Barriers and facilitators to intraosseous access in adult resuscitations when peripheral intravenous access is not achievable.
Studies suggest that intraosseous (IO) access is underutilized in adult resuscitations, despite recommendations from advanced trauma and cardiac life support guidelines. The objective was to determine factors associated with IO access use by physicians during adult resuscitations when intravenous (IV) access is not immediately achievable. This study was an online survey among physicians purposefully recruited from various clinical care areas at three teaching hospitals. Questions were generated from the qualitative results of 20 iterative interviews, verified for internal validity, and piloted. The interview guide was based on the constructs of the Theory of Planned Behavior (TPB), which elicits salient attitudes, social influences, and control beliefs that potentially influence intention to use IO access. Recruitment took place in September 2012 until reaching more than 100% of the required sample size (n = 200). Internal consistency was measured using Cronbach's alpha, and the effect of TPB constructs and specific beliefs were assessed with regression analyses. For the 205 respondents, the mean age was 35 years (range = 20 to 66 years), and 53.3% were male. Participants' departmental affiliations were 50.3% emergency medicine (EM), 16.9% internal medicine, 14.9% anesthesia, 10.8% general surgery, and 7.2% critical care. Residents comprised 60.7% of the sample, and 39.3% were attending physicians. Median intention to use IO access when IV is not immediately achievable was 4.67 (interquartile range [IQR] = 4 to 5) out of 5 (5 highest) and predicted by the following TPB constructs: attitudes (AdjCoefficients = 0.504; 95% confidence interval [CI] = 0.334 to 0.673), social influences (AdjCoefficients = 0.285; 95% CI = 0.172 to 0.398), and control beliefs (AdjCoefficients 0.217; 95% CI = 0.113 to 0.320). Physicians were more likely to use IO access if they believed that it provided rapid vascular access for delivering large volumes of fluids, could prevent delays in care, and was associated with a low complication rate. Conversely, the perception that nurses are not familiar or supportive of IO access and a lack of physician confidence regarding the appropriate indications for IO access were barriers to use. These data are an important step in the knowledge-to-action process, as they identify specific factors associated with physician use of IO access. Interventions addressing these actionable facilitators and barriers are likely to have a positive effect on increasing the appropriate physician use of this potentially life-saving technique in adult patients requiring emergent vascular access.


New methods for estimating the tuberculosis case detection rate in high-HIV prevalence countries: the example of Kenya.
To develop new methods for estimating the sputum smear-positive tuberculosis case detection rate (CDR) in a country where infection with HIV is prevalent. We estimated the smear-positive tuberculosis CDR in HIV-negative and HIV-positive adults, and in all adults in Kenya. Data on time trends in tuberculosis case notification rates and on HIV infection prevalence in adults and in tuberculosis patients were used, along with data on tuberculosis control programme performance. In 2006, the estimated smear-positive tuberculosis CDR in HIV-negative adults was 79% (95% confidence interval, CI: 64-94) and in HIV-positive adults, 57% (95% CI: 26-88), giving a weighted mean of 68% (95% CI: 49-87). The separate estimate for all smear-positive tuberculosis cases was 72% (95% CI: 53-91), giving an overall average for the three estimates of 70% (95% CI: 58-82). As the tuberculosis CDR in 1996 was 57% (95% CI: 47-67), the estimated increase by 2006 was 13 percentage points (95% CI: 6-20), or 23%. This increase was accompanied by a more than doubling of the resources devoted to tuberculosis control in Kenya, including facilities and staff. Using three approaches to estimate the tuberculosis CDR in a country where HIV infection is prevalent, we showed that expansion of the tuberculosis control programme in Kenya led to an increase of 23% in the CDR between 1996 and 2006. While the methods developed here can be applied in other countries with a high prevalence of HIV infection, they rely on precise data on trends in such prevalence in the general population and among tuberculosis patients.


Molecular detection of Gram-positive bacteria in the human lung through an optical fiber-based endoscope.
The relentless rise in antimicrobial resistance is a major societal challenge and requires, as part of its solution, a better understanding of bacterial colonization and infection. To facilitate this, we developed a highly efficient no-wash red optical molecular imaging agent that enables the rapid, selective, and specific visualization of Gram-positive bacteria through a bespoke optical fiber-based delivery/imaging endoscopic device. We rationally designed a no-wash, red, Gram-positive-specific molecular imaging agent (Merocy-Van) based on vancomycin and an environmental merocyanine dye. We demonstrated the specificity and utility of the imaging agent in escalating in vitro and ex vivo whole human lung models (n = 3), utilizing a bespoke fiber-based delivery and imaging device, coupled to a wide-field, two-color endomicroscopy system. The imaging agent (Merocy-Van) was specific to Gram-positive bacteria and enabled no-wash imaging of S. aureus within the alveolar space of whole ex vivo human lungs within 60 s of delivery into the field-of-view, using the novel imaging/delivery endomicroscopy device. This platform enables the rapid and specific detection of Gram-positive bacteria in the human lung.


Soil calcium availability influences shell ecophenotype formation in the sub-antarctic land snail, Notodiscus hookeri.
Ecophenotypes reflect local matches between organisms and their environment, and show plasticity across generations in response to current living conditions. Plastic responses in shell morphology and shell growth have been widely studied in gastropods and are often related to environmental calcium availability, which influences shell biomineralisation. To date, all of these studies have overlooked micro-scale structure of the shell, in addition to how it is related to species responses in the context of environmental pressure. This study is the first to demonstrate that environmental factors induce a bi-modal variation in the shell micro-scale structure of a land gastropod. Notodiscus hookeri is the only native land snail present in the Crozet Archipelago (sub-Antarctic region). The adults have evolved into two ecophenotypes, which are referred to here as MS (mineral shell) and OS (organic shell). The MS-ecophenotype is characterised by a thick mineralised shell. It is primarily distributed along the coastline, and could be associated to the presence of exchangeable calcium in the clay minerals of the soils. The Os-ecophenotype is characterised by a thin organic shell. It is primarily distributed at high altitudes in the mesic and xeric fell-fields in soils with large particles that lack clay and exchangeable calcium. Snails of the Os-ecophenotype are characterised by thinner and larger shell sizes compared to snails of the MS-ecophenotype, indicating a trade-off between mineral thickness and shell size. This pattern increased along a temporal scale; whereby, older adult snails were more clearly separated into two clusters compared to the younger adult snails. The prevalence of glycine-rich proteins in the organic shell layer of N. hookeri, along with the absence of chitin, differs to the organic scaffolds of molluscan biominerals. The present study provides new insights for testing the adaptive value of phenotypic plasticity in response to spatial and temporal environmental variations.


Prolactin--a novel neuroendocrine regulator of human keratin expression in situ.
The controls of human keratin expression in situ remain to be fully elucidated. Here, we have investigated the effects of the neurohormone prolactin (PRL) on keratin expression in a physiologically and clinically relevant test system: organ-cultured normal human hair follicles (HFs). Not only do HFs express a wide range of keratins, but they are also a source and target of PRL. Microarray analysis revealed that PRL differentially regulated a defined subset of keratins and keratin-associated proteins. Quantitative immunohistomorphometry and quantitative PCR confirmed that PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. PRL also up-regulated K15 promoter activity and K15 protein expression in situ, whereas it inhibited K6 and K31 expression. These regulatory effects were reversed by a pure competitive PRL receptor antagonist. Antagonist alone also modulated keratin expression, suggesting that "tonic stimulation" by endogenous PRL is required for normal expression levels of selected keratins. Therefore, our study identifies PRL as a major, clinically relevant, novel neuroendocrine regulator of both human keratin expression and human epithelial stem cell biology in situ.


Epidemiology and etiology of obesity in children and youth of Sarajevo Canton.
The aims of the study were to estimate the prevalence of excessive weight in infants and school-age children in Sarajevo Canton, to isolate the main causative agents and to propose a strategy for its efficient prevention. The methods included anthropometry and originally designed questionnaire. Calculated body mass index was classified according to the criteria proposed by Centre for Disease Control and Prevention (CDC). The research included 3608 students from elementary and secondary schools from Sarajevo Canton. Nearly 1/5 of subjects had excessive body weight while 12.49% of students were malnourished. Elementary school lower graders had the highest grade of excessive weight, while the secondary school students exhibited the lowest grade of excessive weight. During school hours, about 42.47% of students were fed on bakery produces and snacks. Non-sparkling, thickened juices are frequently consumed beverages (20.65%), second only to water (51.82%). 58.15% of children consume sweets on daily basis. This is even more prominent among secondary school students (80.85%). Only 1/3 of students practice sports on daily basis, while 8.51% of them rarely engage in sports. Elementary school lower grade students had the lowest level of activity while the secondary school students were the most active. As many as 27.56% students spend two hours or more sitting by the computer or TV set. The most significant mediators of excessive weight gain are sedentary life-style, frequent consumption of sweets and thickened juices and unsuitable nutrition during school hours. Continuous preventive and therapeutically activities must be undertaken among as wide population as possible.


Molecular simulations of supercritical fluid permeation through disordered microporous carbons.
Fluid transport through microporous carbon-based materials is inherent in numerous applications, ranging from gas separation by carbon molecular sieves to natural gas production from coal seams and gas shales. The present study investigates the steady-state permeation of supercritical methane in response to a constant cross-membrane pressure drop. We performed dual control volume grand canonical molecular dynamics (DCV-GCMD) simulations to mimic the conditions of actual permeation experiments. To overcome arbitrary assumptions regarding the investigated porous structures, the membranes were modeled after the CS1000a and CS1000 molecular models, which are representative of real microporous carbon materials. When adsorption-induced molecular trapping (AIMT) mechanisms are negligible, we show that the permeability of the microporous material, although not significantly sensitive to the pressure gradient, monotonically decreases with temperature and reservoir pressures, consistent with diffusion theory. However, when AIMT occurs, the permeability increases with temperature in agreement with experimental data found in the literature.


Postoperative Serratia marcescens wound infections traced to an out-of-hospital source.
From 25 August to 28 September 1994, 7 cardiovascular surgery (CVS) patients at a California hospital acquired postoperative Serratia marcescens infections, and 1 died. To identify the outbreak source, a cohort study was done of all 55 adults who underwent CVS at the hospital during the outbreak. Specimens from the hospital environment and from hands of selected staff were cultured. S. marcescens isolates were compared using restriction-endonuclease analysis and pulsed-field gel electrophoresis. Several risk factors for S. marcescens infection were identified, but hospital and hand cultures were negative. In October, a patient exposed to scrub nurse A (who wore artificial fingernails) and to another nurse-but not to other identified risk factors-became infected with the outbreak strain. Subsequent cultures from nurse A's home identified the strain in a jar of exfoliant cream. Removal of the cream ended the outbreak. S. marcescens does not normally colonize human skin, but artificial nails may have facilitated transmission via nurse A's hands.


Scavenging effects of terbinafine on free radicals in vitro.
One of the goals of antifungal therapy is to combine an anti-inflammatory activity with antimycotic properties, and therefore it is interesting to evaluate the capacity of active antifungal drugs to interfere with different phases of the inflammatory reaction. In order to identify a possible scavenger property of free radical species of the antifungal agent terbinafine, we studied its activity on the reduction of nitrotetrazolium blue chloride (NTB), induced by superoxide anions with the ultraviolet (UV)- and chemical-induced peroxidation of unsaturated lipid targets. NTB reduction was followed by spectrophotometer and the decomposition of squalene or methyl arachidonate by gas chromatography-mass spectrometry. Terbinafine (20 microgram and over) was capable of significantly inhibiting NTB reduction, indicating that the drug scavenges superoxide anion radicals. In these conditions no modifications of the concentration of the drug, as evaluated by high performance liquid chromatography, were observed. The UV- or chemically induced peroxidation of squalene and arachidonic acid was significantly reduced in the presence of 50 microgram of terbinafine, suggesting that the substance interferes with the chemical properties of peroxyl radicals. In all the tests used the degree of inhibition was proportional to the amount of free radicals generated. In conclusion our results indicate that terbinafine, at therapeutic concentrations, can be considered to be a free radical interceptor in vitro and could exert a mild anti-inflammatory activity in vivo.


Cone Snail Glutaminyl Cyclase Sequences from Transcriptomic Analysis and Mass Spectrometric Characterization of Two Pyroglutamyl Conotoxins.
The post-translational modification of N-terminal glutamine (Q) to a pyroglutamyl (Z) residue is observed in the conotoxins produced by marine cone snails. This conversion requires the action of the enzyme glutaminyl cyclase (QC). Four complete QC sequences from the species C. araneosus, C. frigidus, C. litteratus, and C. monile and two partial sequences from C. amadis and C. miles have been obtained by analysis of transcriptomic data. Comparisons with mammalian enzyme sequences establish a high level of identity and complete conservation of functional active site residues, including a cluster of hydrogen-bonded acidic side chains. Mass spectrometric analysis of crude venom samples coupled to conotoxin precursor protein sequences obtained from transcriptomic data establishes the presence of pyroglutamyl conotoxins in the venom of C. frigidus and C. amadis. The C. frigidus peptide belongs to the M superfamily, with cysteine framework III, whereas the C. amadis peptide belongs to the divergent superfamily with cysteine framework VI/VII. Additionally, gamma carboxylation of glutamic acid and hydroxylation of proline are observed in the C. frigidus peptide. Mass spectral data are available via ProteomeXchange with identifier PXD009006.


Tracking the emergence of conceptual knowledge during human decision making.
Concepts lie at the very heart of intelligence, providing organizing principles with which to comprehend the world. Surprisingly little, however, is understood about how we acquire and deploy concepts. Here, we show that a functionally coupled circuit involving the hippocampus and ventromedial prefrontal cortex (vMPFC) underpins the emergence of conceptual knowledge and its effect on choice behavior. Critically, the hippocampus alone supported the efficient transfer of knowledge to a perceptually novel setting. These findings provide compelling evidence that the hippocampus supports conceptual learning through the networking of discrete memories and reveal the nature of its interaction with downstream valuation modules such as the vMPFC. Our study offers neurobiological insights into the remarkable capacity of humans to discover the conceptual structure of related experiences and use this knowledge to solve exacting decision problems.


Salicylates and pandemic influenza mortality, 1918-1919 pharmacology, pathology, and historic evidence.
The high case-fatality rate--especially among young adults--during the 1918-1919 influenza pandemic is incompletely understood. Although late deaths showed bacterial pneumonia, early deaths exhibited extremely "wet," sometimes hemorrhagic lungs. The hypothesis presented herein is that aspirin contributed to the incidence and severity of viral pathology, bacterial infection, and death, because physicians of the day were unaware that the regimens (8.0-31.2 g per day) produce levels associated with hyperventilation and pulmonary edema in 33% and 3% of recipients, respectively. Recently, pulmonary edema was found at autopsy in 46% of 26 salicylate-intoxicated adults. Experimentally, salicylates increase lung fluid and protein levels and impair mucociliary clearance. In 1918, the US Surgeon General, the US Navy, and the Journal of the American Medical Association recommended use of aspirin just before the October death spike. If these recommendations were followed, and if pulmonary edema occurred in 3% of persons, a significant proportion of the deaths may be attributable to aspirin.


Progression to AIDS in the absence of a gene for vpr or vpx.
Rhesus monkeys (Macaca mulatta) were experimentally infected with strains of simian immunodeficiency virus (SIV) derived from SIVmac239 lacking vpr, vpx, or both vpr and vpx genes. These auxiliary genes are not required for virus replication in cultured cells but are consistently conserved within the SIVmac/human immunodeficiency virus type 2/SIVsm group of primate lentiviruses. All four rhesus monkeys infected with the vpr deletion mutant showed an early spike in plasma antigenemia, maintained high virus burdens, exhibited declines in CD4+ lymphocyte concentrations, and had significant changes in lymph node morphology, and two have died to date with AIDS. The behavior of the vpr deletion mutant was indistinguishable from that of the parental, wild-type virus. Rhesus monkeys infected with the vpx deletion mutant showed lower levels of plasma antigenemia, lower virus burdens, and delayed declines in CD4+ lymphocyte concentrations but nonetheless progressed with AIDS to a terminal stage. The vpr+vpx double mutant was severely attenuated, with much lower virus burdens and no evidence of disease progression. These and other results indicate that vpr provides only a slight facilitating advantage for wild-type SIVmac replication in vivo. Thus, progression to AIDS and death can occur in the absence of a gene for vpr or vpx.


Application of IgG-derived natural Treg epitopes (IgG Tregitopes) to antigen-specific tolerance induction in a murine model of type 1 diabetes.
HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called "Tregitopes") have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigens ex vivo and on the modulation of type 1 diabetes (T1D) in a murine model in vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on T cell responses, we evaluated the effect of Tregitope treatment in DO11.10 mice. Upregulation of FoxP3 in KJ1-26-stained OVA-specific CD4(+) T cells was observed following treatment of DO11.10 mice with Tregitopes, along with reductions in anti-OVA Ig and T effector responses. In ex vivo studies of human T cells, peripheral blood mononuclear cells' (PBMC) responses to GAD65 epitopes in the presence and absence of Tregitope were variable. Suppression of immune responses to GAD65 epitopes ex vivo by Tregitope appeared to be more effective in assays using PBMC from a newly diagnosed diabetic subject than for other more established diabetic subjects, and correlation of the degree of suppression with predicted HLA restriction of the Tregitopes was confirmed. Implementation of these defined regulatory T cell epitopes for therapy of T1D and other autoimmune diseases may lead to a paradigm shift in disease management.


Assessment of charge-transfer excitations with time-dependent, range-separated density functional theory based on long-range MP2 and multiconfigurational self-consistent field wave functions.
Charge transfer excitations can be described within Time-Dependent Density Functional Theory (TD-DFT), not only by means of the Coulomb Attenuated Method (CAM) but also with a combination of wave function theory and TD-DFT based on range separation. The latter approach enables a rigorous formulation of multi-determinantal TD-DFT schemes where excitation classes, which are absent in conventional TD-DFT spectra (like for example double excitations), can be addressed. This paper investigates the combination of both the long-range Multi-Configuration Self-Consistent Field (MCSCF) and Second Order Polarization Propagator Approximation (SOPPA) ansätze with a short-range DFT (srDFT) description. We find that the combinations of SOPPA or MCSCF with TD-DFT yield better results than could be expected from the pure wave function schemes. For the Time-Dependent MCSCF short-range DFT ansatz (TD-MC-srDFT) excitation energies calculated over a larger benchmark set of molecules with predominantly single reference character yield good agreement with their reference values, and are in general comparable to the CAM-B3LYP functional. The SOPPA-srDFT scheme is tested for a subset of molecules used for benchmarking TD-MC-srDFT and performs slightly better against the reference data for this small subset. Beyond the proof-of-principle calculations comprising the first part of this contribution, we additionally studied the low-lying singlet excited states (S1 and S2) of the retinal chromophore. The chromophore displays multireference character in the ground state and both excited states exhibit considerable double excitation character, which in turn cannot be described within standard TD-DFT, due to the adiabatic approximation. However, a TD-MC-srDFT approach can account for the multireference character, and excitation energies are obtained with accuracy comparable to CASPT2, although using a much smaller active space.


Management Strategy Evaluation Applied to Coral Reef Ecosystems in Support of Ecosystem-Based Management.
Ecosystem modelling is increasingly used to explore ecosystem-level effects of changing environmental conditions and management actions. For coral reefs there has been increasing interest in recent decades in the use of ecosystem models for evaluating the effects of fishing and the efficacy of marine protected areas. However, ecosystem models that integrate physical forcings, biogeochemical and ecological dynamics, and human induced perturbations are still underdeveloped. We applied an ecosystem model (Atlantis) to the coral reef ecosystem of Guam using a suite of management scenarios prioritized in consultation with local resource managers to review the effects of each scenario on performance measures related to the ecosystem, the reef-fish fishery (e.g., fish landings) and coral habitat. Comparing tradeoffs across the selected scenarios showed that each scenario performed best for at least one of the selected performance indicators. The integrated 'full regulation' scenario outperformed other scenarios with four out of the six performance metrics at the cost of reef-fish landings. This model application quantifies the socio-ecological costs and benefits of alternative management scenarios. When the effects of climate change were taken into account, several scenarios performed equally well, but none prevented a collapse in coral biomass over the next few decades assuming a business-as-usual greenhouse gas emissions scenario.


Frontal electroencephalogram activation asymmetry, emotional intelligence, and externalizing behaviors in 10-year-old children.
The purpose of the present study was to examine the relations among resting frontal brain electrical activity (EEG) (hypothesized to reflect a predisposition to positive versusnegative affect and ability to regulate emotions), emotional intelligence, and externalizing behaviors in a sample of non-clinical 10-year-old children. We found that boys had significantly lower emotional intelligence than girls, and low emotional intelligence was associated with significantly more externalizing behaviors (i.e., aggression and delinquency), replicating previous work. We also found that children with higher reported externalizing behaviors exhibited significantly greater relative right frontal EEG activity at rest compared with children with little to no externalizing behavioral problems. There was, however, no relation between emotional intelligence and the pattern of resting frontal EEG activity. Thus, emotional intelligence and the pattern of frontal EEG activation at rest are independent predictors of externalizing behaviors in children. Findings also suggest that individual differences in emotional intelligence may not be based on differences in levels of emotional regulation or the generation of positive affect as reflected in frontal EEG asymmetries, but rather other social and cognitive competencies required for adaptive behavior.


Core knowledge.
Human cognition is founded, in part, on four systems for representing objects, actions, number, and space. It may be based, as well, on a fifth system for representing social partners. Each system has deep roots in human phylogeny and ontogeny, and it guides and shapes the mental lives of adults. Converging research on human infants, non-human primates, children and adults in diverse cultures can aid both understanding of these systems and attempts to overcome their limits.


Modulation of collagen metabolism by the topical application of dehydroepiandrosterone to human skin.
Dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEA-S) are the most abundantly produced human adrenal steroids to be reduced with age. DHEA may be related to the process of skin aging through the regulation and degradation of extracelluar matrix protein. In this study, we demonstrate that DHEA can increase procollagen synthesis and inhibit collagen degradation by decreasing matrix metalloproteinases (MMP)-1 synthesis and increasing tisuue inhibitor of matrix metalloprotease (TIMP-1) production in cultured dermal fibroblasts. DHEA was found to inhibit ultraviolet (UV)-induced MMP-1 production and the UV-induced decrease of procollagen synthesis, probably due to the inhibition of UV-induced AP-1 activity. DHEA (5%) in ethanol:olive oil (1:2) was topically applied to buttock skin of volunteers 12 times over 4 weeks, and was found to significantly increase the expression of procollagen alpha1(I) mRNA and protein in both aged and young skin. On the other hand, topical DHEA significantly decreased the basal expression of MMP-1 mRNA and protein, but increased the expression of TIMP-1 protein in aged skin. We also found that DHEA induced the expressions of transforming growth factor-beta1 and connective tissue growth factor mRNA in cultured fibroblasts and aged skin, which may play a role in the DHEA-induced changes of procollagen and MMP-1 expression. Our results suggest the possibility of using DHEA as an anti-skin aging agent.


Long-Term Safety of Guselkumab in Patients with Psoriatic Disease: An Integrated Analysis of Eleven Phase II/III Clinical Studies in Psoriasis and Psoriatic Arthritis.
The benefit/risk profiles of biologics can be affected by comorbidities, certain demographic characteristics, and concomitant medications; therefore, it is important to evaluate the long-term safety profiles of biologics across broad patient populations. Guselkumab was well tolerated and efficacious across individual pivotal clinical studies in adults with moderate-to-severe psoriasis and/or active psoriatic arthritis (PsA). The objective of the current analysis was to evaluate guselkumab safety in a large population of patients with psoriatic disease by pooling adverse event (AE) data from 11 phase II/III studies (seven in psoriasis; four in PsA). Guselkumab was generally administered as 100 mg subcutaneous injections at Week 0, Week 4, then every 8 weeks (Q8W) in psoriasis studies and at Week 0, Week 4, then every 4 weeks (Q4W) or Q8W in PsA studies. Safety data were summarized for the placebo-controlled period (Weeks 0-16 in psoriasis; Weeks 0-24 in PsA) and through the end of the reporting period (up to 5 years in psoriasis; up to 2 years in PsA). Using the integrated data, incidence rates of key AEs were determined post hoc, adjusted for duration of follow-up, and reported per 100 patient-years (PYs). AE rates were also determined in subgroups of patients defined by sex, age, body mass index (BMI), and prior biologic use. During the placebo-controlled period, 1061 patients received placebo (395 PYs) and 2257 received guselkumab (856 PYs). Through the end of the reporting period, 4399 guselkumab-treated patients contributed 10,787 PYs of follow-up. During the placebo-controlled period, in the guselkumab and placebo groups, respectively, rates of AEs were 281 versus 272/100 PYs, and infections were 76.0 versus 72.2/100 PYs. Rates of serious AEs (5.6 vs. 7.8/100 PYs), AEs leading to discontinuation (4.9 vs. 6.6/100 PYs), serious infections (1.0 vs. 2.3/100 PYs), malignancy (0.59 vs. 0.25 patients/100 PYs), and major adverse cardiovascular events (MACE; 0.35 vs. 0.25/100 PYs) were low and comparable between guselkumab and placebo. Among guselkumab-treated patients, safety event rates through the end of the reporting period were numerically lower than or comparable with rates observed during the placebo-controlled period: AEs, 164/100 PYs; infections, 61.2/100 PYs; serious AEs, 5.4/100 PYs; AEs leading to discontinuation, 1.8/100 PYs; serious infections, 1.0/100 PYs; malignancy, 0.6/100 PYs; and MACE, 0.3/100 PYs. No AEs of Crohn's disease, ulcerative colitis, or active tuberculosis were reported among guselkumab-treated patients. In the psoriasis studies, no opportunistic infections were reported among guselkumab-treated patients. Three AEs of opportunistic infections were reported in guselkumab-treated patients with PsA (0.14/100 PYs; all after Week 52 in DISCOVER-2). AE rates were largely consistent across subgroups of guselkumab-treated patients defined by sex, age, BMI, and prior biologic use. In this analysis of 4399 guselkumab-treated patients with psoriatic disease followed for 10,787 PYs, guselkumab had a favorable AE profile. AE rates were similar between guselkumab- and placebo-treated patients and were consistent throughout long-term guselkumab treatment and across broad subgroups of patients with psoriatic disease. Clinicaltrials.gov identifiers: NCT01483599, NCT02207231, NCT02207244, NCT02203032, NCT02905331, NCT03090100, NCT02325219, NCT02319759, NCT03162796, NCT03158285, and NCT03796858.


A robust data-driven approach identifies four personality types across four large data sets.
Understanding human personality has been a focus for philosophers and scientists for millennia1. It is now widely accepted that there are about five major personality domains that describe the personality profile of an individual2,3. In contrast to personality traits, the existence of personality types remains extremely controversial4. Despite the various purported personality types described in the literature, small sample sizes and the lack of reproducibility across data sets and methods have led to inconclusive results about personality types5,6. Here we develop an alternative approach to the identification of personality types, which we apply to four large data sets comprising more than 1.5 million participants. We find robust evidence for at least four distinct personality types, extending and refining previously suggested typologies. We show that these types appear as a small subset of a much more numerous set of spurious solutions in typical clustering approaches, highlighting principal limitations in the blind application of unsupervised machine learning methods to the analysis of big data.


Upper gastrointestinal acute graft-versus-host disease adds minimal prognostic value in isolation or with other graft-versus-host disease symptoms as currently diagnosed and treated.
Upper gastrointestinal acute graft-versus-host disease is reported in approximately 30% of hematopoietic stem cell transplant recipients developing acute graft-versus-host disease. Currently classified as Grade II in consensus criteria, upper gastrointestinal acute graft-versus-host disease is often treated with systemic immunosuppression. We reviewed the Center for International Blood and Marrow Transplant Research database to assess the prognostic implications of upper gastrointestinal acute graft-versus-host disease in isolation or with other acute graft-versus-host disease manifestations. 8567 adult recipients of myeloablative allogeneic hematopoietic stem cell transplant receiving T-cell replete grafts for acute leukemia, chronic myeloid leukemia or myelodysplastic syndrome between 2000 and 2012 were analyzed. 51% of transplants were from unrelated donors. Reported upper gastrointestinal acute graft-versus-host disease incidence was 12.1%; 2.7% of recipients had isolated upper gastrointestinal acute graft-versus-host disease, of whom 95% received systemic steroids. Patients with isolated upper gastrointestinal involvement had similar survival, disease-free survival, transplant-related mortality, and relapse as patients with Grades 0, I, or II acute graft-versus-host disease. Unrelated donor recipients with isolated upper gastrointestinal acute graft-versus-host disease had less subsequent chronic graft-versus-host disease than those with Grades I or II disease (P=0.016 and P=0.0004, respectively). Upper gastrointestinal involvement added no significant prognostic information when present in addition to other manifestations of Grades I or II acute graft-versus-host disease. If upper gastrointestinal symptoms were reclassified as Grade 0 or I, 425 of 2083 patients (20.4%) with Grade II disease would be downgraded, potentially impacting the interpretation of clinical trial outcomes. Defining upper gastrointestinal acute graft-versus-host disease as a Grade II entity, as it is currently diagnosed and treated, is not strongly supported by this analysis. The general approach to diagnosis, treatment and grading of upper gastrointestinal symptoms and their impact on subsequent acute graft-versus-host disease therapy warrants reevaluation.


Observations on spiny dogfish ( Squalus acanthias) captured in late spring in a North Carolina estuary.
Five spiny dogfish were captured in early-mid May during gillnet and longline sampling targeting juvenile coastal sharks in inshore North Carolina waters. Dogfish captures were made within Back Sound and Core Sound, North Carolina. All dogfish were females measuring 849-905 mm total length, well over the size at 50% maturity. Dogfish were caught at stations 1.8-2.7 m in depth, with temperatures 22.9-24.2 °C, 32.8-33.4 ppt salinity, and 6.9-8.0 mg/L dissolved oxygen. These observations are among the latest in the spring for spiny dogfish in the southeastern U.S. and occurred at higher temperatures than previously recorded for this species. It is unclear whether late-occurring spiny dogfish in this area represent a cryptic late-migrating or resident segment of the Northwest Atlantic population.


Two-year effects of an interdisciplinary intervention on recovery following hip fracture in older Taiwanese with cognitive impairment.
This article aims to evaluate the long-term effects of an interdisciplinary intervention program on cognitively impaired older persons after hip fracture in Taiwan. Of 160 subjects randomly assigned to control (n = 81) and intervention (n = 79) groups, 24 (29.6%) and 27 (34.2%) were cognitively impaired in the control and intervention groups, respectively, and outcomes were followed for 2 years after discharge. Among cognitively impaired subjects, more in the intervention group recovered their previous walking ability (odds ratio [OR] =3.49; confidence interval [CI] = 1.64 to 7.42), activities of daily life performance (β = 18.59; p = 0.0002), and more were readmitted to the hospital (OR = 4.44, CI = 1.53 to 12.89) than those in the control group during the first 2 years following discharge. Among subjects without cognitive impairment, more in the intervention group recovered their previous walking ability (OR = 2.6; CI = 1.33 to 5.07), had fewer falls (OR = 0.47; CI = 0.25 to 0.86), and made fewer emergency room visits (OR = 0.33; CI = 0.11 to 0.97) during the first 2 years following discharge than those in the control group. Cognitively impaired individuals benefited from our interdisciplinary intervention by improving their walking ability and physical function during the first 2 years following discharge. Specific strategies on fall prevention following hip fracture need to be further developed for cognitively impaired individuals.


Nanopatterned textile-based wearable triboelectric nanogenerator.
Here we report a fully flexible, foldable nanopatterned wearable triboelectric nanogenerator (WTNG) with high power-generating performance and mechanical robustness. Both a silver (Ag)-coated textile and polydimethylsiloxane (PDMS) nanopatterns based on ZnO nanorod arrays on a Ag-coated textile template were used as active triboelectric materials. A high output voltage and current of about 120 V and 65 μA, respectively, were observed from a nanopatterned PDMS-based WTNG, while an output voltage and current of 30 V and 20 μA were obtained by the non-nanopatterned flat PDMS-based WTNG under the same compressive force of 10 kgf. Furthermore, very high voltage and current outputs with an average value of 170 V and 120 μA, respectively, were obtained from a four-layer-stacked WTNG under the same compressive force. Notably it was found there are no significant differences in the output voltages measured from the multilayer-stacked WTNG over 12 000 cycles, confirming the excellent mechanical durability of WTNGs. Finally, we successfully demonstrated the self-powered operation of light-emitting diodes, a liquid crystal display, and a keyless vehicle entry system only with the output power of our WTNG without any help of external power sources.


A pilot randomised controlled trial of negative pressure wound therapy to treat grade III/IV pressure ulcers [ISRCTN69032034].
Negative pressure wound therapy (NPWT) is widely promoted as a treatment for full thickness wounds; however, there is a lack of high-quality research evidence regarding its clinical and cost effectiveness. A trial of NPWT for the treatment of grade III/IV pressure ulcers would be worthwhile but premature without assessing whether such a trial is feasible. The aim of this pilot randomised controlled trial was to assess the feasibility of conducting a future full trial of NPWT for the treatment of grade III and IV pressure ulcers and to pilot all aspects of the trial. This was a two-centre (acute and community), pilot randomised controlled trial. Eligible participants were randomised to receive either NPWT or standard care (SC) (spun hydrocolloid, alginate or foam dressings). Outcome measures were time to healing of the reference pressure ulcer, recruitment rates, frequency of treatment visits, resources used and duration of follow-up. Three hundred and twelve patients were screened for eligibility into this trial over a 12-month recruitment period and 12/312 participants (3.8%) were randomised: 6 to NPWT and 6 to SC. Only one reference pressure ulcer healed (NPWT group) during follow-up (time to healing 79 days). The mean number of treatment visits per week was 3.1 (NPWT) and 5.7 (SC); 6/6 NPWT and 1/6 SC participants withdrew from their allocated trial treatment. The mean duration of follow-up was 3.8 (NPWT) and 5.0 (SC) months. This pilot trial yielded vital information for the planning of a future full study including projected recruitment rate, required duration of follow-up and extent of research nurse support required. Data were also used to inform the cost-effectiveness and value of information analyses, which were conducted alongside the pilot trial. Current Controlled Trials ISRCTN69032034.


Interferon-beta interferes with the proliferation but not with the cytokine secretion of myelin basic protein-specific, T-helper type 1 lymphocytes.
Interferon-beta (IFN-beta) has beneficial effects on the frequency and severity of relapses, as well as on disease progression in patients suffering from relapsing-remitting MS. Its mode of action, however, is not completely understood. Previous studies on T-lymphocyte bulk cultures and T-lymphocyte lines with specificity for different antigens suggested that the drug might partially act via suppression of T-cell proliferation and secretion of proinflammatory cytokines like interferon-gamma (IFN-gamma) and/or tumor necrosis factor-alpha (TNF-alpha). In this study we investigated the effects of human recombinant IFN-beta 1b on proliferation, interleukin 2 (IL-2) receptor (IL-2R) alpha-chain upregulation, and cytokine and chemokine secretion of myelin basic protein-reactive, MS patient-derived T-cell clones secreting T-helper type 1 (Th1) cytokines. IFN-beta partially suppressed both antigen- and IL-2-driven proliferation of these cells without affecting the expression of either IL-2 or IL-2R alpha-chain. There was no inhibitory effect on the secretion of IFN-gamma, TNF-alpha, and macrophage inflammatory protein (MIP)-1 alpha, but release was rather slightly enhanced. In conclusion, while IFN-beta does reduce proliferation of Th1-like, MBP-specific T cells in vitro, the drug does not result in overall dysfunction of these cells. Therefore, the effect of IFN-beta on MS may not depend on a primary inhibition of potentially encephalitogenic T lymphocytes.


Bayesian evaluation of budgets for endemic disease control: An example using management changes to reduce milk somatic cell count early in the first lactation of Irish dairy cows.
The aim of this research was to determine budgets for specific management interventions to control heifer mastitis in Irish dairy herds as an example of evidence synthesis and 1-step Bayesian micro-simulation in a veterinary context. Budgets were determined for different decision makers based on their willingness to pay. Reducing the prevalence of heifers with a high milk somatic cell count (SCC) early in the first lactation could be achieved through herd level management interventions for pre- and peri-partum heifers, however the cost effectiveness of these interventions is unknown. A synthesis of multiple sources of evidence, accounting for variability and uncertainty in the available data is invaluable to inform decision makers around likely economic outcomes of investing in disease control measures. One analytical approach to this is Bayesian micro-simulation, where the trajectory of different individuals undergoing specific interventions is simulated. The classic micro-simulation framework was extended to encompass synthesis of evidence from 2 separate statistical models and previous research, with the outcome for an individual cow or herd assessed in terms of changes in lifetime milk yield, disposal risk, and likely financial returns conditional on the interventions being simultaneously applied. The 3 interventions tested were storage of bedding inside, decreasing transition yard stocking density, and spreading of bedding evenly in the calving area. Budgets for the interventions were determined based on the minimum expected return on investment, and the probability of the desired outcome. Budgets for interventions to control heifer mastitis were highly dependent on the decision maker's willingness to pay, and hence minimum expected return on investment. Understanding the requirements of decision makers and their rational spending limits would be useful for the development of specific interventions for particular farms to control heifer mastitis, and other endemic diseases.


Ultraviolet lasing in cholesteric liquid crystals.
We report the observation of stimulated emission and mirrorless lasing in pure cholesteric liquid crystals. The lasing action is attributed to the combination of the fluorescence and the distributed feedback that are due to the inherent periodic structure of the liquid crystal. If the reflection band matches the intrinsic emission of the cholesteric liquid crystal, the crystal becomes a natural laser material, which will self-lase, without any optical elements or the addition of dyes, under picosecond excitation at 355 nm. Samples have been made to lase at different wavelengths in the near UV by shifting of the edge of the reflection band in the range of 385-405 nm. Typical linewidths observed are of the order of 0.5 nm.


Radiological Imaging of Rare Intracranial Complications Secondary to Otitis Media and Mastoiditis.
Acute otitis media used to cause fatal results because of its intracranial complications before the introduction of potent and effective antibiotics. After the introduction of antibiotics, complications have started to be observed more frequently as a result of chronic otitis media and especially in children. Because clinical findings changed and became indistinct, the diagnosis of otitis and mastoiditis has been made occasionally with imaging findings only after complications occurred. Multidetector computed tomography and magnetic resonance imaging are efficient and sufficient methods in the rapid diagnosis and should be immediately referred methods.


Overlaps between autism and language impairment: phenomimicry or shared etiology?
Traditionally, autistic spectrum disorder (ASD) and specific language impairment (SLI) are regarded as distinct conditions with separate etiologies. Yet these disorders co-occur at above chance levels, suggesting shared etiology. Simulations, however, show that additive pleiotropic genes cannot account for observed rates of language impairment in relatives, which are higher for probands with SLI than for those with ASD + language impairment. An alternative account is in terms of 'phenomimicry', i.e., language impairment in comorbid cases may be a consequence of ASD risk factors, and different from that seen in SLI. However, this cannot explain why molecular genetic studies have found a common risk genotype for ASD and SLI. This paper explores whether nonadditive genetic influences could account for both family and molecular findings. A modified simulation involving G x G interactions obtained levels of comorbidity and rates of impairment in relatives more consistent with observed values. The simulations further suggest that the shape of distributions of phenotypic trait scores for different genotypes may provide evidence of whether a gene is involved in epistasis.


Mefloquine is highly efficacious against chloroquine-resistant Plasmodium vivax malaria and Plasmodium falciparum malaria in Papua, Indonesia.
During the period of 1996-1999, we prospectively monitored 243 Javanese adults and children after arriving in Papua, Indonesia, and microscopically documented each new case of malaria by active surveillance. In a randomized, open-label, comparative malaria treatment trial, 72 adults and 50 children received chloroquine for each incident case of malaria, and 74 adults and 47 children received mefloquine. Among 975 primary treatment courses, the cumulative 28-day curative efficacies were 26% and 82% for chloroquine against Plasmodium falciparum malaria and Plasmodium vivax malaria, respectively. Mefloquine cure rates were far superior (96% against P. falciparum malaria and 99.6% against P. vivax malaria). Mefloquine is a useful alternative treatment for P. vivax malaria and P. falciparum malaria in areas such as Papua, where chloroquine is still recommended as the first-line therapeutic agent.


Investigation of interfacial thermal transport across graphene and an organic semiconductor using molecular dynamics simulations.
The interfacial thermal transport across graphene and an organic semiconductor, dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DNTT), is investigated using molecular dynamics simulations. The average thermal boundary resistance (TBR) of graphene and DNTT is 4.88 ± 0.12 × 10-8 m2 K W-1 at 300 K. We find that TBR of a graphene-DNTT heterostructure possesses as high as 83.4% reduction after the hydrogenation of graphene. Moreover, as the graphene vacancy increases from 0% to 6%, the TBR drops up to 39.6%. The reduction of TBR is mainly attributed to the coupling enhancement of graphene and DNTT phonons as evaluated from the phonon density of states. On the other hand, TBR keeps a constant value while the vacancy in the DNTT layer increases. The TBR would decrease when the temperature and coupling strength increase. These findings provide a useful guideline for the thermal management of the graphene-based organic electronic devices, especially the large area transistor arrays or sensors.


Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system.
Angiotensin II, acting through type 1 angiotensin (AT(1)) receptors, has potent effects that alter renal excretory mechanisms. Control of sodium excretion by the kidney has been suggested to be the critical mechanism for blood pressure regulation by the renin-angiotensin system (RAS). However, since AT(1) receptors are ubiquitously expressed, precisely dissecting their physiological actions in individual tissue compartments including the kidney with conventional pharmacological or gene targeting experiments has been difficult. Here, we used a cross-transplantation strategy and AT(1A) receptor-deficient mice to demonstrate distinct and virtually equivalent contributions of AT(1) receptor actions in the kidney and in extrarenal tissues to determining the level of blood pressure. We demonstrate that regulation of blood pressure by extrarenal AT(1A) receptors cannot be explained by altered aldosterone generation, which suggests that AT(1) receptor actions in systemic tissues such as the vascular and/or the central nervous systems make nonredundant contributions to blood pressure regulation. We also show that interruption of the AT(1) receptor-mediated short-loop feedback in the kidney is not sufficient to explain the marked stimulation of renin production induced by global AT(1) receptor deficiency or by receptor blockade. Instead, the renin response seems to be primarily determined by renal baroreceptor mechanisms triggered by reduced blood pressure. Thus, the regulation of blood pressure by the RAS is mediated by AT(1) receptors both within and outside the kidney.


Regulation of cytoplasmic dynein function in vivo by the Drosophila Glued complex.
The Drosophila Glued gene product shares sequence homology with the p150 component of vertebrate dynactin. Dynactin is a multiprotein complex that stimulates cytoplasmic dynein-mediated vesicle motility in vitro. In this report, we present biochemical, cytological, and genetic evidence that demonstrates a functional similarity between the Drosophila Glued complex and vertebrate dynactin. We show that, similar to the vertebrate homologues in dynactin, the Glued polypeptides are components of a 20S complex. Our biochemical studies further reveal differential expression of the Glued polypeptides, all of which copurify as microtubule-associated proteins. In our analysis of the Glued polypeptides encoded by the dominant mutation, Glued, we identify a truncated polypeptide that fails to assemble into the wild-type 20S complex, but retains the ability to copurify with microtubules. The spatial and temporal distribution of the Glued complex during oogenesis is shown by immunocytochemistry methods to be identical to the pattern previously described for cytoplasmic dynein. Significantly, the pattern of Glued distribution in oogenesis is dependent on dynein function, as well as several other gene products known to be required for proper dynein localization. In genetic complementation studies, we find that certain mutations in the cytoplasmic dynein heavy chain gene Dhc64C act as dominant suppressors or enhancers of the rough eye phenotype of the dominant Glued mutation. Furthermore, we show that a mutation that was previously isolated as a suppressor of the Glued mutation is an allele of Dhc64C. Together with the observed dependency of Glued localization on dynein function, these genetic interactions demonstrate a functional association between the Drosophila dynein motor and Glued complexes.


Influence of surgical arch reconstruction methods on single ventricle workload in the Norwood procedure.
The study objective was to evaluate various types of Norwood arch reconstruction methods and to show the factors that affect the cardiac workload of the single ventricle. The Norwood procedure is one of the most challenging congenital heart surgeries. Several aortic arch reconstruction techniques have been reported to avoid recoarctation, ensure coronary perfusion, and improve long-term outcomes. Inside the arch, complicated turbulent flow is generated; however, little is known about the cause of the disadvantageous inefficient flow and the surgical techniques to avoid it. We created patient-specific computational hemodynamic models of 9 patients who underwent different types of arch reconstruction methods. Four patients had aortic atresia, and 5 patients had aortic stenosis. Flow profiles were defined by echocardiography data corrected with body surface area. Turbulent pulsatile flow was analyzed with the finite volume method. Flow energy loss was calculated to estimate cardiac workload, and wall shear stress was calculated to estimate vessel wall stiffness increase. Recoarctation and acute arch angles increased wall shear stress and energy loss. In the patients with aortic atresia, a longitudinal incision toward the descending aorta was effective in creating a smooth arch angle. In the patients with aortic stenosis, arch repair with the Damus-Kaye-Stansel procedure in a single anastomotic site was effective in creating sufficient anastomosis space and a smooth arch angle. Creation of a large anastomotic space and a smooth aortic arch angle reduced wall shear stress and energy loss, and should improve long-term cardiac performance after the Norwood procedure.


[Renal Damage and Obesity: a Silent Pairing].
Obesity is recognized as a true chronic disease and an independent risk factor for kidney disease. In particular, a correlation was observed between obesity and the development of focal segmental glomerulosclerosis. The clinical consequences of obesity on the kidney can include albuminuria, nephrotic syndrome, nephrolithiasis, and increased risk of development and progression of renal failure. Conventional therapy, which includes low-calorie diet, exercise, lifestyle changes, and drug therapy, including GLP1-RA, phentermine, phentermine/topiramate, bupropion/naltrexone, orlistat, is not always able to achieve the desired results and above all does not guarantee stabilization of body weight over time. On the other hand, bariatric surgery is giving excellent results in terms of efficacy and duration. Bariatric surgery techniques that are generally divided into restrictive, malabsorptive, and mixed are not free from possible metabolic complications such as anemia, vitamin deficiency, and stones. However, they are able to ensure a good maintenance of weight loss obtained with disappearance or reduction of the incidence and severity of comorbidities related to obesity.


ESMO / ASCO Recommendations for a Global Curriculum in Medical Oncology Edition 2016.
The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.


Comparison of aberrations in different types of progressive power lenses.
Recently, computer numerically controlled machines have permitted the manufacture of progressive power lenses (PPLs) with different designs. However, the possible differences in optical performance among lens designs are not yet well established. In this work, the spatially resolved aberrations, at 20 relevant locations, of three PPLs with different designs were measured with a Hartmann-Shack wavefront sensor. The wavefront aberration (WA), its root mean square error (RMS) and the point-spread function were obtained. Spatially resolved plots are shown for all aberrations, astigmatism alone, and for higher order aberrations. The average RMS of all zones is also compared, and the standard deviation is used as a parameter to evaluate the level of hard-soft design. We find differences in the spatial distribution of the aberrations but not in the global RMS, indicating that current PPLs are rather similar to a waterbed, with the aberrations being the water: they can be moved but they cannot be eliminated.


A qualitative synthesis of gastro-oesophageal reflux in bronchiectasis: Current understanding and future risk.
Gastro-oesophageal reflux disease (GORD) is a common comorbidity in bronchiectasis, and is often associated with poorer outcomes. The cause and effect relationship between GORD and bronchiectasis has not yet been fully elucidated and a greater understanding of the pathophysiology of the interaction and potential therapies is required. This review explores the underlying pathophysiology of GORD, its clinical presentation, risk factors, commonly applied diagnostic tools, and a detailed synthesis of original articles evaluating the prevalence of GORD, its influence on disease severity and current management strategies within the context of bronchiectasis. The prevalence of GORD in bronchiectasis ranges from 26% to 75%. Patients with co-existing bronchiectasis and GORD were found to have an increased mortality and increased bronchiectasis severity, manifest by increased symptoms, exacerbations, hospitalisations, radiological extent and chronic infection, with reduced pulmonary function and quality of life. The pathogenic role of Helicobacter pylori infection in bronchiectasis, perhaps via aspiration of gastric contents, also warrants further investigation. Our index of suspicion for GORD should remain high across the spectrum of disease severity in bronchiectasis. Identifying GORD in bronchiectasis patients may have important therapeutic and prognostic implications, although clinical trial evidence that treatment targeted at GORD can improve outcomes in bronchiectasis is currently lacking.


COPD from an everyday primary care point of view.
The purpose of this study is to use real world evidence on treatment use to evaluate drug superiority within the same treatment group. Retrospective cohort analysis using the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP). Data includes longitudinal routine clinical data extracted from practice records of 7,890,485 patients. All subjects with an incident diagnosis of COPD in the database BIFAP between January 1 2010 and December 31 2012 were included in the cohort study. Cox regression analysis was performed to compare the hazard of COPD exacerbation outcome of the four principal cohorts (no therapy, monotherapy, double therapies with and without corticoids, and triple therapy) and within each principal cohort between the different treatment combinations. 27,739 patients with COPD were included in the analysis. The median age was 64 years, male proportion was 69% and 70% were smokers. 58,042.9 person--years of follow-up were obtained for the cohort with a mean follow-up of 2.09 years per subject. The strongest factor associated with an increased risk of exacerbation was suffering an exacerbation the previous year (HR = 1.82[1.76--1.87 95%CI]). No differences were found between the most frequent monotherapies, double therapies without corticoid, or triple therapy. When comparing the different combinations of double therapies with corticoid, salmeterol/fluticasone combination (HR = 1.16[1.08--1.24]) revealed a higher adjusted hazard of exacerbation when compared with formoterol/budesonide. Treatment with a combination of budesonide/formoterol was associated with lower exacerbations than the treatment with fluticasone/salmeterol. The analysis did not reveal any differences in terms of exacerbation in monotherapy, double therapy without corticoids, and triple therapy combinations.


Exposure to indoor biomass fuel and tobacco smoke and risk of adverse reproductive outcomes, mortality, respiratory morbidity and growth among newborn infants in south India.
Exposure to indoor air pollution due to open burning of biomass fuel is common in low- and middle-income countries. Previous studies linked this exposure to an increased risk of respiratory illness, low birth weight (LBW) and other disorders. We assessed the association between exposure to biomass fuel sources and second-hand tobacco smoke (SHTS) in the home and adverse health outcomes in early infancy in a population in rural south India. A population-based cohort of newborns was followed from birth through 6 months. Household characteristics were assessed during an enrolment interview including the primary type of cooking fuel and smoking behaviour of household residents. Follow-up visits for morbidity were carried out every 2 weeks after delivery. Infants were discharged at 6 months when anthropometric measurements were collected. 11 728 live-born infants were enrolled and followed, of whom 92.3% resided in households that used wood and/or dung as a primary source of fuel. Exposure to biomass fuel was associated with an adjusted 49% increased risk of LBW, a 34% increased incidence of respiratory illness and a 21% increased risk of 6-month infant mortality. Exposed infants also had 45 and 30% increased risks of underweight and stunting at 6 months. SHTS exposure was also associated with these adverse health outcomes except for attained growth. Open burning of biomass fuel in the home is associated with significant health risks to the newborn child and young infant. Community-based trials are needed to clarify causal connections and identify effective approaches to reduce this burden of illnesses.


Lossless compression of hyperspectral images using hybrid context prediction.
In this letter a new algorithm for lossless compression of hyperspectral images using hybrid context prediction is proposed. Lossless compression algorithms are typically divided into two stages, a decorrelation stage and a coding stage. The decorrelation stage supports both intraband and interband predictions. The intraband (spatial) prediction uses the median prediction model, since the median predictor is fast and efficient. The interband prediction uses hybrid context prediction. The hybrid context prediction is the combination of a linear prediction (LP) and a context prediction. Finally, the residual image of hybrid context prediction is coded by the arithmetic coding. We compare the proposed lossless compression algorithm with some of the existing algorithms for hyperspectral images such as 3D-CALIC, M-CALIC, LUT, LAIS-LUT, LUT-NN, DPCM (C-DPCM), JPEG-LS. The performance of the proposed lossless compression algorithm is evaluated. Simulation results show that our algorithm achieves high compression ratios with low complexity and computational cost.


Multiplex RT-PCR assays for the simultaneous detection of both RNA and DNA viruses infecting cassava and the common occurrence of mixed infections by two cassava brown streak viruses in East Africa.
Uniplex and multiplex reverse transcription-polymerase chain reaction (RT-PCR) protocols were developed for the detection of cassava brown streak viruses (CBSVs) in single and mixed infections with cassava mosaic begomoviruses (CMBs) in a tropical crop plant, cassava (Manihot esculenta). CMBs contain ssDNA as their genome (genus Begomovirus, family Geminiviridae) while CBSVs are made up of positive sense ssRNA (genus Ipomovirus, family Potyviridae), and they cause the economically important cassava mosaic and cassava brown streak diseases, respectively, in sub-Saharan Africa. Diagnostic methodologies have long been available for CMBs but they are limited for CBSVs especially in mixed infections. In this study, the two CBSVs, Cassava brown streak virus (CBSV) and Cassava brown streak Uganda virus (CBSUV) occurring singly or in mixed infection with CMBs, African cassava mosaic virus and East African cassava mosaic virus were detected in a single RT-PCR using both previously described and newly designed virus-specific primers. These protocols were highly efficient for detecting CBSVs compared to the existing methods and have great potential to minimize sample handling and contamination. As well as improving the diagnosis of cassava viruses, the development of multiplex RT-PCR protocols have revealed the common occurrence of mixed infections by CBSV and CBSUV in cassava fields of Tanzania and Kenya, which was contrary to the common belief until recently that these two viruses have existed separately. These protocols have implications for diagnosis and epidemiological studies on cassava virus diseases in Eastern Africa.


Defects in glucuronate biosynthesis disrupt Wingless signaling in Drosophila.
In vitro experiments suggest that glycosaminoglycans (GAGs) and the proteins to which they are attached (proteoglycans) are important for modulating growth factor signaling. However, in vivo evidence to support this view has been lacking, in part because mutations that disrupt the production of GAG polymers and the core proteins have not been available. Here we describe the identification and characterization of Drosophila mutants in the suppenkasper (ska) gene. The ska gene encodes UDP-glucose dehydrogenase which produces glucuronic acid, an essential component for the synthesis of heparan and chondroitin sulfate. ska mutants fail to put heparan side chains on proteoglycans such as Syndecan. Surprisingly, mutant embryos produced by germ-line clones of this general metabolic gene exhibit embryonic cuticle phenotypes strikingly similar to those that result from loss-of-function mutations in genes of the Wingless (Wg) signaling pathway. Zygotic loss of ska leads to reduced growth of imaginal discs and pattern defects similar to wg mutants. In addition, genetic interactions of ska with wg and dishevelled mutants are observed. These data demonstrate the importance of proteoglycans and GAGs in Wg signaling in vivo and suggest that Wnt-like growth factors may be particularly sensitive to perturbations of GAG biosynthesis.


A pooled analysis of thyroid cancer studies. V. Anthropometric factors.
To assess the relation between anthropometric factors and thyroid cancer risk in a pooled analysis of individual data from 12 case-control studies conducted in the US, Japan, China and Europe. 2056 female and 417 male cases, 3358 female and 965 male controls were considered. Odds ratios (OR) were derived from logistic regression, conditioning on age, A-bomb exposure (Japan) and study, and adjusting for radiotherapy. Compared to the lowest tertile of height, the pooled OR was 1.2 for females for the highest one, and 1.5 for males, and trends in risk were significant. With reference to weight at diagnosis, the OR for females was 1.2 for the highest tertile, and the trend in risk was significant, whereas no association was observed in males. Body mass index (BMI) at diagnosis was directly related to thyroid cancer risk in females (OR = 1.2 for the highest tertile), but not in males. No consistent pattern of risk emerged with BMI during the late teens. Most of the associations were observed both for papillary and follicular cancers, and in all age groups. However, significant heterogeneity was observed across studies. Height and weight at diagnosis are moderately related to thyroid cancer risk.


Ras oncogene mutations in childhood brain tumors.
Although N-nitroso compounds (NNC) are ubiquitous in the human environment and are known neurocarcinogens in animal models, results of epidemiological studies have not yet convincingly associated NNCs with brain tumor occurrence in humans. Animal studies have suggested that specific codons (12, 13, and 61) in the ras family are mutable by exposure to NNCs. The purpose of this study was to measure the presence of mutations in the ras family of oncogenes in tissue from childhood brain (CB) tumors as a preliminary step toward investigating their potential use as biomarkers of chemical exposure. DNA was extracted from paraffin-embedded formalin-fixed CB tumors from tissues resected during neurosurgical operations. Using the PCR, designed RFLP-screening methods, and sequencing, we attempted to screen brain tumors from 46 children for the presence of H, K, and N-ras mutations at codons 12, 13, and 61. Screening for oncogene mutations using PCR, RFLP methods, and DNA sequencing was successfully completed for a high proportion of the available specimens. Astrocytoma specimens from three children for whom screening with PCR was successfully completed were found to contain CAA-->GAA point mutations in K-ras at codon 61. None of the specimens contained mutations at any of the other locations. These results, although preliminary, provide a potential clue for future mechanistic studies of CB tumors. The possible roles of NNCs in inducing this mutation, or of this mutation as an early or late event in tumor progression, however, remain unclear.


Impact of Zr-Doped Bi2O3 Radiopacifier by Spray Pyrolysis on Mineral Trioxide Aggregate.
Mineral trioxide aggregates (MTA) have been developed as a dental root repair material for a range of endodontics procedures. They contain a small amount of bismuth oxide (Bi2O3) as a radiopacifier to differentiate adjacent bone tissue on radiographs for endodontic surgery. However, the addition of Bi2O3 to MTA will increase porosity and lead to the deterioration of MTA's mechanical properties. Besides, Bi2O3 can also increase the setting time of MTA. To improve upon the undesirable effects caused by Bi2O3 additives, we used zirconium ions (Zr) to substitute the bismuth ions (Bi) in the Bi2O3 compound. Here we demonstrate a new composition of Zr-doped Bi2O3 using spray pyrolysis, a technique for producing fine solid particles. The results showed that Zr ions were doped into the Bi2O3 compound, resulting in the phase of Bi7.38Zr0.62O12.31. The results of materials analysis showed Bi2O3 with 15 mol % of Zr doping increased its radiopacity (5.16 ± 0.2 mm Al) and mechanical strength, compared to Bi2O3 and other ratios of Zr-doped Bi2O3. To our knowledge, this is the first study of fabrication and analysis of Zr-doped Bi2O3 radiopacifiers through the spray pyrolysis procedure. The study reveals that spray pyrolysis can be a new technique for preparing Zr-doped Bi2O3 radiopacifiers for future dental applications.


Tracheal intubation in patients with cervical spine immobilization: A comparison of McGrath(®) video laryngoscope and Truview EVO2(®) laryngoscope.
Literature suggests that glottic view is better when using McGrath(®) Video laryngoscope and Truview(®) in comparison with McIntosh blade. The purpose of this study was to evaluate the effectiveness of McGrath Video laryngoscope in comparison with Truview laryngoscope for tracheal intubation in patients with simulated cervical spine injury using manual in-line stabilisation. This prospective randomised study was undertaken in operation theatre of a tertiary referral centre after approval from the Institutional Review Board. A total of 100 consenting patients presenting for elective surgery requiring tracheal intubation were randomly assigned to undergo intubation using McGrath(®) Video laryngoscope (n = 50) or Truview(®) (n = 50) laryngoscope. In all patients, we applied manual-in-line stabilisation of the cervical spine throughout the airway management. Statistical testing was conducted with the statistical package for the social science system version SPSS 17.0. Demographic data, airway assessment and haemodynamics were compared using the Chi-square test. A P < 0.05 was considered significant. The time to successful intubation was less with McGrath video laryngoscope when compared to Truview (30.02 s vs. 38.72 s). However, there was no significant difference between laryngoscopic views obtained in both groups. The number of second intubation attempts required and incidence of complications were negligible with both devices. Success rate of intubation with both devices was 100%. Intubation with McGrath Video laryngoscope caused lesser alterations in haemodynamics. Both laryngoscopes are reliable in case of simulated cervical spine injury using manual-in-line stabilisation with 100% success rate and good glottic view.


A structurally unique Fusobacterium nucleatum tannase provides detoxicant activity against gallotannins and pathogen resistance.
Colorectal cancer pathogenesis and progression is associated with the presence of Fusobacterium nucleatum and the reduction of acetylated derivatives of spermidine, as well as dietary components such as tannin-rich foods. We show that a new tannase orthologue of F. nucleatum (TanBFnn ) has significant structural differences with its Lactobacillus plantarum counterpart affecting the flap covering the active site and the accessibility of substrates. Crystallographic and molecular dynamics analysis revealed binding of polyamines to a small cavity that connects the active site with the bulk solvent which interact with catalytically indispensable residues. As a result, spermidine and its derivatives, particularly N8 -acetylated spermidine, inhibit the hydrolytic activity of TanBFnn and increase the toxicity of gallotannins to F. nucleatum. Our results support a model in which the balance between the detoxicant activity of TanBFnn and the presence of metabolic inhibitors can dictate either conducive or unfavourable conditions for the survival of F. nucleatum.


Tyrosinase is a new marker for cell populations in the mouse neural tube.
Tyrosinase, the key enzyme in melanin synthesis, is expressed in pigment cells derived from both neural crest and neuroectoderm. The present study was performed to detect tyrosinase promoter activity and tyrosinase gene expression during murine brain development. Mouse tyrosinase 5' region (6.1 Kb) was used to direct lacZ expression in transgenic mice. During embryogenesis, the transgene reproduced tyrosinase expression in pigment cells but was also observed in embryonic neuroectoderm and migrating neural crest cells. Both tyrosinase and lacZ were detected in cell populations often organized in columnar arrangements and found throughout the entire neural tube, in the cranial region as well as in the spinal chord. In the developing brain, the highest density of positive cells was localized to ventricular and subventricular zones and to evaginations of the neural tube such as optic vesicle, pineal gland, and olfactory bulbs. These results demonstrate that tyrosinase promoter activity and tyrosinase expression are not restricted to differentiated pigment cells. We suggest that tyrosinase is a new marker for cell populations in the neural tube, and that expression is correlated to regions undergoing rapid cell proliferation.


Laparoscopic radical hysterectomy with lymphadenectomy in patients with early cervical cancer: our instruments and technique.
The purpose of this study is to describe the technique of total laparoscopic radical hysterectomy (type III procedure) with lymphadenectomy as performed at the Advanced Gynecological Endoscopy Center of the Malzoni Medical Center, Avellino, Italy. Seventy-seven patients underwent total laparoscopic radical hysterectomy (type II, III) with lymphadenectomy between January 2000 and March 2008. FIGO stage included five patients Ia1 with LVSI (lymph-vascular involvement), 24 patients Ia2, and 48 patients Ib1. 60 patients underwent a class III procedure and 17 patients a class II procedure according to the Piver classification. Histological types included squamous cell carcinoma in 65 patients, adenocarcinomas in 10 patients, and adenosquamous carcinoma in two. Para-aortic lymphadenectomy was performed up to the level of the inferior mesenteric artery in eight cases with positive pelvic lymph nodes at frozen section evaluation. Total laparoscopic radical hysterectomy can be considered a safe and effective therapeutic procedure for the management of early stage cervical cancer with a low morbidity; moreover, the laparoscopic route may offer an alternative option for patients undergoing radical hysterectomy, although multicenter studies and long-term follow-up are required to evaluate the oncologic outcomes of this procedure.


Cytotoxic and sublethal effects of silver nanoparticles on tendon-derived stem cells - implications for tendon engineering.
Tendon injuries occur commonly in sports and workplace. Tendon-derived stem cells (TDSCs) have great potential for tendon healing because they can differentiate into functional tenocytes. To grow TDSCs properly in vivo, a scaffold is needed. Silver nanoparticles (AgNPs) have been used in a range of biomedical applications for their anti-bacterial and -inflammatory effects. AgNPs are therefore expected to be a good scaffolding coating material for tendon engineering. Yet, their cytotoxicity in TDSCs remains unknown. Moreover, their sublethal effects were mysterious in TDSCs. In our study, decahedral AgNPs (43.5 nm in diameter) coated with polyvinylpyrrolidone (PVP) caused a decrease in TDSCs' viability beginning at 37.5 μg ml-1 but showed non-cytotoxic effects at concentrations below 18.8 μg ml-1. Apoptosis was observed in the TDSCs when higher doses of AgNPs (75-150 μg ml-1) were used. Mechanistically, AgNPs induced reactive oxygen species (ROS) formation and mitochondrial membrane potential (MMP) depolarization, resulting in apoptosis. Interestingly, treating TDSCs with N-acetyl-l-cysteine (NAC) antioxidant significantly antagonized the ROS formation, MMP depolarization and apoptosis indicating that ROS accumulation was a prominent mediator in the AgNP-induced cytotoxicity. On the other hand, AgNPs inhibited the tendon markers' mRNA expression (0-15 μg ml-1), proliferation and clonogenicity (0-15 μg ml-1) in TDSCs under non-cytotoxic concentrations. Taken together, we have reported here for the first time that the decahedral AgNPs are cytotoxic to rat TDSCs and their sublethal effects are also detrimental to stem cells' proliferation and tenogenic differentiation. Therefore, AgNPs are not a good scaffolding coating material for tendon engineering.


Incidence of cervical dysplasia and cervical cancer in women living with HIV in Denmark: comparison with the general population.
Women living with HIV (WLWH) are reportedly at increased risk of invasive cervical cancer (ICC). WLWH in Denmark attend the National ICC screening program less often than women in the general population. We aimed to estimate the incidence of cervical dysplasia and ICC in WLWH in Denmark. We studied a nationwide cohort of WLWH and a cohort of age-matched females from the general population in the period 1999-2010. Pathology samples were obtained from The Danish Pathology Data Bank containing nationwide records of all pathology specimens. The cumulative incidence and hazard ratios (HRs) for time from inclusion to first cervical intraepithelial neoplasia (CIN)/ICC and time from first normal cervical cytology to first CIN/ICC were estimated. Sensitivity analyses were performed to include prior screening outcome, screening intensity and treatment of CIN/ICC in the interpretation of results. We followed 1,143 WLWH and 17,145 controls with no prior history of ICC for 9,509 and 157,362 person-years. Compared to controls, the overall incidence of CIN1 or worse (CIN1+), CIN2+ and CIN3+ was higher in WLWH and predicted by young age and CD4 count <200 cells/µL. In women with normal baseline cytology, incidences of CIN1+ and CIN2+ were higher in WLWH. However, incidences were comparable between WLWH and controls adherent to the National ICC screening program. Overall, WLWH develop more cervical disease than controls. However, incidences of CIN are comparable amongst WLWH and controls adherent to the National ICC screening program and with a normal baseline cytology.


Evidence of dissipative solitons in Yb³⁺:CaYAlO₄.
Operation of an end-pumped Yb³⁺:CaYAlO₄ laser operating in the positive dispersion regime is experimentally investigated. The laser emitted strongly chirped pulses with extremely steep spectral edges, resembling the characteristics of dissipative solitons observed in fiber lasers. The results show that dissipative soliton emission constitutes another operating regime for mode locked Yb³⁺-doped solid state lasers, which can be explored for the generation of stable large energy femtosecond pulses.


Implementation fidelity of a computer-assisted intervention for children with speech sound disorders.
Implementation fidelity refers to the degree to which an intervention or programme adheres to its original design. This paper examines implementation fidelity in the Sound Start Study, a clustered randomised controlled trial of computer-assisted support for children with speech sound disorders (SSD). Sixty-three children with SSD in 19 early childhood centres received computer-assisted support (Phoneme Factory Sound Sorter [PFSS] - Australian version). Educators facilitated the delivery of PFSS targeting phonological error patterns identified by a speech-language pathologist. Implementation data were gathered via (1) the computer software, which recorded when and how much intervention was completed over 9 weeks; (2) educators' records of practice sessions; and (3) scoring of fidelity (intervention procedure, competence and quality of delivery) from videos of intervention sessions. Less than one-third of children received the prescribed number of days of intervention, while approximately one-half participated in the prescribed number of intervention plays. Computer data differed from educators' data for total number of days and plays in which children participated; the degree of match was lower as data became more specific. Fidelity to intervention procedures, competency and quality of delivery was high. Implementation fidelity may impact intervention outcomes and so needs to be measured in intervention research; however, the way in which it is measured may impact on data.


Controlled positioning of carbon nanotubes by dielectrophoresis: insights into the solvent and substrate role.
We demonstrate the ability to precisely control the deposition of a defined number of carbon nanotubes (CNTs) from solution onto microfabricated electrodes using dielectrophoresis. The solvation shell around the CNTs, exhibiting a high dielectric constant which is possibly larger than the intrinsic dielectric constant of CNTs, is found to play a crucial role in electrophoretic processes. Substrate resistivity is also very important: The spatial repartition of the electric field between the substrate and the microelectrodes leads to deviations from the precise location of the CNTs. A recipe is given for the dielectrophoresis of CNTs which can be extended to other nanowires or nanotubes.


Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family.
Rieger syndrome is one of the most serious causes of tooth agenesis. Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome. We have studied a three-generation Chinese family affected with Rieger syndrome and showing prominent dental abnormalities. Mutational screening and sequence analysis of the PITX2 gene revealed a previously unidentified four-base-pair deletion of nucleotides 717-720 in exon 5 in all affected members. The mutation causes a frame shift after Thr44, the 7th amino acid of the homeo-domain, and introduces a premature stop codon in the gene sequence. This deletion is the first unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that the oligodontia and other phenotypes of Rieger syndrome observed in this family are due to this PITX2 mutation, and these data further support the critical role of PIXT2 in tooth morphogenesis.


Impaired central processing of emotional faces in anorexia nervosa.
To elucidate the potential relationship between classification of emotional faces and impaired central processing in eating disorders and to investigate the potential mediatory role of alexithymia and depression in this relationship. Visual-evoked potentials (VEPs) to emotional faces and classification performance were assessed in 12 anorexic females and matched healthy controls. Patients with anorexia nervosa showed no modulation of emotional face processing and displayed significantly increased N200 amplitudes in response to all emotional categories and decreased VEPs in response to unpleasant emotional faces in the P300 time range as compared with healthy controls. They also made more mistakes in emotional face recognition, in particular, for neutral, sad, and disgusted content. There are marked differences in evoked potentials and emotion recognition performances of patients with anorexia nervosa and controls in facial processing. Differences in brain dynamics might contribute to difficulties in the correct recognition of facially expressed emotions, deficits in social functioning, and in turn the maintenance of eating disorders.


Genetic diversity and ecological niche modelling of wild barley: refugia, large-scale post-LGM range expansion and limited mid-future climate threats?
Describing genetic diversity in wild barley (Hordeum vulgare ssp. spontaneum) in geographic and environmental space in the context of current, past and potential future climates is important for conservation and for breeding the domesticated crop (Hordeum vulgare ssp. vulgare). Spatial genetic diversity in wild barley was revealed by both nuclear- (2,505 SNP, 24 nSSR) and chloroplast-derived (5 cpSSR) markers in 256 widely-sampled geo-referenced accessions. Results were compared with MaxEnt-modelled geographic distributions under current, past (Last Glacial Maximum, LGM) and mid-term future (anthropogenic scenario A2, the 2080s) climates. Comparisons suggest large-scale post-LGM range expansion in Central Asia and relatively small, but statistically significant, reductions in range-wide genetic diversity under future climate. Our analyses support the utility of ecological niche modelling for locating genetic diversity hotspots and determine priority geographic areas for wild barley conservation under anthropogenic climate change. Similar research on other cereal crop progenitors could play an important role in tailoring conservation and crop improvement strategies to support future human food security.


National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in clinical practice: quality requirements.
This report presents updated National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines summarizing quality requirements for the use of tumor markers. One subcommittee developed guidelines for analytical quality relevant to serum and tissue-based tumor markers in current clinical practice. Two other subcommittees formulated recommendations particularly relevant to the developing technologies of microarrays and mass spectrometry. Prerequisites for optimal use of tumor markers in routine practice include formulation of the correct clinical questions to ensure selection of the appropriate test, adherence to good clinical and laboratory practices (e.g., minimization of the risk of incorrect patient and/or specimen identification, tube type, or timing), use of internationally standardized and well-characterized methods, careful adherence to manufacturer instructions, and proactive and timely reactions to information derived from both internal QC and proficiency-testing specimens. Highly desirable procedures include those designed to minimize the risk of the reporting of erroneous results attributable to interferences such as heterophilic antibodies or hook effects, to facilitate the provision of informative clinical reports (e.g., cumulative and/or graphical reports, appropriately derived reference intervals, and interpretative comments), and when possible to integrate these reports with other patient information through electronic health records. Also mandatory is extensive validation encompassing all stages of analysis before introduction of new technologies such as microarrays and mass spectrometry. Provision of high-quality tumor marker services is facilitated by dialogue involving researchers, diagnostic companies, clinical and laboratory users, and regulatory agencies. Implementation of these recommendations, adapted to local practice, should encourage optimization of the clinical use of tumor markers.


A Very Unlikely Finding in a Male Child: Urethral Prolapse.
Urethral prolapse is a disease of prepubertal black girls and postmenopausal women with an unknown cause. It may be congenital in origin or an acquired condition. It has never been reported in males. We report a 10-year-old Caucasian boy who presented because of recurrent right undescended testis. He had been operated on for bilateral undescended testes 7 years ago in another hospital, and circumcision was done during the same operation. The boy complained of a weak urinary stream during voiding. The physical examination was consistent with recurrent right undescended testis. Penile examination showed a circumferential urethral prolapse around the meatus. The urethral meatal appearance was apparent right after the circumcision. An orchiopexy operation as well as circumferential excision of the perimeatal urethral tissue with primary repair was done. The pathological examination of the specimen revealed keratinized stratified squamous epithelium consistent with urethral mucosa. The postoperative course was uneventful, and the patient urinates normally at the 8 postoperative month with a normal uroflowmetry study. This is the first report of urethral prolapse in a male. Because circumcision is a widely employed practice in many cultures, it is unlikely to be a predisposing factor. It is a benign condition that can be cured with simple resection and anastomosis.


Are the fluctuations in dynamic anterior surface aberrations of the human eye chaotic?
The purpose of the study is to measure chaos in dynamic anterior surface aberrations and examine how it varies between the eyes of an individual. Noninvasive tear breakup time and dynamic corneal surface aberrations were measured for two open-eye intervals of 15 s. The maximal Lyapunov exponent (MLE) was calculated to test the nature of the fluctuations of the dynamic anterior surface aberrations. The average MLE for total higher-order aberration (HOA) was found to be small (+0.0102±0.0072) μm/s. No significant difference in MLE was found between the eyes for HOA (t-test; p=0.131). Data analysis was carried out for individual Zernike coefficients, including vertical prism as it gives a direct measure of the thickness of the tear film over time. The results show that the amount of chaos was small for each Zernike coefficient and not significantly correlated between the eyes.


Oncolytic adenovirus based on serotype 3.
Oncolytic adenoviruses have been safe in clinical trials but the efficacy has been mostly limited. All published trials have been performed with serotype 5 based viruses. The expression level of the Ad5 receptor CAR may be variable in advanced tumors. In contrast, the Ad3 receptor remains unclear, but is known to be abundantly expressed in most tumors. Therefore, we hypothesized that a fully serotype 3 oncolytic adenovirus might be useful for treating cancer. Patients exposed to adenoviruses develop high titers of serotype-specific neutralizing antibodies, which might compromise re-administration. Thus, having different serotype oncolytic viruses available might facilitate repeated dosing in humans. Ad3-hTERT-E1A is a fully serotype 3 oncolytic adenovirus controlled by the promoter of the catalytic domain of human telomerase. It was effective in vitro on cell lines representing seven major cancer types, although low toxicity was seen in non-malignant cells. In vivo, the virus had anti-tumor efficacy in three different animal models. Although in vitro oncolysis mediated by Ad3-hTERT-E1A and wild-type Ad3 occurred more slowly than with Ad5 or Ad5/3 (Ad3 fiber knob in Ad5) based viruses, in vivo the virus was at least as potent as controls. Anti-tumor efficacy was retained in presence of neutralizing anti-Ad5 antibodies whereas Ad5 based controls were blocked. In summary, we report generation of a non-Ad5 based oncolytic adenovirus, which might be useful for testing in cancer patients, especially in the context of high anti-Ad5 neutralizing antibodies.


Molecular docking studies to map the binding site of squalene synthase inhibitors on dehydrosqualene synthase of Staphylococcus aureus.
Dehydrosqualene synthase of Staphylococcus aureus is involved in the synthesis of golden carotenoid pigment staphyloxanthin. This pigment of S. aureus provides the antioxidant property to this bacterium to survive inside the host cell. Dehydrosqualene synthase (CrtM) is having structural similarity with the human squalene synthase enzyme which is involved in the cholesterol synthesis pathway in humans (Liu et al., 2008). Cholesterol lowering drugs were found to have inhibitory effect on dehydrosqualene synthase enzyme of S. aureus. The present study attempts to focus on squalene synthase inhibitors, lapaquistat acetate and squalestatins reported as cholesterol lowering agents in vitro and in vivo but not studied in context to dehydrosqualene synthase of S. aureus. Mode of binding of lapaquistat acetate and squalestatin analogs on dehydrosqualene synthase (CrtM) enzyme of S. aureus was identified by performing docking analysis with Scigress Explorer Ultra 7.7 docking software. Based on the molecular docking analysis, it was found that the His18, Arg45, Asp48, Asp52, Tyr129, Gln165, Asn168 and Asp172 residues interacted with comparatively high frequency with the inhibitors studied. Comparative docking study with Discovery studio 2.0 also confirmed the involvement of these residues of dehydrosqualene synthase enzyme with the inhibitors studied. This further confirms the importance of these residues in the enzyme function. In silico ADMET analysis was done to predict the ADMET properties of the standard drugs and test compounds. This might provide insights to develop new drugs to target the virulence factor, dehydrosqualene synthase of S. aureus.