributions of two chemicals (one a growth activating factor, the other a growth inhibitory factor) are compared with the experimentally and clinically observed spatial heterogeneity of cancer cells in small, solid spherical tumours such as multicell spheroids and carcinomas. Moreover, we suggest a number of chemicals which are known to be produced by tumour cells (autocrine growth factors), and are also known to interact with one another, as possible growth promoting and growth inhibiting factors respectively. In order to connect more concretely the numerical method to this application, we compute spatially heterogeneous patterns on the surface of a growing spherical tumour, modelled as a moving-boundary problem. The numerical results strongly support the theoretical expectations in this case. Finally in an appendix we give a brief analysis of the numerical method.


Change in medical spending attributable to diabetes: national data from 1987 to 2011.
Diabetes care has changed substantially in the past 2 decades. We examined the change in medical spending and use related to diabetes between 1987 and 2011. Using the 1987 National Medical Expenditure Survey and the Medical Expenditure Panel Surveys in 2000-2001 and 2010-2011, we compared per person medical expenditures and uses among adults ≥ 18 years of age with or without diabetes at the three time points. Types of medical services included inpatient care, emergency room (ER) visits, outpatient visits, prescription drugs, and others. We also examined the changes in unit cost, defined by the expenditure per encounter for medical services. The excess medical spending attributed to diabetes was $2,588 (95% CI, $2,265 to $3,104), $4,205 ($3,746 to $4,920), and $5,378 ($5,129 to $5,688) per person, respectively, in 1987, 2000-2001, and 2010-2011. Of the $2,790 increase, prescription medication accounted for 55%; inpatient visits accounted for 24%; outpatient visits accounted for 15%; and ER visits and other medical spending accounted for 6%. The growth in prescription medication spending was due to the increase in both the volume of use and unit cost, whereas the increase in outpatient expenditure was almost entirely driven by more visits. In contrast, the increase in inpatient and ER expenditures was caused by the rise of unit costs. In the past 2 decades, managing diabetes has become more expensive, mostly due to the higher spending on drugs. Further studies are needed to assess the cost-effectiveness of increased spending on drugs.


Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes.
Nicotine dependence is moderately heritable, but identified genetic associations explain only modest portions of this heritability. We analyzed 3369 SNPs from 349 candidate genes and investigated whether incorporation of SNP-by-environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence. Specifically, we incorporated the interaction between allele count and age at onset of regular smoking (AOS) into association analyses of nicotine dependence. Subjects were from the Collaborative Genetic Study of Nicotine Dependence and included 797 cases ascertained for Fagerström nicotine dependence and 811 non-nicotine-dependent smokers as controls, all of European descent. Compared with main effect models, SNP x AOS interaction models resulted in higher numbers of nominally significant tests, increased predictive utility at individual SNPs and higher predictive utility in a multi-locus model. Some SNPs previously documented in main effect analyses exhibited improved fits in the joint analysis, including rs16969968 from CHRNA5 and rs2314379 from MAP3K4. CHRNA5 exhibited larger effects in later-onset smokers, in contrast with a previous report that suggested the opposite interaction (Weiss et al. 2008). However, a number of SNPs that did not emerge in main effect analyses were among the strongest findings in the interaction analyses. These include SNPs located in GRIN2B (P = 1.5 x 10(-5)), which encodes a subunit of the N-methyl-D-aspartate receptor channel, a key molecule in mediating age-dependent synaptic plasticity. Incorporation of logically chosen interaction parameters, such as AOS, into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery.