Universal occurrence of the phase-flip bifurcation in time-delay coupled systems.
Recently, the phase-flip bifurcation has been described as a fundamental transition in time-delay coupled, phase-synchronized nonlinear dynamical systems. The bifurcation is characterized by a change of the synchronized dynamics from being in-phase to antiphase, or vice versa; the phase-difference between the oscillators undergoes a jump of pi as a function of the coupling strength or the time delay. This phase-flip is accompanied by discontinuous changes in the frequency of the synchronized oscillators, and in the largest negative Lyapunov exponent or its derivative. Here we illustrate the phenomenology of the bifurcation for several classes of nonlinear oscillators, in the regimes of both periodic and chaotic dynamics. We present extensive numerical simulations and compute the oscillation frequencies and the Lyapunov spectra as a function of the coupling strength. In particular, our simulations provide clear evidence of the phase-flip bifurcation in excitable laser and Fitzhugh-Nagumo neuronal models, and in diffusively coupled predator-prey models with either limit cycle or chaotic dynamics. Our analysis demonstrates marked jumps of the time-delayed and instantaneous fluxes between the two interacting oscillators across the bifurcation; this has strong implications for the performance of the system as well as for practical applications. We further construct an electronic circuit consisting of two coupled Chua oscillators and provide the first formal experimental demonstration of the bifurcation. In totality, our study demonstrates that the phase-flip phenomenon is of broad relevance and importance for a wide range of physical and natural systems.


The global spread of 2019-nCoV: a molecular evolutionary analysis.
The global spread of the 2019-nCoV is continuing and is fast moving, as indicated by the WHO raising the risk assessment to high. In this article, we provide a preliminary phylodynamic and phylogeographic analysis of this new virus. A Maximum Clade Credibility tree has been built using the 29 available whole genome sequences of 2019-nCoV and two whole genome sequences that are highly similar sequences from Bat SARS-like Coronavirus available in GeneBank. We are able to clarify the mechanism of transmission among the countries which have provided the 2019-nCoV sequence isolates from their patients. The Bayesian phylogeographic reconstruction shows that the 2019-2020 nCoV most probably originated from the Bat SARS-like Coronavirus circulating in the Rhinolophus bat family. In agreement with epidemiological observations, the most likely geographic origin of the new outbreak was the city of Wuhan, China, where 2019-nCoV time of the most recent common ancestor emerged, according to molecular clock analysis, around November 25th, 2019. These results, together with previously recorded epidemics, suggest a recurring pattern of periodical epizootic outbreaks due to Betacoronavirus. Moreover, our study describes the same population genetic dynamic underlying the SARS 2003 epidemic, and suggests the urgent need for the development of effective molecular surveillance strategies of Betacoronavirus among animals and Rhinolophus of the bat family.


Synthesis and characterization of thermoresponsive ZIF-8@PNIPAm-co-MAA microgel composites with enhanced performance as an adsorption/release platform.
Composite materials featuring a synergic combination of interesting properties such as stimuli responsiveness and tailored porosity are highly appealing due to their multiple possible applications. We hereby present an example which brings together such features by using poly(N-isopropyl-acrylamide)-derived thermo-responsive microgels and Zn-based Metal Organic Framework (MOF) ZIF-8, capable of selective adsorption. Such a composite was obtained by including methacrylic acid as a co-monomer in the microgel, in order to position carboxylic acid moieties within the polymeric matrix, which via preconcentration of MOF precursors would trigger confined heterogeneous nucleation. The highly integrated composite obtained features thermoresponsivity and permanent porosity. Methylene blue adsorption/desorption experiments were performed, revealing a dramatic enhancement of its cargo capacity together with an increased release efficiency.


International health electives: strengthening graduate medical education.
An international health elective (IHE) can be an important component of the medical education and professional development of a physician. It provides essential global health skills that are crucial in a globalized society. Graduate medical education has an opportunity to deliver such skills to our health care workforce while addressing the pending workforce shortage and the uneven distribution of primary care physicians across the United States. Currently, there is a call for graduate medical education programs to create more training sites and to undergo reform that will help fill residency slots and train more primary care physicians. The author proposes that graduate medical education programs incorporate international health electives into their accredited residency programs. This addition could potentially strengthen their programs while making them more appealing to qualified candidates.


Gene Evolutionary Trajectories and GC Patterns Driven by Recombination in Zea mays.
Recombination occurring during meiosis is critical for creating genetic variation and plays an essential role in plant evolution. In addition to creating novel gene combinations, recombination can affect genome structure through altering GC patterns. In maize (Zea mays) and other grasses, another intriguing GC pattern exists. Maize genes show a bimodal GC content distribution that has been attributed to nucleotide bias in the third, or wobble, position of the codon. Recombination may be an underlying driving force given that recombination sites are often associated with high GC content. Here we explore the relationship between recombination and genomic GC patterns by comparing GC gene content at each of the three codon positions (GC1, GC2, and GC3, collectively termed GCx) to instances of a variable GC-rich motif that underlies double strand break (DSB) hotspots and to meiocyte-specific gene expression. Surprisingly, GCx bimodality in maize cannot be fully explained by the codon wobble hypothesis. High GCx genes show a strong overlap with the DSB hotspot motif, possibly providing a mechanism for the high evolutionary rates seen in these genes. On the other hand, genes that are turned on in meiosis (early prophase I) are biased against both high GCx genes and genes with the DSB hotspot motif, possibly allowing important meiotic genes to avoid DSBs. Our data suggests a strong link between the GC-rich motif underlying DSB hotspots and high GCx genes.


Recent advances in the chemistry of organic thiocyanates.
Organic thiocyanates are important synthetic intermediates to access valuable sulfur-containing compounds. In this review the different methods for their preparation and their synthetic applications will be presented. The literature of the last 15 years will be covered, highlighting selected recent advances in the chemistry of this class of compounds. We hope to offer chemists the tools to have a good grasp of this singular functionality and open the door to further progress in this chemistry.


Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier.
Organic anion-transporting polypeptides (Oatps) are a rapidly growing gene family of polyspecific membrane transporters. In rat brain, Oatp1 (gene symbol Slc21a1) and Oatp2 (Slc21a5) are localized at the apical and basolateral domains, respectively, of the choroid plexus epithelium. Furthermore, Oatp2 is strongly expressed at the rat blood-brain barrier (BBB). This study localizes the human OATP (now called OATP-A; SLC21A3) at the BBB in humans. Furthermore, with the Xenopus laevis oocyte system the delta-opioid receptor agonists [D-penicillamine(2,5)]enkephalin (DPDPE) and deltorphin II were identified as new transport substrates of OATP-A. This OATP-A-mediated DPDPE and deltorphin II transport exhibited apparent K(m) values of approximately 202 and 330 microM, respectively, and OATP-A-mediated deltorphin II transport was inhibited by the mu-opioid receptor agonist Tyr-D-Ala-Gly-N-methyl-Phe-glycinol, the endogenous peptide Leu-enkephalin, and the opiate antagonists naloxone and naltrindole. DPDPE also was transported by rat Oatp1 (K(m) approximately 48 microM) and Oatp2 (K(m) approximately 19 microM), whereas deltorphin II was only transported by Oatp1 (K(m) approximately 137 microM). These results demonstrate that OATP-A can mediate transport of the analgesic opioid peptides DPDPE and deltorphin II across the human BBB. Furthermore, because rat Oatp1 and Oatp2 exhibit similar but not identical transport activities as OATP-A, the results generally indicate that members of the Oatp/OATP gene family of membrane transporters play an important role in carrier-mediated transport of opioid peptides across the BBB and blood-cerebrospinal fluid barrier of the mammalian brain.


Exploring the nuclear envelope of herpes simplex virus 1-infected cells by high-resolution microscopy.
Herpesviruses are composed of capsid, tegument, and envelope. Capsids assemble in the nucleus and exit the nucleus by budding at the inner nuclear membrane, acquiring tegument and the envelope. This study focuses on the changes of the nuclear envelope during herpes simplex virus 1 (HSV-1) infection in HeLa and Vero cells by employing preparation techniques at ambient and low temperatures for high-resolution scanning and transmission electron microscopy and confocal laser scanning microscopy. Cryo-field emission scanning electron microscopy of freeze-fractured cells showed for the first time budding of capsids at the nuclear envelope at the third dimension with high activity at 10 h and low activity at 15 h of incubation. The mean number of pores was significantly lower, and the mean interpore distance and the mean interpore area were significantly larger than those for mock-infected cells 15 h after inoculation. Forty-five percent of nuclear pores in HSV-1-infected cells were dilated to more than 140 nm. Nuclear material containing capsids protrude through them into the cytoplasm. Examination of in situ preparations after dry fracturing revealed significant enlargements of the nuclear pore diameter and of the nuclear pore central channel in HSV-1-infected cells compared to mock-infected cells. The demonstration of nucleoporins by confocal microscopy also revealed fewer pores but focal enhancement of fluorescence signals in HSV-1-infected cells, whereas Western blots showed no loss of nucleoporins from cells. The data suggest that infection with HSV-1 alters the number, size, and architecture of nuclear pores without a loss of nucleoporins from altered nuclear pore complexes.


A New Approach to Investigate the Association between Brain Functional Connectivity and Disease Characteristics of Attention-Deficit/Hyperactivity Disorder: Topological Neuroimaging Data Analysis.
Attention-deficit/hyperactivity disorder (ADHD) is currently diagnosed by a diagnostic interview, mainly based on subjective reports from parents or teachers. It is necessary to develop methods that rely on objectively measureable neurobiological data to assess brain-behavior relationship in patients with ADHD. We investigated the application of a topological data analysis tool, Mapper, to analyze the brain functional connectivity data from ADHD patients. To quantify the disease severity using the neuroimaging data, the decomposition of individual functional networks into normal and disease components by the healthy state model (HSM) was performed, and the magnitude of the disease component (MDC) was computed. Topological data analysis using Mapper was performed to distinguish children with ADHD (n = 196) from typically developing controls (TDC) (n = 214). In the topological data analysis, the partial clustering results of patients with ADHD and normal subjects were shown in a chain-like graph. In the correlation analysis, the MDC showed a significant increase with lower intelligence scores in TDC. We also found that the rates of comorbidity in ADHD significantly increased when the deviation of the functional connectivity from HSM was large. In addition, a significant correlation between ADHD symptom severity and MDC was found in part of the dataset. The application of HSM and topological data analysis methods in assessing the brain functional connectivity seem to be promising tools to quantify ADHD symptom severity and to reveal the hidden relationship between clinical phenotypic variables and brain connectivity.


An iron triangle ROI model for health care.
Few, if any, return on investment (ROI) analyses of health programs make systematic considerations of patient access, instead focusing principally on gains related to cost and quality. The objective of this study was to develop an open-source model that adds an estimation of gains in patient access to a traditional ROI analysis. A classification system for quantifying gains in patient access is proposed. An Excel-based ROI model was built that not only incorporated traditional ROI considerations - cost savings and patient cases avoided - but also addressed changes in patient access. The model was then applied in a case study using New Mexico Medicaid data and two proposed initiatives - a statewide health information exchange (HIE) and a community health worker (CHW) program that focused on chronic disease patients. Savings, Health, Outreach, and Access estimates were derived from the literature. ROI estimates were produced that also incorporated relative gains in patient access. Combined, the HIE and CHW programs are predicted to generate a positive ROI by the fourth year, growing to 45% by the program's tenth year. Total estimated cumulative cost for both programs after 10 years is $9,555,226. Total estimated cumulative saving for both programs after 10 years is $11,332,899. Access-related costs begin moderately in year 1 at $122,766 and grow to $1,858,274 by year 10. The model estimates an Access score of 19 in year 1. This figure grew to 380 by year 10. Our model shows that a rough estimation of gains in to patient access can be incorporated to traditional ROI analyses. The results of our case study suggest that a CHW program and statewide HIE can generate a positive ROI for the state's Medicaid program.


Induction of lung cancer cell apoptosis through a p53 pathway by [6]-shogaol and its cysteine-conjugated metabolite M2.
Dietary chemoprevention of cancer offers the possibility to suppress or inhibit cancer growth before it develops into more advanced and lethal stages. To this end, identification of novel compounds and their mechanisms of action is constantly needed. In this study, we describe that a major component of dry ginger (Zingiber officinalis), [6]-shogaol (6S), can be quickly metabolized in A549 human lung cancer cell line. One of the resulting metabolites, the cysteine-conjugated 6S (M2), exhibits toxicity to cancer cells similar to the parent compound 6S, but is relatively less toxic toward normal cells than 6S. We further demonstrate that both compounds can cause cancer cell death by activating the mitochondrial apoptotic pathway. Our results show that the cancer cell toxicity is initiated by early modulation of glutathione (GSH) intracellular content. The subsequently generated oxidative stress activates a p53 pathway that ultimately leads to the release of mitochondria-associated apoptotic molecules such as cytochrome C, and cleaved caspases 3 and 9. In a xenograft nude mouse model, a dose of 30 mg/kg of 6S or M2 was able to significantly decrease tumor burden, without any associated toxicity to the animals. This effect was correlated with an induction of apoptosis and reduction of cell proliferation in the tumor tissues. Taken together, our results show that 6S metabolism is an integral part of its anticancer activities in vitro and in vivo. This allows us to characterize M2 as a novel compound with superior in vivo chemopreventive properties that targets similar anticancer mechanisms as 6S.


Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain.
The motor neuron disease spinal muscular atrophy (SMA) is caused by recessive, loss-of-function mutations of the survival motor neuron 1 gene (SMN1). Alone, such mutations are embryonically lethal, but SMA patients retain a paralog gene, SMN2, that undergoes alternative pre-mRNA splicing, producing low levels of SMN protein. By mechanisms that are not well understood, reduced expression of the ubiquitously expressed SMN protein causes an early-onset motor neuron disease that often results in infantile or childhood mortality. Recently, striking clinical improvements have resulted from two novel treatment strategies to increase SMN protein by (a) modulating the splicing of existing SMN2 pre-mRNAs using antisense oligonucleotides, and (b) transducing motor neurons with self-complementary adeno-associated virus 9 (scAAV9) expressing exogenous SMN1 cDNA. We review the recently published clinical trial results and discuss the differing administration, tissue targeting, and potential toxicities of these two therapies. We also focus on the challenges that remain, emphasizing the many clinical and biologic questions that remain open. Answers to these questions will enable further optimization of these remarkable SMA treatments as well as provide insights that may well be useful in application of these therapeutic platforms to other diseases.


Olfactory repeated discrimination reversal in rats: effects of chlordiazepoxide, dizocilpine, and morphine.
Effects of a benzodiazepine (chlordiazepoxide), an N-methyl-D-aspartate receptor antagonist (dizocilpine), and an opiate agonist (morphine) were studied with a procedure designed to assess effects of drugs and other manipulations on nonspatial learning in rats. In each session, rats were exposed to 2 different 2-choice odor-discrimination problems with food reinforcement for correct responses. One problem (performance discrimination) remained the same throughout the study. That is, 1 odor was always correct (S+) and the other was never correct (S-). For the other problem (reversal discrimination), stimuli changed every session. Six different odors were used to program the reversal discrimination; on any given session, S+ was a stimulus that had served as S- the last time it had appeared, S- was a stimulus that had been S+ on its last appearance. Thus, in each session, learning a discrimination reversal could be studied along with the performance of a comparable, but previously learned, discrimination. Chlordiazepoxide interfered with reversal learning at doses that had no effect on the performance discrimination. Morphine and dizocilpine also impaired reversal learning but only at doses that also affected performance of the well-learned performance discrimination.


Drug cessation in complex older adults: time for action.
general opinion is growing that drug cessation in complex older patients is warranted in certain situations. From a clinical viewpoint, drug cessation seems most warranted in four situations, i.e., falls, delirium, cognitive impairment and end-of-life situations. To date, little information about the effects of drug cessation in these four situations is available. to identify the effects and effectiveness of drug cessation on falls, delirium and cognitive impairment. For end-of-life situations, we reviewed cessation of inappropriate drug use. electronic databases were searched using MeSH terms and relevant keywords. Studies published in English were included if they evaluated the effects of drug cessation in older persons, aged ≥65 years, with falls, delirium or cognitive impairment; or cessation of inappropriate drug use in end-of-life situations. we selected seven articles for falls, none for delirium, two for cognition and two for end-of-life situations. Withdrawal of psychotropics reduced fall rate; a prescribing modification programme for primary care physicians reduced fall risk. Withdrawal of psychotropics and a systematic reduction of polypharmacy resulted in an improvement of cognition. Very little rigorous research has been conducted on reducing inappropriate medications in patients approaching end of life. little research has focussed on drug cessation. Available studies showed a beneficial impact of cessation of psychotropic drugs on falls and cognitive status. More research in this field is needed. The issue of systematic drug withdrawal in end-of-life cases is controversial, but is increasingly relevant in the face of rising numbers of older people of this clinical status.


Association between air pollution and risk of vascular dementia: A multipollutant analysis in Taiwan.
Evidence regarding the association of specific air pollutants with vascular dementia (VaD) risk is limited. In this nested case-control study, we enrolled 831 adults aged >65 years with VaD (International Classification of Diseases, Ninth Revision, Clinical Modification code 290.4x) newly diagnosed during 2005-2013; 3324 controls were age-, sex-, and VaD diagnosis year-matched with the study patients. Both patients with VaD and controls were selected from among a cohort of one million beneficiaries of Taiwan's National Health Insurance program, all of whom were registered in 2005. Exposure to the mean daily air pollutant concentration, derived from 76 fixed air quality monitoring stations, in 3, 5, and 7 years before VaD diagnosis was assessed using the spatial analysis method (i.e., ordinary kriging) on ArcGIS. A logistic regression model was used to calculate covariate-adjusted odds ratios (ORs) of VaD in relation to specific air pollutants. After potential confounders and other air pollutants were controlled for, high concentrations of coarse particulate matter (10 µm or less in diameter) and carbon monoxide (CO) were sporadically associated with higher OR of VaD. The most prominent association was observed for nitrogen dioxide (NO2) exposure within 5 and 7 years before diagnosis. Compared with the <25th percentile of NO2 exposure, the 25th-50th, 50th-75th, and >75th percentiles of NO2 exposure significantly increased ORs (95% confidence intervals): 1.62 (1.28-2.23), 1.61 (1.11-2.33), and 2.22 (1.35-3.65) within 5 years before diagnosis, respectively, and 1.59 (1.20-2.11), 1.65 (1.15-2.37), and 2.05 (1.28-3.28) within 7 years before diagnosis, respectively. We found that higher NO2 exposure in the past was significantly associated with an elevated risk of VaD. Although less consistent, higher exposure to CO was also associated with a higher risk of VaD. Most NO2 in cities originates from motor vehicle exhaust; other sources of NO2 are petrol and metal refining, electricity generation from coal-fired power stations, other manufacturing industries, and food processing. Future studies should investigate associations of VaD with specific sources of NO2.


Effects of hop extracts on nasal rubbing and sneezing in BALB/c mice.
The effects of hop extracts (Humulus lupulus L.) on histamine release from rat peritoneal mast cells and human basophilic KU812 cells were studied. Hop water extract (HWE) and XAD-4 50% methanol fraction of HWE (MFH) inhibited histamine release from rat mast cells induced by compound 48/80 at concentrations of 100 and 10 mug/ml, respectively. Almost the same findings were observed with A23187-induced histamine release from KU812 cells. Next, we studied the effects of hop extracts on antigen-induced nasal rubbing and sneezing in sensitized BALB/c mice. HWE caused a significant inhibition of nasal rubbing and sneezing at a dose of 500 mg/kg. MFH also inhibited nasal rubbing and sneezing dose-dependently. A significant difference was observed from 100 mg/kg in nasal rubbing and 200 mg/kg in sneezing. The effects of both extracts became clear after repeated administration. HWE and MFH significantly inhibited both nasal rubbing and sneezing, respectively, after consecutive treatment for 15 d at smaller doses compared with single administration. This finding indicates that the active component of hop is included in MFH, which was absorbed to Amberlite XAD-4 and eluted with 50% methanol. These results clearly demonstrated that hop extracts may be effective in the relief of symptoms of allergic rhinitis.


Drug delivery options to increase patient adherence and satisfaction in the management of rheumatoid arthritis -- focus on subcutaneous tocilizumab.
Rheumatoid arthritis (RA) is a chronic, progressive, inflammatory disease associated with joint destruction. Tocilizumab (TCZ) is a humanized monoclonal anti-interleukin-6 receptor antibody that was initially developed for use as an intravenous (IV) infusion. Previous studies have shown that TCZ-IV is an important treatment option in patients with moderate-to-severe RA. A subcutaneous (SC) formulation of 162 mg TCZ that was recently developed and approved provides an additional treatment option for RA patients. In the present review, we provide an update on the efficacy and safety of TCZ-SC, compared with TCZ-IV. The TCZ-SC doses of 162 mg every 2 weeks (q2w) or weekly (qw) were selected based on pharmacokinetic and pharmacodynamic studies. Both TCZ-SC q2w and qw regimens showed equivalent effects to TCZ-IV in most patients; however, the TCZ-SC qw regimen consistently showed a more rapid effect in terms of C-reactive protein normalization. Randomized controlled studies showed that TCZ-SC monotherapy or combined with disease-modifying antirheumatic drugs demonstrated comparable efficacy to TCZ-IV in patients who were both biologic-naïve and refractory to tumor necrosis factor inhibitors. TCZ-SC at both qw and q2w were generally well-tolerated for up to 24 weeks. There was a low rate of withdrawal due to adverse events, and their incidence was comparable with that seen with TCZ-IV. An injection site reaction was seen in approximately 10% of patients who received the subcutaneous formulation. In conclusion, although clinical results are still limited, the currently available evidence suggests that TCZ-SC is a promising treatment for moderate-to-severe RA, both as monotherapy and combination therapy. More data is needed to determine the optimal dosing schedule.


Older People's Descriptions of Their Engagement in Fall Prevention.
Evidence-based strategies to decrease fall rates are well established. However, little is understood about how older people engage in fall prevention strategies. Motivational Interviewing (MI) sessions aimed to facilitate individuals' engagement in fall prevention can be analyzed to learn what it means for older people to engage in fall prevention. Thus, the purpose of this study was to explore how older people describe their engagement in fall prevention. Participants in our parent project, MI for Fall Prevention (MI-FP), who received MI sessions were purposively selected for maximum variation in age, sex, fall risks, and MI specialist assigned. The first (of 8) MI sessions from 16 participants were recorded, transcribed, and analyzed using qualitative content analysis. Three researchers first deductively analyzed fall prevention strategies that participants described using an evidence-based fall prevention guideline as a reference. Then, we inductively analyzed the characteristics of these strategies and how participants engaged in them. Finally, we used the Capability, Opportunity, Motivation, Behavior (COM-B) model to organize our results about factors influencing engagement. We found (1) older adults engage in unique combinations of fall prevention strategies and (2) decisions about engagement in fall prevention strategies were influenced by multiple factors that were personal (e.g., who I am, capability, motivation, and opportunities). This study highlighted how fall prevention can be a life-long lifestyle decision for older people. Understanding older people's perspectives about engaging in fall prevention is essential to develop interventions to promote evidence-based fall prevention strategies in real-world settings.


Systematic review of knowledge of, attitudes towards, and practices for newborn hearing screening among healthcare professionals.
The success of newborn hearing screening programs lies in the timely identification, diagnosis, and management of children with hearing loss accomplished via a multidisciplinary newborn hearing screening (NHS) team. The team is typically comprised of various healthcare professionals who act as decision makers as well as facilitators for different stages in the screening process. Team members' knowledge of, attitudes towards, and practices for early hearing detection and intervention programs are critical for success and prevention of loss to follow up. In this context, it becomes crucial to understand their knowledge of, attitudes towards, and practices for towards newborn hearing screening. A systematic review was conducted on the following databases; PubMed/Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science, Science Direct and Cochrane Library. This search was carried out using various keywords such as practitioners, newborn hearing screening, knowledge, attitudes, and practices in different combinations. The review was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guidelines. A total of 271 hits were obtained of which 20 articles were found suitable for inclusion in the final review. Overall, similar results were found regarding team members' knowledge of NHS programs, regardless of country of origin. Similarly, attitudes toward NHS programs were positive. Team members' experiences with NHS programs varied from country-to-country and across healthcare professionals. Results consistently showed gaps in team members' knowledge suggesting the need for outreach and professional education programs on NHS. NHS teams members from different countries, healthcare systems, and early hearing detection and intervention programs show gaps in critical knowledge warranting outreach and educational programs.


Asymmetric perceptual confounds between canonical lightings and materials.
To better understand the interactions between material perception and light perception, we further developed our material probe MatMix 1.0 into MixIM 1.0, which allows optical mixing of canonical lighting modes. We selected three canonical lighting modes (ambient, focus, and brilliance) and created scenes to represent the three illuminations. Together with four canonical material modes (matte, velvety, specular, glittery), this resulted in 12 basis images (the "bird set"). These images were optically mixed in our probing method. Three experiments were conducted with different groups of observers. In Experiment 1, observers were instructed to manipulate MixIM 1.0 and match optically mixed lighting modes while discounting the materials. In Experiment 2, observers were shown a pair of stimuli and instructed to simultaneously judge whether the materials and lightings were the same or different in a four-category discrimination task. In Experiment 3, observers performed both the matching and discrimination tasks in which only the ambient and focus light were implemented. Overall, the matching and discrimination results were comparable as (a) robust asymmetric perceptual confounds were found and confirmed in both types of tasks, (b) performances were consistent and all above chance levels, and (c) observers had higher sensitivities to our canonical materials than to our canonical lightings. The latter result may be explained in terms of a generic insensitivity for naturally occurring variations in light conditions. Our findings suggest that midlevel image features are more robust across different materials than across different lightings and, thus, more diagnostic for materials than for lightings, causing the asymmetric perceptual confounds.


PROPERTIES OF THE CAUSATIVE AGENT OF A CHICKEN TUMOR : II. THE INACTIVATION OF THE TUMOR-PRODUCING AGENT BY MONOCHROMATIC ULTRA-VIOLET LIGHT.
Even though part of the energy of the incident light is probably absorbed by chemical entities which play no part in the specific reaction of inactivation, nevertheless the wave lengths most active in destroying biological cells or agents will presumably be found to be among those absorbed in the highest proportion. This would indicate that the curves here presented are approximately reciprocal to the coefficients of absorption of particular substances, the destruction of which caused the inactivation of the agents or the death of the cells. The similarity between the curves for bacteria, virus, and phage, both in shape and in total involved energies, suggests the presence of a common factor, or of closely related chemical entities, sensitive to ultra-violet light, whereas the data for the tumor agent suggest that its inactivation is due to the destruction of a substance having an essentially different spectral absorption, and therefore of a different chemical character. While the amount of ultra-violet energy required to affect the tumor agent is great, it is still less than that involved in the inactivation of some of the enzymes (7). A study is under way to compare the deduced spectral analysis with the actual coefficients of absorption of the highly purified tumor agent.


Resistance, remission, and qualitative differences in HIV chemotherapy.
To understand the role of qualitative differences in multidrug chemotherapy for human immunodeficiency virus (HIV) infection in virus remission and drug resistance, we designed a mathematical system that models HIV multidrug chemotherapy including uninfected CD4+ T cells, infected CD4+ T cells, and virus populations. The model, which includes the latent and progressive stages of the disease and introduces chemotherapy, is a system of differential equations describing the interaction of two distinct classes of HIV (drug-sensitive [wild type] and drug-resistant [mutant]) with lymphocytes in the peripheral blood; the external lymphoid system contributes to the viral load. The simulations indicate that to preclude resistance, antiviral drugs must be strong enough and act fast enough to drive the viral population below a threshold level. The threshold depends upon the capacity of the virus to mutate to strains resistant to the drugs. Above the threshold, mutant strains rapidly replace wild-type strains. Below the threshold, resistant strains do not become established, and remission occurs. An important distinction between resistance and remission is the reduction of viral production in the external lymphoid system. Also the virus population rapidly rebounds when treatment is stopped even after extended periods of remission.


Predictors of emergency contraceptive use among regular female students at Adama University, Central Ethiopia.
One of the key interventions to reduce unintended pregnancy and unsafe abortion outlined in the national youth strategy is availability of emergency contraception. However, there are no studies which document emergency contraception use and the factors influencing the use of emergency contraceptives among university girls in Ethiopia. This study was carried out to assess emergency contraception use and its predictor factors among regular female students at Adama University. A cross-sectional study was conducted during the month of February 2009, among randomly selected 660 female students of Adama University Central Ethiopia. Data were collected through pre-tested self-administered questionnaire. Bivariate and multivariable logistic regression models were fitted to identify variables predicting emergency contraception use. One hundred ninety four (29.4%) students were sexually active and 63 (9.4%) had a previous history of pregnancy. And most of the pregnancies (92%) were unintended. Majority (77.7%) of pregnancies were terminated by way of induced abortions carried out by untrained persons. Only 26.7% of those who had unprotected sex used emergency contraception. Lack of knowledge, fear of being seen by others, and inconvenient service delivery were pointed out as the main reasons for not using emergency contraceptives. Previous use of contraceptives (AOR: 1.953; 95% CI = 1.72- 6.345), being married (AOR: 9.254; 95% CI = 2.538-20.73) and age of 20 years and above (AOR: 2.372; 95% CI = 1.102-7.246) were significant predictors use of emergency contraception, while poor knowledge of emergency contraception was a significant predictor of non-use of emergency contraception (AOR: 0.09; 95% CI = 0.041-0.189). The study pointed out the need for increasing the knowledge of university-going young women about emergency contraception, and the need for availing youth friendly reproductive health services to promote preventive behavior.


Data Resource Profile: The European Union Statistics on Income and Living Conditions (EU-SILC).
Social and economic policies are inextricably linked with population health outcomes in Europe, yet few datasets are able to fully explore and compare this relationship across European countries. The European Union Statistics on Income and Living Conditions (EU-SILC) survey aims to address this gap using microdata on income, living conditions and health. EU-SILC contains both cross-sectional and longitudinal elements, with nationally representative samples of individuals 16 years and older in 28 European Union member states as well as Iceland, Norway and Switzerland. Data collection began in 2003 in Belgium, Denmark, Ireland, Greece, Luxembourg and Austria, with subsequent expansion across Europe. By 2011, all 28 EU member states, plus three others, were included in the dataset. Although EU-SILC is administered by Eurostat, the data are output-harmonized so that countries are required to collect specified data items but are free to determine sampling strategies for data collection purposes. EU-SILC covers approximately 500,000 European residents for its cross-sectional survey annually. Whereas aggregated data from EU-SILC are publicly available [http://ec.europa.eu/eurostat/web/income-and-living-conditions/data/main-tables], microdata are only available to research organizations subject to approval by Eurostat. Please refer to [http://epp.eurostat.ec.europa.eu/portal/page/portal/microdata/eu_silc] for further information regarding microdata access.


Unscheduled Procedural Sedation: A Multidisciplinary Consensus Practice Guideline.
The American College of Emergency Physicians (ACEP) organized a multidisciplinary effort to create a clinical practice guideline specific to unscheduled, time-sensitive procedural sedation, which differs in important ways from scheduled, elective procedural sedation. The purpose of this guideline is to serve as a resource for practitioners who perform unscheduled procedural sedation regardless of location or patient age. This document outlines the underlying background and rationale, and issues relating to staffing, practice, and quality improvement.


Chemotherapy with or without low-dose interleukin-2 in advanced non-small cell lung cancer: results from a phase III randomized multicentric trial.
Non-small cell lung cancer (NSCLC) is associated with IL-2-dependent cell-mediated immunodeficiency. As IL-2 is the main lymphocyte growth factor, a phase III randomized multicenter trial was conducted to evaluate the impact of subcutaneous low-dose IL-2 added to standard chemotherapy (CT) on overall survival (OS) in advanced NSCLC patients. Patients (n=241) with histologically confirmed stage IIIb or IV non-operable NSCLC underwent stratified randomization on the basis of center, ECOG PS, stage of disease and percentage of weight loss. Patients received gemcitabine (1000 mg/m2) on days 1 and 8 + cisplatin (100 mg/m2) on day 2 every 21 days for a maximum of 6 cycles [chemotherapy (CT) arm]. In the CT+IL-2 arm, patients also received low-dose subcutaneous IL-2 3,000,000 IU/die on days 3-5, 9-11, 15-17. The study had 90% power to detect a 20% absolute increase in 1-year OS with 118 patients/arm. An overall response (OR) rate of 12.8% (14% in the CT+IL-2 arm and 11.4% in CT arm) was observed. Stable disease was 70 and 66.7%, and progressive disease 16 and 21.8% in the CT+IL-2 and CT arms, respectively. No differences in response were found in any subgroup analysis. At a median follow-up of 32 months, 1-year OS was 45% for the CT+IL-2 arm vs. 51% for the CT arm (p=0.456 log-rank). Median progression-free survival was 6.6 months in the CT+IL-2 arm vs. 6.9 months in the CT arm (p=0.573, log-rank). A higher number of grade 4 toxicities were reported with CT+IL-2. The most common grade ≥3 adverse events were gastrointestinal toxicity (mainly nausea and diarrhea) and myelosuppression. No relevant differences in clinical outcome were observed from the addition of IL-2 to CT. Future studies investigating the role of T-regulators in chemoimmunotherapeutic regimens could be performed.


That was a game changer: clinical impact of an emergency department-based palliative care communication skills training workshop.
To explore the impact of an adapted goals-of-care communications skills workshop created for ED physicians from the physicians' perspective. Semi-structured, one-on-one audio-recorded interviews lasting 30-60 min were conducted with twelve physicians who had completed the training workshop. Interviews explored the experience of undertaking the workshop, its impact on their clinical practice and their ability to teach new skills to other clinicians using learnt techniques. Descriptive content analysis was performed on interview transcripts. Participants reported positive experiences of the workshop. The analysis identified four main themes and ten subthemes dealing with workshop content and its impact on subsequent ED-based clinical practice. There were: 1) value and future improvements for the course; 2) value of the course to practice; 3) value of the course for teaching residents and 4) barriers to application of learning. Specifically recommended components include the use of mnemonics, mechanisms to introduce difficult conversations and a positive feedback environment. Participant-recommended refinements to the workshop included emphasising urgency, replicating the chaotic ED environment and expanding content to include more ED-focused goals-of-care discussions. A short, focused training workshop directed at improving palliative care communication skills among ED clinicians appears to be welcomed and useful.


Loss of expression of the Hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells.
The homeobox gene Hoxa-9 is normally expressed in primitive bone marrow cells, and overexpression of Hoxa-9 markedly expands hematopoietic stem cells, suggesting a function in early hematopoiesis. We present evidence for major functional defects in Hoxa-9-/- hematopoietic stem cells. Hoxa-9-/- marrow cells have normal numbers of immunophenotypic stem cells (Lin(-)c-kit(+)flk-2(-)Sca-1+ [KLFS] cells). However, sublethally irradiated Hoxa-9-/- mice develop persistent pancytopenia, indicating unusual sensitivity to ionizing irradiation. In competitive transplantation assays, Hoxa-9-/- cells showed an 8-fold reduction in multilineage long-term repopulating ability, a defect not seen in marrow cells deficient for the adjacent Hoxa-10 gene. Single-cell cultures of KLFS cells showed a 4-fold reduction in large high-proliferation potential colonies. In liquid cultures, Hoxa-9-deficient Lin(-)Sca-1(+) cells showed slowed proliferation (a 5-fold reduction in cell numbers at day 8) and delayed emergence of committed progenitors (a 5-fold decrease in colony-forming cells). Slowing of proliferation was accompanied by a delay in myeloid maturation, with a decrease in Gr-1hiMac-1hi cells at the end of the culture. Retroviral transduction with a Hoxa-9 expression vector dramatically enhanced the cytokine-driven proliferation and in vivo engraftment of Hoxa-9-/- marrow cells. Hoxa-9 appears to be specifically required for normal hematopoietic stem cell function both in vitro and in vivo.


The impact of marine recreational fishing on key fish stocks in European waters.
Marine recreational fishing (MRF) has been shown to substantially contribute to fishing mortality of marine fish. However, European MRF catches are only quantified for a small number of stocks, so it is unclear whether a significant part of fishing mortality is excluded from stock assessments. This study estimated: (i) European MRF removals, which were defined as landings plus dead releases; and (ii) impact at stock level by comparing the percentage contribution to total removal by MRF and commercial fishing. As MRF data were limited for some European countries, catches were reconstructed using a mixture of average release proportions, average fish weights, and extrapolation using the catch per fisher of the nearest country providing catch estimates. Where catch reconstructions exceeded 50%, data were excluded from further analysis. Furthermore, as MRF survey methodology can be variable, semi-quantitative estimates of bias and error were calculated for each stock. Only 10 of the 20 stocks assessed in this study had sufficient MRF data for full reliable estimates. Percentage contribution to total removals (MRF + commercial removals) by MRF ranged between 2% for Atlantic mackerel in the North Sea and Skagerrak and 43% for Atlantic pollack in the Celtic Seas and English Channel. The biomass removed ranged between 297 (± 116) tonnes (Atlantic cod in the western English Channel and southern Celtic seas) and 4820 (± 1889) tonnes (Atlantic mackerel in the North Sea and Skagerrak), but the errors were substantial. Additionally, the bias in the estimated removals was low for most stocks, with some positive biases found. The present study indicates that removals by MRF can represent a high proportion of the total removals for some European marine fish stocks, so inclusion in stock assessments should be routine. To achieve this, regular surveys of MRF are required to collect data essential for stock assessments.


Evidential value of polymeric materials-chemometric tactics for spectral data compression combined with likelihood ratio approach.
Polymers have become a ubiquitous element of our culture. Therefore, these materials may play an important role in forensic investigations, serving as mute witnesses of occurrences such as car accidents. In this study, the possibilities provided by the likelihood ratio (LR) approach to estimate the evidential value of observed similarities and differences, and to discriminate among NIR spectral data originating from polypropylene automotive parts and household items, were investigated. Since the construction of LR models requires the introduction of only a few variables, the main objective was to reduce the dimensionality of registered spectra, which are characterised by over a thousand variables. The applied strategy was based on compression of NIR signals using discrete wavelet transform (DWT) followed by use of the SELECT algorithm for the selection and decorrelation of the most informative DWT coefficients. Selected features eventually served as an input for LR models. The performance of the developed models was assessed by measuring the rates of false positive and false negative answers as well as by applying an empirical cross entropy approach. Despite relatively small databases of polymeric objects, both univariate and multivariate LR models showed acceptable performances. The latter, however, gave the most satisfactory results, as it enabled successful discrimination of compared samples and delivered the lowest error rates. In addition, in order to verify the potential of NIR spectroscopy, the obtained results were compared with those obtained after application of the proposed tactics to the FTIR data, which is a well-established method in the forensic sphere.


Durations of unitary synaptic potentials help time a behavioral sequence.
Recordings in identified neurons and muscles that mediate crayfish tailflips reveal inhibitory postsynaptic potentials of two distinct durations. Those of long duration are recorded in five classes of cells in the flexion circuit, while those of short duration are recorded in three classes of cells in the extension circuit. The durations of the inhibitory postsynaptic potentials are matched to the durations of inhibition required by the different phases of the behavior.


Resveratrol inhibits cell cycle progression in U937 cells.
Resveratrol, a naturally occurring stylbene present in grapes, is proposed to be responsible for the positive effects of red wine consumption on cardiovascular diseases (French paradox). In recent years this molecule has also been proposed as a cancer chemopreventive agent. The aim of the present study was to investigate the mechanisms by which resveratrol inhibits tumor growth. For this purpose, U937 cells were exposed to resveratrol at concentrations usually present in red wine, and the effects on proliferation, death and cell cycle machinery were assessed. The U937 cell growth was impaired due to reduced cell proliferation, without significant induction of apoptosis. This anti-proliferative effect is associated with modulations in the pattern of DNA distribution, with a reduction of G0/G1, particularly G2-M peaks and accumulation in the S phase of the cell cycle. This result was confirmed by the observation that the rate of [3H]-thymidine incorporation into DNA was significantly reduced in resveratrol-treated U937 cells. Consistent with this observation, in the same experimental conditions, the activity of ribonucleotide reductase, an enzyme critically involved in the process of DNA duplication, decreased. The altered progression in the cell cycle could depend on modulations in the activity of cyclin dependent kinases and their inhibitors. After exposure of U937 cultures to resveratrol, the expression of cyclins A and E, as well as that of CDK2 increased, while that of p21CIP was significantly reduced. The data shown in this report suggests that the prevention of cancer development exerted by resveratrol may result from modulations of molecules involved in the regulation of cell cycle progression, which block the cells at the S phase checkpoint.


Perennial growth of hermatypic corals at Rottnest Island, Western Australia (32°S).
To assess the viability of high latitude environments as coral refugia, we report measurements of seasonal changes in seawater parameters (temperature, light, and carbonate chemistry) together with calcification rates for two coral species, Acropora yongei and Pocillopora damicornis from the southernmost geographical limit of these species at Salmon Bay, Rottnest Island (32°S) in Western Australia. Changes in buoyant weight were normalised to colony surface areas as determined from both X-ray computed tomography and geometric estimation. Extension rates for A. yongei averaged 51 ± 4 mm y(-1) and were comparable to rates reported for Acroporid coral at other tropical and high latitude locations. Mean rates of calcification for both A. yongei and P. damicornis in winter were comparable to both the preceding and following summers despite a mean seasonal temperature range of ∼6 °C (18.2°-24.3 °C) and more than two-fold changes in the intensity of downwelling light. Seasonal calcification rates for A. yongei (1.31-2.02 mg CaCO3 cm(-2) d(-1)) and P. damicornis (0.34-0.90 mg CaCO3 cm(-2) d(-1)) at Salmon Bay, Rottnest Island were comparable to rates from similar taxa in more tropical environments; however, they appeared to decline sharply once summer temperatures exceeded 23 °C. A coral bleaching event observed in December 2013 provided further evidence of how coral at Rottnest Island are still vulnerable to the deleterious effects of episodic warming despite its high latitude location. Thus, while corals at Rottnest Island can sustain robust year-round rates of coral growth, even over cool winter temperatures of 18°-19 °C, there may be limits on the extent that such environments can provide refuge against the longer term impacts of anthropogenic climate change.


Automatic brachytherapy seed placement under MRI guidance.
The paper presents a robotic method of performing low dose rate prostate brachytherapy under magnetic resonance imaging (MRI) guidance. The design and operation of a fully automated MR compatible seed injector is presented. This is used with the MrBot robot for transperineal percutaneous prostate access. A new image-registration marker and algorithms are also presented. The system is integrated and tested with a 3T MRI scanner. Tests compare three different registration methods, assess the precision of performing automated seed deployment, and use the seeds to assess the accuracy of needle targeting under image guidance. Under the ideal conditions of the in vitro experiments, results show outstanding image-guided needle and seed placement accuracy.


Nanoparticulate drug delivery platforms for advancing bone infection therapies.
The ongoing surge of resistance of bacterial pathogens to antibiotic therapies and the consistently aging median member of the human race signal an impending increase in the incidence of chronic bone infection. Nanotechnological platforms for local and sustained delivery of therapeutics hold the greatest potential for providing minimally invasive and maximally regenerative therapies for this rare but persistent condition. Shortcomings of the clinically available treatment options, including poly(methyl methacrylate) beads and calcium sulfate cements, are discussed and their transcending using calcium-phosphate/polymeric nanoparticulate composites is foreseen. Bone is a composite wherein the weakness of each component alone is compensated for by the strength of its complement and an ideal bone substitute should be fundamentally the same. Discrepancy between in vitro and in vivo bioactivity assessments is highlighted, alongside the inherent imperfectness of the former. Challenges entailing the cross-disciplinary nature of engineering a new generation of drug delivery vehicles are delineated and it is concluded that the future for the nanoparticulate therapeutic carriers belongs to multifunctional, synergistic and theranostic composites capable of simultaneously targeting, monitoring and treating internal organismic disturbances in a smart, feedback fashion and in direct response to the demands of the local environment.


Optimized synthesis of π-extended squaraine dyes relevant to organic electronics by direct (hetero)arylation and Sonogashira coupling reactions.
This study reports on the synthesis and characterization of four molecular π-extended squaraine compounds relevant to the field of organic electronics. The compounds each consist of a bis-indole squaraine core end-capped with indoloquinoxaline units employing three different bridging units, namely thiophene, thiazole, and acetylene. Compound 10 bears a thiophene bridge, 11 consists of a thiophene bridge and fluorinated indoloquinoxaline terminal units, and compounds 12 and 13 are bridged by thiazole and acetylene, respectively. The final compounds are constructed using the atom economical direct (hetero)arylation or the classic Sonogashira carbon-carbon bond formation protocols. Each carbon-carbon bond forming reaction employing thiophene bridges (i.e. synthesis of compounds 10 and 11) has been optimized using the stable and reusable silica supported Pd catalyst, SiliaCat® DPP-Pd, streamlining the synthetic procedure. While compounds 12 and 13 were also accessible using the SiliaCat® DPP-Pd catalyst, the use of Herrmann-Beller and Pd(PPh3)4 catalysts, respectively, lead to improved isolated yields of the final materials. Compounds 10-13 were characterized by thermal gravimetric analysis, cyclic voltammetry, optical absorption spectroscopy, photoluminescence spectroscopy, and each structure was analysed using density functional theory. All compounds exhibit high thermal stability and good solubility in common organic solvents, including in the greener alternative 2-methyl tetrahydrofuran. The reported compounds display stable ambipolar redox behaviour, furthermore, we have demonstrated that the frontier molecular energy levels can be effectively tuned by changing the bridging unit as predicted by density functional theory. Most striking is the drastic optical absorption profile changes observed from this class of materials upon post-deposition film annealing, suggesting molecular rearrangement in the solid-state. The induced changes and fine structure observed upon post-deposition annealing is unique to these π-extended squaraines with nothing like it reported in the literature for related squaraine based materials.


Tracking the fate of her4 expressing cells in the regenerating retina using her4:Kaede zebrafish.
The Basic-Helix-Loop-Helix-Orange (bHLH-O) transcription factor Hairy-related 4 (her4) is a downstream effector of Notch-Delta signaling that represses expression of typically pro-neural genes in proliferative domains of the central nervous system. Notch-Delta signaling in the retina has been shown to increase in response to injury and influences neuroprotective properties of Müller glia. In contrast to mammals, teleost fish are able to regenerate retinal neurons in response to injury. In zebrafish, her4 is upregulated in the regenerating neural retina in response to both acute and chronic photoreceptor damage, but the contribution of her4 expressing cells to neurogenesis following acute or chronic retinal damage has remained unexplored. Here we investigate the role of her4 in the regenerating retina in a background of chronic, rod-specific degeneration as well as following acute light damage. We demonstrate that her4 is expressed in the persistently neurogenic ciliary marginal zone (CMZ), as well as in small subsets of slowly proliferating Müller glia in the inner nuclear layer (INL) of the central retina. We generated a transgenic line of zebrafish that expresses the photoconvertible Kaede reporter driven by a her4 promoter and validated that expression of the transgene faithfully recapitulates endogenous her4 expression. Lineage tracing analysis revealed that her4-expressing cells in the INL contribute to the rod lineage, and her4 expressing cells in the CMZ are capable of generating any retinal cell type except rod photoreceptors. Our results indicate that her4 is involved in a replenishing pathway that maintains populations of stem cells in the central retina, and that the magnitude of the her4-associated proliferative response mirrors the extent of retinal damage.


ICRP 67 Biokinetic Models for AM-241 Applied to Nonhuman Primates.
Between 1960 and 1985, Patricia Durbin and colleagues performed studies on the distribution of intravenously and intramuscularly injected Am citrate with dosages ranging from 16 to 32 kBq kg in 30 male and female non-human primates (NHP). Dr. Durbin died unexpectedly in March of 2009, leaving much of the extensive serial blood, bioassay, and autopsy data from these NHP studies unanalyzed. As part of the experimental design, serial blood samples were taken, and urine and feces samples were collected separately for the duration of the study. The measurements of urine, fecal excretion, blood samples, and organ burden data obtained from the animals were used to evaluate the transfer rates of the ICRP 67 biokinetic model for Am. Seven cases, in which the primates were administered Am citrate by intravenous injection, were evaluated using the ICRP 67 systemic model. There were differences ranging from 51.4% underestimated to 102.7% overestimated activity between the predicted intake, which was calculated using IMBA Professional Plus software and based upon the urine bioassay data and the actual activity. The difference between the predicted activity at the time of death in the liver and skeleton using IMBA professional software and the value of the measured activity at the time of death were also compared. Generally, the ratios of predicted activity in the liver and skeleton at the time of death to the measured activity were consistently more than 1. However, the ratios were less than 1 in the skeleton for animals that were sacrificed 2,199 and 973 d post injection. The posterior probability distributions for model parameters derived using WeLMoS method were inconsistent with the ICRP 67 default parameters. The prediction made based on the posterior probability distributions for model parameters derived using WeLMoS gave the best fit to these data; however, the modified parameters overestimated the activity in almost all cases. The difference between the predicted Am activity and the value of the measured activity may be due to the physiological age-related characteristics relative to the age of the animal at the time of the injection and early and long scarified time.


GLAD: GLycan Array Dashboard, a visual analytics tool for glycan microarrays.
Traditional glycan microarray data is typically presented as excel files with limited visualization and interactivity. Thus, comparisons and analysis of glycan array data have been difficult, and there is need for a tool to facilitate data mining of glycan array data. GLAD (GLycan Array Dashboard) is a web-based tool to visualize, analyze, present and mine glycan microarray data. GLAD allows users to input multiple data files to create comparisons. GLAD extends the capability of the microarray data to produce more comparative visualizations in the form of grouped bar charts, heatmaps, calendar heatmaps, force graphs and correlation maps in order to analyze broad sets of samples. Additionally, it allows users to filter, sort and normalize the data and view glycan structures in an interactive manner, to facilitate faster visual data mining. GLAD is freely available for use on the Web at https://glycotoolkit.com/Tools/GLAD/ with all major modern browsers (Edge, Firefox, Chrome, Safari). Full documentation and video tutorials for GLAD can be found on https://glycotoolkit.com/GLAD.


Parsimonious Model of Vascular Patterning Links Transverse Hormone Fluxes to Lateral Root Initiation: Auxin Leads the Way, while Cytokinin Levels Out.
An auxin maximum is positioned along the xylem axis of the Arabidopsis root tip. The pattern depends on mutual feedback between auxin and cytokinins mediated by the PIN class of auxin efflux transporters and AHP6, an inhibitor of cytokinin signalling. This interaction has been proposed to regulate the size and the position of the hormones' respective signalling domains and specify distinct boundaries between them. To understand the dynamics of this regulatory network, we implemented a parsimonious computational model of auxin transport that considers hormonal regulation of the auxin transporters within a spatial context, explicitly taking into account cell shape and polarity and the presence of cell walls. Our analysis reveals that an informative spatial pattern in cytokinin levels generated by diffusion is a theoretically unlikely scenario. Furthermore, our model shows that such a pattern is not required for correct and robust auxin patterning. Instead, auxin-dependent modifications of cytokinin response, rather than variations in cytokinin levels, allow for the necessary feedbacks, which can amplify and stabilise the auxin maximum. Our simulations demonstrate the importance of hormonal regulation of auxin efflux for pattern robustness. While involvement of the PIN proteins in vascular patterning is well established, we predict and experimentally verify a role of AUX1 and LAX1/2 auxin influx transporters in this process. Furthermore, we show that polar localisation of PIN1 generates an auxin flux circuit that not only stabilises the accumulation of auxin within the xylem axis, but also provides a mechanism for auxin to accumulate specifically in the xylem-pole pericycle cells, an important early step in lateral root initiation. The model also revealed that pericycle cells on opposite xylem poles compete for auxin accumulation, consistent with the observation that lateral roots are not initiated opposite to each other.


Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization.
Lipoic acid (thiotic acid) is being used as a dietary supplement, and as a therapeutic agent, and is reported to have beneficial effects in disorders associated with oxidative stress, but its mechanism of action remains unclear. We present evidence that lipoic acid induces a substantial increase in cellular reduced glutathione in cultured human Jurkat T cells human erythrocytes, C6 glial cells, NB41A3 neuroblastoma cells, and peripheral blood lymphocytes. The effect depends on metabolic reduction of lipoic acid to dihydrolipoic acid. Dihydrolipoic acid is released into the culture medium where it reduces cystine. Cysteine thus formed is readily taken up by the neutral amino acid transport system and utilized for glutathione synthesis. By this mechanism lipoic acid enables cystine to bypass the xc- transport system, which is weakly expressed in lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key enzyme of glutathione synthesis, gamma-glutamylcysteine synthetase, which is regulated by uptake-limited cysteine supply, to work at optimum conditions. Flow cytometric analysis of freshly prepared human peripheral blood lymphocytes, using monobromobimane labeling of cellular thiols, reveals that lipoic acid acts mainly to normalize a subpopulation of cells severely compromised in thiol status rather than to increase thiol content beyond physiological levels. Hence lipoic acid may have clinical relevance in restoration of severely glutathione deficient cells.


In vivo and in vitro effects of vortioxetine on molecules associated with neuroplasticity.
Neuroplasticity is fundamental for brain functions, abnormal changes of which are associated with mood disorders and cognitive impairment. Neuroplasticity can be affected by neuroactive medications and by aging. Vortioxetine, a multimodal antidepressant, has shown positive effects on cognitive functions in both pre-clinical and clinical studies. In rodent studies, vortioxetine increases glutamate neurotransmission, promotes dendritic branching and spine maturation, and elevates hippocampal expression of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) at the transcript level. The present study aims to assess the effects of vortioxetine on several neuroplasticity-related molecules in different experimental systems. Chronic (1 month) vortioxetine increased Arc/Arg3.1 protein levels in the cortical synaptosomes of young and middle-aged mice. In young mice, this was accompanied by an increase in actin-depolymerizing factor (ADF)/cofilin serine 3 phosphorylation without altering the total ADF/cofilin protein level, and an increase in the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation at serine 845 (S845) without altering serine 831 (S831) GluA1 phosphorylation nor the total GluA1 protein level. Similar effects were detected in cultured rat hippocampal neurons: Acute vortioxetine increased S845 GluA1 phosphorylation without changing S831 GluA1 phosphorylation or the total GluA1 protein level. These changes were accompanied by an increase in α subunit of Ca2+/calmodulin-dependent kinase (CaMKIIα) phosphorylation (at threonine 286) without changing the total CaMKIIα protein level in cultured neurons. In addition, chronic (1 month) vortioxetine, but not fluoxetine, restored the age-associated reduction in Arc/Arg3.1 and c-Fos transcripts in the frontal cortex of middle-aged mice. Taken together, these results demonstrated that vortioxetine modulates molecular targets that are related to neuroplasticity.


Hormonal and behavioral attachment responses in infant guinea pigs.
Infant guinea pigs, 11/12 and 18/19 days of age, exhibited high rates of vocalizing and increases in plasma concentrations of cortisol when separated from their mothers for 30 min in a novel environment (unfamiliar cage in an unfamiliar room). Levels of vocalizations and plasma cortisol were significantly reduced when the pup was exposed to the novel environment with its own conscious or anesthetized mother, but not when it was exposed with an unfamiliar anesthetized lactating female. Pups spent equivalent amounts of time in physical contact with their own conscious mother, their own anesthetized mother and an unfamiliar anesthetized lactating female. Unexpectedly, when the unfamiliar cage was placed in an environmental chamber during separation, pups showed negligible increases in vocalizations and plasma cortisol levels, even when administered footshock just prior to exposure. These findings demonstrate that guinea pig pups exhibit adrenocorticoid as well as behavioral responses to maternal separation, provide further evidence for the existence of filial attachment in this species, and document an unexpected role of the test environment in determining responses during maternal separation. The guinea pig may afford a rodent model for examining the effects of attachment-object separation on the activity of the pituitary-adrenal system.


Antifungal Therapy: New and Evolving Therapies.
Invasive fungal diseases primarily occur in immunocompromised patients. Immunosuppression has become more prevalent due to novel treatments, and this has led to a rise in the incidence of invasive fungal diseases. The antifungal armamentarium has long been insufficient and has taken quite some time to become diverse. Antifungal spectrum, tolerability, and toxicity are critical issues. Amphotericin B and its lipid formulations still have the widest spectrum, but, in spite of the better tolerance of the lipid formulations, toxicity remains a drawback, mostly with regard to renal function. Azoles constitute a heterogeneous antifungal class, in which newer molecules have an improved spectrum of activity. The main concern for the clinician when using azoles relates to the management of their many potential drug-drug interactions in an often fragile patient population. Echinocandins are better tolerated but possess a narrower antifungal spectrum and lack an oral route of administration. Still, their fungicidal activity makes them a weapon of first choice against Candida species. For certain uncommon fungal infections, antifungals such as flucytosine and terbinafine can also be useful. This article will give an overview of the mechanisms of action of currently used antifungals, as well as their spectrum of activity, clinically relevant pharmacological features, drug-drug interactions, and frequent side effects, all of which should drive the clinician's choice of agent when managing invasive fungal infections.


The influence of electro-acupuncture stimulation to female constipation patients.
This study aims to examine electro-acupuncture stimulation (EA) assisted therapy with analysis of heart rate variability to understand autonomic nervous activity variability (ANAV) and to track the changes in female patients with constipation. The average ages were 42 ± 12 years old. The participants were divided by a single-blind and randomized trial into two groups: the electro-acupuncture-point group, and the non-electro-acupuncture-point group. Both of the groups had eight treatments, once a week. For the electro-acupuncture (EA) group, needles were inserted into their Zusunli (ST36), Shangiuxu (ST37), Tiensu (ST25), Shueidao (ST28), Guanyuan (CV4) and Qihai (CV6) points. For the sham electro-acupuncture (SA) group, needles were inserted into acu-points that were not the ones mentioned for the EA group. While inserting needles, needles were inserted lightly into the participants' skin and removed quickly (mock Transcutaneous Electrical Nerve Stimulation, TENTS). After an eight-week treatment period, the autonomic nervous system activities of the SA group did not show significant differences in their heart rate variability. However, the autonomic nervous system activities of the EA group had continuously increased after each session. The normalized high frequency powers (nHFP) of their autonomic nervous system activities were 26.79 in the first week, and they increased to 32.28 in the fourth week. In the eighth week, their nHFP had increased to 37.60 (p < 0.05). The normalized low frequency power (nLFP) was 30.81 in the first week. However, it decreased to 25.98 after three weeks of treatment. After the eight-week treatment period, the nLFP decreased to 24.84 (p < 0.05). After the eight-week treatment, the control group did not appear to undergo any physiological change, while the constipation had been improved for the experimental group. It was found that the activation of parasympathetic nervous system in the experimental group increased after the eight-week treatment. The effects of such a result on the enhancement of the activation of parasympathetic nervous system and the improvement of constipation should be further discussed.


Quantification of myelin and axon pathology during relapsing progressive experimental autoimmune encephalomyelitis in the Biozzi ABH mouse.
Multiple sclerosis is an immune-mediated demyelinating disease, with axonal loss underlying long-term progressive disability. In this study, we have analyzed axonal and myelin pathology in a chronic relapsing-remitting experimental autoimmune encephalomyelitis model in Biozzi ABH mice induced by immunization with a syngeneic spinal cord homogenate. The animals were followed for3 months; inflammation, T-cell infiltration, demyelination, and axonal loss were examined at various time points throughout the disease course. We found that macrophage infiltration and microglia activation preceded detectable T-cell infiltration. Axonal loss was first evident at the acute phase of disease before demyelination was detected. Demyelination and axonal loss occurred after each relapse and correlated with increasing residual motor deficits in remission. The resulting lesions displayed evidence of demyelination, remyelination, axonal degeneration, and axon loss. After a series of 3 relapses, animals entered a chronic progressive phase with permanent paralysis and a relative absence of inflammation. Axonal loss continued in this phase, although demyelinated axons persisted. These findings indicate that experimental autoimmune encephalomyelitis in Biozzi ABH mice has important similarities to multiple sclerosis with a relapsing-remitting disease course followed by a secondary progressive phase; it is thus a suitable model in which to explore remyelination and neuroprotective therapies for multiple sclerosis.


Electrospray ionization-induced protein unfolding.
Electrospray ionization mass spectrometry (ESI-MS) measurements were performed under a variety of solution conditions on a highly acidic sub-fragment (B3C) of the C-terminal carbohydrate-binding repeat region of Clostridium difficile toxin B, and two mutants (B4A and B4B) containing fewer acidic residues. ESI-MS measurements performed in negative ion mode on aqueous ammonium acetate solutions of B3C at low ionic strength (I < 80 mM) revealed evidence, based on the measured charge state distribution, of protein unfolding. In contrast, no evidence of unfolding was detected from ESI-MS measurements made in positive ion mode at low I or in either mode at higher I. The results of proton nuclear magnetic resonance and circular dichroism spectroscopy measurements and gel filtration chromatography performed on solutions of B3C under low and high I conditions suggest that the protein exists predominantly in a folded state in neutral aqueous solutions with I > 10 mM. The results of ESI-MS measurements performed on B3C in a series of solutions with high I at pH 5 to 9 rule out the possibility that the structural changes are related to ESI-induced changes in pH. It is proposed that unfolding of B3C, observed in negative mode for solutions with low I, occurs during the ESI process and arises due to Coulombic repulsion between the negatively charged residues and liquid/droplet surface charge. ESI-MS measurements performed in negative ion mode on B4A and B4B also reveal a shift to higher charge states at low I but the magnitude of the changes are smaller than observed for B3C.


Increased risk of cancer in infertile men: analysis of U.S. claims data.
Aberrations in reproductive fitness may be a harbinger of medical diseases in men. Data suggest a higher risk of testicular cancer in infertile men. However, the relationship between infertility and other cancers remains uncertain. We analyzed subjects from the Truven Health MarketScan® claims database from 2001 to 2009. Infertile men were identified through diagnosis and treatment codes. Comparison groups were created of men who underwent vasectomy and a control cohort of men who were not infertile and had not undergone vasectomy. The incidence of cancer was compared to national U.S. estimates. Infertile men were also compared to men who underwent vasectomy and the control cohort using a Cox regression model. A total of 76,083 infertile men were identified with an average age of 35.1 years. Overall 112,655 men who underwent vasectomy and 760,830 control men were assembled. Compared to age adjusted national averages, infertile, vasectomy and control subjects in the study cohorts had higher rates of all cancers and many individual cancers. In time to event analysis, infertile men had a higher risk of cancer than those who underwent vasectomy or controls. Infertile men had a higher risk of testis cancer, nonHodgkin lymphoma and all cancers than the vasectomy and control groups. Consistent with prior reports, we identified an increased risk of testicular cancer in infertile men. The current data also suggest that infertile men are at an increased risk of all cancers in the years after infertility evaluation. Future research should focus on confirming these associations and elucidating pathways between infertility and cancer.


Achieving maximum entanglement between two nitrogen-vacancy centers coupling to a whispering-gallery-mode microresonator.
We investigate the entanglement generation between two nitrogen-vacancy (NV) centers in diamond nanocrystal coupled to a high-Q counterpropagating twin whispering-gallery modes (WGMs) of a microtoroidal resonator. For looking into the degree and dynamics of the entanglement, we calculate the concurrence using the microscopic master equation approach. The influences of the coupling strength between the WGMs (or the size of the two spherical NV centers), the distance between two NV centers, the frequency detuning between the NV center and microresonator, and the initial state of the system on the dynamics of concurrence are discussed in detail. It is found that the maximum entanglement between the two NV centers can be created by properly adjusting these controllable system parameters. Our results may provide further insight into future solid-state cavity quantum electrodynamics (CQED) system for quantum information engineering.


Efficacy of contrast-enhanced CT in assessing the endometrium.
The purpose of our study was to determine the efficacy of contrast-enhanced CT in detecting a thickened endometrium. We used transvaginal sonography as the reference standard. Between March 2005 and January 2007, data from 259 patients (mean age, 47 years; age range, 18-90 years) who underwent transvaginal sonography and contrast-enhanced CT of the pelvis were analyzed retrospectively. The endometrium was quantitatively measured in millimeters on sonography. On CT it was qualitatively categorized as normal, thickened, indeterminate, or not visualized and compared with the sonography findings and original radiology reports. When the endometrium was indeterminate (thickened or triangular in shape on axial images), sagittal reconstructions were performed for final categorization. Two reviewers evaluated the CT scans and sonograms jointly with differences resolved by consensus. Kappa, Wilcoxon's rank sum test, and intraclass correlation statistics were derived. The overall sensitivity and specificity of CT in detecting the thickened endometrium was 53.1% and 93.5%, respectively, relative to transvaginal sonography. The positive and negative predictive values were 66.7% and 89.1%, respectively. Kappa, the statistical measure of agreement between CT and sonography data, was 0.5049. All cases of a triangular endometrium were normal in size on sagittal reconstruction images. Routine pelvic CT correctly identifies a normal endometrium in most patients. Sagittal reconstruction images are helpful to further evaluate the endometrium on CT in cases with a prominent or triangular endometrium because these are often related to uterine version. CT is relatively insensitive in detecting the thickened endometrium but better able to identify gross rather than subtle thickening, which must be further characterized by transvaginal sonography.


Oral colostrum priming shortens hospitalization without changing the immunomicrobial milieu.
Oral colostrum priming (OCP) after birth in preterm infants is associated with improved weight gain and modification of the oral immunomicrobial environment. We hypothesized that OCP would modify salivary immune peptides and the oral microbiota in preterm infants. We conducted a prospective, randomized clinical trial to determine the effects of OCP on salivary immune peptide representation in preterm infants (<32 weeks completed gestation at birth). Saliva samples were collected before and after OCP. Salivary immune peptide representation was determined via mass spectroscopy. Oral microbiota representation was determined via sequencing of the 16S rRNA gene. Neonates who received OCP (n=48) had a 16-day reduction in the median length of hospitalization as compared with infants who did not receive OCP (n=51). No differences in salivary immune peptide sequence representation before OCP between groups were found. Longitudinal changes in peptides were detected (lysozyme C, immunoglobulin A, lactoferrin) but were limited to a single peptide difference (α-defensin 1) between primed and unprimed infants after OCP. We found no difference in microbial diversity between treatment groups at any time point, but diversity decreased significantly over time in both groups. OCP treatment marginally modified oral taxa with a decline in abundance of Streptococci in the OCP group at 30 days of life. OCP had neither an effect on the salivary peptides we examined nor on overall oral bacterial diversity and composition. Infants who received OCP had a reduced length of hospitalization and warrants further investigation.


The economic burden placed on healthcare systems by childhood obesity.
The obesity epidemic has transformed children's healthcare, such that diabetes, hypertension and the metabolic syndrome are phrases more commonly used by child health providers than ever before. This article reviews the economic consequences of this epidemic for healthcare delivery systems, both in the short term when obesity has been associated with increased utilization, and in the long term where increased likelihood of adult obesity and cardiovascular disease is well documented. Large investments through research and prevention are needed and are likely to provide strong returns in cost savings, and would optimally emerge through a cooperative effort between private and government payers alike.


Breast cancer risk reduction options: awareness, discussion, and use among women from four ethnic groups.
With recent advances in breast cancer risk reduction practices, it is increasingly important to assess both the breadth of and disparities in use across different racial/ethnic groups. We conducted telephone interviews with 1,700 women ages 40 to 74, from four racial/ethnic groups, without prior history of breast cancer, who received mammograms at one of five mammography facilities in San Francisco. Main outcomes measured included recognition of tamoxifen, raloxifene, genetic testing, and prophylactic surgery. Global indicators (recognition of any therapy, discussion of breast cancer risk) were developed from original outcome measures and analyzed using logistic regression. Multivariate analyses indicate that race/ethnicity and interview language affected recognition of therapies and discussion of risk. White women were more likely than all other women to recognize any therapy and more likely than Asian-Americans to discuss risk. Women at high risk, who had a prior abnormal mammogram, who perceived themselves to be at high risk, or who were exposed to breast health information were more likely to discuss risk. Women are aware of preventive therapies, although discussion and use is limited. Interventions to increase use of therapies should focus on those at high risk.


Can executive cognitive measures differentiate between patients with spinal- and bulbar-onset amyotrophic lateral sclerosis?
Although executive functions in sporadic non-demented amyotrophic lateral sclerosis (ALS) patients are mostly affected, it remains unclear whether executive measures can differentiate between patients with bulbar and spinal ALS forms. Thirty spinal and 18 bulbar-onset ALS patients (ALS-s and ALS-b, respectively) as well as 47 demographically related healthy controls were examined in executive processes (Trail Making Test-part B [TMT-(B-A)]; Stroop Neuropsychological Screening Test [SNST]; Similarities subtest of the Wechsler Adult Intelligence Scale [WAIS Similarities]; Wisconsin Card Sorting Test [WCST]). ALS subgroups were similar with regard to demographic characteristics and disease duration; yet, ALS-b showed greater disease severity compared with ALS-s patients (p = .006). Both ALS-s and ALS-b patients were significantly inferior to healthy controls on TMT-(B-A) (p < .001), SNST (p = .009 and p = .02, respectively) and WAIS Similarities (p = .031 and p = .021, respectively), whereas ALS-s performed significantly worse than controls on the WCST perseverative responses (p = .005). However, neuropsychological measures did not significantly differ between ALS subgroups (p > .05). Despite the fact that ALS-b patients may present greater disease severity, specific executive impairments that are present early in the course of ALS seems to be independent of the site of onset.


The burden of legionnaires' disease in Belgium, 2013 to 2017.
Legionnaires' disease (LD) is a severe bacterial infection causing pneumonia. Surveillance commonly underestimates the true incidence as not all cases are laboratory confirmed and reported to public health authorities. The aim of this study was to present indicators for the impact of LD in Belgium between 2013 and 2017 and to estimate its true burden in the Belgian population in 2017, the most recent year for which the necessary data were available. Belgian hospital discharge data, data from three infectious disease surveillance systems (mandatory notification, sentinel laboratories and the national reference center), information on reimbursed diagnostic tests from the Belgian National Institute for Health and Disability Insurance and mortality data from the Belgian statistical office were used. To arrive at an estimate of the total number of symptomatic cases in Belgium, we defined a surveillance pyramid and estimated a multiplication factor to account for LD cases not captured by surveillance. The multiplication factor was then applied to the pooled number of LD cases reported by the three surveillance systems. This estimate was the basis for our hazard- and incidence-based Disability-Adjusted Life Years (DALYs) calculation. To account for uncertainty in the estimations of the DALYs and the true incidence, we used Monte Carlo simulations with 10,000 iterations. We found an average of 184 LD cases reported by Belgian hospitals annually (2013-2017), the majority of which were male (72%). The surveillance databases reported 215 LD cases per year on average, 11% of which were fatal within 90 days after diagnosis. The estimation of the true incidence in the community yielded 2674 (95% Uncertainty Interval [UI]: 2425-2965) cases in 2017. LD caused 3.05 DALYs per case (95%UI: 1.67-4.65) and 8147 (95%UI: 4453-12,426) total DALYs in Belgium in 2017, which corresponds to 71.96 (95%UI: 39.33-109.75) DALYs per 100,000 persons. This analysis revealed a considerable burden of LD in Belgium that is vastly underestimated by surveillance data. Comparison with other European DALY estimates underlines the impact of the used data sources and methodological approaches on burden estimates, illustrating that national burden of disease studies remain essential.


Hepatitis C virus genotypes in chronic hepatitis C patients and in first time blood donors in northeastern Bosnia and Herzegovina.
Prevalence of hepatitis C virus (HCV) genotypes in Bosnia and Herzegovina (B&H) is an issue that is not sufficiently researched and there is a need for studies that would explore this in detail.The aim of this study was to determine the distribution of HCV genotypes in the group of patients with chronic hepatitis C and also in the group of first time blood donors that tested positive for anti HCV antibodies during the blood screening process. Our secondary goal was to compare the proportions of HCV genotypes between these two groups.We analyzed 75 blood samples of patients with confirmed chronic hepatitis C. We also analyzed 13/16082 blood samples of first time blood donors found to be HCV positive during the blood screening process. We also determined HCV genotype in HCV RNA positive samples.We have found that genotype 1b was more prevalent in chronic hepatitis C patients (52/75; 69,3%) than in first time blood donors (6/13; 46,1%), however this difference was not statistically significant (c2=1,721; df=1; p=0,19). Genotype 1a was more prevalent in the group of first time blood donors (3/13; 23,1%) than in the group of chronic hepatitis C patients (3/75; 4%), but this was also with limited statistical significance (c2=3,71; df=1; p=0,054). We have not found any significant difference in prevalence of genotypes 1a (p=0,2) and genotypes 3 (p=0,70) when compared between chronic patients (3/75 and 16/75; respectively) and first time blood donors (3/13 and 4/13; respectively). Our study confirmed domination of genotype 1b in the region of northeastern B&H which is in accordance with HCV genotype prevalence in other countries in our part of Europe.


Combined VEGF-A and VEGFR-2 concentrations in plasma: diagnostic and prognostic implications in patients with advanced NSCLC.
The vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFR) play an important role in tumor angiogenesis. Increased expression of angiogenic factors in tumors or in blood is associated with poor prognosis. The aim of this study was to investigate the role of VEGF-A and soluble VEGFR-2 (sVEGFR-2) as biomarkers in advanced non-small-cell lung cancer (NSCLC). We studied 432 patients with advanced NSCLC (stages IIIB-IV) treated with cisplatin and docetaxel and 89 healthy age-matched controls. Blood samples were collected before chemotherapy, and VEGF-A and sVEGFR-2 levels were determined by ELISA. VEGF-A and sVEGFR-2 levels were higher in NSCLC patients than in the controls, but VEGF-A behaves as a better diagnostic biomarker. There were no significant associations between VEGF-A and sVEGFR-2 concentrations and clinical characteristics, such as ECOG-PS, gender, stage, histology, metastases, and treatment response. A patient subgroup characterized by a combination of high VEGF-A and low sVEGFR-2 levels exhibited the worst patient prognoses in terms of TTP and OS. VEGF-A and sVEGFR-2 levels were significantly higher in patients than in the controls. A combination of VEGF-A and sVEGFR-2 can be used as an independent prognostic biomarker in advanced NSCLC.


Hospital-Level Factors Associated With Mortality After Endovascular and Open Abdominal Aortic Aneurysm Repair.
Endovascular technology has become ubiquitous in the modern care of abdominal aortic aneurysm (AAA), yet broad estimates of its efficacy among variable hospital and regional settings is not known. To perform a preliminary analysis of hospital effects on mortality following open AAA repair (OAR) and endovascular AAA repair (EVAR). A retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program database was conducted on all patients undergoing OAR or EVAR from July 1, 2010, to November 30, 2012, using Current Procedural Terminology codes. Weight-adjusted 30-day observed to expected mortality ratios were compared based on hospital type (academic vs community) and size (100-299 beds vs 300-500 beds vs >500 beds). Data on 11,250 patients (2466 underwent OAR and 8784 underwent EVAR) were analyzed. Endovascular AAA repair was performed more frequently than OAR at both academic (78.8%) and community (68.2%) hospitals. Overall 30-day mortality was 14.0% for OAR and 4.3% for EVAR (P < .001). Hospital size was significantly associated with mortality for OAR (observed to expected mortality ratio: >500 beds, 0.88 vs 300-500 beds, 1.11 vs 100-299 beds, 1.59; P = .01) but not for EVAR (P = .27). In contrast, hospital type was significantly associated with mortality for EVAR (observed to expected mortality ratio: academic, 0.60 vs community, 2.60; P < .001) but not OAR (P = .46). Multivariable analysis of hospital-level factors suggested that, for all outcomes, academic hospital type was the single most significant predictor of reduced mortality following AAA repair (observed to expected mortality ratio: academic, 0.91 vs community, 2.00; P = .05). Based on this preliminary report, outcomes for both OAR and EVAR appear to depend greatly on hospital-level effects. The relative safety of EVAR vs OAR may depend on appropriate patient selection and adequate access to multidisciplinary care in order to minimize failure to rescue rates and improve survival.


Influence of Gag-protease-mediated replication capacity on disease progression in individuals recently infected with HIV-1 subtype C.
HLA class I-mediated selection of immune escape mutations in functionally important Gag epitopes may partly explain slower disease progression in HIV-1-infected individuals with protective HLA alleles. To investigate the impact of Gag function on disease progression, the replication capacities of viruses encoding Gag-protease from 60 individuals in early HIV-1 subtype C infection were assayed in an HIV-1-inducible green fluorescent protein reporter cell line and were correlated with subsequent disease progression. Replication capacities did not correlate with viral load set points (P = 0.37) but were significantly lower in individuals with below-median viral load set points (P = 0.03), and there was a trend of correlation between lower replication capacities and lower rates of CD4 decline (P = 0.09). Overall, the proportion of host HLA-specific Gag polymorphisms in or adjacent to epitopes was negatively associated with replication capacities (P = 0.04), but host HLA-B-specific polymorphisms were associated with higher viral load set points (P = 0.01). Further, polymorphisms associated with host-specific protective HLA alleles were linked with higher viral load set points (P = 0.03). These data suggest that transmission or early HLA-driven selection of Gag polymorphisms results in reduced early cytotoxic T-lymphocyte (CTL) responses and higher viral load set points. In support of the former, 46% of individuals with nonprotective alleles harbored a Gag polymorphism exclusively associated with a protective HLA allele, indicating a high rate of their transmission in sub-Saharan Africa. Overall, HIV disease progression is likely to be affected by the ability to mount effective Gag CTL responses as well as the replication capacity of the transmitted virus.


Level of use of 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) in humans correlates with EEG power and coherence.
Despite animal studies implicating 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) in serotonergic neurotoxicity, there is little direct evidence of changes in neural function in humans who use MDMA as a recreational drug. The present study investigated whether there is a correlation between quantitative EEG variables (spectral power and coherence) and cognitive/mood variables, and level of prior use of MDMA. Twenty-three recreational MDMA users were studied. Resting EEG was recorded with eyes closed, using a 128-electrode geodesic net system, from which spectral power, peak frequency and coherence levels were calculated. Tests of intelligence (NART), immediate and delayed memory, frontal function (card sort task), and mood (BDI and PANAS scales) were also administered. Pearson correlation analyses were used to examine the relationship between these measures and the subject's consumption of MDMA during the previous 12-month period. Partial correlation was used to control for the use of other recreational drugs. MDMA use was positively correlated with absolute power in the alpha (8-12 Hz) and beta (12-20 Hz) frequency bands, but not with the delta (1-3 Hz) or theta (4-7 Hz) bands. MDMA use was negatively correlated with EEG coherence, a measure of synchrony between paired cortical locations, in posterior brain sites thought to overly the main visual association pathways of the occipito-parietal region. MDMA use did not correlate significantly with any of the mood/cognitive measures except the card sort task, with which it was weakly negatively correlated. Alpha power has been shown to be inversely related to mental function and has been used as an indirect measure of brain activation in both normal and abnormal states. Reduced coherence levels have been associated with dysfunctional connectivity in the brain in disorders such as dementia, white-matter disease and normal aging. Our results may indicate altered brain function correlated with prior MDMA use, and show that electroencephalography may be a cheap and effective tool for examining neurotoxic effects of MDMA and other drugs.